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Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assumes any liability for any injury and/or damage to persons or property arising out or related to any use of the material contained in this book. The Publisher
Library of Congress Cataloging-in-Publication Data Warner, Thomas T., 1963Practical guide to neurogenetics / Thomas T. Warner, Simon R. Hammans. – 1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-0-7506-5410-4 1. Nervous system–Diseases–Genetic aspects. 2. Neurogenetics. I. Hammans, Simon R. II. Title. [DNLM: 1. Nervous System Diseases–genetics. 2. Genetics, Medical. WL 140 W284p 2009] RC346.4.W37 2009 2008030067 616.80 0442--dc22
Acquisitions Editor: Adrianne Brigido Developmental Editor: Joan Ryan Project Manager: David Saltzberg Design Direction: Karen O’Keefe Owens Printed in The United States of America Last digit is the print number: 9 8 7 6
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Dedication
We dedicate this book to the late Prof. Anita Harding, who inspired our interest in the field of neurogenetics.
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Contributors
Lucinda Carr, MD, FRCP, FRCPH Honorary Senior Lecturer, Institute of Child Health Consultant Pediatric Neurologist, Department of Neurosciences Great Ormond Street Hospital, London, United Kingdom Susan M. Downes, MD, FRCOphth Honorary Clinical Senior Lecturer, Oxford University Consultant Ophthalmic Surgeon, Oxford Eye Hospital John Radcliffe Hospital, Oxford, United Kingdom Diana M. Eccles, MD, FRCP Professor of Cancer Genetics, Wessex Clinical Genetics Service Princess Anne Hospital, Southampton, United Kingdom Simon R. Hammans, MA, MD, FRCP Consultant Neurologist, Wessex Neurological Centre Southampton General Hospital, Southampton Consultant Neurologist, St. Richard’s Hospital, Chichester Honorary Senior Lecturer, University of Southampton United Kingdom Andrea H. Nemeth, BSc, MD, DPhil (Oxon), FRCP Honorary Senior Lecturer in Clinical (Neuro) Genetics Weatherall Institute of Molecular Medicine, University of Oxford Consultant in Clinical Genetics, Churchill Hospital Oxford, United Kingdom Thomas T. Warner, BA, BM, BCh, PhD, FRCP Reader in Clinical Neurosciences, Department of Clinical Neurosciences UCL Institute of Neurology Consultant Neurologist, Department of Neurology, Royal Free Hospital Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom
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Preface
The field of neurogenetics has expanded dramatically in the past 20 years, becoming a recognized separate subspecialty. It is practiced by both neurologists with an interest in genetics and clinical geneticists. Both of these disciplines require extensive knowledge and clinical skills, and for this reason many specialist neurogenetics clinics are run jointly by geneticists and neurologists. However, all practicing neurologists and geneticists will come across neurogenetic disorders as part of their everyday practice, and it is for these individuals that we have produced this book. There are a number of comprehensive texts of neurogenetics available, and increasingly, online resources supplement our knowledge. It was not our purpose to compete with these sources. The main goal of this book is to offer an easy-to-read and pragmatic approach to individuals with, or at risk from, neurogenetic conditions. The first two chapters cover the basic facts concerning molecular genetics and genetic counseling. The subsequent chapters take an approach based on the clinical presentation as it occurs in any clinic, rather than on underlying pathophysiology or genetic mechanisms. Therefore, each chapter focuses on the main symptom complex, such as ataxia, dementia, or movement disorder. The potential diagnoses are discussed, including key clinical hints and investigations, followed by descriptions of the specific conditions and their genetics. Our hope is that the layout of this book will allow rapid reference for clinicians, either before or after they have seen a patient with a potential neurogenetic condition. It is designed to guide the thought process through diagnosis and investigation, genetic counseling, and testing in such individuals. Where it is clear that there is more complexity to the case, the potential diagnoses are listed in tables with key clinical features and cross-references to other chapters. In addition, we have guided the reader to other sources of information. This book does not provide comprehensive lists of genes and mutations, as these lists inevitably become outdated rapidly. This information and more detailed references are increasingly available on the Internet, and we use online resources before, during, and after clinical contact. This book is intended to be an accessible handbook summarizing practical and clinical issues to help patients with the most common forms of neurogenetic disease. xi
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We therefore hope that it will guide the reader to allow even more effective use of these new and powerful online resources in helping their patients. We hope that it will be of use to both general neurologists and geneticists with an interest in neurological disorders, whether fully qualified or still in training. Thomas T. Warner Simon R. Hammans
Acknowledgments
We wish to thank a number of individuals for their invaluable help, comments, and advice regarding various chapters in this book. We are particularly grateful to the clinical geneticists Prof. Diana Eccles and Dr. Andrea Nemeth, and pediatric neurologist Lucinda Carr, who authored a number of the chapters in the book. In addition, Diana also critically reviewed several of the other chapters. Susan Downes coauthored Chapter 5 on Disorders of Vision. We have also been ably assisted by colleagues with expertise in other fields who have reviewed the chapters, given constructive advice, or provided figures: Sarah Tabrizi, Daniela Pilz, Nick Dennis, Anneke Lucassen, Dominic McCabe, Richard Orrell, Lionel Ginsberg, Fiona Norwood, Jane Hurst, Simon Farmer, Jonathan Schott, Ros King, Georgina Burke, and Susan Huson. We are also grateful to Prof. Robert Surtees for his helpful discussion and guidance with Chapter 16. His death before the publication of this book is a great loss to us all. Finally, we would like to thank our respective wives and children (Nisha, Si^an, Rhian, and Sam Warner; Diana, Charlie, Lucy, Rosie, and Harriet Hammans) for their tolerance during the prolonged gestation of this book!
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Chapter 1 DNA, Genes, and Mutations Thomas T. Warner
INTRODUCTION The study of genetic disorders manifesting with neurological disease is a rapidly evolving field. Many neurological disorders are heritable and it is estimated that around one-third of recognizable Mendelian disease traits have phenotypic expression in the nervous system. The isolation of disease genes and subsequent analysis of molecular mechanisms holds the promise of developing new treatments or protective strategies. Gene identification also offers the prospect of more accurate genetic and prognostic advice as well as diagnostic, predictive, and prenatal testing. This chapter describes the basis of heritability in terms of the structure of DNA, genes, and various forms of mutation. It will also describe the fundamental concepts of molecular biology that form the basis of disease gene mapping and isolation.
PATTERNS OF INHERITANCE Patterns of inheritance were recognized long before the identification of DNA as the basic molecule of heredity. Gregor Mendel recognized that physical characteristics were the product of interplay between genetic factors inherited from each parent. Since Mendel laid down the first (the principle of independent segregation) and second (the principle of independent assortment) laws of inheritance it has become clear that there are many cases where a single gene is both necessary and sufficient to express a character. These characters are called Mendelian. A Mendelian character is considered dominant if it manifests itself in a heterozygous individual. If the character is masked it is considered recessive. In other words, a dominant allele exerts its effect despite the presence of a corresponding normal allele on the homologous chromosome, whereas in autosomal recessive inheritance both alleles must be abnormal for the disease trait to be expressed. The four common patterns of inheritance seen in genetic disease are described in Chapter 2. 1
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NUCLEIC ACIDS AND GENES Deoxyribonucleic acid (DNA) is the macromolecule that stores the genetic blueprint for all the proteins of the human body. DNA is the hereditary material of all organisms with the exception of some viruses, which use ribonucleic acid (RNA), and prions, which only contain protein. DNA is made of two antiparallel helical polynucleotide chains wrapped around each other and held together with hydrogen bonds to form a double helix. The backbone of the helices is made from alternating phosphate and deoxyribose sugars. Each sugar molecule is joined to one of four nitrogenous bases, adenine, cytosine, guanine, or thymine. These bases face into the center of the helix and hydrogen bond with their partner on the opposite strand. Adenine can only form hydrogen bonds with thymine, and guanine is only able to hydrogen bond with cytosine. The entire genetic code relies upon these four bases and their specificity of binding. The direction of the helices is described as either 50 to 30 or 30 to 50 depending on which carbon atom in the deoxyribose sugar the chain begins and ends with. DNA is divided into functional units known as genes, and it is believed that the human genome comprises approximately 30,00050,000 genes. A gene is a sequence of bases that determines the order of monomers: i.e., amino acids in a polypeptide, or nucleotides in a nucleic acid molecule. DNA is organized into a three-letter code. Each set of three is called a codon, and, with four possible bases in each position, there are 64 different combinations, which are more than enough for the 21 amino acids from which proteins are built. There is approximately 2 meters of DNA in each of our cells and this is achieved by packing the DNA into chromosomes. Humans have 23 pairs of chromosomes in the majority of cells in their body. One of each pair is inherited from each parent, and most cells have diploid status, in that they contain homologous pairs of each chromosome. One of these pairs is the sex chromosomes (XY in males and XX in females) and the remainder are called autosomes. Genes are arranged in linear order on the chromosome, each having a specific position or locus. With the exception of the sex chromosomes, each of a pair of chromosomes carries the same genes as its partner. For any particular character coded for by a gene there may be a number of different forms, which are called alleles. If an individual carries two different alleles for a particular characteristic, this is termed heterozygous; if both alleles are the same this is called homozygous. The human genome is a term used to describe all the DNA in human cells and actually comprises two genomes. First there is the nuclear genome, which accounts for 3300 million base pairs (Mb) of the total genetic makeup of the cell. Second there is the much smaller mitochondrial genome. Mitochondria are cytoplasmic organelles that generate energy in the form of ATP by oxidative phosphorylation. They contain two to 15 copies of mitochondrial DNA, which comprises a 16,539 base-pair circle of double-stranded DNA. This contains 37 genes specifying 13 polypeptides, 22 transfer RNAs (tRNAs), and two ribosomal RNAs. Production of the protein product for a gene consists of two steps. Transcription describes the synthesis of messenger RNA (mRNA) from the original DNA template. Translation is the process by which the mRNA code
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is translated into a polypeptide chain. Controlled synthesis of a gene product is initiated by its promoter, which is the collective name for a number of short sequences, called cis-acting elements, that are usually clustered upstream of the coding sequence of the gene. Transcription factors bind to these sequences and allow the attachment of RNA polymerase. The remainder of the gene can be divided into coding and non-coding regions called exons and introns, respectively. The average exon is between 150 and 250 nucleotides in length. Genes can have a very large number of exons, such as the dystrophin gene (responsible for Duchenne muscular dystrophy) with 79 exons, or just one. The purpose of introns is not known. However, their presence in all eukaryotes and in most genes means there is either no selective disadvantage to having them, or they have a positive function that is not yet clear. It is estimated that up to 97% of the human genome consists of non-coding sequence.
FROM GENE TO PROTEIN Synthesis of a protein begins with an appropriate signaling molecule binding to the promoter of the gene. This initiates transcription, which creates a singlestranded RNA copy of the gene. RNA, like DNA, is composed of a linear sequence of nucleotides, but the sugarphosphate backbone consists of ribose sugar instead of deoxyribose and the base thymine is replaced by a very similar base uracil. Before the RNA molecule leaves the nucleus it undergoes a process known as splicing to create a messenger RNA molecule, mRNA. Splicing removes intron sequences from the RNA, leaving a small molecule containing all the information of the original gene. The expression of the gene can also be modified at this level through a mechanism known as alternative splicing. This is where different forms of mRNA, and hence protein, are produced by altering which sequences are cut from the original transcribed RNA. Once spliced, the mRNA can then move into the cytoplasm to direct protein synthesis. There are two other important molecules that are required for protein synthesis. The first of these are ribosomes. Ribosomes are found free in the cytoplasm and attached to the surface of the rough endoplasmic reticulum. Once the mRNA has entered the cytoplasm these molecules bind to it and read along the sequence until an AUG is reached. These three bases mark the beginning of translation, the process of reading the sequence and turning it into the appropriate protein molecule. The nucleic acid bases are read in sets of three called codons, where AUG is the start signal and also sets the frame for reading the remaining codons. The second molecule required for protein synthesis is transfer RNA (tRNA). For every codon there is a tRNA with a domain of complementary sequence that will selectively bind to it (an anticodon). Each codon codes for a specific amino acid, and the tRNA with the matching anticodon is responsible for bringing it to the ribosome where it will bind to the amino acid from the tRNA molecule attached to the previous codon. Any one of three stop or nonsense codons (UAA, UAG, or UGA) signals the termination of protein synthesis. Further information is contained within the protein sequence itself and signal peptides can direct the newly formed protein to particular cell organelles for post-translational modifications
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(e.g., glycosylation, addition of metal ions or other polypeptides), and allow its insertion into membranes.
DNA REPLICATION AND CELL DIVISION The constant replacement of somatic cells occurs by the process of mitosis, which is the simple division of a parent cell into two identical daughter cells. This process is divided into four steps; prophase, metaphase, anaphase, and telophase (see Fig. 1.1). In this process the chromosomes are condensed and pulled to the equatorial plane at metaphase. The centromere splits in anaphase and the two chromatids of each chromosome are pulled to opposite poles. In telophase the chromosomes reach the poles and start to decondense. The nuclear membrane reforms and the cytoplasm starts to divide, yielding the two daughter cells. The other form of cell division is the production of gametes by meiosis. There are a number of important differences between mitosis and meiosis. First, in meiosis the daughter cells produced are not identical to the original parent cell. Meiosis consists of two divisions, but the cellular DNA is only replicated once. This means the daughter cells produced are haploid. Second, during prophase I an important event called crossover occurs. Visible manifestations of this event, called chiasmata, can be seen during metaphase I. Crossover is recombination between two non-sister chromatids, where there is a precise break, swap, and repair of DNA, thus exchanging genetic material. This is a very important process that creates genetic diversity within the gametes and therefore the next generation. This phenomenon is also of great
Figure 1.1. Process of mitosis and meiosis.
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significance in the study of genetics as it is the fundamental concept behind genetic mapping and linkage analysis.
IDENTIFYING DISEASE GENES Numerous neurological disease genes have been identified using molecular biological techniques over the past 20 years. Most have been the cause of single gene (monogenic) disorders and have relied on the process of positional cloning, or identification of the gene based solely on its chromosomal map position. Gene identification by positional cloning starts with the collection of families in which the disease is segregating. Genetic linkage analysis is then used to localize the disease gene to a particular chromosome between two defined markers. The candidate interval is then refined further by study of other genetic markers in this interval. This region of DNA is then cloned, usually in the form of a series of overlapping fragments inserted in vectors (known as a contig). Finally, candidate genes are isolated from within the cloned contig and mutations in these genes sought in affected individuals. The basic premise underlying linkage analysis relies on the fact that if two genetic loci are close to each other on a chromosome, they do not segregate independently during meiosis, and the degree to which this happens is a reflection of their physical proximity. As stated above, during meiosis recombination can occur and is the process whereby genetic information is exchanged at chiasmata when homologous chromosomes pair. For loci close together, the chance of recombination between them is small, and they will tend to be inherited together. Loci further apart are more likely to have a recombination event occurring between them. The probability of a recombination event occurring between two loci during meiosis is termed the recombination fraction (y), which is taken as a measure of the genetic distance between loci. The recombination fraction can vary from y=0.0 for loci right next to each other, to y=0.5 for loci far apart (or on different chromosomes). The function which relates genetic to physical distance is called a mapping function, and translates recombination frequency (in percent) into mapping distance measured in centimorgans (cM). To map a disease gene, therefore, the segregation of the disease locus and a known genetic marker through one large family, or a number of pedigrees, is analyzed to determine whether the loci are linked and then the level of recombination between them is assessed. Using the likelihood method, LOD (likelihood of odds ratio) scores are generated over a range of y. A LOD score is defined as log10 of the odds ratio for cosegregation of the loci versus independent assortment. The value of y at which the LOD score is largest represents the best estimate of genetic distance between the two loci under study (referred to as two-point LOD scores). Linkage is considered significant when the LOD score is >3.0, corresponding to the odds for linkage of at least 1000:1. In practice this correlates with a probability for linkage of 20:1, due to the prior probability that two autosomal loci are linked because they must be on one of the 22 pairs of chromosome. A LOD score of <2.0 is taken as rejection of linkage.
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To undertake linkage analysis there are two basic requirements: (1) families in which the disease segregates as a mendelian trait, and (2) polymorphic genetic markers distributed throughout the human genome. Polymorphisms are natural variations in the human genome and enable distinction between the two chromosomes of a homologous pair. The more polymorphic a locus, the more suitable it is for linkage analysis, as it is more likely that a given meiosis will be informative for that marker. Nowadays, microsatellite markers are used for genetic mapping. These consist of repeated dinucleotides, such as (CA)n. The polymorphism results from a difference in the number of repeat units. They can be readily genotyped by polymerase chain reaction (PCR) and are localized throughout the genome at small genetic intervals. Microsatellites are available in the form of panels of markers which can be amplified by PCR in a large number of samples. The resulting PCR products are then electrophoresed and analyzed by automated DNA sequencers which use fluorescent labeling to genotype each sample. The genotypes can then be used to generate LOD scores using various computer programs. More recent advances have led to use of single nucleotide polymorphisms (SNPs), which, although less informative than microsatellites, are found in much greater numbers and allow greater saturation of the genome with markers. Linkage analysis in autosomal recessive disorders can be more difficult as affected individuals are usually confined to a single sibship, and families containing three or more patients are rare. Alternative strategies have been devised for these situations, including use of inbred families for homozygosity mapping. Alternatively, screening the genome for regions of identity-by-descent can be performed by pooling samples from affected individuals and comparing the distribution of alleles in the pooled sample with a control pool from unaffected family members. The ideal situation is to have a single family large enough to allow significant LOD scores to be generated. Frequently this is not the case, and linkage analysis is performed on a number of families and LOD scores are added. This is based on the assumption that the disorder is genetically homogeneous, i.e., the same gene is responsible for the disorder in all the families. If this assumption is incorrect, linkage to a particular locus may be erroneously rejected. Once two-point analysis has detected linkage between a marker and a disease locus, multipoint analysis can be performed to determine which two loci most closely flank the disease gene. The genetic markers that flank the candidate region delineate the genetic distance. One centimorgan genetic distance is roughly equivalent to 1 million base pairs (1 Mb) of physical distance. This candidate region must then be physically linked by cloning the intervening DNA segment into a series of overlapping vectors (such as yeast or bacteriophage artificial chromosomes, cosmids) to form a contig, or by long-range mapping using a technique called pulse field gel electrophoresis. This region is then searched for candidate genes by a number of techniques which identify either familiar sequences found at the 50 end of genes or evolutionarily conserved sequences, or isolation of expressed coding sequences (so called exon trapping). Proof that a candidate gene is actually the disease gene requires demonstration that a mutation found in affected individuals is not present in unaffected
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ones, and also should not occur as a benign polymorphism in the normal population. In addition, mutations should be able to cause a pathogenic affect, e.g, disrupt the coding sequence of the gene. This process of positional cloning can be accelerated by initially examining candidate genes already known to map to the critical region. This method, sometimes referred to as the positional candidate approach, is becoming increasingly used with the completion of the Human Genome Project and the availability of cDNA libraries.
TYPES OF MUTATION The human genome is not a static entity and is subject to a variety of different types of heritable change (mutation). The main types of mutation are described in Table 1.1. In general mutations can produce their effect in one of two ways: 1. The gene product has reduced or no function (loss of function mutation). Loss of function mutations often produce recessive phenotypes. For most gene products the precise quantity is not critical and a reduction by half can be coped with. Thus most inborn errors of metabolism are recessive. However, for some gene products 50% of the normal level is not sufficient for normal function, and haplo-insufficiency produces an abnormal phenotype which is therefore inherited in a dominant manner. An example of this is seen in dopa-responsive dystonia, where a dominant mutation in the gene for GTP-cyclohydrolase I, the rate-limiting step in producing tetrahydrobiopterin (key cofactor in monoamine synthesis), produces the phenotype. Sometimes, the mutant non-functional polypeptide interferes with the function of the normal protein in heterozygous individuals, leading to a dominant negative effect. There has been debate as to whether this truly represents a loss of function or is due to gain of function, as described below. 2. The gene product gains a new abnormal function (gain of function mutation). Gain of function mutations usually cause dominant phenotypes, because the presence of the normal allele does not prevent the mutant allele from behaving abnormally. Sometimes the gain of function involves the product having a novel function: e.g., if the protein product contains expanded polyglutamine tracts which appear to cause it to form aggregates (see below). Table 1.1 Mutation Types Chromosomal abnormalities Deletions Insertions (including duplications) Single base substitutions Missense mutations Nonsense mutations Splice site mutations Frame shifts Dynamic mutations
Alteration in number or structure of chromosomes Deletions of DNA from 1 base to megabases Insertion of DNA One amino acid replaced with another in gene product Amino acid codon replaced with a stop codon Creation or destruction of signals for exonintron splicing Disruption of open reading frame, can be produced by deletion, insertions, or splicing errors Repeat sequences that can change size on transmission, e.g., triplet repeat disorders
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Trinucleotide Repeat Diseases Unstable trinucleotide repeats are a novel disease mechanism, first discovered in 1991, and an important cause of neurogenetic disease. A feature of these conditions is anticipation, with earlier onset and more severe phenotype in successive generations, which appears to correlate with increasing repeat size during gamete formation. Two different classes of expansion have been identified: 1. Highly expanded repeats outside the gene coding region causing loss of function by reducing or abolishing transcription. Examples in this group include Fragile X syndrome, Friedreich’s ataxia, and myotonic dystrophy. 2. CAG repeats within the coding region that are translated into polyglutamine tracts, which lead to protein aggregation and cell death. The typical example in this group is Huntington’s disease, but it also includes the dominant spinocerebellar ataxias and spinobulbar muscular atrophy (Kennedy’s disease). Huntington’s disease will be described in more detail in the following section because it illustrates a number of principles of genetics, is the prototype for CAG repeat disorders, and has become the model for genetic testing in other adult-onset genetic inherited disorders (see Chapter 2). Huntington’s Disease (HD) HD is a dominantly inherited neurodegenerative disorder involving the basal ganglia and cortex and presents with movement disorder (typically chorea) plus behavioral or cognitive problems. It usually has onset in midlife, but can occur as young 23 years of age, or as late as 80 years. Penetrance is full, so that children of affected parents have a 50% chance of developing HD. The gene was mapped by linkage analysis to chromosome 4p16.3 in 1983 and genetic testing programs with linkage testing (see below) began in 1986, until 1993 when the gene was isolated by positional cloning. The CAG repeat in exon 1 of the gene varies from 6 to 34 repeats on unaffected chromosomes and 36121 on disease alleles. Repeats between 36 and 39 are very rare and are associated with reduced penetrance, whilst this is not the case for disease alleles greater than or equal to 40 repeats. A strong inverse relationship between age at onset and repeat number has been identified, although most of this comes from the small number of juvenileonset cases who have very large numbers of repeats. Therefore, repeat size for most individuals is a poor predictor of age of onset. Long before the gene was isolated, it was noted that a disproportionate number of cases with juvenile onset had inherited the HD gene from their fathers. Subsequently, this ‘‘anticipation’’ was shown to be due to meiotic instability of the HD repeat in paternal transmission, where there is a propensity to large increases in repeat size during spermatogenesis, a feature not seen in maternal transmission. Significant familial aggregation for age of onset in HD is seen and it has been estimated that 5565% of the variation in age of onset which is not attributable to repeat size can be attributed to modifier genes. A small effect on age of onset comes from the size of the normal allele but, in contrast to the HD repeat itself,
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larger normal repeats are associated with later onset. Studies to identify modifying loci have identified possible linkage at three genomic sites.
MUTATION DETECTION Once a disease gene is isolated, detection of mutations can be an important diagnostic tool. The ease with which this can be done depends on the type of mutation (e.g., deletion versus point mutation) and the structure and size of the gene to be examined. Large DNA rearrangements such as the deletions seen in the dystrophin gene in Duchenne muscular dystrophy can be detected by restriction digest and Southern blotting to identify size differences. As most of the deletions occur in specific regions of this large gene, a PCR-based technique has been devised which simultaneously amplifies the different regions of interest with products that differ in size. The absence of one of these products implies that there is a deletion involving the region where one of the primers would have annealed. Trinucleotide CAG repeat disorders can be easily tested for with a PCR assay using primers that flank the repeat sequence. For the conditions with a very large expansion, such as myotonic dystrophy, Southern blotting analysis using a probe from a region flanking the trinucleotide is used to identify a larger-size fragment containing the expanded repeat. Point mutations within a gene can be more difficult to detect, particularly in large genes. There are a number of methods that rely on the fact that fragments of gene amplified by PCR containing a point mutation migrate with different mobility on a gel compared with the wild-type fragment. The techniques use different conditions and include heteroduplex analysis, single-strand conformational polymorphism (SSCP) analysis and denaturing gradient gel electrophoresis (DGGE). For mutations that lead to premature termination of translation and a smaller mutant protein, the mutation detection system called protein truncation test can be used. Many laboratories now rely on large-scale automated DNA sequencing to detect mutations rather than rely on the methods above, and this is likely to be increasingly used in neurogenetic service testing in the future. However, this can be expensive and it is vital that tests are appropriately requested depending on the level of clinical suspicion. It is also vital to note that all techniques have the potential to miss mutations.
CLINICAL APPLICATION OF DISEASE GENE MAPPING AND CLONING Knowledge of the map position of a gene can have clinical use, even if the causal gene itself has not been isolated. A good example of this is Huntington’s disease. Prior to the discovery of an expanded CAG repeat within the first exon of the gene encoding huntingtin, it was known that almost all cases were linked to chromosome 4p. Predictive and prenatal tests were available using markers closely linked to the Huntington’s disease locus, provided DNA was available from other family members, including
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at least one affected (see Chapter 2). Linked markers can still be useful even if the disease gene has been identified. If the gene is large with many exons and there are numerous point mutations known to cause the phenotype, it is impossible to screen for all of these. The use of markers within the gene can be used again to determine whether the disease chromosome(s) has been inherited. Once a gene has been isolated and mutation(s) identified, direct testing for mutations can be performed. The ideal situation is where a single mutation type is readily detectable and is responsible for the majority of cases of the disease. Examples of this include the CAG repeat expansion for Huntington’s disease, the GAG deletion in the DYT1 gene causing childhood-onset autosomal dominant primary torsion dystonia, and the 1.5 Mb duplication including the PMP22 gene in 70% of patients with HMSN1A. The ability to identify a specific molecular lesion in a patient is important as it can establish a definite diagnosis, prevent further investigations and may provide prognostic information. It also makes it possible to diagnose or exclude a diagnosis with a simple blood test in other family members at risk of developing the condition, and in some cases allows prenatal testing to be offered. Finally, the identification of disease genes is an important step in establishing the pathogenetic mechanisms underlying many neurological diseases.
Chapter 2 Genetic Advice and Testing: Basics of Inheritance, Counseling, and Rationale for Testing Diana M. Eccles
INTRODUCTION This chapter is a brief introduction to the process of genetic diagnosis, information-giving, and genetic testing. The broad principles are similar in all genetic conditions although the practical implications may differ between diseases and modes of inheritance. The chapter covers the practice of genetic counseling and testing.
GENETIC COUNSELING The special features of genetic medicine arise from the fact that a clinical diagnosis, or test result, in one individual has implications for his or her close relatives. Special circumstances, including genetic testing in childhood, may raise specific ethical and legal considerations. The following is a descriptive definition of the elements of genetic counseling taken from Professor Peter Harper’s textbook Practical Genetic Counselling (1998). ‘‘Genetic counselling is a process by which patients or relatives at risk of a disorder that may be hereditary are advised of the consequences of the disorder, the probability of transmitting it and of the ways in which it can be prevented, avoided or ameliorated.’’ This definition covers information-giving but the process may also involve investigative and diagnostic elements. Patients may be referred to the genetics service with a known or suspected diagnosis such as von Hippel-Lindau disease or a definite family history of a condition such as Huntington’s disease (HD). Standard practice prior to genetic testing being discussed is to confirm at least the clinical diagnosis, and if possible obtain molecular confirmation of the diagnosis.
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Diagnosis When a referral is received from primary or secondary care it is important to gather as much information about the putative diagnosis in the family or individual as possible. The source of the diagnostic information must be considered. An experienced neurogeneticist referring a patient with Huntington’s disease is unlikely to have made an incorrect diagnosis. However, a general practitioner referring a young adult who has recently found out that his estranged father has developed Huntington’s disease will be communicating a diagnosis at least third-hand. This would need to be confirmed to ensure the correct genetic information and ultimately the correct genetic test are discussed with that young adult. Errors might arise if, for example, the diagnosis turned out to be the much less common DRPLA (dentatorubropallidoluysian atrophy), also due to an autosomal dominant triplet repeat expansion, but in a completely different gene. Testing the young adult in question for expansion in the HD gene would give a negative (normal) result even if they had inherited the DRPLA disease gene.
The Family History Careful documentation of the family history with a three-generation pedigree is important. Details of medical treatment, disease manifestations and management, and any contact of affected relatives with other genetic services can be useful. This process has become more difficult in recent years because of (understandable) concerns about data protection. Standard procedures now involve obtaining written consent for the genetics service to access an individual’s confidential medical records. It may also be appropriate to refer an affected relative in another part of the country to their local genetics service for genetic investigations to facilitate the development of a genetic test for the individuals at risk in the family.
Examination and Investigations Collecting and reviewing medical records, histopathology reports, death certificates, and molecular genetic testing records may all be relevant in certain conditions. Availability of such key records at the time of genetic consultation can be invaluable and considerable effort should go towards retrieving medical records. This may require written consent to access records from an affected family member if they are not the person being seen by the geneticist. Where there is diagnostic uncertainty, a thorough medical history, clinical examination of an affected individual from the family and additional clinical tests may be necessary. For example, a patient referred with a retinal angioma aged 30 years may have been told that they could have von Hippel-Lindau (VHL) disease. However, before accepting this diagnosis and giving advice about risks to other family members and ongoing surveillance for that individual, it is important to explore the family history in detail, examine the patient for other possible manifestations of the condition and arrange imaging of brain
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and spinal cord, kidneys, and adrenals, and check for excess adrenaline metabolites in a 24-h urine collection. If no other manifestations of the disease are found, the patient does not meet agreed diagnostic criteria, and the diagnosis is still an isolated retinal angioma, the diagnosis of VHL is not secure. A patient presenting with possible muscular disease may require expert neurological assessment and a muscle biopsy with neuropathology review, to help clarify a diagnosis. Thus diagnosis often requires multidisciplinary input. The neurologist is a key member of the neurogenetics team, especially for the diagnostic process. The main work of the neurogenetics team is to determine the mode of inheritance and implications of the diagnosis for the individual and their family and to search for a diagnostic genetic test.
THE GENETIC CONSULTATION Once a diagnosis is secure then the inheritance pattern is usually clear and can be explained to the family. The mode of inheritance and the risk to that individual of inheriting the condition can be calculated. This risk may be modified by both other genetic factors and the environment, but the effect of such modifiers is poorly understood at present.
Inheritance The main patterns of inheritance are described below and also in Figure 2.1. B
A
Autosomal Recessive
Autosomal Dominant
D
C
X-linked Recessive
Mitochondrial
Figure 2.1. Patterns of inheritance.
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Autosomal Dominant (AD) Inheritance (Fig. 2.1a) All ‘‘autosomal’’ genes (i.e., genes not on the X or Y chromosome) are present in pairs. One is inherited from the mother and one from the father. A gene mutation on an autosome will be passed on to 50% of offspring on average (Fig. 2.2). For a dominant gene, only one mutant gene is required to manifest the disease. Neurological examples of AD conditions include Huntington’s and von Hippel-Lindau disease, neurofibromatosis types I and II, some types of hereditary motor and sensory neuropathy, and more common forms of hereditary spastic paraplegia. Autosomal Recessive (AR) Inheritance (Fig. 2.1b) In recessively inherited disease there is not usually any disease effect for mutation carriers who have one normal copy and one faulty copy of the gene. If two carriers of mutations in the same disease gene have children then 25% (1 in 4) of their offspring will on average be affected with the disease (Fig. 2.3). For an individual who is known to be a carrier (often because of the diagnosis of the recessive condition in a relative and subsequent cascade genetic testing in the family) but whose partner is of unknown carrier status, the risk of affected offspring depends on the carrier rate in the population at large. The carrier frequency for Wilson’s disease, for example, is about 1 in 90. A couple who have had a child with this diagnosis have a 1 in 4 chance of having another affected child (Fig. 2.4). However, if either parent (both carriers) decide to have children with an alternative partner then the chance of an affected offspring is reduced to 1 in 360 (1/2 1/2 1/90). AR conditions are often metabolic and other neurological examples include Tay-Sachs disease, Krabbe and metachromatic leukodystrophy, and the commonest form of inherited ataxia, Friedreich’s ataxia.
wt
wt
Affected
M
M
wt
wt
Unaffected
wt
wt
M
wt
Affected
wt
wt
Unaffected
Figure 2.2. Autosomal dominant inheritance. For an individual affected by a disease caused by a dominantly acting gene mutation (M), each offspring will inherit either the wild-type (wt) allele or the mutant (M) allele. For a gene with 100% penetrance the risk of an offspring being affected is 1 in 2.
Genetic Advice and Testing: Basics of Inheritance, Counseling, and Rationale for Testing
A
M1
A
M2
A
Carrier 1/4
A
M2
M1
M2
M1
Carrier 1/4
A
Affected 1/4
15
A
Non-carrier 1/4
Figure 2.3. Autosomal recessive inheritance. For two known carriers, the risk of an offspring being affected or of not carrying the disease gene at all is 1 in 4; the chance an offspring will be a carrier is 1 in 2.
X-linked Inheritance (Fig. 2.1c) Females have two X chromosomes, males an X and a Y. The chromosome passed to the offspring by the father determines the sex. Having two X chromosomes protects females from manifesting features of disease genes located on the X chromosome that may severely affect boys this is termed X-linked recessive inheritance. Classical X-linked recessive neurological disorders
A
A
M1
Carrier 1/2 x 1/2 x 1/90
M1
A
M2
Carrier 1/2 x 1/2 x 1/90
A
M1
1/100
M2
Affected 1/2 x 1/2 x 1/90
A
A
Non-carrier 1/2 x 1/2 x 1/90
Figure 2.4. For a known carrier of Wilson’s disease where the population carrier rate is 1 in 90 the risk of an affected offspring is 1 in 360.
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PRACTICAL GUIDE TO NEUROGENETICS
include Duchenne and Becker muscular dystrophy and Fragile X syndrome. In some disorders, female carriers can manifest mild features of the condition, often in later life, such as X-linked spinal and bulbar atrophy and adrenoleukodystrophy. Some X-linked gene mutations are lethal in males and only affected females are observed (these are called X-linked dominant conditions). Mitochondrial Inheritance (Fig. 2.1d) Mitochondrial DNA (MtDNA) is distinct from nuclear DNA. Many copies are present in each cell as each mitochondrion contains the mitochondrial genome sequence. Sperm contain very little cytoplasm, so when the sperm and oocyte fuse the mitochondria are passed on in the maternal cytoplasm. Diseases mediated by mitochondrial mutations are usually inherited from the mother (although they can arise de novo). A mother with a mitochondrial disease mutation is likely to pass some mitochondria with the mutation to her offspring. However, since the mutations are often present in only a proportion of the mitochondria (heteroplasmy), predicting the clinical consequences can be difficult. MtDNA disorders commonly have a neurological phenotype and include Leber’s hereditary optic neuropathy, and various encephalomyopathies such as myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).
Factors Affecting Genetic Disease Manifestations Penetrance This is the chance that a given gene mutation will manifest itself in an individual or not. Penetrance may be 100%, as in Down’s syndrome where all individuals with trisomy 21 will be affected with typical dysmorphic features and some degree of mental retardation. However, in a condition such as von Hippel-Lindau disease, penetrance is age-dependent. In some inherited conditions, despite the presence of a disease allele, disease may never develop (incomplete penetrance). The degree of observed penetrance often relates to the diligence of searching for features of the disease. For example, in autosomal dominant primary torsion dystonia caused by mutation of the DYT1 gene, although most individuals who develop symptoms do so by age 30, only about 3040% of people with the disease gene actually develop dystonia at all. Expressivity This term is used in reference to the variation in severity of disease manifestations in an individual. The expression (disease manifestations) of a particular gene mutation may vary considerably between individuals with the same gene mutation. Two other features relating to the phenotypic manifestation of disease are also important: anticipation, which describes the appearance of a more severe clinical phenotype in successive generations, and imprinting, which
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refers to variation in phenotype depending on the parent of origin of the mutant allele. Modifiers A number of inherited and environmental factors can affect the way a disease gene manifests itself. For example, malignant hyperthermia has been shown to be due to a dominantly inherited mutation in one of a number of genes, including the ryanodine receptor gene RYR1. However, the penetrance is affected by numerous environmental triggers such as severe exercise in hot conditions, neuroleptic drugs, alcohol, and infections, and probably strongly influenced by other genes so that predictive genetic testing indicates susceptibility, not affected status. Genetic Heterogeneity Many diseases that appear similar clinically can be due to several different genetic mechanisms. For example, tuberous sclerosis is due either to mutations in the TSC1 gene on chromosome 9q or to mutations in the TSC2 gene on chromosome 16p. There is no easy way to distinguish the two clinically so both genes have to be examined in seeking molecular confirmation of a clinical diagnosis.
Genetic Testing The human genome contains around 3 billion bases in a haploid or germ cell (sperm or egg), which equates to 6 billion in a diploid or somatic cell. Much of the sequence of the human genome is now known. However, when a genetic diagnosis is made on clinical grounds it is analogous to standing at the door of the very large library and knowing that within the library there is a book with a small spelling mistake (maybe a letter missing). If the disease is known to be caused by a single gene and the location and sequence of the gene are known then it is (relatively) simple to look at the gene sequence for anomalies that explain malfunction of the gene. If the disease gene has not been mapped and the sequence is not known then there is no reference for the ‘‘book’’ in the library and you are unlikely to be able to find the spelling mistake (gene fault). In Huntington’s disease, a triplet repeat expansion in a single gene is the underlying pathogenesis. In neurofibromatosis type I (NF1), the gene spans 350 kb and mutations may arise anywhere in the gene as small insertions or deletions, single base changes, or large deletions or rearrangements. Hence, mutation testing for HD is easy, but for NF1 is extremely challenging. If on clinical grounds a clear diagnosis can be made and the molecular basis for that diagnosis can be determined, a genetic test will be available for other family members. One example is myotonic dystrophy; expansion of a triplet repeat in the 30 untranslated region of a protein kinase gene on chromosome 19q is usually the causative mutation in this disease. The larger the expansion, the more severe are the manifestations. However, genetic testing is not always so straightforward and becomes increasingly complex the more genes there are
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that can, when mutated, give rise to a given condition. Subtle clinical differences in phenotype may give clues to one or other gene, so meticulous clinical description and carefully chosen additional clinical tests may be critical to an accurate, targeted molecular test. This is also true for myotonic dystrophy, where mutations in the DM2 gene can produce a phenotype that is rarer, but clinically indistinguishable from those produced by mutations in the myotonic dystrophy protein kinase gene. There are many different types of mutations that can disrupt gene function (see Chapter 1). Currently most genetic tests are based on DNA sequence analysis in one or a small number of genes. In the future, a greater emphasis on functional genomics (tests of the integrity of gene function) may be helpful in overcoming some of the limitations of DNA-based testing, especially for diseases with considerable underlying genetic heterogeneity. Diagnostic Testing If the gene for a genetic condition has been identified and the clinical diagnosis is definite or suspected, molecular confirmation of the diagnosis may be possible. DNA from the clinically affected individual is examined for the presence of a mutation that is predicted to disrupt the function of the protein product of the relevant gene or genes. If a search for a specific underlying gene mutation draws a blank, this may reflect one or more of a number of problems with genetic testing. The following are typical reasons why a disease mutation is not found: the techniques used may be insufficiently sensitive to detect the causative mutation in that individual/family a mutation of unclear pathogenic significance may be found the disease may be heterogeneous and the wrong gene has been tested the disease may run in the family but the individual tested does not carry the disease gene (this is potentially a risk where a condition is common enough in the population that by chance a family member could develop symptoms that mimic the inherited form of the disease the tested individual is a non-genetic phenocopy). Carrier Testing For X-linked and autosomal recessive conditions in particular, individuals may be concerned about risks to offspring rather than risks to themselves. The information may help them to make reproductive choices. For relatively common recessive disorders with a simple molecular test, such as Friedreich’s ataxia, an unaffected heterozygous carrier may wish to know the risks to offspring. In this situation it is relatively easy to offer a test to see whether the spouse is also heterozygous for an expansion in the gene. Since expansions account for the vast majority (98%) of pathogenic mutations, the risk to offspring if the spouse had two normal-sized alleles would be extremely low. For rare recessive conditions, where carrier rate in the population is low and simple genetic tests are not available, carrier testing of a spouse is not a reasonable option. In these situations the risk to offspring is very low and can be estimated
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on the basis of the carrier rate in the population, unless a carrier is marrying a relative. Predictive Testing Once the precise gene mutation giving rise to the disease in a family is known, other relatives can be advised of the likelihood that they have inherited the same mutation and their risk of having or developing the disease caused by that mutation. They can be offered a genetic test to clarify whether they have or have not inherited the condition. Before such a test is undertaken, particularly in an individual who is well and may develop the disease in the future, it is standard practice to discuss the advantages and disadvantages of such knowledge. Understanding the Disease. A genetic diagnosis caused by an identified gene alteration can allow a more specific understanding of inheritance and disease risks. Good communication skills are vital in sharing clear and unambiguous information with family members and helping them to view the test in the context of their own circumstances. Chance of Being a Gene Carrier. For diseases where the onset is age-dependent, the older the family member undergoing genetic predictive testing, the lower is the likelihood that they have inherited the disease, assuming there are no clinical manifestations at the time of testing. Care must be taken in interpreting offspring and sibling risks. For example, dominantly inherited gene mutations can sometimes be present in individuals in mosaic form (a mutation arising as a new mutation after the start of embryogenesis will affect a variable proportion of cells but not all). This can present with mild or atypical features of the disease in that individual and is well described for example in neurofibromatosis type II (NF2). In this situation the disease-causing mutation is assumed to have arisen post-zygotically and to affect an unknown and currently indeterminable proportion of various tissues. Thus the risk to siblings should be zero and the risk to offspring is anywhere between 0% and 50% depending on the level of mosaicism in the gonads. For disease caused by mitochondrial mutations the situation can be even more difficult to predict because of varying proportions of mitochondria carrying the deleterious mutation (heteroplasmy). Chance of Developing the Disease. Prior to genetic testing, for a disease where penetrance is 100%, the likelihood of an individual carrying the gene mutation is the same as the chance that the individual will develop the disease. An inherited mutation in the Duchenne muscular dystrophy (DMD) gene will always result in a boy developing the disease. Some highly penetrant genes may often result in disease development but not always at a predictable age at onset: for example, Huntington’s disease. Genetic Testing in Childhood. Testing of a child for an inherited condition may take place for the purposes of diagnosis or prognosis where the child is already affected or likely to become affected during childhood. This may be particularly helpful where some sort of intervention may ameliorate the effects of an
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inherited disorder. An example of a disease where predictive testing does take place in childhood is von Hippel-Lindau disease, where screening for retinal hemangiomas commences at around 5 years of age and where timely laser photocoagulation may prevent retinal detachment and loss of sight. As a general rule, predictive testing for later-onset diseases where the only outcome is knowledge of genetic status is not often carried out. For most adult-onset diseases predictive testing in childhood is unlikely to be medically helpful and may cause considerable problems within families. Parents have to consent on behalf of their children to a genetic test and need to be informed about the pros and cons of testing for the child both now and in the future. In addition, the child must be allowed to be involved in discussions and decision-making at a level appropriate to the age and understanding of the child. Interventions. Knowledge of the genetic status and a better understanding of disease mechanisms may lead to interventions that could delay or prevent the onset of disease or ameliorate the effect of the disease. The options available after and before genetic testing must be fully explored. Reproductive Choices For some conditions, associated for example with devastating childhood disease, couples may elect to avoid the birth of an affected child if possible. A couple who are fully informed about the disease and options for management would be given the following choices: accept the risk of an affected child being born do not have children or adopt children conceive using donor sperm or eggs to ensure the child will not inherit the disease have prenatal diagnosis at 10 weeks via chorionic villous sampling or at 1416 weeks via amniocentesis (these early pregnancy tests are associated with a small risk of miscarriage) and terminate a pregnancy with an affected fetus have pre-implantation genetic diagnosis at present there are considerable technical and funding hurdles to overcome in most instances with a relatively low chance of a successful pregnancy ensuing compared with other options. Follow-up Social and emotional support is important during the process of genetic predictive testing and prenatal testing. Support is provided by the genetics services, but also primary care services and close relatives may have key supporting roles. The Family. Dissemination of risk information within families can be difficult. There is a trade-off between a family member’s right not to know and their right to be informed of a condition that may have significant medical consequences for themselves and their offspring. A general letter of explanation about the disease, genetic testing, and where to seek advice can be given to the
Genetic Advice and Testing: Basics of Inheritance, Counseling, and Rationale for Testing
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individual(s) who is attending the genetics clinic to pass on to relatives. This individual takes responsibility for disseminating information to the wider family with the help of this letter; relatives then have a choice about seeking further advice and intervention. Where families are fragmented and contact is lost this can be a difficult barrier to surmount. Family members do not like to be the bearer of bad news and will often find it very difficult to approach family members. In these circumstances the genetic team may be able to help. Striking a balance between respecting an individual’s right not to know and their right to have information relevant to their or their children’s future health can present difficult ethical and legal dilemmas. Genetic Registers. Follow-up can be facilitated by genetic registers; a register of families with Duchenne muscular dystrophy, for example, can be a useful tool for recalling female family members who may be gene carriers when they reach an age where they may start a family. This may be 10 or 20 years or longer after the diagnosis is made in a brother or uncle; issues about resources to maintain such registers need careful consideration. Genetic Nurses and Associates. Nurses or science graduates trained in genetics are a valuable part of the clinical genetics team and are often involved in the preliminary information-gathering described above, establishing a relationship with the patient and their family, acting as an advocate for the patient during the clinical consultation, and offering support through the process of genetic testing and communication with the wider family. They may visit the patient at their home and may help to reinforce and clarify sometimes complex information discussed during a clinic appointment. They can also be a valuable point of contact for ongoing follow-up and coordination of surveillance strategies in conditions where early detection of complications can lead to improved clinical outcomes such as with von Hippel-Lindau disease and NF2.
Summary of Genetic Counseling and Testing Process The process of counseling must balance carefully the potential benefits and harms and allow sufficient time for sometimes complex information to be absorbed. It should also permit reflection on the wider implications of predictive testing such that individuals come to a comfortable decision with regard to their own predictive test. This is often not a simple process; Figure 2.5 shows the model for predictive testing in Huntington’s disease that is used by most genetic centers and has also been adapted for other conditions, particularly where testing is being undertaken for a fatal disease with no known effective therapeutic intervention. Such a protocol can be shortened in exceptional circumstances, such as an early pregnancy where one or other parent is at risk of being a carrier for HD. In practice, where this situation arises an alternative approach is to offer exclusion testing. This might be helpful where the parents want to avoid having a child who may develop HD but where the ‘‘at risk’’ parent does not wish to know their own genetic status; the process for this is illustrated in Figure 2.6.
Huntington’s disease diagnosed Index cases referred for genetic counseling First contact with genetics service • Disease and inheritance explained • Family tree constructed • Information provided to facilitate contact of at-risk relatives with genetics services
• • •
SESSION 1 New contact with at-risk relative Disease and inheritance explained Risk to individual estimated using Bayesian method Implications of possible test outcome for self and close relatives explored
SESSION 2 Second contact with at-risk relative • Explore individual’s understanding of risk and perception of potential impact of test, e.g., insurance, employment, relationships • Assess emotional and social support Test declined/postponed Long-term follow-up by genetics service
• • •
Test accepted Agree date for blood to be taken
SESSION 3 Blood taken Date set for disclosure of result Individual encouraged to come with supporting person
Disclosure
Disclosure
Test result is negative – disease-associated allele has not been inherited
Test result is positive – disease-associated allele has been inherited
Follow-up (about 1 month later) A further appointment or telephone call to ensure there are no outstanding questions or adverse psychological sequelae
Follow-up (about 2–4 weeks later) Discuss implications again Negotiate what further follow-up the individual would find helpful (often annual review in neurogenetic clinic)
Disease onset Coordinate specialist input from neurology, social services, primary care, psychiatry
Figure 2.5. Model for predictive testing in Huntington’s disease.
Genetic Advice and Testing: Basics of Inheritance, Counseling, and Rationale for Testing
• • •
Chorionic villous sample obtained at 10 weeks gestation Blood sample from both parents and from affected grandparent DNA extracted
A 2
B 2
23
C 1
B 2
G
H
J
B 2
K
A 1
C 2
A 1
N
Exclusion testing: H is no longer alive. DNA from the unaffected grandparent and both parents allows polymorphic areas of the genetic code flanking the Huntington’s disease gene to be tested and indirectly to establish that fetus has inherited the B2 allele from her mother and the A1 allele from her father. The B2 allele was inherited from her mother since she must have inherited one or other of these clearly distinct alleles. The child therefore has clearly not inherited the “atrisk” allele and has a low chance of having inherited HD. Had the child inherited the C1 allele, the child, like individual J, would have a 50% chance of having inherited HD. If the mother subsequently had a direct test for the expanded HD allele or developed the disease then it would be clear that the child would also have the disease allele.
Figure 2.6. Exclusion testing.
Genetic testing for disease predisposition involves several steps, any of which can present particular challenges. Understanding the potential pitfalls is important in order that individuals and families are fully informed with correct information to allow them to make potentially difficult choices.
REFERENCE Harper PS (1998). Genetic counselling: an introduction. Practical Genetic Counselling. 5th ed. Oxford: Butterworth-Heinemann.
Chapter 3 Dementia Thomas T. Warner
INTRODUCTION Dementia is a generic term that describes chronic or progressive dysfunction of cerebral cortical or subcortical function resulting in complex cognitive decline. These cognitive changes are often accompanied by disturbances of mood, behavior, and personality. Dementia affects around 5% of the population over the age of 65 years, with overall incidence increasing with age. The commonest cause of dementia is Alzheimer’s disease, but many other forms are now recognized. While the majority of cases of dementia appear sporadic, there are many single-gene disorders with dementia as the primary manifestation, exhibiting autosomal or sex-linked inheritance. In addition, there are genes that act as risk factors for the development of dementia. This chapter focuses on conditions where dementia is the predominant feature. The dementias have traditionally been classified according to clinical features and neuropathology. A new classification has been proposed based on the protein abnormality that appears central to pathogenesis. Thus, Alzheimer’s disease is predominantly an amyloidopathy due to the central role of the amyloid precursor protein. Tauopathies describe dementias associated with abnormal deposition of protein tau, and include frontotemporal lobe dementia and progressive supranuclear palsy. Synucleinopathies (abnormal function of a-synuclein) include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Table 3.1 lists the hereditary dementias according to this classification.
Clinical Assessment of Patient with Dementia A careful history should be taken, including the following key points: Onset and Progression of Disease Gradual and insidious onset over months to years favors a neurodegenerative cause whereas sudden and stepwise deterioration is more frequently seen in 24
Dementia
25
Table 3.1 Hereditary Dementias Disease (OMIM)
Gene
Amyloidopathies Sporadic Alzheimer’s disease (104300) Familial Alzheimer’s disease Hereditary cerebral hemorrhage with amyloidosis (Dutch; 609065) Hereditary cerebral hemorrhage with amyloidosis (Icelandic; 105150) Familial British dementia (176500) Familial Danish dementia (117300) Tauopathies Frontotemporal dementia with parkinsonism (FTDP-17; 157140) Frontotemporal dementia (Jutland; 600795) Inclusion body myopathy, Paget’s disease and frontotemoporal dementia (167320) Prion diseases Familial Creutzfeld-Jacob disease (123400) Gerstmann-Straussler-Scheinker disease (137440) Familial fatal insomnia (600072) Other dementias Familial encephalopathy with neuroserpin inclusion bodies (604218) Frontotemporal dementia (tau negative; 607485)
ApoE b-Amyloid precursor protein, presenilin-1 and -2 b-Amyloid precursor protein Cystatin C Integral transmembrane protein 2B gene Integral transmembrane protein 2B gene Microtubule-associated protein tau (MAPT) Charged multivesicular body protein 2B (CHMP2B) Valosin-containing protein (VCP)
Prion protein (PrP) Prion protein (PrP) Prion protein (PrP) Protease inhibitor 12 (neuroserpin) Progranulin (PGRN)
vascular forms of dementia. Subacute onset and progression over weeks and months indicates a more aggressive pathology (e.g., prion disease). The age of onset is also helpful. Onset earlier than 65 years of age is associated with a higher probability that the dementia is genetic in origin. Nature of Symptoms It is important to ascertain the type of cognitive problem. Predominant shortterm memory loss suggests temporal lobe pathology, as seen in Alzheimer’s disease. Frontal lobe symptoms with personality change, disinhibition, and emotional lability would favor other forms including frontotemporal dementia. More global forms of dementia are associated with parietal symptoms of neglect and sensory apraxia. Fluctuation of symptoms with nocturnal hallucinations is suggestive of Lewy body dementia. Family History It is also important to ask about a family history of dementia and neurological disorders. Additional Neurological Features These should be sought by history and examination including jerks (myoclonus) and seizures, visual disturbance or neglect, hallucinations, speech and language
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Table 3.2 Clinical Features of Genetic Dementias Type of Dementia Onset (yrs)
Progression
Main Cognitive Defect
Other Features
Alzheimer’s disease
4060 familial
Slow years
Seizures, myoclonus
Frontotemporal
5060
Slow years
Short-term memory, attention and concentration Behavior and personality change, progressive aphasia
Prion disease
5070
Rapid months
Global
Parkinsonism, amyotrophic lateral sclerosis, corticobasal degeneration, progressive supranuclear palsy Ataxia, myoclonus, cortical blindness, hallucinations
disturbance, loss of balance and coordination, evidence of parkinsonism with slowness, stiffness and tremor of limbs, weakness, sensory loss, and bladder dysfunction. A mental-state examination assists in gauging the type and severity of the cognitive problem. The presence of depression, either primary or secondary, and hypothyroidism should also be sought. Table 3.2 gives clinical clues to assist diagnosis of the major genetic forms of dementia. Differential Diagnosis There are a number of diagnoses that should be considered in any case of progressive cognitive decline, particularly as some are treatable. These include depression, thyroid disease, vitamin deficiencies (especially B12 and thiamine), chronic drug or alcohol intoxication, chronic CNS infection (e.g., syphilis, HIV), CNS vasculitis, neoplasms, vascular dementia, and normal-pressure hydrocephalus. Investigations For any new case of dementia there are a number of mandatory investigations: cranial imaging with CT or MRI, routine hematology and biochemistry, including thyroid function, vitamin B12, ESR and CRP, and syphilis serology. Other investigations depend on the clinical picture and may include formal psychometry, autoantibody screen and serology for other infections (e.g., HIV), EEG, CSF analysis, cerebral angiography, and occasionally brain and/or meningeal biopsy.
AMYLOIDOPATHIES Alzheimer’s Disease (OMIM 104300) Clinical Features Alzheimer’s disease is the most common neurodegenerative disease of aging, and the most frequent cause of dementia. Clinical presentation typically begins with subtle, poorly recognized failure of memory which slowly becomes
Dementia
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more severe and incapacitating. Other common symptoms include confusion, withdrawal, language disturbance, lack of judgment, agitation, and hallucinations. Seizures and myoclonus are more common in Alzheimer’s disease than the general population and are more prevalent in advanced disease. Patients may also develop increased muscle tone, parkinsonism, or incontinence. Pathologically, Alzheimer’s disease is characterized by two types of neuropathological inclusions, neurofibrillary tangles, and senile plaques. Neurofibrillary tangles are composed of paired helical filaments of hyperphosphorylated tau protein, whereas the main component of senile plaques is b-amyloid. Studies show that the clinical diagnosis of Alzheimer’s disease (prior to autopsy) is correct in 8090% of cases. Prognosis Alzheimer’s disease is progressive and leads to increasing cognitive failure and dependency. Death usually results from general debility, effects of poor nutrition and pneumonia. The typical clinical duration is 810 years. Genetics and Pathophysiology The majority of cases of Alzheimer’s disease are sporadic. In less than 5% of cases it is inherited as an autosomal dominant trait with almost complete penetrance. No environmental agents (e.g., trauma, toxins) have been proven to be directly involved in the pathogenesis of Alzheimer’s disease. However, it has been suggested that late-onset sporadic Alzheimer’s disease results from interaction of environmental factors acting on a background of genetic susceptibility. This is reflected by the finding that, whilst the greatest risk factor for developing Alzheimer’s disease is increasing age, the presence of an affected first-degree relative doubles the relative risk for an individual. Apolipoprotein E (ApoE; OMIM 107741). There is evidence for involvement of several genes in the development of sporadic Alzheimer’s disease the bestdocumented being the gene encoding apolipoprotein E (ApoE). There are three common alleles for APOE: e2, e3, and e4. In Caucasian populations, individuals carrying the e4 allele are three (heterozygotes) to eight (homozygotes) times more likely to develop Alzheimer’s disease than individuals without an e4 allele. One hypothesis is that the e4 allele may increase the rate of b-amyloid deposition. Genome-wide screens have been performed to attempt to identify other major genetic susceptibility loci. Areas on chromosomes 6, 9, 10, and 12 have been implicated as harboring Alzheimer’s disease risk genes, but none has yet been identified. Three genes are known to cause autosomal dominant Alzheimer’s disease: bamyloid precursor protein (APP), presenilin 1, and presenilin 2. Individuals with familial Alzheimer’s disease have earlier age of onset of symptoms (<65 years) and usually in the 40s or early 50s. This group comprises less than 5% of all Alzheimer’s disease. b-Amyloid Precursor Protein (APP; OMIM 104760). Mutations in the APP gene have been identified in 1015% of early-onset (<65 years) familial
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Alzheimer’s disease. The gene is located on chromosome 21q21 and has 19 exons. It encodes an alternatively spliced transcript that, in its longest form, codes for a 770 amino acid transmembrane spanning polypeptide. The polypeptide is processed by two major pathways. The critical pathway involves sequential action of b and g secretases, which generate Ab peptides of 4043 amino acids. Accumulation of Ab-42 species, which is highly amyloidogenic, within neuritic plaques is central to the amyloid cascade hypothesis of Alzheimer’s disease. In support of this is the finding that individuals with Down’s syndrome (trisomy 21) develop the neuropathological hallmarks of Alzheimer’s disease by the age of 40, many with evidence of cognitive decline. Life-long overexpression of the APP gene is thought to lead to excessive Ab-amyloid deposition in the brain. All pathogenic APP mutations cluster around the secretase sites, imposing a direct influence on APP processing. Within a given family, age of onset of Alzheimer’s disease can be very consistent, generally between 40 and 60 years, although onset may be influenced by ApoE genotype. There are no clear clinical features that reliably distinguish patients with APP mutations from either sporadic Alzheimer’s disease or familial Alzheimer’s disease caused by other genes. The exception is a mutation in codon 692 with substitution of glycine and alanine, which is associated with hereditary cerebral hemorrhage with amyloidosis of Dutch type (see later). Presenilins (PS-1; OMIM 104311: PS-2; OMIM 600759). Mutations in presenilin-1 (PS-1) are much commoner than those in APP, accounting for around 50% of early-onset familial Alzheimer’s disease. PS-2 mutations are rarer and are responsible for <1% of cases, most of which are of Volga German ancestry living in the USA. The presenilins are a highly homologous group of proteins and there is increasing evidence to support their role in the g-secretase proteolysis of APP. Mutations in PS-1 appear to favor overproduction of Ab-42. Over 100 PS-1 mutations have been described and the clinical spectrum is wide. Onset varies from 20 to 60 years, even within the same family. Penetrance is complete by the age of 65 years. Some families have specific phenotypes, such as a spastic paraparesis (associated with deletion of exon 9) or prominent myoclonus, although the latter feature is not specific to a certain mutation. Seizures and language deficits are often associated with PS-1 mutations. Families with PS-2 mutations may have an older age of onset with reported range of 5060 years. Treatment The mainstay of treatment is supportive care and dealing with symptoms on an individual basis (e.g., treating depression, agitation). In general, affected individuals eventually require assisted living arrangements or care in a nursing home. Use of acetylcholinesterase inhibitors has shown a modest but useful behavioral or cognitive benefit in some patients and has led to widespread use of these drugs (e.g., donepezil, rivastigmine, and galantamine) in patients with mild to moderate Alzheimer’s disease. Trials of non-steroidal anti-inflammatory drugs, estrogen, growth factors, and antioxidants are currently under way. Immunization of a mouse Alzheimer’s disease model with b-amyloid was
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found to attenuate the pathology and led to hope of a vaccination approach to human treatment. However, a human trial using this approach was halted due to development of encephalitis in a few subjects. Genetic Advice and Testing The overall lifetime risk of developing dementia for any individual is approximately 10% and Alzheimer’s disease is responsible for over half of these cases. First-degree relatives of a person with late-onset sporadic Alzheimer’s disease have a cumulative lifetime risk of developing Alzheimer’s disease of around 2025%. There is conflicting evidence as to whether the age of onset of the affected person changes the risk to first-degree relatives. The number of additional affected relatives probably increases the risk to first-degree relatives in excess of that for a sporadic case, but the magnitude of the increase is unclear unless there is obvious autosomal dominant inheritance. Where there is clear evidence of early-onset (< 65 years) autosomal dominant familial Alzheimer’s disease, the risks are those for any dominant condition. For APP and PS-1 mutations penetrance appears complete, but for PS-2 reduced penetrance has been reported. Testing for ApoE Genotype. Although the ApoE e4 allele is a major risk factor for Alzheimer’s disease, 4070% of late-onset Alzheimer’s disease patients do not carry the e4 allele and a significant proportion of the population who carry the e4 allele do not develop cognitive impairment. For these reasons there is general agreement that ApoE testing should not be used as a predictive test for Alzheimer’s disease in asymptomatic persons. Testing for Mutations in PS-1, PS-2, and APP. Testing of at-risk asymptomatic adults is clinically available for PS-1 and PS-2, and has been performed on a research basis for APP. Screening for PS mutations generally assesses exons 2 to 12 (PS-1) and 4, 5, and 7 (PS-2), the sites of the common mutations. Testing for PS-1 mutations detects 3060% of early-onset familial cases. The testing is not useful for predicting age of onset, type of symptoms, or rate of progression. Prenatal testing for PS-1 mutations for pregnancies at 50% risk is possible following appropriate genetic counseling.
Hereditary Cerebral Hemorrhage with AmyloidosisDutch Type (HCHWA-D; OMIM 609065) Cerebral amyloid angiopathy is a relatively common finding at autopsy in the elderly population. It ranges from asymptomatic amyloid deposition in otherwise normal cerebral vessels to complete replacement and breakdown of the cerebrovascular wall. Severe cerebral amyloid angiopathy can cause lobar cerebral hemorrhage, transient neurological symptoms, and dementia with leukoencephalopathy. In the general population the ApoE e2 and 4 alleles are associated with increased risk and earlier age of first hemorrhage. Several genetic mutations associate with dominantly inherited cerebral hemorrhage with amyloidosis, of which HCHWA-D is best characterized.
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HCHWA-D is characterized by recurrent strokes caused by cerebral and cerebellar lobar hemorrhage as well as infarction, with onset in the fifth decade. Migraine and cognitive change have been reported to precede the hemorrhages and dementia frequently develops later. In life, diffuse white matter hyperintensities are seen early on MRI, followed by focal hemorrhages and infarcts. At autopsy, extensive amyloid deposition is seen in leptomeningeal arteries and cortical arterioles. Unlike Alzheimer’s disease, parenchymal amyloid plaques are not prominent in HCHWA-D, although diffuse parenchymal amyloid-b is found. Mutations in the Ab domain of APP have been shown to cause the cerebrovascular pathology in HCHWA-D, but do not lead to the full range of Alzheimer’s disease pathology. A point mutation at codon 693 has been shown to cause the majority of cases. A second mutation at codon 692 has also been identified. A specific form of cerebral amyloid angiopathy with hemorrhage has also been described in Icelandic families, segregating as an autosomal dominant trait (OMIM 105150). Age of onset is younger than HCHWA-D, with mean age of the first stroke of 27 years. The condition has been shown to be caused by mutation in the gene for the protease inhibitor cystatin C (OMIM 604312) leading to a leucine to glutamine substitution at codon 68.
Familial British (OMIM 176500) and Danish (OMIM 117300) Dementias Familial British dementia with amyloid angiopathy is a rare autosomal dominant condition characterized by dementia, progressive spastic tetraparesis, and ataxia with usual onset in the sixth decade. A point mutation in the integral transmembrane protein 2B (ITM2B) gene on chromosome 13 results in generation of the ABRI peptide (a 4-kDa protein subunit). This is deposited as amyloid fibrils and leads to neuronal dysfunction and neurodegeneration. A duplication of this gene causes the related Danish familial dementia characterized by cataracts, often occurring before the age of 30 and preceding other clinical features including deafness, progressive ataxia, and dementia.
TAUOPATHIES Frontotemporal Dementia (OMIM 600274) Frontotemporal dementia (FTD) is a term used to describe a heterogeneous group of neuropsychiatric diseases. It is characterized clinically by progressive personality change and language impairment related to frontal and temporal lobe atrophy. Age of onset is in general younger than sporadic Alzheimer’s disease, primarily between 35 and 75 years, and it is believed to account for up to 20% of cases of dementia. A significant proportion of these cases have a positive family history. Pick’s disease (OMIM 172700) is the archetypal pathological form of FTD, characterized pathologically by the presence of swollen B-crystalline positive neurons (Pick cells) and argyrophilic, tau-positive round inclusions (Pick bodies) that are particularly seen in the hippocampus and frontotemporal cortex.
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Clinical Features The two core clinical phenotypes of FTD are: 1. Gradual and progressive changes in behavior, often presenting with early change in social and personal conduct and lack of inhibition. This leads to impulsive actions and poor judgment. Repetitive or compulsive behaviors may develop and overeating is common. In comparison with Alzheimer’s disease, individuals with FTD do not have a true amnestic syndrome. 2. Early and progressive change in language function. Many present with expressive problems, such as using the correct word or naming objects. Difficulties in reading and writing then develop, and as the condition progresses the patient may become virtually mute. This is referred to as primary progressive aphasia, or semantic dementia if there is loss of language comprehension. A third rarer subtype of FTD is frontotemporal dementia with parkinsonism-17 (FTDP-17; OMIM 157140), which has an identified genetic component in families caused by mutations in the gene for microtubule-associated protein tau (MAPT; OMIM 157140) on chromosome 17. Clinical presentation is of FTD with extrapyramidal signs (bradykinesia, rigidity without rest tremor, postural instability, supranuclear palsy). Families exhibit autosomal dominant inheritance and individual kindreds can also have psychotic features and some amyotrophy. Onset is between 40 and 60 years. Pathologically it involves the frontal and temporal lobes and subcortical nuclei. It has become clear that MAPT mutations can also cause classic FTD with behavioral and language changes without parkinsonism. In addition, other phenotypes have been described with associated features of amyotrophic lateral sclerosis, corticobasal degeneration, or progressive supranuclear palsy. Many families with FTD do not have MAPT mutations, and in these pathology usually consists of ubiquitin-positive, tau-negative neuronal inclusions. In these families, mutations in the progranulin (PGRN; OMIM 138945) gene were identified. Cases caused by PGRN mutations have a higher incidence of primary progressive aphasia and hallucinations.
Figure 3.1. MRI scan of patient with FTD and a tau mutation showing prominent anterior medial temporal lobe atrophy.
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Investigations CT and MRI scanning of the brain may initially be normal, but later shows cortical atrophy and ventricular enlargement that may be symmetrical or asymmetrical and worsens with time (Fig. 3.1). SPECT shows decreased cerebral perfusion anteriorly, present in early disease. Prognosis For FTD and FTDP-17, usual disease duration is of between 5 and 10 years, although occasionally may be up to 20 years. The course is progressive with increasing debility, as for Alzheimer’s disease. Pathophysiology In FTDP-17, deposition of hyperphosphorylated tau is present in neurons. Tau pathology consists of abundant neurofibrillary tangles in the hippocampus, cortical regions and subcortical nuclei. The MAPT gene consists of 15 exons. Normal MAPT promotes tubulin polymerization, reduces microtubule instability and maintains neuronal integrity, axonal transport, and axonal polarity. Missense mutations have been reported, as well as intronic and exonic mutations affecting alternative splicing of exon 10. Most appear to increase the number of 4-repeat tau isoforms, although others alter microtubule binding and appear to disrupt normal MAPT function, leading to abnormal tau aggregation and cell death. The function of progranulin in neurons is unclear, but the mutations appear to result in haploinsufficiency. Treatment The behavioral changes and loss of insight and judgment in patients with FTD can become a major burden for carers. Likewise, the language problems can be immensely difficult to cope with. Information and psychological support for partners and carers is important. More extreme behavioral or psychiatric symptoms can be treated with sedative or antipsychotic drugs. There is limited evidence to suggest that L-dopa may benefit some patients with parkinsonian signs. Genetic Advice A number of families with FTD and those with FTDP-17 demonstrate autosomal dominant inheritance, and risks should be given appropriately. Mutations in the MAPT gene have been identified in between 25 and 40% of families with autosomal dominant FTD in research studies. Some centers offer testing for a panel of three mutations, although the detection rate for this is unknown. Sequence analysis of the MAPT gene is available only on a research basis. There is little clear genotypephenotype correlation, although the P301S mutation appears to be associated with an early onset (2030 years) and the occurrence of epilepsy or myoclonus.
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The frequency of PRGN mutations in typical FTD is about 5%, which rises to <20% in familial FTD. Penetrance is estimated at 90% by 70 years. It is likely that mutation testing will be available in the near future. Other families with autosomal dominant FTD have been linked to chromosome 9, and in one Danish kindred, to chromosome 3. In the latter, a mutation has been identified in the CHMP2B gene (OMIM 609512).
PRION DISEASES Prions cause a group of neurodegenerative conditions which have the core pathogenic feature of posttranslational modification of a normal human prion protein (PrPC), to an abnormal form (PrPSC). PrPC is coded for by a single exon on the long arm of chromosome 20. The function of the normal 3335 kDa protein is unknown, but it is known to be anchored to the external surface of cells by a glycolipid moiety. The underlying neuropathological hallmark of prion diseases is spongiform (vacuolar) degeneration of neurons and their processes, with neuronal loss and reactive astrogliosis and deposition of PrPSC. Prion diseases may be sporadic, inherited or transmissible. Prion diseases are rare, with worldwide incidence estimated at 1 case per million per year. Most cases appear sporadic and only 15% appear to have a genetic basis. The human prion diseases are kuru, Creutzfeld-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), and fatal familial insomnia (Table 3.3).
Creutzfeld-Jakob Disease (CJD; OMIM 123400) Clinical Features The commonest form of prion disease is CJD, which is usually sporadic, can be transmitted, and in the minority of cases is inherited due to PrP gene mutations. Age of onset is in late adult life, with peak onset between 60 and 65 years. CJD in individuals under the age of 40 is very rare. The clinical picture is of subacute progressive dementia with myoclonus. Twenty-five percent of patients have a prodrome of altered sleep patterns and appetite, and loss of weight and libido. Table 3.3 Human Prion Diseases Disease
Etiology
Kuru Creutzfeld-Jacob disease Iatrogenic Sporadic Familial Gerstmann-Straussler-Scheinker disease Fatal familial insomnia
Infection Infection Unknown PrP mutation PrP mutation PrP mutation
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The dementia progresses over weeks and months with problems of memory, concentration, and problem-solving. Behavior is altered, with apathy, disinhibition, paranoia, and self-neglect. Patients can also have hallucinations and disorientation. Ataxia can be present at onset in around 30%, and overall occurs in 70% of cases. Accidental transmission of CJD to humans has occurred by corneal transplantation, cadaveric dura mater grafts, human growth hormone, and contaminated EEG and surgical instruments. Familial CJD is clinically indistinguishable from sporadic apart from having a slightly earlier age of onset (mean 55 years). Inheritance is autosomal dominant. Variant CJD (vCJD) is a newer form linked to transmission of the agent of bovine spongiform encephalopathy, predominantly in the UK. Onset is younger than sporadic CJD (mean age 29) and vCJD has a clinical presentation in which behavioral and psychiatric disturbances predominate, in some cases associated with marked sensory phenomena. Depression is a frequent presenting symptom, which can be accompanied by delusions, aggression, insomnia, and hallucinations. A progressive cerebellar syndrome develops and myoclonus is usually present. The clinical course is more protracted (median 14 months) compared with late-onset sporadic CJD. Two other familial forms of prion disease have been described with specific phenotypes.
Gerstmann-Straussler-Scheinker Disease (GSS; OMIM 137440) GSS is an autosomal dominant disorder that presents classically as a chronic cerebellar ataxia with pyramidal features, with dementia occurring much later in the illness. The mean duration is about 5 years. Extrapyramidal features, gaze palsies, deafness, pseudobulbar palsy, and cortical blindness may also develop in some families, whilst myoclonus is rare. Examination often reveals loss of tendon reflexes with extensor plantar responses.
Fatal Familial Insomnia (FFI; OMIM 600072) FFI is an autosomal dominant disorder that presents with intractable progressive insomnia and dysautonomia with sympathetic overactivity causing hypertension, hyperthermia, hyperhidrosis, and tachycardia. Motor abnormalities also occur with tremor, myoclonus, and hyperreflexia. Memory function is reported to show characteristic abnormalities with severe impairment of concentration and memory in the face of preserved intellect.
Investigations MRI scanning can be useful in CJD. Basal ganglia hyperintensities have been observed in over 60% of patients. It may also allow discrimination between CJD and vCJD, as in the latter the most pronounced signal change is in the
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Figure 3.2. Patient with 102 val to leu prion protein mutation with a GSS phenotype demonstrating cerebellar atrophy.
posterior thalamus (‘‘pulvinar sign’’). In GSS, cerebellar atrophy can be present (Fig. 3.2). Electroencephalograms (EEG) can also be helpful and bilateral alpha activity with generalized theta and delta waves may be seen in early CJD. The characteristic findings, however, are of periodic sharp and slow wave complexes (PSWCs). PSWCs are also seen in patients with familial CJD with codon 200 and codon 210 mutations, but are absent in GSS and FFI. Cerebrospinal fluid constituents are in general normal. However, detection of the 14-3-3 family of proteins in the CSF can help substantiate the diagnosis. Levels of these proteins are high in 95% of sporadic CJD patients. Again in familial CJD with codon 200 or 210 mutations, the 14-3-3 assay has similar diagnostic value, but levels are absent in FFI and uncommon in GSS. Tonsillar biopsy is of particular use for vCJD, which can be diagnosed by detection of characteristic PrPSC immunostaining. Other forms of prion disease are not detectable in this way.
Prognosis CJD is usually rapidly progressive over a period of weeks to months, leading to an akinetic mute state and death in as little as 34 months. Around 70% of those afflicted die within 6 months. vCJD has a more prolonged course, as do some of the inherited forms. Patients with GSS and FFI also have a more indolent course.
Treatment Treatment for this devastating form of illness is basically supportive for the patient and family/carers. Experimental therapies targeting PrPSC have been devised, but to date none has been successful.
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Genetic Advice and Testing All the inherited forms of prion disease have been associated with mutations in the PrP gene. Mutations are all inherited as an autosomal dominant trait. Familial CJD The most common mutation is at codon 200 of the prion gene. Mutations at codons 208 and 210 have been reported in Italian kindreds and all three of these mutations appear to have reduced penetrance. The second most common mutation, at codon 178, produces disease at an earlier age (fifth decade) and longer duration (1 year). All clinical cases of vCJD to date have been homozygous for methionine at codon 129, suggesting a genetic susceptibility to this particular form of CJD. The relevance of this to its actual pathogenesis is unclear and polymorphism testing currently is a research tool only.
Table 3.4 Adult-Onset Hereditary Diseases with Prominent Dementia Disease (OMIM)
Inheritance
Other Features
Useful Tests
Huntington’s disease (143100) DRPLA (125370)
AD
Chorea, neuropsychiatric features
AD
Adrenoleucodystrophy (300100)
XL
Ataxia, myoclonus, chorea, seizures Spasticity, reduced vision, adrenal failure
CAG repeat analysis in gene for huntingtin CAG repeat in gene for atrophin
Wilson’s disease (277900)
AR
Mitochondrial diseases
Maternal
Niemann-Pick type C (257220)
AR
Parkinson’s disease (168600) CADASIL (125310)
AD/AR
Lewy body dementia (127750) Spinocerebellar ataxia
Extrapyramidal features, abnormal liver function, Kayser-Fleischer rings Seizures, ataxia, myoclonus, migraine, stroke-like episodes, retinopathy, ophthalmoplegia, neuropathy, diabetes, cardiac problems Supranuclear gaze palsy, hepatosplenomegaly, dystonia, spasticity
Parkinsonism-rigidity, akinesia, rest tremor AD Stroke, transient ischemic attack, depression AD Fluctuating cognitive function, (3 kindreds) visual hallucinations, parkinsonism AD Ataxia, pyramidal and extrapyramidal signs, neuropathy
MRI, long-chain fatty acid analysis, genetic analysis ABCD1 gene Serum ceruloplasmin, copper, liver biopsy, genetic analysis, Cu2+transporting ATPase Lactic acid, muscle biopsy (red ragged fibers), genetic analysis for mitochondrial DNA mutations Bone marrow for foam cells, assay for cholesterol esterification, genetic analysis for NPC1 gene Clinical diagnosis MRI brain scan, analysis of NOTCH3 gene Clinical diagnosis
Analysis of SCA genes
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GSS The majority of cases of GSS are associated with a point mutation at codon 102 of the PrP gene. A second mutation at codon 117 appears to be associated with a more complicated phenotype with additional neurological features, including extrapyramidal signs, gaze and pseudobulbar palsy, and deafness. FFI This disease is associated with the same codon 178 mutation that can cause familial CJD. The phenotype appears to be influenced by a polymorphic variation at codon 129: when this encodes a valine on the mutant 178 allele, the result is CJD; when it encodes a methionine, the result is FFI. Testing for PrP mutations is clinically available for an individual with a suspicious clinical picture, especially in the presence of a family history. This is normally performed by sequencing the entire open reading frame of the prion gene (approximately 750 bp).
Other Genetic Causes of Dementia Many genetic diseases present with dementia as part of their clinical phenotype. Those where adult onset dementia is a prominent part are listed in Table 3.4.
Familial Encephalopathy with Neuroserpin Inclusions Bodies (FENIB; OMIM 604218) FENIB is a rare autosomal dominant condition characterized by progressive dementia, with relative sparing of recall memory. Pathologically there is accumulation of cytoplasmic inclusions in the deep cortical layers, substantia nigra, and subcortical nuclei. A point mutation has been detected in the gene encoding neuroserpin (chromosome 3).
BIBLIOGRAPHY Collinge J (2001). Prion diseases of animals and humans; their causes and molecular basis. Annu Rev Neurosci, 24, 519550. Goldman JS, Adamson J, Karydas A, Miller BL & Hutton M (2008). New genes, new dilemmas: FTLD genetics and its implications for families. Am J Alzheimers Dis Other Demen, 22, 507515. Ritchie K & Lovestone S (2002). The dementias. Lancet, 360, 17591766. Schott JM, Fox NC & Rosser MN (2002). Genetics of the dementias. J Neurol Neurosurg Psychiatry, 73(Suppl II), 2731.
Chapter 4 Epilepsy Simon R. Hammans
INTRODUCTION Epilepsy is defined as a tendency to recurrent unprovoked seizures. Epilepsy has a cumulative lifetime incidence of approximately 3%, but the prevalence of active epilepsy is 0.41%, indicating that the condition is temporary in many patients. Probably all epilepsy has both genetic and non-genetic determinants. Genes are likely to play a role in setting the seizure threshold in any individual. At one extreme, epilepsy can be caused by one or more genes sufficient to cause a severe seizure disorder that is subject to modifications by environmental factors (e.g., tuberous sclerosis). At the other extreme, epilepsy may be primarily determined by environmental influences, such as brain trauma. Even in this situation it is likely that expression of seizures is modulated by genetic determinants. Evidence for the importance of genetic factors comes from twin studies. A large study by Berkovic et al. (1998) found that that monozygous pairs are more often concordant for seizures (62%) than dizygous pairs (18%). The genetic component appeared particularly important in the idiopathic generalized epilepsies, but also played a significant role in febrile seizures and symptomatic epilepsies. Epileptologists have consistently recommended that an attempt should be made to make a syndromic diagnosis of the seizure disorder. A precise formulation has many clinical benefits, including allowing more precise advice on prognosis, drug treatment, causes, and genetic risks. A full description of the assessment of a seizure disorder is beyond the scope of this text. Nevertheless, the assessment of genetic risk is dependent on a precise syndromic diagnosis in the proband and a careful assessment of the presence and nature of seizures in relatives, with analysis of clinical records if necessary (see Manford 2003). Seizures are heavily influenced by the maturity of the brain. In evaluating the genetics of epileptic disorders, the importance of the phenotype often depends on the age profile of the disorder. For example, if the disorder is not associated with interictal neurological impairment and the seizures remit before adulthood, then it may not be considered a major disability. 38
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The following classification will be used in this chapter: Single-gene disorders with epilepsy as one manifestation * With mental retardation, neurodegenerative, structural, or metabolic abnormalities * Neuronal migration defects * Progressive myoclonic epilepsies Idiopathic epilepsies associated with cytogenetic abnormality Idiopathic epilepsies with Mendelian inheritance Idiopathic epilepsies with complex inheritance Febrile seizures Symptomatic epilepsy associated with central nervous system insults.
SINGLE-GENE DISORDERS WITH EPILEPSY AS ONE MANIFESTATION With Mental Retardation, Neurodegenerative, Structural, or Metabolic Abnormalities There are over 200 single-gene disorders with epilepsy as one manifestation of the phenotype. Together they account for approximately 1% of all epilepsies, although most are individually rare. Some have epilepsy as a minor part of the phenotype (e.g., seizures seen as part of a leukodystrophy). Table 4.1 summarizes some of the commoner disorders with epilepsy as a significant part Table 4.1 Examples of Single-Gene Disorders with Epilepsy and Mental Retardation, Structural, or Metabolic Abnormalities Disorder: Mode of Inheritance
Phenotype Including Seizures
Genetic Cause
Neurofibromatosis 1: autosomal dominant (OMIM 162200) Tuberous sclerosis: autosomal dominant (OMIM 191100) Dentatorubral-pallidoluysian atrophy: autosomal dominant (DRPLA; OMIM 125370) Rett syndrome: X-linked dominant (OMIM 312750)
See Chapter 15
Mutations in NF1 gene
See Chapter 15
Mutations in TSC1 and TSC2 genes Triplet expansion in atrophin 1
Phenylketonuria: autosomal recessive (OMIM 261600)
Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: autosomal recessive (OMIM 138140)
Combinations of myoclonic epilepsy, dementia, ataxia, and movement disorders Develop normally until 618 months, Mutations in methyl-CpGthen speech decline, stereotypical binding protein 2 (MECP2) hand movements, microcephaly, seizures, autism, and ataxia Mutations in phenylalanine Mental retardation in untreated hydroxylase gene patients, including a ‘‘mousy’’ odor, light pigmentation, abnormalities of gait, stance and sitting posture, eczema; and epilepsy. Treated by diet Developmental delay, seizures, Mutations in SLC2A1 gene microcephaly. Low CSF glucose. Treatable with ketogenic diet
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of the phenotype. The disorders are diverse. Some are neurocutaneous disorders (NF1, tuberous sclerosis) or neurodegenerative (DRPLA), others classic metabolic disorders (phenylketonuria). With these disorders the management and genetic advice are individual to that disease. Neuronal migration defects and progressive myoclonic epilepsies are distinctive subgroups, which may be caused by single genes and are summarized separately.
Neuronal Migration Disorders This group of disorders includes important causes of chronic epilepsy. Clinical presentation is heterogeneous, ranging from infantile encephalopathy to chronic epilepsy. Genetic advances have led to better understanding and classification of these disorders. Environmental insults, however, can also lead to defects of cortical development, such as polymicrogyria. Genetic or environmentally derived insults may affect one or more of three processes of cerebral development, neuronal proliferation and eventual apoptosis of selected cells, neuronal migration, and cortical organization. Clinical variability is determined by differences in etiology, cortical areas affected, and the gestational age at which abnormal migration occurred.
Table 4.2 Phenotypes and Genes Associated with Lissencephaly and Heterotopias Condition
Phenotype
Mutation
Isolated lissencephaly sequence (ILS; OMIM 601545): autosomal dominant
Classic lissencephaly. Severe mental retardation, subtle MDS-like appearance, epilepsy, and neurological abnormalities. Gyral malformations more severe posteriorly Severe lissencephaly. Prominent forehead, short nose, protuberant upper lip, thin vermillion border Classical lissencephaly. Males affected. Gyral malformation more severe anteriorly Milder phenotype of XLIS. Mental retardation may be evident at onset. Females affected
Two-thirds of patients have deletions/mutations in LIS1 (17p13.3)
Females with normal intelligence, partial seizures with or without secondary generalization. Some have systemic features, including patent ductus arteriosus. Usually lethal in males, but some sporadic males reported Intermediate cortical thickness, gyral malformations more severe posteriorly, abnormal basal ganglia, absence of the corpus callosum
Filamin A (FLNA), Xq28
Miller-Dieker syndrome (MDS; OMIM 247200): microdeletion syndrome X-linked lissencephaly (XLIS; OMIM 300067) Subcortical band heterotopia* (SBH)/ doublecortex (DCX): X-linked dominant Periventricular heterotopia (PH; OMIM 300049): X-linked dominant
X-linked lissencephaly with abnormal genitalia (OMIM 300215)
Almost all have deletions in LIS1 (PAFAH1B1) (17p13.3) DCX, Xq2124 DCX, Xq2124
ARX mutations, Xp22
Somatic mosaic mutations of DCX and LIS1 are also found with SBH in both males and females.
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Clinical Hint Classification of neuronal migration defects is made on cranial MR scan appearances. High-quality scanning and expert neuroradiological review prior to genetic diagnosis and advice are necessary.
Lissencephaly is characterized by the presence of fewer gyri over the brain surface. The definition overlaps with pachygyria, which refers to thicker gyri. The organization of the cortex is abnormal. The associated clinical syndrome varies from severe psychomotor retardation with death before the age of 2 to near normal development and intelligence. Periventricular heterotopia (PH) refers to a condition where failure of migration of cortical cells leaves nodules of cortical cells lining the walls of the ventricles. It is commonly an X-linked dominant condition, and most affected males die at the embryonic stage. Affected females have normal intelligence, but have seizures. PH is evident on MR brain scan. Diagnosis and classification of these disorders is now performed on the basis of the appearance on MR brain scan (Table 4.2). The grade of lissencephaly, presence of dysmorphism, cortical thickness and anteriorposterior gradient of lissencephaly may help predict the genetic diagnosis. Lissencephaly with posteriorly predominant gyral abnormality predicts mutations of the lissencephaly 1 (LIS1) gene on chromosome 17 (Figs. 4.1 and 4.2). Anteriorly predominant lissencephaly in males and subcortical band heterotopia (SBH) in females predict mutations of the X-linked lissencephaly (XLIS or DCX) gene (Fig. 4.3). A diagnostic algorithm can be found in the review by Kato and Dobyns (2003).
Figure 4.1. Axial T1-weighted image of a female patient with posterior predominant pachygyria and a LIS1 mutation.
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Figure 4.2. Axial T2-weighted image of a female patient with LIS1 deletion. There is posterior agyria with some gyration (pachygyria) frontally.
Figure 4.3. Axial T2-weighted image of a female patient with bilateral SBH and a DCX mutation.
Progressive Myoclonic Epilepsies (PMEs) The PMEs are a group of disorders that have overlapping phenotypes but are genetically distinct (Table 4.3). Clinically they are characterized by generalized tonic-clonic seizures, stimulus-sensitive myoclonus, and progressive neurological dysfunction, including dementia and ataxia. Whereas Unverricht-Lundborg
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Table 4.3 Progressive Myoclonic Epilepsies Condition
Diagnosis
Predominant Features
Unverricht-Lundborg disease (OMIM 254800): autosomal recessive MERRF syndrome: matrilineal
Genetic analysis; see Chapter 6
Myoclonic ataxia
Genetic analysis; see Chapter 14
Myoclonic ataxia with other manifestations of mitochondrial disease Myoclonic ataxia, visual loss, normal intelligence, cherry-red macular spots Rapid motor, cognitive, and visual decline Progressive cognitive, motor, and visual decline and seizures
Sialidosis (rare) (OMIM 256550): autosomal recessive Lafora disease (OMIM 254780): autosomal recessive Neuronal ceroid lipofuscinoses: most are autosomal recessive
Urinary oligosaccharides, cultured fibroblasts for neuraminidase assay Lafora bodies on skin biopsy Tissue diagnosis, genetic analysis, enzyme studies; see Chapter 16
disease, MERRF syndrome, and sialidosis may have a variable but relatively long course leading to disability or death in middle life, Lafora disease and the ceroid lipofuscinoses (Chapter 16) have a poorer prognosis.
IDIOPATHIC EPILEPSIES ASSOCIATED WITH CYTOGENETIC ABNORMALITY CNS abnormalities are associated with most detectable cytogenetic abnormalities. The best-studied is Down’s syndrome (trisomy 21), where prevalence of epilepsy is 310%. Some chromosomal disorders have a clear association with epilepsy. These comprise: Wolf-Hirschhorn (4p-) syndrome, Miller-Dieker syndrome (del 17p13.3), Angelman syndrome (del 15q11-q13), the inversion duplication 15 syndrome, terminal deletions of chromosome 1q and 1p (KCNAB2 within deleted region), and ring chromosomes 14 and 20. Abnormalities of other chromosomal segments had a weaker association with seizures. There are no clear data on the precise nature of epileptic syndromes or epidemiology. In total, epilepsies associated with cytogenetic abnormality are unlikely to contribute more than 1% of all epilepsy.
IDIOPATHIC EPILEPSIES WITH MENDELIAN INHERITANCE Analysis of families with autosomal dominant inheritance has led to the identification of single genes that can cause epilepsy (Table 4.4). The familial nature and diagnostic features may be easily overlooked. Although rare, recognition may help in advising about prognosis, treatment, and genetic risk. So far, identified causative genes either code for a voltage gated ion channel (KCNQ2, KCNQ3, SCN1B, SCN1A) or a neurotransmitter (CHRNA4, CHRNB2, GABRG2). At the time of writing, new associations of ion channel or neurotransmitter genes are being described regularly. Clinically, these disorders can be easily overlooked and emphasize the importance of a careful family history.
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Table 4.4 Idiopathic Epilepsies with Mendelian Inheritance Condition
Gene
Locus
ADNFL1 (OMIM 600513)
Neuronal nicotinic acetylcholine receptor a-4 subunit, CHRNA4 Linked to CHRNA3/CHRNA5/CHRNB4 cluster Neuronal nicotinic acetylcholine receptor b-2 subunit, CHRNB2 Voltage-gated potassium channel, KCNQ2
20q13.2-13.3
20q13.3
Voltage-gated potassium channel, KCNQ3 Voltage gated neuronal sodium channel b-1 subunit, SCN1B Voltage gated neuronal sodium channel a-1 subunit, SCN1A Gamma-aminobutyric acid receptor, GABRG2 Leucine-rich, glioma-inactivated 1 gene (LGI1)
8q24 19q13.1 2q24 5q31.1-33.1 10q24
ADNFL2 (OMIM 603204) ADNFL3 (OMIM 605375) BFNC1 (OMIM 121200) (commonest form) BFNC2 (OMIM 121201) GEFS+ (OMIM 604233) GEFS+2 (OMIM 604233) GEFS+3 (OMIM 604233) ADPEAF (OMIM 600512)
15q24 1p21
ADNFL, autosomal dominant nocturnal frontal lobe seizures; BFNC, benign familial neonatal convulsions; GEFS+, generalized epilepsy with febrile seizures plus; ADPEAF, autosomal dominant partial epilepsy with auditory features.
Clinical Hint Epilepsies with Mendelian inheritance are uncommon disorders that may be easily overlooked because of remission in childhood or because seizures occur exclusively at night.
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFL) This disorder usually begins in childhood and persists through adult life, with considerable intrafamily variation in severity. It is characterized by clusters of brief nocturnal motor seizures, with hyperkinetic or tonic manifestations. Subjects often experience an aura, and remain aware throughout the attacks. Seizures typically occur in clusters (with a mean of eight attacks per night) as the individual dozes, or shortly before awakening. Seizures can be misdiagnosed as parasomnias or psychogenic attacks. Scalp EEG studies may be normal even during seizures. Ictal video-EEG studies show that the attacks are partial seizures with typical frontal lobe seizure features. Neuroimaging is normal. Carbamazepine is frequently effective. Penetrance varies between families but has been estimated at 75%.
Benign Familial Neonatal Convulsions (BFNC) Autosomal dominant benign neonatal convulsions have onset typically on the second day of life, although onset may be delayed to be within the first few weeks. The child is otherwise healthy with normal development. Cases may be familial or isolated. The seizures are frequent and brief, occasionally occurring many times within a day. Status epilepticus is uncommon. The episodes resolve within a few days with no neurological sequelae. Other causes need to be excluded and therefore the diagnosis of benign neonatal convulsions is usually made in retrospect. BFNC is uncommon and most families are of western European origin. There is an 1116% chance of seizures later in life.
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Generalized Epilepsy with Febrile Seizures Plus (GEFS+) GEFS+ is a familial idiopathic generalized epilepsy. This syndrome consists of febrile seizures with typical onset at 1 year of age with subsequent afebrile generalized tonic-clonic seizures, absences, and less commonly myoclonic-astatic seizures. The epilepsy usually remits by teenage years. Penetrance has been estimated at 60%. Most families follow a complex pattern of inheritance, but some have mutations in SCN1A or other genes (Table 4.4). Dravet syndrome (formerly known as severe myoclonic epilepsy in infancy) is an epileptic encephalopathy resulting in motor and cognitive impairment. This is the most severe phenotype within the GEFS+ spectrum, and more than 70% of patients harbor a de novo SCN1A mutation, with a further 5% of cases having familial SCN1A mutations within families with GEFS+.
Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF) Auditory hallucinations as part of a familial partial epilepsy are the most common and diagnostic feature of this syndrome. Other sensory symptoms (visual, olfactory, vertiginous, and cephalic) may occur.
IDIOPATHIC EPILEPSIES WITH COMPLEX INHERITANCE Most idiopathic generalized epilepsies (IGEs) display a complex pattern of inheritance. This common group of epilepsies includes juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), childhood absence epilepsy (CAE), and epilepsy with generalized tonic-clonic seizures on awakening. Because there is no other explanation it is often assumed these epilepsies are genetic in etiology. A twin study of IGE estimated concordance between MZ and DZ twin pairs of 76% and 33%, respectively, suggesting that IGE is a highly genetic condition and that only a few genes are involved in its etiology. Population studies have shown that lower recurrence risks apply to sibs and offspring. The following guidelines on recurrence risks are established from epidemiological study. It is important to note that in the general population, there is a cumulative population risk of epilepsy of approximately 1% prior to the age of 20, rising to 1.52% at higher ages (excluding acute symptomatic seizures and febrile seizures). Sibling Risk 1. When a proband has idiopathic epilepsy with onset before age 15, a sibling’s risk for any epilepsy is increased about 3-fold, giving an approximate risk of 5%. 2. The risk is higher if there is more than one first-degree relative with epilepsy, when the proband has had additional febrile seizures, or onset prior to 5 years. A mildly higher risk is also associated with spike and wave or photoconvulsive response on EEG in the proband. 3. Even with two or more additional risk factors, the recurrence risk is unlikely to be greater than 1015%.
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4. IGE with later onset implies lower recurrence risks; onset over the age of 35 does not cause increased risk to relatives. 5. If relatives of patients with IGE have no fits by the age of 35 then their risk is no greater than the rest of the population. 6. In families containing more than one member with IGE, the type of IGE may differ. Risks in Offspring Fewer studies have reported risks in offspring, and epidemiological data are often conflicting, with difficulties caused by incomplete follow-up. The following figures are estimates based on available data. 1. If either parent has epilepsy, the overall risk of epilepsy to offspring is approximately 6%. 2. Risks are higher if the mother has epilepsy (estimated at 8.7%) than if the father has (2.4%). 3. Increased risks probably apply if the proband had early-onset epilepsy or more than one family member is affected. 4. Points 3 to 6 concerning sibling risk (above) probably also apply to offspring.
CRYPTOGENIC EPILEPSY This entity is not easily defined. The term cryptogenic is usually used to designate conditions that do not satisfy the criteria for idiopathic epilepsy, or are presumed to be symptomatic, when the etiology has not been determined. With more sensitive investigations and fuller clinical assessment this will become a less common label. Ottman et al. (1996) found that cryptogenic epilepsy was associated with an incidence of familial epilepsy similar to that of IGE and therefore genetic advice can follow the above guidelines. This indicates that some cryptogenic epilepsies have genetic etiology, as is illustrated by disorders such as ADNFL and ADPEAF which would have previously been classified as cryptogenic partial epilepsy (Table 4.4). A locus for benign rolandic epilepsy (benign epilepsy with centrotemporal spikes), an idiopathic partial epilepsy that shows a complex mode of inheritance, has been mapped to chromosome 15q. There is an estimated risk to siblings of about 15% of any seizure, but most will not have troublesome epilepsy.
FEBRILE SEIZURES (FS) Febrile seizures represent the most frequent seizure disorder, with a rate in Western populations of 2.4% (substantially higher in Japan). One-third of children with FS will have a further FS. In total, children with FS have a 36-fold increased risk of developing epilepsy compared with the general population. The overall sibling risk of FS is 8%, compared with the population risk of 2.4%. This risk is substantially modified by other factors. The risk is greater to
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a sibling if a parent also had FS. The risk also increases with the number of febrile seizures in the proband. The risks of any epilepsy in siblings of patients with FS are increased 2.4-fold, demonstrating the relationship of FS to other epilepsies. It should be noted that population studies were performed before the recognition of the autosomal dominant disorders described above. The above risks are greater in Japanese populations, where FS is more common.
SYMPTOMATIC EPILEPSY ASSOCIATED WITH CENTRAL NERVOUS SYSTEM INSULTS Symptomatic epilepsy can be defined as epilepsy that follows an injury to the brain known to be capable of causing epilepsy. Examples include significant head injury, CNS infection, stroke, brain tumor, and surgery. Although twin studies have shown concordance for epilepsy in symptomatic generalized epilepsy, epidemiological studies have shown that there is no significantly increased risk of epilepsy in relatives of patients with postnatally acquired symptomatic epilepsy. Currently, it is reasonable to advise families of patients with symptomatic epilepsy that their risk of epilepsy is not significantly raised above the population risk.
STURGE-WEBER SYNDROME (OMIM 185300) Sturge-Weber syndrome has an incidence of approximately 1 per 50,000. The disease is characterized by leptomeningeal angiomatosis, often involving the occipital and posterior parietal lobes. The most common clinical features include facial cutaneous vascular malformations, seizures (in approximately 90%), and glaucoma. The clinical course is highly variable and some children experience intractable seizures, mental retardation, and recurrent stroke-like episodes, as a result of vascular stasis and ischemia. Familial cases are very rare. The condition is thought to arise from a hypothesized somatic mutation. Clinical Hints Only a minority of infants with a facial port wine stain will have Sturge-Weber syndrome. Sturge-Weber syndrome is associated with a high incidence of ophthalmological complications, particularly childhood glaucoma, and regular ophthalmological review is required.
HYPEREKPLEXIA (OMIM 149400) This rare autosomal dominant disorder is caused by mutations in the gene for the a-1 subunit of the glycine receptor. Patients present with transient congenital hypertonia and hypokinesia in the waking state, and, later in life, greatly exaggerated startle reaction with myoclonus sometimes associated with falling.
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There are abnormally prominent brainstem reflexes (head retraction, palmomental and snout reflexes). Startles can be elicited by touching the patient’s nose, clapping, or jolting the patient’s chair. Children have an excess of hip dislocation and umbilical hernia. Treatment with clonazepam is useful.
BIBLIOGRAPHY Anderson VE & Hauser WA (1993). Genetics. In: Laidlaw J, Richens A, Chadwick D (eds.), A Textbook of Epilepsy. 4th ed. Churchill Livingstone.
REFERENCES Berkovic S, Howell RA, Hay DA & Hopper JL (1998). Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol, 43, 435445. Kato M & Dobyns WB (2003). Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet, 12, R89R96. Manford M (2003). Practical Guide to Epilepsy. Butterworth Heinemann. Ottman R, Annegers JF, Risch N, Hauser WA & Susser M (1996). Relations of genetic and environmental factors in the etiology of epilepsy. Ann Neurol, 39, 442449.
Chapter 5 Disorders of Vision Andrea H. Nemeth and Susan M. Downes
INTRODUCTION Most cases of retinal degeneration and optic atrophy occur in isolation and affect the eye alone. Where these disorders are described in association with other systemic features they are referred to as syndromic. Associated systemic features are protean, but some predominantly affect the nervous system (e.g., Friedreich’s ataxia), whilst others are complex multisystem disorders. This chapter presents an overview of the non-syndromic retinal and optic nerve degenerations as well as those associated with neurological disease. Developmental disorders of the eye (e.g., anophthalmia, aniridia, etc.) and disorders of the anterior chamber (e.g., cataracts, glaucoma, etc.) will not be discussed. Disorders of eye movements per se rarely cause severe visual disturbance. Non-syndromic inherited retinal degenerations and optic atrophy are usually managed by an ophthalmologist, whereas syndromic disorders may involve input from numerous different medical specialties. Important features that can help distinguish syndromic from non-syndromic cases are highlighted in the box below. Clinical geneticists have an important role in identifying specific syndromes and assessing recurrence risks, and offer predictive or prenatal testing, where appropriate. Some units run joint eye/genetics clinics to provide this service.
Structure and Function of the Eye Basic Facts Retina: the retina is a thin transparent structure that lines the inside of the eye. It comprises several layers which incorporate a number of different highly specialized first- and second-order cells which receive and transmit visual information via complex retinal circuitry of primarily chemical synapse type. Macula: this is both an anatomical and clinical term to describe the central portion of the retina used for fine vision. The macula is contained within 49
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Clinical Hints When Assessing Retinal Degeneration (Retinitis Pigmentosa and Optic Atrophy) In the history look for: Other medical problems: other neurological features: mitochondrial disease, autosomal dominant cerebellar ataxia (ADCA), Refsum, abetalipoproteinemia, vitamin E deficiency, Cockaynes, neuronal ceroid lipofuscinoses (NCL), Bardet-Biedl, Behr, Mohr-Tranebjaerg, Walker-Warburg, Smith-Lemli-Opitz deafness: Usher, Refsum, Alstrom, Cohen, Cockayne, Mohr-Tranebjaerg NB: RP in Refsum’s disease may present before other clinical features and all children presenting with RP should be screened for Refsum diabetes: Friedreich’s ataxia, Bardet-Biedl syndrome, Wolfram, mitochondrial renal: Bardet-Biedl syndrome urogenital: Bardet-Biedl syndrome endocrine: septo-optic dysplasia cardiac: Alstrom, mitochondrial gastrointestinal: failure of weight gain, malabsorption in abetalipoproteinemia developmental delay/learning disability/developmental regression: mild: Bardet-Biedl syndrome; severe: NCL, Cockayne, Joubert, mucolipidosis IV NB: visual loss may be first sign of Batten’s disease (childhood NCL) in an otherwise healthy child, whereas patients with adult NCL have normal ophthalmological investigations Obtain specific genetic information: take a three-generation pedigree look for evidence of unaffected obligate carriers (penetrance) ask specifically about consanguinity determine age of onset, rate of progression, variation between males and females On examination look for: ophthalmic features: refer for full ophthalmic assessment if not yet done spasticity: mucolipidosis IV ataxia: abetalipoproteinemia, vitamin E deficiency, Behr, Wolfram, SCAs, FRDA, Bardet-Biedl, congenital disorder of glycosylation type 1, mitochondrial weight: obesity in Bardet-Biedl syndrome, Cohen, Alstrom: measure height and head circumference for comparison of centiles blood pressure: renal tract disease in Bardet-Biedl syndrome teeth: prominent incisors in Cohen cardiac murmurs/cardiomyopathy: vitamin E deficiency, Bardet-Biedl syndrome, mitochondrial, Alstrom postaxial polydactyly: Bardet-Biedl syndrome acanthosis nigricans: Alstrom
the temporal arcades and has a specialized arrangement of retinal layers allowing better resolution and color vision than the rest of the retina. Fovea: located at the center of the macula (350 mm in diameter), the fovea is rod-free at its center, with unique features enabling fine vision (visual acuity, detailed discrimination, and color vision). Photoreceptors: these are highly specialized neurons of the vertebrate retina. These receptors, known as rods and cones, are morphologically and functionally distinct. Rods: there are about 110125 million rods in the retina, with a peak density at about 5 mm from the center of the fovea. These photoreceptors are responsible for vision under dim lighting and for motion detection. Cones: there are about 6 million cones in the vertebrate retina and most are located at the center of the macula, at the fovea. Cones of different spectral types (long, medium, and short wave) connect to interconnecting neurons with
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consequent integration and processing of spectral information. They are responsible for color and fine discriminating vision. Retinal pigment epithelium (RPE): the RPE is a single layer of cells situated between the retina and the choroid. RPE cells are multifunctional in nature, providing an interface with barrier capabilities between blood and retina. Functions include transportation of metabolites, recycling of degradation products, vitamin A metabolism and transport, fatty acid transport, detoxification reactions, and light absorption.
Investigating Retinal and Optic Nerve Disease (Table 5.1) Functional testing of the retina and optic nerve can be carried out electrophysiologically. The electroretinogram (ERG) is an objective test when performed using International Society for Clinical Electrophysiology of Vision (ISCEV) criteria, and is a vital test for diagnosing retinal and optic nerve disease and assessing the extent of disease. It is possible to determine the degree of both cone and rod photoreceptor involvement. The ERG is an electrical potential that arises in the retina after light stimulation representing a composite response of millions of retinal cells. Specific testing conditions include scotopic (dark) and photopic (light) aimed at testing rod and cone function separately. The visual evoked potential (VEP) is commonly used to assess the visual pathway and is useful in optic nerve disease. The pattern ERG can also Table 5.1 Investigation of Retinitis Pigmentosa and Optic Atrophy Ophthalmology assessment including ERG, visual fields, and acuity, VEPs, fluoroscein angiography Biochemistry: renal and liver function, fasting blood sugar, if indicated: phytanic acid (Refsum), very longchain fatty acids, and pristanic acid, which are elevated in some other conditions with high phytanic acid levels, lipoprotein B (absent in abetalipoproteinemia), diabetes, renal and liver degeneration in Alstrom, and thyroid function (hypothyroidism in Alstrom) Hematology: FBC (neutrophils low in Cohen), peripheral blood smear (acanthocytes in abetalipoproteinemia and neuronal brain accumulation of iron/hypoprebetalipoproteinemia acanthocytosis and retinitis pigmentosa, NBAI/HARP), vacuolated lymphocytes Endocrinology (growth hormone deficiency in Alstrom, cranial diabetes insipidus in Wolfram, various in septo-optic dysplasia) Transferrin isoelectrophoresis (abnormal in congenital disorders of glycosylation) Renal ultrasound or IVP (Bardet-Biedl syndrome) Urogenital imaging (Bardet-Biedl syndrome) ECG/echocardiography (Bardet-Biedl syndrome, vitamin E deficiency, Alstrom, mitochondrial disorders) MRI brain: ‘‘eye of the tiger’’ sign (NBAI/HARP) CSF: elevated protein in Refsum Muscle biopsy: mitochondrial disorders Nerve conduction studies: Refsum Nerve biopsy: onion bulb formation in Refsum Skin or other tissue biopsy: storage disorders (neuronal ceroid lipofuscinosis, mucolipidosis IV, DNA repair disorders) DNA for diagnostic testing (genetic testing for ADRP, ARRP, XLRP, LCA, and other types may be available on clinical or research basis, mitochondrial, SCA7, SCA2, SCA6, neuronal ceroid lipofuscinosis, Bardet-Biedl syndrome), storage for future studies Consider chromosome analysis
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contribute more information and, when analyzed in combination with the VEP and the ERG, can aid in differentiation of optic nerve and macular disease. The electro-oculogram is helpful in diagnosis of certain specific conditions, such as Best vitelliform macular dystrophy. It can be affected in severe rod damage and RPE disease. Psychophysical testing, primarily looking at visual fields, is helpful in characterizing retinal and optic nerve disease and documentation of functional performance. Whilst electrophysiological tests provide information regarding cell population and dysfunction, visual-field testing can highlight the actual functional disability, i.e., show central visual-field loss in macular disease and peripheral field loss in classical retinitis pigmentosa (RP). Imaging techniques such as color photography, fluorescein, and indocyanine angiography (injections of different dye types to look at choroidal and retinal circulations), autofluorescence imaging (using a scanning laser ophthalmoscope to image autofluorescence signals at the level of the RPE), and optical coherence tomography (using a technique analogous to ultrasonography; using light to image the layers of the retina) can all contribute to phenotypic clinical characterization.
INHERITED RETINAL DEGENERATION The outer retinal dystrophies comprise a large number of disorders characterized by progressive retinal degeneration, but are recognized to be variable in the severity and age of onset and may have particular distinguishing phenotypic and functional features. There are also retinal pigment epithelial and ‘chorioretinal’ dystrophies which give rise to varying degrees of visual disability. Retinal degenerations may occur in isolation or form part of a multisystem syndrome. Most inherited retinal dystrophies are due to mutations in a single gene, although rarely digenic and multiallelic inheritance have been described. In the past, careful description of the clinical phenotype supplemented by functional evaluation by electrophysiology and psychophysics led to clinical categorization of retinal dystrophies into three main categories: retinitis pigmentosa (peripheral) (Fig. 5.1), macula (central), and cone-rod dystrophies (mixed). Further subdivision was added if the inheritance pattern was known. Dystrophies that principally or exclusively affect the macular region are characterized by early-onset central visual acuity and color vision loss. Mixed central and peripheral dystrophies demonstrate characteristics of both RP and macular dystrophy. Each of these categories represents an extremely wide phenotypic spectrum of degeneration. In many cases it is now also possible to reclassify these disorders on the basis of the target cell of disease. For example, RP, cone, and cone-rod dystrophies are photoreceptor dystrophies whereas Best vitelliform dystrophy is described as a disorder of the RPE (confirmed by identification of the causative gene whose gene product is found in the RPE). However, this categorization is imperfect since the gene product expressed in one particular cell or tissue may actually exert deleterious effects elsewhere. In addition, certain genes are expressed in more than one cell type, which confuses this form of classification.
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Figure 5.1. Photograph of fundus of the left eye demonstrating intraretinal bone spicule pigmentation, attenuated retinal vessels and retinal thinning typical of retinitis pigmentosa.
For example, the ABCA4 gene in Stargardt disease is expressed in both rods and cones and can give rise to a number of phenotypes. This is also seen with peripherin/RDS where central, mixed, and peripheral outer receptor and RPE dystrophies have been described in one family with a common 153/154 codon mutation. For similar reasons, a classification system based only on the mutated gene is confounded as this does not always give an accurate indication of the cell type involved or the clinical phenotype. Therefore, whilst it is recognized that there is marked phenotypic and genetic heterogeneity, a basic division is to describe the peripheral degenerations as RP, central disorders as macular dystrophies, and those with both peripheral and central involvement may be described by either the known eponymous name or the cell population involved.
Retinitis Pigmentosa (Non-Syndromic) Clinical Features RP describes a heterogeneous group of progressive retinal degenerations sharing a common set of clinical characteristics comprising night blindness, constricted visual fields, intraretinal pigment deposition, arteriolar narrowing, pallor of the optic nerve head, and a diminished or extinguished ERG. As the condition progresses, cone photoreceptors also become affected, compromising central vision. In some individuals cystoid macular edema may occur which can lead to blurred central vision, which occasionally responds to a carbonic anhydrase inhibitor. However, the phenotype is variable and it is not possible to infer severity of disease from the degree of pigmentation. RP without pigment deposition (sine pigmento) has also been described. The age of onset of RP can be very variable. In Leber congenital amaurosis, onset is at birth or early childhood, whereas in some autosomal dominant RP families some carriers may be asymptomatic, even late in life. In general the earlier the onset, the more severe the clinical course is likely to be.
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Unilateral RP refers to unilateral functional and ophthalmoscopic changes which look like RP. This appearance is thought to be due to an inflammatory process and not due to an inherited retinal degeneration. Sector RP is a term used to describe changes confined to part of the fundus with non-progressive changes and specific electrophysiology. The diagnosis of RP is made on the basis of the results of electrophysiology. Visual fields are useful for diagnosis and regular field testing is also mandatory for drivers to ensure that an individual has adequate fields. However, until successful therapy becomes available, regular field testing is not required in a person who is not a driver. Genetics of RP The molecular genetics of RP are unusually complicated. Over 35 RP loci have been mapped and to date 27 disease genes identified (Tables 5.2, 5.3, and 5.4). Genes associated with RP encode proteins that are involved in phototransduction (the process by which the energy of a photon of light is converted in the photoreceptor cell outer segment into a neuronal signal); the visual cycle (production and recycling of the chromophore of rhodopsin); photoreceptor structure; and photoreceptor cell transcription factors. The function of many other genes associated with RP remains unknown. Genetic heterogeneity is significant in retinal degenerations. In addition, different mutations in the same gene may cause different diseases. For example, different mutations in RHO may cause autosomal dominant RP, autosomal dominant congenital stationary night blindness, or, rarely, autosomal recessive RP. Clinical severity and disease phenotype often differ among individuals with the same mutation, most likely as the result of other genetic and/or environmental factors. Inheritance patterns in RP may be autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), and mitochondrial. However, many cases are sporadic (‘‘simplex RP’’). The prevalence rates are variably quoted at: ADRP 2025%, ARRP 520%, XLRP 1633%, and simplex 1040%. Digenic inheritance is very rare. ADRP (Table 5.2) In general, ADRP tends to be later-onset and milder than ARRP, and certainly compared with XLRP. However, this is variable and depends on the gene, and the position and character of the mutation. Some rhodopsin mutations are associated with very mild disease (e.g., sector RP). RHO, RP1, and RDS account for approximately 2530%, 510%, and 510% of ADRP cases, respectively. RDS mutations are associated with clinical phenotypes ranging from RP to macular dystrophy. Of the RP1 mutations known, two, Arg677stop and 2280del5, account for half of ADRP cases caused by this gene. Other identified ADRP genes, such as PRPF31, cause a substantial number of cases, but the specific prevalence rates are not known. It is important to note that reduced penetrance exists in ADRP, associated with mutations in guanylate cyclase 2D (GUCY2D), guanylate cyclase activator 1B (GUCA1B), and precursor mRNA processing factor 31 (PRPF31) genes.
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Table 5.2 Common Genes Causing Autosomal Dominant RP and CORD Locus (OMIM) Name
Locus
Protein
Also Causes
Percent of ADRP
RP4 (180380)
RHO
3q22.1
Rhodopsin
3040%
RP7 (608133)
RDS
6p21.2
Peripherin 2
Recessive RP; Dominant CSNB Dominant MD; digenic RP with ROM1 Dominant adult vitelliform MD
RP10 (180105)
IMPDH1
7q32.1
RP1 (180100)
RP1
8q12.1
(180721)
ROM1
11q12.3
RP11 (600138)
PRPF31
19q13.4
Inosine monophosphate dehydrogenase 1 Oxygen-regulated protein 1 (RP1 protein) Retinal outer segment Digenic RP with membrane protein 1 RDS Pre-mRNA splicing factor 31
510% Dom RP 35% 510% Rare 1520% NB reduced penetrance
ARRP (Table 5.3) Recessive disease is usually characterized by earlier onset and more severe disease than ADRP. At present there are 11 genes and five loci described in association with non-syndromic ARRP. XLRP (Table 5.4) X-linked RP is characterized by very-early-onset severe disease in males. This may present in childhood and generally these individuals are severely visually handicapped before adulthood. Genetic counseling is important in these families, particularly if prenatal diagnosis or preimplantation embryo selection Table 5.3 Common Genes Causing Autosomal Recessive RP and CORD Locus (OMIM)
Name
Locus
Protein
ABCA4 (601691)
ABCA4
1p22.1
LCA2 (204100) RP12 (600105)
RPE65 CRB1
1p31.2 1q31.3
ATP binding cassette Stargardt AR RP transporter flippase for all-trans retinal RPE-specific protein LCA Crumbs protein LCA ARRP with parahomolog 1 arteriolar preservation of the RPE (PPRPE) Usherin Usher syndrome, type 2 Rod cGMP-specific 30 ,50 -cyclic phosphodiesterase subunit
USH2A (276901) PDE6A (180071)
1q41 5q33.1
Also Causes
Percent of ARRP 5%
2% 913%
at least 45% 34%
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Table 5.4 Genes Causing X-Linked RP and CORD Locus (OMIM) RP3 (300389) RP2 (312600)
Name RPGR RP2
Locus Xp21.1 Xp11.2
Protein Retinitis pigmentosa
Also Causes
Percent of XLRP
Cone dystrophy
70%
GTPase regulator XRP2 protein
is requested. Female carriers vary in severity of presentation from asymptomatic to manifesting RP at a later age. Very rarely they may be as severely affected as males. RPGR (also called RP3) and RP2 are the most common causes of XLRP and linkage studies suggest that they account for 7090% and 1020% of X-linked RP, respectively. RP6, RP23, and RP24 are three other X-linked loci which have been identified. Digenic RP Digenic RP is caused by the simultaneous presence of a mutation in the RDS gene and a mutation in the ROM1 gene. In all cases reported, the same RDS mutation (L185P) was found, although three different ROM1 mutations have been identified in these families. It is possible that unrecognized digenic or polygenic disease exists which may account for the variability of phenotype seen for a given mutation. Simplex RP This accounts for 1040% of all RP patients and may be the result of a new autosomal dominant mutation, an X-linked mutation or autosomal recessive inheritance. Seemingly sporadic cases may also occur in cases of non-paternity, in asymptomatic but affected relatives or in reduced penetrance. For this reason, assessment of family members is an important part of the diagnostic work-up, especially if there is a history of visual disturbance. Leber Congenital Amaurosis (LCA) This is a specific type of retinitis pigmentosa characterized by very severe, early-onset disease. The incidence is 23 per 100,000 births and represents 5% of retinal dystrophies. Clinical features include early onset of blindness or poor vision, usually before 6 months of age, sluggish pupillary reactions, roving eye movements/nystagmus and inability to fix or follow, and oculodigital signs (eye poking, eye rubbing, etc.). The fundus appearance is highly variable (e.g., normal, typical RP with intraretinal pigment clumping and vessel attenuation, retinitis punctata albescens, macular ‘‘coloboma,’’ optic atrophy, marbled, albinotic with pigmentation). Electrophysiological tests show extinguished or severely reduced scotopic and photopic ERG usually by 3 months of age and absent or abnormal VEPs.
10%
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Table 5.5 Genes Causing Leber Congenital Amaurosis Locus/Name (OMIM)
Locus
Product
Also Causes
LCA9 (608553) LCA2 (204100) CRB1/LCA8 (604210) RP12
1p36 1p31.2 1q31.2
Unknown RPE65 Crumbs homolog 1
TULP1 (602280) LCA5 (604537) LCA10/CEP290 (610142)
6p21.31 6q11-q16 12q21.32
Tubby-like protein 1 Unknown CEP290 protein associates with microtubule proteins in centrosomes and cilia
Autosomal recessive RP Recessive RP with paraarteriolar preservation of the RPE (PPRPE) Recessive RP Recessive RP
LCA4 (604393)
17p13.2
LCA1 (600179)
17p13.1
AIPL1 (arylhydrocarboninteracting receptor protein-like 1) GUCY2D retinal-specific guanylate cyclase Cone-rod otx-like photoreceptor Homeobox transcription factor
CRX/CORD2/ LCA7 (602225) 19q13.32
Recessive Joubert syndrome Recessive Meckel syndrome Dominant CORD
Percent of LCA 716% 15%
Unknown Unknown At least 21%
10%
Dominant CORD
6%
Dominant CORD
13%
Recessive, dominant, and de novo LCA dominant RP
LCA is genetically heterogeneous. Most are autosomal recessive but rare autosomal dominant forms have also been described. Several genes have been identified and other loci mapped (see Table 5.5). LCA may be associated with neurodevelopmental delay, mental retardation, associated systemic/syndromic anomalies (such as Senior-Loken, Joubert, Saldino-Mainzer), and infantile neuronal ceroid lipofuscinosis, abetalipoproteinemia, hyperthreoninemia, and peroxisomal and mitochondrial dysfunction. Table 5.6 summarizes the syndromes with which RP/LCA is seen. Genetic Counseling for Non-Syndromic RP Counseling depends on the mode of inheritance. Some forms of ADRP, especially those with PRPF31 mutations, show reduced penetrance and this should be taken into account when estimating genetic risk. It is important to take a careful family history and be aware of this entity. In sporadic cases the clinical features and age of onset may give an indication of mode of inheritance. There is considerable overlap between ages of onset in ADRP, ARRP, and XLRP. In sporadic male cases where genetic advice has been requested, family members should be examined for fundus abnormalities, and ERG testing and mutation analysis, where available, may be helpful. Female carriers may have characteristic fundus abnormalities. A careful family history may
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Table 5.6 Causes of Syndromic RP Clinical Features
Specialist Investigations
RP with Mental Retardation Hematological indices Cohen syndrome (216550) Onset: congenital Characteristic facial appearance (short, upturned philtrum, grimacing smile, prominent upper incisors) Mental retardation Joint hyperextensibility Truncal obesity High myopia Severe retinal dystrophy Benign neutropenia RP with Deafness Infantile Refsum (266510) Onset: congenital (see Chapter 11) Mental retardation Pigmentary retinopathy Sensorineural deafness Dysmorphic features Hepatomegaly Peripheral neuropathy Cataracts (less common) Seizures (less common)
Differential Diagnosis
Inheritance Gene Locus Gene
BBS, other mental retardation syndromes
AR
AR Other disorders Elevated phytanic acid Deficiency of peroxisomes of peroxisomal biogenesis (neonatal in hepatocytes and cultured skin fibroblasts adrenoleukodystrophy (intermediate severity) is demonstrable and Zellweger syndrome (most severe))
Elevated VLCFA levels Neonatal adrenoleukodys- Onset: congenital Liver biopsy shows trophy (300100) Mental retardation absence of (see Chapter 7) Pigmentary retinopathy (may peroximsomes be leopard spot) retinopathy Optic atrophy Sensorineural deafness (not always present) Dysmorphic features Hepatomegaly Peripheral neuropathy Cataracts (less common) Seizures (less common)
AR
8q22
COH1 novel gene with presumed role in vesiclemediated sorting and intracellular protein transport.
7q21-q22
PEX1 or PEX2
Xq28
ATP-binding cassette sub-family D member
PRACTICAL GUIDE TO NEUROGENETICS
Condition (OMIM)
RP with Ataxia (see Chapter 6) Cerebellar hypoplasia (with Cerebello-oculo-renal complex brainstem syndromes (CORS) malformation represented (608091). Includes: as the ‘‘molar tooth sign’’ Joubert syndrome on magnetic resonance imaging) and ataxia hypotonia
MRI (Molar tooth sign)
AR
16q12.2
NPHP4 NPHP1 (JBTS4) NPHP3 JBTS3 (AH1) NPHP2 JBTS1 (CORS1) JBTS 2 (CORS2) CEP290 NPHP6 CCA10 JBTS7 (RPGRIP1L)
2q13 9q22 3q22 1q36
NPHP1 NPHP2 NPHP3 NPHP4
1p36.21 2q12 3q22.1 6q23 9q31.1 9q34.3 11p12-q13.3 12q21.32
AR AR
Developmental delay Abnormal respiratory patterns Abnormal eye movements Plus: Mainzer-Saldino syndrome (266920)
Juvenile nephronophthisis Pigmentary retinopathy resembling Leber amaurosis Cone-shaped epiphyses of hands
Renal function and imaging Ophthalmic review
AR AR (probable)
Skeletal survey
Cystic dysplastic kidneys Pigmentary retinopathy resembling Leber congenital amaurosis
Renal function and imaging Ophthalmic review
AR
Senior-Loken syndrome (266900)
Juvenile nephronophthisis Pigmentary retinopathy resembling Leber congenital amaurosis
Renal function and imaging Ophthalmic review
AR
COACH syndrome (216360)
Iris or choroid colobomas Liver fibrosis
Disorders of Vision
Arima Syndrome (243910)
AR
59
Continued
60
Table 5.6 Causes of Syndromic RP—cont’d Clinical Features
Specialist Investigations
Differential Diagnosis
Congenital disorders of glycosylation CDG-1a (212065)
Congenital ataxia with cerebellar atrophy Pigmentary retinopathy Inverted nipples Abnormal subcutaneous fat pads Psychomotor retardation Decreased nerve conduction velocity Joint contractures Skeletal deformities Renal cysts
Other CDGs Isoelectric focusing of serum transferrin Nerve conduction studies Enzyme assay of phosphomannomutase 2 (PMM2)
Bassen-Kornzweig (abetalipoproteinemia) (200100)
Diagnosis: on small bowel Onset: first or second histology (characteristic decade of life yellow discoloration, Ataxia normal villi, unlike Acanthocytosis celiac disease, lipid Pigmentary retinal content of mucosa degeneration several times normal, Reduction of deep tendon EM shows fat droplets reflexes in mucosal cells, and Loss of vibration sense and serum lipid estimations proprioception (check) low Mental retardation or low chylomicrons and intellect in some cases VLDL, no Apo B). Severe anemia Plasma TG only a few Fat malaborption with mg per dl and vomiting, diarrhea, and cholesterol half of failure to gain weight normal, triglyceride fails Treatment: neurological to rise after fat intake progression inhibited and retinopathy prevented or stabilized if started early. Treatment is with vitamin E, large doses orally. Also low-fat diet
Inheritance Gene Locus Gene AR
16p13
PMM2
AR
4q22-q24
Microsomal trigylceride transport protein
PRACTICAL GUIDE TO NEUROGENETICS
Condition (OMIM)
Vitamin E deficiency (277460)
Serum vitamin E levels Onset: childhood/ <2 mg/L adolescence Gait and limb ataxia Dysarthria Lower limb areflexia Loss of vibration sense Extensor plantar reflexes Muscle weakness Head titubation Cardiomyopathy Pigmentary retinopathy, pale optic disks, and decreased visual acuity Abnormal conscious level/ dementia Treatment: oral vitamin E (10 mg/kg per day, or 800 mg/day for adults in two divided doses)
Friedreich ataxia, abetalipoproteinemia Refsum’s disease
Spinocerebellar ataxia (SCA) type 7 (164500)
Genetic testing Onset 1535 years for SCA7 Pigmentary retinopathy predominantly macula Ataxia Supranuclear ophthalmoplegia Dementia Extrapyramidal features
SCA2 and SCA3 may AD also have a pigmentary retinopathy
Neuhauser-Boucher syndrome (215470)
Early childhood to 4th decade Endocrine work-up Ataxia Retinopathy Hypogonadism
8q13.1-q13.3 -Tocopherol transfer protein
3p21
CAG trinucleotide repeat gene
AR
AR
See Table See Table 16.7, 16.7, Chapter 16 Chapter 16
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Continued
Disorders of Vision
RP with Neurodegenerative Disease (see Chapter 16) Vacuolated lymphocytes Neuronal ceroid Onset: variable enzyme assay, EM of lipofuscinosis (NCL) Clinically subgrouped into: leukocytes (buffy coat), (Batten disease) (204200) infantile (INCL), late or skin punch or infantile (LINCL), conjunctival biopsies juvenile (JNCL) and adult (ANCL)
AR
62
Condition (OMIM)
Clinical Features
Specialist Investigations
Diffuse pigmentary retinopathy or maculopathy causing visual deterioration and progressing to blindness in a few years Dementia Epilepsy Premature death Excretion of large Mucopolysaccharidosis Onset: amounts of chondroitin type II (Hunter disease) Dysostosis with dwarfism sulfate B and heparitin (309900) Dysmorphic coarse facies sulfate in the urine Hepatosplenomegaly from mucopolysaccharide deposits Cardiovascular disorders from mucopolysaccharide deposits in the intima Deafness Conjunctival biopsy shows fibroblast inclusion bodies on skin biopsy showing: accumulation of ganglioside and mucopolysaccharide dysplastic or absent splenium, cerebellar atrophy in older patients
Differential Diagnosis
Inheritance Gene Locus Gene
X-linked
Xq28
Iduronate 2 sulfatase deficiency
AR
19p13
Mucolipin 1
Type A: 5q12 Type B: 10q11
Group 8 excision repair crosscomplementing protein
Mucolipidosis type IV (252650)
Onset: Corneal clouding Severe psychomotor delay Retinal dystrophy Optic atrophy resulting in visual impairment Spasticity and hypotonia Achlorhydria
Cockayne syndrome (216400)
AR Skin biopsy: reduction of Growth failure in infancy RNA synthesis after Xeroderma pigmentosum Severe progressive UV irradiation (usually no RP but neurological impairment overlap syndromes with mental retardation and occur) microcephaly
PRACTICAL GUIDE TO NEUROGENETICS
Table 5.6 Causes of Syndromic RP—cont’d
Pigmentary retinopathy (in 60100%) (‘‘salt and pepper’’ variety) Skin sensitivity to sunlight
Cerebro-oculo-facioskeletal syndrome (COFS)
Unknown
AR Age of onset usually in first ‘‘Eye of the tiger’’ on T2- Chorea-acanthocytosis Other causes of dystonia weighted magnetic decade, ‘‘atypical’’ form resonance imaging (1.5 more commonly in second Tesla or greater) or third decade Dystonia Rigidity Choreoathetosis Dysarthria Pigmentary retinopathy: need full ophthalmic evaluation About 25% of patients have ‘‘atypical’’ presentation with later onset, prominent speech defects, psychiatric disturbances, more gradual progression of disease
Glutaric aciduria type 1 (231670)
Microencephalic macrocephaly Subdural hematoma and acute retinal hemorrhage Acute striatal necrosis causing dystonia Pigmentary retinopathy, intraretinal hemorrhages, cataract, gaze palsy, strabismus, ametropia
LCHAD deficiency (609016)
Hypoketotic hypoglycemia Chorioretinal atrophy Hepatic steatosis Cardiomyopathy Rhabdomyolysis Peripheral neuropathy
Treatment includes low-fat highcarbohydrate diet
Other beta-oxidation defects
20p13-p12.3 PANK2
AR
19p13.2
Glutaryl-CoA dehydrogenase deficiency
AR
2p23
Long-chain 3hydroxyl-CoA dehydrogenase
Continued
Disorders of Vision
Pantothenate kinaseassociated neurodegeneration (PKAN) (234200)
63
64
Condition (OMIM)
Clinical Features
Specialist Investigations
RP with Spasticity Kjellin syndrome (SPG15) Progressive spastic paraplegia (270700) Macular distribution of retinal pigmentation Mental retardation (variable) Small hand muscle wasting Cerebellar ataxia (variable) RP with Peripheral Neuropathy Neuropathy, RP, optic -Methylacyl-CoA racemase deficiency atrophy (604489)
Pristanate elevated Enzyme activity reduced
Differential Diagnosis
Inheritance Gene Locus Gene
AR
14q22-q24
Spastizin
AR
5p13.2-q11.1 -MethylacylCoA racemase
PRACTICAL GUIDE TO NEUROGENETICS
Table 5.6 Causes of Syndromic RP—cont’d
Disorders of Vision
65
give clues to the pattern of inheritance: the presence of male-to-male transmission excludes X-linked inheritance, whereas the presence of less severely affected females should suggest X-linked disease if the disease in the male proband or male relatives is early-onset and severe. An experienced ophthalmologist should be able to give some guidance on the likely mode of inheritance. Empiric recurrence risk figures for offspring of simplex males cases is 1/9, representing a composite of cases of differing inheritance patterns. Genetic testing for the X-linked genes RPGR (RP3) and RP2 is available in some centers and this is gradually being extended to include the common genes for ADRP and ARRP. Other genetic testing may be available on a research basis and details can be found on websites at the end of this chapter. Prenatal and/or predictive testing is occasionally requested by patients or relatives. Specialist genetic counseling is recommended to consider all the ethical and practical implications for each case. Differential Diagnosis of Non-Syndromic RP Gyrate Atrophy of the Choroid and Retina (OMIM 258870). This is a rare inborn error of amino acid metabolism caused by deficiency of ornithineketoacid aminotransferase. The clinical features include: myopia and night blindness in early childhood progressing to circumferential chorioretinal atrophy, with sharply defined, scalloped defects of the pigment epithelium and choroid (‘‘gyrate’’ atrophy) occurring between 25 and 45 years of age. Some individuals may also have progressive or stable abnormalities in the central nervous system and muscle. The diagnosis is made by identification of 1020-fold elevation of plasma ornithine level and assay of ornithine-ketoacid aminotransferase in skin fibroblasts. It is an autosomal recessive condition caused by mutations in the ornithine aminotransferase (OAT) gene. Bietti Corneal/Retinal Dystrophy (OMIM 210370). Bietti crystalline retinopathy is a retinal degeneration characterized by multiple glistening intraretinal crystals scattered over the fundus, with degeneration of the retina, sclerosis of the choroidal vessels, progressive night blindness, and constriction of the visual fields. It is an autosomal recessive condition caused by mutations in the CYP4V2 gene, part of the cytochrome P450 system. Choroideremia (OMIM 300390). This is an X-linked disorder presenting with symptoms that are usually similar to RP. The ERG may demonstrate rod-cone degeneration, but is commonly extinguished. There is a characteristic fundus appearance with patchy areas of chorioretinal degeneration, which gradually coalesce into pale yellow confluent areas. The function and anatomy of the central macula is preserved until late in the disease process. Carrier females have fundus changes that are distinctive, and in general are asymptomatic and do not experience significant visual impairment. The ERG may be normal in obligate carriers or in carriers with characteristic fundus changes. The diagnosis is made on the clinical features and mutation analysis. The gene mutated in choroideremia is for a Rab escort protein (REP-1). Genetic testing is available in some centers.
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PRACTICAL GUIDE TO NEUROGENETICS
Usher Syndrome. This condition is characterized by RP and sensorineural hearing loss. Three clinical types have been described and nine genes (11 loci) identified and are characterized by varying degrees of deafness and RP. Some patients with non-syndromic ARRP have mutations in USH2A.
Macular Dystrophies (Central Dystrophies) (Non-Syndromic) Dystrophies that principally or exclusively affect the macular region are characterized by reduction or loss of central visual acuity. Color vision is affected and photophobia may occur, which depends on the degree of cone involvement. There is clinical overlap, with some macular dystrophies sharing clinical, electrophysiological and histopathological features. AD, AR, X-linked, and mitochondrial inheritance patterns have all been described. The commonest inherited macular dystrophies are described below. Autosomal Recessive Macular Dystrophies The commonest is Stargardt fundus dystrophy, otherwise known as fundus flavimaculatus. Typical yellow fleck-like deposits are seen at the level of the RPE. The onset is usually in childhood, but may be later in adulthood also. Stargardt disease can be extremely variable and electrophysiologically can be characterized into macular, cone, cone-rod, or rod-cone dystrophy. The phenotype depends on the type of mutation in the ABCA4 gene. Autosomal Dominant Macular Dystrophies Best Disease (Vitelliform Dystrophy; OMIM 153700). This is characterized by early-onset macular changes with yellow deposits which are usually bilateral and symmetrical. Phenotypic variation is well recognized and about 50% of patients have good vision, and normal or near normal fundi throughout life. The loss of the EOG light rise is a hallmark of the disease. The causative gene is bestrophin (VMD2). Pattern Dystrophy. Pattern dystrophy, like Best disease, is a disorder of the RPE characterized by yellow deposits in a pattern-like distribution. Genes associated with pattern dystrophy include ELOV4, peripherin/RDS. This condition is usually seen in isolation, but pattern dystrophy has been described in association with diabetes and cerebellar ataxia. X-linked Macular Dystrophy Congenital X-linked Retinoschisis. The prevalence of congenital X-linked retinoschisis is estimated at 1/5000 to 1/25,000. Central visual loss is the main feature and this seems to reach a steady state in adulthood. Affected males have a characteristic foveal schisis and a negative ERG (selective reduction of the b wave amplitude). The peripheral retina is sometimes involved and retinal
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67
detachment can occur. Female carriers do not normally have any identifying characteristics. Retinoschisin is a secreted protein containing a discoidin domain which may be involved in cellular adhesion or cellcell interactions.
Cone-Rod Dystrophies (CORD) Cone-rod dystrophies are considered as a separate clinical entity from RP as the cone degeneration is either earlier onset or with greater involvement than the rods. This diagnosis is made on the basis of electrophysiology. Pure cone dystrophy is rare and usually rod involvement occurs at some point. Clinical features include loss of central visual acuity, photophobia, and color vision defects. Patients may have rod involvement at presentation or may develop it later. Fundus changes range from granular abnormalities of RPE to bull’s eye appearance of macula, and the optic disk may show temporal pallor. There is nystagmus in early-onset severe cases. Various genes have been described in cone and cone-rod dystrophies, including ABCA4, which is also associated with autosomal recessive fundus flavimaculatus/Stargardt disease. This is one of the commonest autosomal retinal degenerations with a specific phenotype. Several genes causing autosomal dominant cone or cone-rod dystrophies have also been identified (see below). X-linked cone dystrophy may be caused by mutations in RPGR (also associated with XLRP). Tables 5.2, 5.3, 5.4, and 5.5 demonstrate the significant genetic heterogeneity found with CORD. Cone-rod dystrophies are often syndromic; examples include Alstrom syndrome, Bardet-Biedl syndrome, and the neuronal ceroid lipofuscinoses (Table 5.6).
Syndromic Inherited Retinal Degeneration The retinal phenotype in many of these disorders is heterogeneous: patients may have typical RP, or an atypical pigmentary retinopathy, macular dystrophy, or cone-rod dystrophy. The RP may be very early onset and described as LCA in some cases. The most commonly recognized syndromic retinal degenerations are described below, the less common are listed in Table 5.6. Bardet-Biedl Syndrome (BBS) (OMIM 209900) This is the commonest syndromic pigmentary retinopathy seen in clinic. Many of the features are present in early childhood but the atypical conerod dystrophy seen in >90% of patients may not be diagnosed until later. The ocular phenotype includes an early and severe reduction of visual acuity, constantly altered color vision, high incidence of strabismus and nystagmus, mild-to-severe atrophic changes of the optic disk, and frequently absent or minimal pigmentary retinal changes. Other features include post-axial polydactyly, early-onset obesity, learning difficulties, hypogonadism in males,
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PRACTICAL GUIDE TO NEUROGENETICS
structural and functional renal abnormalities, ataxia, diabetes mellitus, and cardiac abnormalities. Investigations should include: fasting glucose, renal U/S or IVP, urogenital imaging, ECG/echocardiography. There are at least eight genetic loci associated with BBS, with evidence of triallelic inheritance in some cases, and several genes have been identified. Many have been shown to involve function of the cilia in photoreceptors and elsewhere. Genetic testing in an individual family may be available. Alstrom Syndrome (AS; OMIM 203800) This needs to be distinguished from BBS since they share the features of obesity, diabetes mellitus, and renal and cardiac abnormalities. However, there is usually no polydactyly and typically no learning disability in AS. Other features include: sensorineural deafness, acanthosis nigricans, hepatic degeneration, hypothyroidism, growth hormone deficiency, hyperuricemia, hypercholesterolemia, hypertriglyceridemia. The ocular phenotype includes pendular or searching nystagmus and photodysphoria (98%) during the first year of life (age range, birth to 40 weeks) and reduced visual acuity in childhood. Patients are usually blind by 15 years of age. Electroretinograms initially show an absence of cone function and progressive deterioration of rod function, with degeneration of the retinal pigment epithelium, attenuated vessels, and optic disk pallor. Subcapsular cataracts may be present. Investigations should include: renal and liver biochemistry, fasting blood sugar/insulin levels, growth hormone, and ECG/echocardiography. AS is an autosomal recessive disorder, and the gene has been identified (ALMS1) on chromosome 2p. Joubert Syndrome (OMIM 213300) This is a clinically and genetically highly heterogeneous disorder characterized by hypotomia, ataxia, psychomotor delay, and variable occurrence of oculomotor apraxia and neonatal breathing abnormalities. Other clinical features include renal abnormalities (nephronophthisis) and retinitis pigmentosa. The neuroradiological hallmark is the ‘‘molar tooth sign,’’ which represents a complex malformation of the midbrain/hindbrain associated with cerebellar vermis aplasia or hypoplasia, thickened superior cerebellar peduncles, and a deepened interpeduncular fossa. The condition overlaps with cerebello-oculorenal syndromes (CORS) and numerous genes have now been identified (see Table 5.6). Usher Syndrome (OMIM 276900) This is characterized by childhood- or adolescent-onset sensorineural hearing loss and RP which occurs later. There are three main types: USH1: severe congenital hearing loss, usually deaf with poor speech, vestibular dysfunction, and retinal degeneration beginning in childhood. Six genes have been mapped, and four identified. USH2: moderate-severe hearing impairment, normal vestibular function, and later-onset retinal degeneration. Three genes have been mapped, and
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Figure 5.2. Photograph showing syndactyly and bilateral short 4th toes typical of epiphyseal dysplasia seen in Refsum’s disease.
one identified. However, mutations in the USH2A gene are also associated with ARRP without hearing loss. USH3: progressive hearing and visual loss, occasional vestibular dysfunction. One gene has been mapped. Inheritance is autosomal recessive in all cases and may be seen in genetic isolates. Pigmentary retinopathy in a child with hearing impairment differentiates it from non-syndromic RP and an early ERG should be performed in any deaf child at risk of Usher syndrome. This is important as the decision whether to carry out cochlear implants may be influenced by the discovery of RP. Refsum’s Disease (OMIM 266500; see Chapter 6) This condition usually presents in adolescence or adulthood, although there is a juvenile form with progressive retinitis pigmentosa. Other features include: sensorineural deafness and ataxia, anosmia, demyelinating polyneuropathy, cranial nerve involvement, nerve hypertrophy, ichthyosis, and cardiac arrythmias. There are associated skeletal anomalies which are helpful in diagnosis, in particular short fourth metacarpals or metatarsals (Fig. 5.2). Often the eye signs develop early, prior to the neurological signs, and it is therefore important to test all simplex or recessive cases of RP for phytanic acid levels, as treatment with a strict diet may prevent or lessen the development of clinical features. Inheritance is AR and is caused by mutations in phytanoyl-CoA hydroxylase (PAHX) leading to raised serum phytanic acid levels (>200 mmol/L, normal <30 mmol/L) which are pathognomic of Refsum’s disease. Other investigations should include: nerve conduction studies (slowed conduction velocities), elevated CSF protein, abnormal ERG, and onion bulb formation on nerve biopsy. Mitochondrial Disorders Mutations in mitochondrial DNA (mtDNA) cause a range of neurological findings including dementia, stroke-like episodes, peripheral neuropathy, and ataxia, as well as retinal dystrophy (pigmentary retinopathy and macular pattern dystrophy) or Leber hereditary optic neuropathy. Systemic abnormalities
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include hearing loss and diabetes mellitus. See Chapter 14 for review of mitochondrial diseases. Spinocerebellar Ataxia (see Chapter 6) Autosomal dominant spinocerebellar ataxia is clinically and genetically heterogeneous. Spinocerebellar ataxia type 7 is associated with either a predominantly macular pigmentary retinopathy or a cone-rod dystrophy. The neurological phenotype includes ataxia, supranuclear ophthalmoplegia, dementia, and extrapyramidal features. Age of onset is 1535 years and the genetic mutation is an expanded CAG repeat. There are case reports of SCA2 and SCA6 being associated with a pigmentary retinopathy, but RP is common enough that this may be coincidence and investigations and genetic counseling should address this possibility.
Neurological Disorders Associated with Cherry-Red Spots Cherry-red spots of the macula are produced when ganglion cells filled with lipid degenerate, thereby exposing the vascular choroidal tissue behind these cells. The commonest conditions associated with cherry-red spots include neuronal ceroid-lipofuscinosis, Farber lipogranulomatosis, galactosialidosis, Gaucher’s disease, GM1 and GM2 gangliosidoses, metachromatic leukodystrophy, Niemann-Pick type A and B, Sandhoff’s disease, and sialidoses type 1, 2, and 3 (Chapter 17 for further detail). The presence of a cherry-red spot should prompt the clinician to investigate the cause.
Vitreoretinal Dystrophies This is a group of conditions characterized by retinal and vitreous involvement. These include Stickler (108300) and Wagner syndromes (143200) and familial exudative vitreoretinopathy, the commonest of which is Stickler syndrome. This is an autosomal dominant disorder with characteristic ophthalmological and orofacial features, deafness, and arthritis. There are pathognomonic abnormalities of the vitreous gel, usually associated with high myopia which is congenital and non-progressive. There is a substantial risk of retinal detachment. The majority of families with Stickler syndrome have mutations in the COL2A1 gene. The remainder have mutations in COL11A1 or other loci yet to be identified. Mutations in COL111A2 can give rise to a syndrome with the systemic features of Stickler syndrome but no ophthalmological abnormality.
Management of Inherited Retinal Degeneration There is no therapy for treating inherited retinal degenerations apart from manipulation of diet in patients with Refsum’s disease, abetalipoproteinemia (Bassen-Kornzweig), gyrate atrophy, or vitamin E deficiency. In individuals who are vitamin A deficient, supplements can lead to improvement in their
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71
RP-like symptoms. Treatments aimed at symptomatic improvement include diamox for cystoid macular edema, and lens extraction for cataract if affecting vision. Low-vision aids such as CCTV, magnifiers, dark eyewear, and other gadgets may be of assistance. There are local support groups who provide useful information and support to individuals and families. It is important to encourage registration for visual loss, which can activate other support mechanisms. Several experimental therapeutic options being investigated include growth factor treatments, gene therapies, stem cell progenitor therapies, retina transplants, and retinal prostheses. Interest in gene therapy for RP has been generated by the successful restoration of vision using recombinant adeno-associated virus carrying wild-type RPE65 in a naturally occurring canine model of LCA, and there has been some success in animal models of growth factor treatments to prevent or slow down apoptosis.
OPTIC ATROPHY Definition This is a heterogeneous group of disorders in which there is cell death of the retinal ganglion cells leading to typical fundal changes with pallor of the optic disk (Fig. 5.3). It may be non-syndromic (often called primary hereditary optic neuropathy) or associated with other neurological abnormalities. The papillomacular bundle appears to be preferentially affected.
Non-Syndromic Optic Atrophy Primary Hereditary Optic Neuropathy Onset is usually in childhood, but it may develop later in life, and prevalence is 1/12,000 to 1/50,000. The main clinical features include loss of central vision
Figure 5.3. Photograph showing optic atrophy.
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with reduced visual acuity, loss of color vision, and central visual field defects. The optic disks can show complete atrophy, temporal pallor, or subtle pallor. Visual loss is typically gradual, bilateral, symmetrical, and irreversible (except in LHON; see below). The VER is usually delayed. The flash ERG is normal but the pattern ERG shows a reduced N95 component, a feature typical of ganglion cell dysfunction. MRI shows reduced optic nerve-sheath complex throughout the length of the intraorbital nerve with no signal abnormality and clearly visible CSF (in contrast to LHON, where there is bright signal and no visible CSF). When considering the diagnosis it is vital to exclude Leber’s hereditary optic neuropathy (LHON; see Chapter 14; OMIM 535000), and acquired causes, particularly glaucomatous optic neuropathy. Rarer acquired causes include tobacco-alcohol amblyopia (TAA), the Cuban epidemic of optic neuropathy (CEON) and other dietary (vitamins B, folate deficiencies) optic neuropathies, toxic optic neuropathies due to chloramphenicol, ethambutol, or more rarely to carbon monoxide, methanol and cyanide, and previous trauma. Optic atrophy (OA) may be inherited as an autosomal dominant condition. The OPA1 gene (165500) on chromosome 3q28-qter is a mitochondrial dynamin-related GTP protein. The penetrance may be reduced, depending on the specific mutation, and this is important for genetic counseling. A second locus for autosomal dominant OA has been found on 18q12.2-q13. Autosomal recessive early-onset, slowly progressive OA has been found in one consanguineous family, and the gene localized to 8q21-q22. X-linked inheritance has also been described. Genetic testing for OPA1 may be available as a research protocol.
Syndromic Optic Atrophy Several inherited neurological disorders are associated with OA. The most commonly recognized are described below and the less common disorders are listed in Table 5.7. Friedreich’s Ataxia (OMIM 229300; see Chapter 6) This is characterized by adolescent-onset progressive ataxia and dysarthria with various systemic features, including diabetes and a cardiomyopathy. Optic pallor or frank optic atrophy is present in less than 20%. The visual loss is usually very slowly progressive and rarely severe although some patients may eventually lose their vision. It has been reported to occur more frequently in compound heterozygotes than GAA expansion homozygotes. Wolfram Syndrome (OMIM 222300) Patients present with diabetes mellitus and optic atrophy in the first decade, and later develop cranial diabetes insipidus and sensorineural deafness (second decade), dilated renal outflow tracts (third decade), and multiple neurological abnormalities including ataxia, myoclonus, dementia, and/or psychiatric illness (fourth decade). There may also be primary gonadal atrophy. Investigations
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Table 5.7 Rare Causes of Syndromic Optic Atrophy Condition (OMIM)
Clinical Features
Optic Atrophy with Ataxia Behr syndrome Optic atrophy beginning in (210000) early childhood Ataxia Spasticity Mental retardation Posterior column sensory loss
Inheritance
Gene Locus
Gene
AR (probable)
Unknown
Unknown
X-linked
Xq22
TIMM8A
9q34.1
POMT1
9q31
Fukutin
11q12
7-Dehydrocholesterol reductase 7DHCR
Optic Atrophy with Diabetes Wolfram syndrome See text (222300) See text Friedreich’s ataxia (229300) Optic Atrophy with Deafness Childhood onset Deafness dystonia Sensorineural hearing loss optic Dystonia neuronopathy Dementia syndrome Psychotic features (MohrOptic atrophy Tranebjaerg Mental retardation syndrome; Hip fractures 304700) Peripheral neuropathy Progressive neurodegenerative syndrome Optic Atrophy with Neurodegenerative Disease Walker-Warburg Onset in infancy syndrome Optic atrophy (WWS; 236670) Type II lissencephaly (‘‘cobblestone’’) Agenesis of corpus callosum Encephalocoele Microphthalmia Congenital cataract Retinal dysplasia Congenital muscular dystrophy Optic Atrophy with Dysmorphic Features Smith-LemliDysmorphic face microcephaly Opitz syndrome Ptosis (270400) Cataracts Mental retardation Hypogenitalism in males Skeletal abnormalities Cleft palate Congenital heart defects Pyloric stenosis Cholestatic liver disease Renal anomalies Congenital sensorineural hearing loss Structural CNS malformations
AR
AR
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should include: glucose tolerance test, renal imaging, and endocrine/ENT evaluation. The condition is inherited as an autosomal recessive trait and the gene has been identified (WFS1) on chromosome 4p16.1. Genetic testing may be available. Septo-optic Dysplasia (OMIM 182230) This is not strictly a cause of optic atrophy, but the optic nerve is hypoplastic and it may be difficult to make the distinction on clinical grounds. It is thought to be a disorder of midline prosencephalic development which also causes dysgenesis of the septum pellucidum and other cerebral malformations. Clinical features include visual defects, endocrine abnormalities (hypothalamic and pituitary), developmental delay, motor deficits, and epileptic seizures. Homozygous, heterozygous, and compound heterozygous mutations have been shown in HESX1, and genetic testing may be available.
BIBLIOGRAPHY www.eddnal.com www.sph.uth.tmc.edu/Retnet/ www.geneclinics.org
ABBREVIATIONS ADRP = autosomal dominant retinitis pigmentosa ARRP = autosomal recessive retinitis pigmentosa CORD = cone-rod dystrophy CSNB = congenital stationary night blindness EOG = electro-oculogram ERG = electroretinogram MD = macular degeneration NCL = neuronal ceroid lipofuscinosis OA = optic atrophy RP = retinitis pigmentosa VEP = visual evoked potentials XLRP = X-linked retinitis pigmentosa
Chapter 6 Cerebellar and Spinocerebellar Disorders Simon R. Hammans
INTRODUCTION This chapter considers the clinical manifestations of cerebellar disorders and their differential diagnosis. Genetic disorders with ataxia as a principal manifestation are discussed within a classification of congenital, autosomal recessive and autosomal dominant disorders, with reference to ataxias associated with metabolic defects. Sporadic and non-genetic causes of ataxias are outlined. The specific and general management of ataxic disorders is described.
Clinical Manifestations Disorders of the cerebellum and its connections manifest clinically with ataxia, which is recognizable by the following features. Limb ataxia: an incoordination of the limbs often accompanied by an intention tremor, which characteristically is exaggerated as the limb reaches for a target. Gait ataxia: an unsteadiness of standing, walking, or running. Cerebellar dysarthria: a characteristic slurring of speech. Disorders of eye movement, including gaze evoked nystagmus. Ataxia may be caused by a lesion in the cerebellum itself (‘‘cerebellar ataxia’’), but may also be produced by impaired cerebellar input, particularly defects of proprioception (‘‘sensory ataxia’’). Evidence of sensory ataxia includes: Impaired joint position sense, particularly at the fingers and toes. Increased unsteadiness with the eyes closed (Rombergism). New genetic advances challenge the traditional classification of ataxias. For example, ataxia with vitamin E deficiency might have been thought of as a metabolic ataxia and Friedreich’s ataxia as an idiopathic genetic ataxia. However, the pathophysiology of Friedreich’s ataxia involves defects of mitochondrial iron handling, which might be classified as ‘‘metabolic’’. The two conditions are 75
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both autosomal recessive and manifest with very similar clinical phenotypes. Such observations blur traditional clinical distinctions, but the possibility of therapeutic intervention requires identification of metabolic causes. Ultimately, the classification will rest on genetic data, which are not yet complete.
Investigation of Ataxias The cerebellum and its connections are susceptible to damage by many different mechanisms, which means that diagnosis of a genetically determined ataxia necessarily requires exclusion of other causes. This may be relatively straightforward in the context of an established family history of ataxia, but in a sporadic case may require careful assessment and investigation. It is important to identify those ataxias with an underlying metabolic defect. Such an ataxia is suggested by the following:
Early onset Intermittent or variable course Disturbance of consciousness including coma Mental retardation and seizures Non-neurological features (e.g., cataracts, fat malabsorption).
In the presence of one or more of these features, screening for a metabolic disorder is necessary, and depending on the clinical picture might include (see Table 6.1 for specific information): Blood biochemistry, including: * * * * * *
Liver function tests Plasma ammonia Plasma lactate Serum uric acid Ceruloplasmin Vitamin E
Smears for acanthocytes, vacuolated lymphocytes Amino acid screening in plasma, urine, and CSF Urine organic acid profile Biotinidase levels Plasma cholesterol, triglycerides, lipoprotein electrophoresis Serum cholestanol Transferrin isoelectric focusing Magnetic resonance (MR) scan of the brain EEG Invasive testing *
Skin and muscle biopsy
Specific enzyme assay, e.g., hexosaminidase A, white cell enzymes, etc. Specific genetic analysis Specialist examination, e.g., ophthamological examination for KayserFleischer rings, retinopathy, etc.
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Table 6.1 Metabolic Ataxias (all are autosomal recessive other than some hyperammonemias and mitochondrial disease) Disease
Other Clinical Features
Diagnostic Tests
Therapy
Wilson’s disease
May also have psychiatric or extrapyramidal features Titubation, but may closely resemble Friedreich’s ataxia Fat malabsorption
Slit lamp examination for Kayser-Fleischer rings, ceruloplasmin Vitamin E level
Penicillamine
Vitamin E, lipoproteins and other fat-soluble vitamins Urinary amino acids Plasma and urine branched-chain amino acids Plasma ammonia and enzyme assays
High-dose vitamin E with other vitamins
Organic aciduria, biotinidase deficiency
Biotin
Serum cholestanol
Chenodeoxycholic acid
Phytanic acid
Phytanic acid restriction
Transferrin isoelectric focusing
Some forms respond to dietary therapy
Ataxia with vitamin E deficiency Abetalipoproteinemia
Hartnup disease Maple syrup urine disease
Hyperammonemias
Biotinidase deficiency
Cerebrotendinous xanthomatosis Refsum’s disease (see Chapter 11) Carbohydrate-deficient glycoprotein
Hexosaminidase A deficiency Mitochondrial encephalopathies (see Chapter 16) Leukodystrophies including adrenoleukodystrophy (see Chapter 7)
Rash, intermittent ataxia Ataxia, drowsiness seizures, mental retardation Intermittent ataxia, seizures, coma, mental retardation Early-onset seizures with ataxia and other features Premature cataracts, tendon xanthomas, mental retardation Neuropathy, ichthyosis, short fourth metacarpal, deafness Abnormal subcutaneous fat distribution. Some with pigmentary retinopathy, seizures, and multiorgan failure Usually cherry-red spot at the macula, spasticity Variable but ataxia common Spasticity and other features
See text
Nicotinamide Diet, thiamine, dialysis
Diet and other treatments
Enzyme assay
Genetic analysis, muscle biopsy Brain imaging, enzyme assay
With no pointers to suggest metabolic disease, the list of screening tests may be abbreviated. A vitamin E assay is an exception to this guideline, as vitamin E deficiency can mimic an idiopathic genetic ataxia and should always be performed in the absence of a specific diagnosis. An MR brain scan often helps to refine the differential diagnosis. It can exclude structural disorders, and may indicate the likely pathological process, e.g., leukodystrophy, multiple sclerosis, or a mitochondrial encephalopathy, although only rarely will it define a specific genetic diagnosis. Further diagnostic pointers are given in the box below.
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Diagnostic Hints The history is very important. Age of onset and evidence of progression is helpful in refining the genetic differential diagnosis. Friedreich’s ataxia is a sensory ataxia and is usually suspected on clinical grounds. An ECG is a useful outpatient diagnostic test. Although ataxia is a very common manifestation of multiple sclerosis, it seldom progresses steadily as in genetic ataxias, and is usually accompanied by sensory and other focal and asymmetrical symptoms unusual in genetic ataxias. Neuropathies such as the demyelinating form of CMT may cause a sensory ataxia. Ataxia secondary to alcohol excess may cause more prominent heelshin ataxia than fingernose ataxia. Be aware that some ataxias are treatable and need to be specifically excluded.
The differential diagnosis of ataxia varies with age (Table 6.2). In childhood the differential diagnosis is between acquired cerebellar damage, congenital ataxias, metabolic causes, and early-onset genetic ataxias. Ataxia can also be a feature of many syndromic disorders (e.g., Angelman syndrome). In the context of ataxia with onset in later childhood without pointers to metabolic disease, an early-onset genetic ataxia may be suspected. Autosomal dominant disease is less likely in the absence of a family history. Friedreich’s ataxia is statistically the most likely diagnosis and can usually be confirmed or excluded by genetic analysis. Adult-onset ataxia is more often autosomal dominant than recessive. Depending on clinical presentation it may be necessary to exclude non-genetic causes.
CONGENITAL ATAXIAS Congenital ataxias are usually apparent from infancy. Often initial non-specific motor impairment and delay evolves into the more specific features of truncal ataxia and limb incoordination, sometimes with eye movement abnormalities. By definition, they cause a static rather than a progressive ataxia. Clues to the diagnosis may come from dysmorphic features, such as the facial appearance in Table 6.2 Differential Diagnosis of Ataxias by Age 012 months
110 years 1020 years 20+years
Perinatal cerebellar damage Congenital ataxias Genetic/metabolic ataxias Genetic/metabolic ataxias Genetic ataxias (AR>AD) Metabolic ataxias* Genetic ataxia (AD>AR) Sporadic/neurodegenerative disease Multiple sclerosis/demyelination Vascular disease Drug intoxication Tumors Infective
Note that most metabolic ataxias will have a genetic cause
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Table 6.3 Congenital Ataxias Syndrome (OMIM)
MRI Appearances
Additional Clinical Features
Dandy-Walker syndrome (220200) heterogeneous, low recurrence risk (15%)
Complete or partial agenesis of the vermis, cystic dilatation of the fourth ventricle with upper displacement of the lateral venous sinuses and tentorium Vermal aplasia; ‘‘molar tooth sign’’
Variable cranial nerve palsies, nystagmus and truncal ataxia
Joubert syndrome (213300): autosomal recessive; at least 4 genes identified Gillespie syndrome (206700): autosomal recessive Hoyeraal-Hreidarsson syndrome (300240) (X-linked)
Cerebral and cerebellar atrophy with white matter changes Microcephaly
Episodic hyperpnoea, abnormal eye movements, and psychomotor retardation; may have dysmorphic and/or systemic features Fixed dilated pupils (aniridia); mental retardation Dyskeratosis congenital; pancytopenia, growth retardation
some patients with Joubert syndrome. Additional non-neurological features may aid genetic classification (e.g., aniridia in Gillespie syndrome). Congenital ataxias are rare and are not prominent in the differential diagnosis of early-onset motor disorders until brain imaging (usually magnetic resonance imaging) has refined the diagnosis. Specifically, ataxia in early childhood requires brain imaging to exclude hydrocephalus or structural lesions. In congenital ataxias, imaging defines structural abnormalities of the posterior fossa such as Dandy-Walker or Arnold-Chiari malformations, or cerebellar atrophy (Table 6.3). MR may also identify specific abnormalities to aid diagnosis of the other congenital ataxias such as the ‘‘molar tooth’’ sign of Joubert syndrome, referring to the brainstem appearance. Congenital ataxias are probably underdiagnosed because of the overlap in clinical features with ‘‘ataxic cerebral palsy’’ or intrauterine infections. Carbohydrate-deficient glycoprotein disorders frequently present in infancy and cerebellar hypoplasia may be evident, and therefore should be considered in the differential diagnosis of congenital ataxias (see Table 6.3). Further congenital ataxias have been clinically and genetically characterized but are too rare to be described here.
AUTOSOMAL RECESSIVE ATAXIAS Friedreich’s Ataxia (FA; OMIM 229300) FA is the most common genetically determined ataxia. Originally defined clinically, it is now defined genetically as an ataxia arising from defects in the frataxin gene on chromosome 9q13.
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Table 6.4 Friedreich’s Ataxia Core Features of ‘‘Typical’’ FA
Wider, Genetically Defined Phenotype
Onset earlier than 25 years Presentation with progressive ataxia of limb and gait Tendon areflexia in legs Extensor plantar responses Motor nerve conduction velocity >40 m/s in upper limbs with small or absent sensory nerve action potentials
Onset up to sixth decade Presentation may be with a spastic gait; rarely may have chorea Reflexes may be normal or brisk Usually present Remains a core feature with few exceptions
Clinical Features Onset may be as early as infancy or as late as the sixth decade, although typically onset is around puberty. Although pathology does develop in the cerebellum, FA is primarily a sensory ataxia. The history may disclose this; the ataxia may be worse in the dark or when the eyes are closed. The commonest presenting features are gait ataxia and/or scoliosis. In most cases this is followed by limb ataxia and dysarthria. Clinical examination may confirm the sensory ataxia by showing impaired proprioception and Rombergism. Tendon areflexia in the legs is usual. As the disease progresses additional features such as peripheral vibration sense loss, pyramidal leg weakness, and wasting of the small hand muscles may be evident. Eye movement abnormalities such as broken pursuit movements are common, but nystagmus and optic atrophy are seen in only 2025%. Whereas the majority of patients with FA will have the core features listed in Table 6.4, molecular genetic diagnosis has widened the phenotype. Presentations with a spastic paraparesis, spastic ataxia, chorea, or sensory neuropathy are well described. Some patients may present with cardiac manifestations, although cardiac symptoms more usually appear later in the disease course. Later onset of disease (e.g., later than the age of 25) often follows a more benign course with a fairly pure sensory ataxia, with less obvious non-neurological features. FA is a multisystem disorder (Table 6.5). Non-neurological features are more prominent in cases of early onset. Skeletal manifestations may be clinically important, particularly scoliosis.
Table 6.5 Other Features in Friedreich’s Ataxia Skeletal Cardiac
Endocrine Other cranial nerves
Scoliosis Pes cavus Hypertrophic cardiomyopathy Abnormal electrocardiogram Arrhythmias, especially atrial fibrillation Diabetes mellitus (1020%) Optic atrophy (25%) Deafness (10%)
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Investigations It is possible to diagnose FA clinically, particularly in the presence of a typical phenotype and an abnormal ECG (see Fig. 6.1). However, it is crucial to confirm all cases genetically, because of the close resemblance to the condition of ataxia with vitamin E deficiency (AVED), which responds to vitamin E supplementation. FA and AVED have varying prevalences in different populations. FA is more frequently diagnosed in Europe but AVED is commoner in North Africa. FA is caused by mutations within the frataxin gene. In more than 90% of disease alleles the mutation is an expansion of the GAA repeat in the first intron. Some of the remaining disease alleles have point mutations within one of the six exons. At the time of writing, all point mutations have been identified in compound heterozygotes with a GAA expansion on the other chromosome. Some point mutations are specifically associated with mild, severe, or spastic phenotypes. It should be remembered when assessing the specificity of the genetic findings that the population frequency of FA heterozygotes is not low (approximately 1%). Arguably, in all cases of possible FA (and certainly if the genetic findings are not clear-cut), serum vitamin E should be assayed. Following the discovery of the genetic basis of FA, confirmation of the diagnosis is usually straightforward. The sensory neuropathy is a relatively constant feature and neurophysiology may be useful in cases where the genetic test is unavailable or the expansion is not seen on both chromosomes. MRI examination usually reveals a normal cerebellum, but the cervical spinal cord may be atrophic.
Figure 6.1. ECG in Friedreich’s ataxia showing T-wave inversion in inferior and lateral leads and ventricular hypertrophy.
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Pathophysiology The size range of the disease-causing repeat varies between 66 and more than 1700 repeats, but is more commonly 8001000 copies. Somatic mosaicism for the repeat number has been demonstrated, and variation of repeat length between generations is also observed. Frataxin is highly conserved between species and is present in mitochondria. Studies of yeast, mouse models, and patient tissues indicate iron accumulation within mitochondria. Impairment of mitochondrial oxidative phosphorylation has also been demonstrated but the precise pathophysiology is still unclear. Prognosis The disease is progressive. Gait ataxia typically causes inability to walk 15 years after the onset of symptoms. Age at death is less predictable and is dependent on the presence and degree of scoliosis, cardiac involvement, and diabetes. A normal lifespan is possible, particularly if these features are absent or successfully managed. Treatment No specific treatment for FA is available although treatment trials continue. Studies of idebenone show some reduction in cardiac hypertrophy, but no improvement in neurological symptoms. Surgery for scoliosis and foot deformity may be of benefit in carefully selected patients. Attention to posture in chair-bound patients is important. Cardiac complications become commoner as the disease progresses. Cardiac failure and arrhythmias require specialist cardiological assessment and management. Genetic Advice Families should be advised as described in the context of an autosomal recessive disease. Unfortunately as disease onset is typically at puberty, the family may be have been completed at this time. Because of the frequency of heterozygotes there is a small risk of disease in children of FA patients. In European populations the heterozygote frequency is approximately 1/100, causing a recurrence risk to children of affected patients of approximately 0.5%. It is therefore reasonable to offer genetic analysis to partners of FA patients. If one parent is affected and the other is a heterozygous carrier, the risk of developing FA in each child is 50%.
Other Early-Onset Autosomal Recessive Cerebellar Ataxias Epidemiological studies have established that in Western populations, FA is the most common genetic ataxia, and therefore usually considered as a likely explanation of an early-onset cerebellar ataxia. Even when clinical features are not typical of FA (e.g., with preservation of the leg reflexes), it is prudent to
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Table 6.6 Other Frataxin-Negative Early-Onset Ataxias (all are autosomal recessive) Condition
OMIM Number
Ataxia with oculomotor apraxia 1 (AOA1)
208920
Ataxia with oculomotor apraxia 2 (AOA2) also known as SCAR1
606002
Infantile-onset spinocerebellar ataxia (IOSCA)
271245
€ Marinesco-Sjogren
248800
CharlevoixSaguenay; spastic ataxia
270550
Useful Clinical Features
Diagnostic Tests
Genetic Basics
Hypoalbuminemia and Mutations in aprataxin Described in Portuguese hypercholesterolemia gene. Chromosome and Japanese patients; usually evident after 9p13 early onset, 116 years, age 15 ocular apraxia, early areflexia, late peripheral neuropathy, slow progression, severe motor handicap Increased Mutations in senataxin Onset 1022 years, alphafetoprotein and gene. Chromosome worsens until 20s then creatine kinase 9q34 stable; severe gait ataxia, mild limb ataxia; dystonia, hypomimia, absent leg reflexes, Babinski response, absent sensory action potentials; variable ocular apraxia; progression may cease in early 20s Twinkle (C10ORF2) Usually Finnish families; onset before 2 years; additional neurological features SIL1 Cataracts, skeletal features, Muscle biopsy shows rimmed vacuoles and muscle pathology and other changes (probably identical to congenital cataracts, facial dysmorphism, and neuropathy syndrome; CCFDN) Sacsin gene: deletions In French-Canadians, or point mutations Tunisia; spastic producing stop codon paraparesis; retinal myelinated nerve fibers; usually early onset
Do not forget the possibility of a metabolic ataxia some are treatable Some dominant ataxias may present in childhood, particularly SCA7, SCA3
analyze the gene for frataxin. When frataxin analysis is negative there is an ever-widening list of less common alternative diagnoses, described below and listed in Table 6.6. Clinical Hint With a childhood-onset cerebellar ataxia without systemic features, consider including a MR brain scan, frataxin analysis, and vitamin E assay as early investigations.
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Ataxia with Vitamin E Deficiency (AVED; OMIM 277460) Although ‘‘metabolic’’, this disorder is considered here because it closely resembles Friedreich’s ataxia. This autosomal recessive ataxia is important because early recognition and treatment may prevent disability. Onset is from childhood to middle age. While often clinically indistinguishable from FA, it is more likely to have associated head titubation, and a retinopathy may be evident later in the course of the disease. Dystonia, deafness, and bladder dysfunction may occur. Cardiac manifestations are less prominent and neurophysiology reveals a lesser neuropathy than is characteristic of FA. The disease is relatively common in North Africa, but has also been reported in other populations. AVED is caused by mutations in the gene encoding the a-tocopherol transfer protein (a-TTP). Patients with this disease absorb dietary a-tocopherol, and incorporate it into chylomicrons normally. Abnormal a-TTP function prevents transfer of a-tocopherol to very low-density lipoproteins secreted by the liver, and therefore impairs delivery to peripheral tissues. Patients have low plasma vitamin E and show abnormally rapid clearance of tocopherol from plasma. Patients should be treated with daily a-tocopheryl acetate supplements to return plasma vitamin E concentrations to those seen in normal subjects. Daily dosage of 0.81g has been used. Specialist advice on replacement therapy is advised. Even after prolonged supplementation, cessation of therapy results in a profound decline in plasma tocopherol concentrations within 72 hours, suggesting that supplementation may need to be continued indefinitely. Although there are few long-term studies it appears that therapy may prevent neurological decline and cause a modest improvement in neurological function.
Unverricht-Lundborg Disease (Baltic Myoclonus, EPM1; OMIM 254800) Unverricht-Lundborg disease is an autosomal recessive disorder characterized by severe, stimulus-sensitive myoclonus, tonic-clonic seizures, and ataxia. Onset is usually between 6 and 15 years of age with myoclonus and seizures, with a progressive ataxia emerging later. Cognitive decline eventually develops, but may be due in part to sedative drug therapy. The condition is considered as one of the progressive myoclonic epilepsies (Chapter 4), although epilepsy is usually milder and prognosis less severe than other causes, such as Lafora body disease. EPM1 is also one of the causes of the heterogeneous Ramsay Hunt syndrome. The disease typically runs a course of 2535 years prior to death, although patients can survive (with disability) to a normal lifespan. EPM1 is caused by mutations in the cystatin B gene, most commonly an expansion of the dodecamer repeat located within the transcription start site. There is no correlation between repeat size and phenotype. Treatment is with anticonvulsants that also suppress myoclonus. Valproate is often used; clonazepam and phenobarbitone are used but are sedative. Levetiracetam has also been suggested.
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Ataxia Telangiectasia (AT; OMIM 208900) Ataxia telangiectasia is an autosomal recessive disorder caused by mutations of the ATM gene on chromosome 11q22-23. Onset is typically between 1 and 3 years of age with progressive cerebellar ataxia. Dystonia, telangiectasias of conjunctivae and skin (after 5 years), and immunodeficiency are more variably present. Later onset does occur and usually is associated with slower neurological deterioration. Oculomotor apraxia and a sensory neuropathy may be evident. There is a predisposition to neoplasia, particularly leukemia, and lymphoma. Serum alphafetoprotein (AFP) is elevated above 10 ng/mL in more than 90% of patients. Testing is not useful before 24 months since normal infants have elevated levels. Increased access to mutational analysis allows earlier direct diagnosis in many patients. Certain ethnic groups have associated mutations and this may guide analysis. In the absence of genetic confirmation, investigations of cellular radiosensitivity, chromosome stability, and immunocompetence may be necessary. IgA and IgE are reduced. Most patients with AT survive into the third decade, but survival beyond the fourth decade is uncommon. No proven therapy exists although patients are often prescribed vitamin E. Supportive therapy is required. Surveillance for malignancy is recommended. Genetic advice is as appropriate for an autosomal recessive condition. Heterozygotes may have a higher incidence of malignancy (especially breast cancer) and coronary heart disease. Other disorders thought to affect DNA/RNA integrity such as Cockayne syndrome and xeroderma pigmentosum may have ataxia or tremor as prominent features.
METABOLIC ATAXIAS Although most metabolic ataxias are genetic and autosomal recessive they can usefully be considered separately because of common features. Most affect organs outside the cerebellum, most have readily identifiable biochemical abnormalities, and many allow specific treatments that fully or partly reverse or arrest neurological abnormalities (Table 6.1).
AUTOSOMAL DOMINANT CEREBELLAR ATAXIAS (ADCAs) Anita Harding suggested a clinical classification of dominant ataxias (Table 6.7). This rudimentary classification is sufficiently robust to withstand the recent elucidation of the genetic basis of the ADCAs. Simply put, the majority of ADCA patients are type I, with the exception of those who develop blindness secondary to a pigmentary maculopathy (type II) and ADCAs of late onset (usually taken as greater than 50 years of age), designated type III. The different genetic loci responsible for the ADCAs are designated spinocerebellar ataxia (SCA)1, SCA2, and so on.
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Table 6.7 Harding Classification of Autosomal Dominant Cerebellar Ataxias Designation
Clinical Features
Genetic Correlate
ADCA I
Ataxic syndrome +/ optic atrophy, ophthalmoplegia, dementia, extrapyramidal features; amyotrophy As above with pigmentary retinal degeneration Pure ataxia of later onset
SCA 1, 2, 3, and others
ADCA II ADCA III
SCA 7 SCA 6 and others
Clinical Features ADCA may have onset at any age, from childhood to the eighth decade. Typically, presentation is with gait ataxia, with the subsequent emergence of limb ataxia and dysarthria. The additional features seen in ADCA I may become evident as the disease progresses. The commonest are ophthalmoplegia and optic atrophy, extrapyramidal manifestations, peripheral nerve involvement, cognitive impairment, and seizures. The late stages of these disorders result in immobility and bulbar failure, although the prognosis may be more benign if ataxia is later in onset. ADCA II/SCA7 is associated with a pigmentary maculopathy, which is often subtle on examination. Clinically, retinal involvement is suspected because of symptoms, initially of yellow-blue color blindness, followed by a decline in visual acuity leading to optic atrophy and blindness. Of the triplet repeat disorders, the SCA7 repeat is the most unstable. Rarely children as young as 18 months may present with a rapidly progressive neurodegenerative or multisystem disorder before manifestations are apparent in the parent. Approximately two-thirds of patients present with ataxia, but a minority may present with visual failure. In general, visual failure is more likely to be the presenting symptom in youngeronset patient with more triplet repeats. In ataxic SCA7 patients the onset of visual symptoms may be delayed for many years after the onset of ataxia. More than 20 genes are implicated in ADCA (Table 6.8). The clinical correlates of each separate genetic entity have been closely studied and most differ only subtly. In clinical practice the phenotypes overlap sufficiently to prevent confident prediction of genotype within any particular family, with a few exceptions. The only value of such predictions is to guide priorities in molecular genetic investigation. There are two main exceptions to this. The first is the recognition of ADCA II the visual failure is a unique association of SCA7. Second, a late-onset pure ataxia (ADCA III) is, in most populations, predictive of SCA6. Investigations Most genetic laboratories adopt the strategy of systematic screening of the commoner mutations in ADCAs. Strategies may be influenced by the ethnic origin of the patient because of the geographical variation in the genetic epidemiology (e.g., SCA2 is common in India, SCA3 in Portugal and Brazil). At the time of writing, most laboratories would include SCA1, SCA2, SCA3, SCA6, and SCA7 (sometimes with SCA12 and SCA17), with the other known genes being sought in some laboratories. Some laboratories
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Table 6.8 Genetic Classification of Autosomal Dominant Cerebellar Ataxias Frequency (but varies with ethnic origin)
Genetic Basis
Gene Product
Increased tendon reflexes Slow saccades, decreased/absent reflexes, frequent neuropathy Nystagmus
<10%
CAG repeat; 6p23
Ataxin-1
15%
CAG repeat; 12q24.1
Ataxin-2
20%
CAG repeat; 14q32
Ataxin-3
Sensory neuropathy Pure ataxia
Probably rare Probably rare
Linked to 16q22 Mutations; 11p13
Late onset, pure ataxia Retinal degeneration, see text Phenotype controversial
15%
CAG repeat; 19p13
Spectrin b chain, brain2 a1A Ca2+ channel
<5%
CAG repeat 3p13
Ataxin-7
?
13q21 CTG repeat
Repeat within untranslated region of transcribed RNA
Probably rare Probably rare
ATTCT repeat; 22q13 Ataxin-10
Probably rare
Mutations; 15q14
Tau-tubulin kinase
Probably rare (but 7% in India)
CAG repeat 5q31
Probably rare
19q13.3-q13.4
Protein phosphatase 2 (PPP2R2B) KCNC3
Probably rare
19q13.4-qter
Designation
‘‘Predictive’’ Features
SCA1 SCA2
SCA3 (MachadoJoseph disease) SCA4 SCA5 SCA6 SCA7 SCA8
SCA9 SCA10
SCA11 SCA12
SCA13 SCA14 SCA15 SCA16 SCA17
Pure ataxia, sometimes with seizures Pure cerebellar syndrome Arm tremor
Early onset, mental retardation Myoclonus, tremor
Probably rare Head and hand Probably rare tremor Dysphagia, intellectual 12% deterioration
Deletion; 3p26-p25 8q23
Protein kinase Cg (PRKCG) ITPR1 Contactin-4
TATA-box-binding protein (TBP) gene Other ADCAs with designations (so far) up to SCA28 have been described, some linked to chromosomal loci Other Autosomal Dominant Ataxias EA1 See text EA2 See text DRPLA See Chapter 8 Prion disease (Gerstmann Straussler syndrome)
See Chapter 3
Rare in West, commoner in Japan
CAG repeat; 6q27
12p13 Mutations; 19p13 CAG repeat; 12p
KCNA1 a1A Ca2+ channel Atrophin 1
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include analysis of the DRPLA repeat, but this diagnosis is normally suggested by clinical clues (see Chapter 8). SCA8 mutations may not be included because of variable penetrance and high incidence in normal controls, which makes interpretation difficult. If visual loss is noted then SCA7 analysis should be performed first. SCA1, 2, 3, 6, and 7 probably account for 5070% of ADCA families in most populations. It is unclear whether any other locus will account for a substantial percentage of the remaining families or whether there will be continuing discovery of ‘‘private’’ loci accounting for single or rare families. The distribution of pathological changes depends on the genetic cause. However, MR brain scan usually demonstrates cerebellar atrophy, with variable brain stem atrophy. Nerve conduction studies will indicate the degree of peripheral nerve involvement. The SCA mutations are not associated with pathology outside the nervous system. Pathophysiology Pathophysiology is dependent on the particular genetic defect, but ADCAs caused by CAG repeats have features in common. CAG repeats and the resulting polyglutamine repeats are discussed in Chapter 1. In SCA1, as in several other polyglutamine diseases, the mutant protein aggregates as an abnormal nuclear inclusion. Aggregations are seen when the repeat exceeds a critical number. In the case of SCA1 this is between 39 and 44 depending on whether the CAG repeat is pure or has CAT interruptions. Nuclear inclusions also contain cellular protein refolding and degradation machinery chaperones, ubiquitin, and proteosomal subunits. It is likely that impaired protein clearance underlies the pathogenesis of SCA1 and some other CAG diseases. Prognosis A retrospective study of SCA1, SCA2, and SCA3 shows that time from onset until wheelchair dependence is a median of 17 years, and a median survival of 2125 years from onset. Progression is slightly faster in SCA1 than in SCA2 and SCA3. Females may have more rapid progression than males. Progression was correlated with repeat length and age of onset to some extent. Progression in ADCA III (often SCA6) patients is more benign, with up to 25 years elapsing before the need for walking aids. Additional features are less common in ADCA III, which can be thought of as a later onset, slowly progressing and purer variant of ADCA I. Genetic Advice Counseling in ADCAs follows similar lines to counseling in HD, when the familial mutation is known. Prenatal and predictive test protocols are similar to HD. The instability of repeat number varies at the different loci and may be important in giving advice. In most situations expansion of the repeat is more likely than contraction, giving rise to the phenomenon of anticipation. SCA6 is the most stable expansion and does not vary between affected family members, although age of onset does vary. In contrast, SCA7 is very unstable and other SCAs have intermediate instability.
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Table 6.9 Episodic Ataxias Type 1 and 2 Genetic basis Onset Duration Provocation Between episodes Associated features
Treatment Prognosis
EA1 (12p13: OMIM 160120) Missense point mutations in potassium voltagegated channel (KCNA 1) 2nd decade Minutes Abrupt postural change, startle, movement No ataxia Neuromyotonia manifesting as limb stiffness, myokymia (muscle rippling) may be clinically evident; hyperhidrosis, seizures Phenytoin, carbamazepine, ? acetazolamide May abate after early adulthood
EA2 (19p13: OMIM 108500) Point mutations or small deletions in CACNA1A gene (allelic with SCA6) 1st or 2nd decade 30 min to 6 hr Emotional or physical stress Downbeating nystagmus
Acetazolamide May have progressive ataxia
Episodic Ataxia Most patients with an ADCA will report variation in ataxia due to fatigue, intercurrent illness, and other factors. In episodic ataxias, patients experience more distinct attacks of incoordination lasting from minutes to hours. Most will be due to episodic ataxia (EA) type 1 or 2, which differ clinically (Table 6.9). Recognition of these autosomal dominant disorders is important, particularly as the patients are likely to be responsive to therapy (see Table 6.9). EA2 does not give rise to a fixed ataxia. It is not clear what proportion of patients with EA2 evolve into a progressive ataxia, although in practice the course of the disease can be estimated from the experience of other family members. Episodic ataxias not linked to the EA1 or 2 loci exist but are rare.
X-LINKED ATAXIAS X-linked ataxias are rare, and the few families reported may have unique disorders. A few families with X-linked sideroblastic anemia and ataxia (OMIM 301310) have been described. The hematological abnormalities are subtle and may be overlooked.
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) A triplet repeat of the Fragile X gene is the commonest cause of inherited mental retardation in males. Affected boys also show some morphological abnormalities in the craniofacies and genitalia, more obviously after puberty. Females may manifest with lesser effects. The range of CGG repeats in the Fragile X gene in the normal population is 10 to 50. Mental retardation is associated with a full mutation in the Fragile X gene sufficient to silence the Fragile X gene promoter, corresponding to greater than 200 CGG repeats. Repeat numbers corresponding to 50200 repeats (a ‘‘premutation’’) were not thought to cause clinical effects, although potentially giving rise to the full mutation in offspring. Recently it has become apparent that females carrying the premutation have a greater incidence of premature ovarian failure.
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It is also apparent that males with the premutation may develop a late-onset neurological disorder, with the core features of gait ataxia and tremor. Additional common, but less frequent, manifestations include cognitive impairment, parkinsonism, neuropathy, and autonomic features. Not all males with the premutation are affected. Clinical features are seen with increasing age, with an incidence of up to 40% by 70, and 50% by 80. Onset before 50 appears rare. Females with the premutation may also be at risk, but manifestations are less frequent and milder. MR brain imaging is useful in diagnosis, with most patients having white matter lesions involving the middle cerebellar peduncle. Additional but less specific abnormalities include cerebral white matter lesions and atrophy. FXTAS is important because its recognition requires discussion during genetic counseling of families identified with Fragile X expansions. In addition, FXTAS may present to neurologists masquerading as a late-onset ataxia, tremor, or parkinsonism (including multiple system atrophy (MSA)). A family history of Fragile X syndrome may not be present to alert the neurologist to the possibility of FXTAS. The combination of testing for the premutation and MR imaging is likely to clarify the diagnosis.
SPORADIC ATAXIA Patients with a sporadic ataxia with adult onset are not uncommon and present a diagnostic challenge. Investigation has to be rigorous to exclude acquired nongenetic causes of ataxia, including multiple sclerosis, primary or metastatic tumors, alcoholism, metabolic disorders, vascular disease, or paraneoplastic syndromes associated with carcinoma of the lung, ovary, or breast. If investigation does not reveal a cause then the patient is classified under the term ‘‘idiopathic late onset cerebellar ataxia’’, which can sometimes progress to MSA. Unlike sporadic chorea, which can signify HD with a negative family history, genetic investigation of an adequately assessed patient with sporadic ataxia seldom reveals a genetic diagnosis. However, some series of sporadic ataxia have yielded some positive genetic results, with Friedreich’s ataxia and SCA6 being the commonest diagnoses, representing 510% of this population. FXTAS may also account for a small percentage. Despite the low yield, analysis of SCA mutations, frataxin mutations and the Fragile X premutation should be considered in these patients, in order to facilitate estimation of recurrence risks. Vitamin E deficiency and the list of ataxias in Table 6.10 should also be considered. A patient with lateonset ataxia without family history and without known mutations can be reassured that genetic risks to offspring are low.
TREATMENT OF ATAXIAS The treatment of ataxias falls into two categories. The majority of ataxias have no disease-modifying therapies. Supportive treatment is required and drug therapies have modest value if any. Less commonly the metabolic basis of an ataxia is revealed by investigation and in some cases this allows intervention,
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Table 6.10 Relevant Investigations in Adult-Onset Sporadic Ataxia Suspected Cause
Investigation
Comments
All patients
A good history and examination
MS Alcohol
MR brain Mean corpuscular volume; gamma glutaryl transferase MR brain MR brain Anti-gliaden and other antibodies; gut biopsy Paraneoplastic antibodies; scans of chest and pelvis and mammography Nerve conduction studies
Include drug history and exposure to prion risk factors (e.g., growth hormone) Usually evident on history Heelshin ataxia often prominent
Brain neoplasm Vascular disease Celiac disease Paraneoplastic ataxia Sensory ataxia Ataxia associated with thyroid disease
Frequency of celiac-associated ataxia is controversial History usually <1 year and rarely >2 years Usually suspected from neurological examination
Thyroid function and autoantibodies
which may modify the course of disease (Table 6.1). These ataxias, therefore, assume particular importance despite their rarity. Other ataxias have no disease-modifying therapies, but there remain opportunities to help. Associated spasticity, myoclonus, and seizures may require drug therapy. The tremor of ataxia may be disabling. Propranalol or clonazepam may be tried but results are usually disappointing. Treatment trials for the genetic forms of ataxias are under way and referral may be appropriate. There is sometimes clinical overlap between the progressive ataxia of SCA6 and the episodic ataxia of EA2, which are allelic disorders. As with EA2, some patients with the SCA6 expansion appear to have a modest response to acetazolamide. Patients benefit from access to a multidisciplinary neurorehabilitation team. Walking aids may be required; a rollator frame may be useful when walking becomes difficult.
BIBLIOGRAPHY www.geneclinics.org Abele M, Burk K, Schols L, Schwartz S, Besenthal I, Dichgans J, Zuhlke C, Riess O & Klockgether T (2002). The aetiology of sporadic adult-onset ataxia. Brain, 125, 961968. Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A & Koenig M (1996). Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med, 335, 1691175. Schols L, Bauer P, Schmidt T Schulte T & Riess O (2004). Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis, Lancet Neurol, 3, 291304.
Chapter 7 Disorders of Myelin: Multiple Sclerosis and Leukodystrophies Simon R. Hammans
INTRODUCTION Disorders of CNS myelin predominantly affect the white matter of the brain and spinal cord. Some disorders may also affect peripheral nerve myelin. This chapter will focus on the leukodystrophies, which are inherited, progressive single-gene disorders primarily affecting myelin, and multiple sclerosis (MS), a demyelinating disease whose cause remains largely unknown, although a proven genetic contribution has been identified.
LEUKODYSTROPHIES Leukodystrophies are a heterogeneous group of disorders giving rise to impaired myelination and/or demyelination. Clinical presentation reflects the predominant involvement of cerebral white matter, with motor manifestations such as spasticity and ataxia being common. Age of onset, typically in childhood, varies from birth to adulthood. Imaging techniques are often used early in the investigation of a CNS disorder. In this situation MR imaging can usually confirm or exclude a leukodystrophy. The pattern of cerebral white matter abnormality may further refine the differential diagnosis. The epidemiology of leukodystrophies in different populations is incompletely studied, but it appears that adreno-, metachromatic, and Krabbe leukodystrophy are the commonest, perhaps together affecting 10/100,000 births. These are summarized in Table 7.1 and contrasted with other leukodystrophies. Despite refinement of the diagnostic techniques (using MR imaging and biochemical and genetic analysis) there remains a significant proportion of patients with leukodystrophies without a specific diagnosis. The three commonest leukodystrophies are described in more detail below.
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Table 7.1 Leukodystrophies Inheritance
White Matter Involvement on Cerebral MR*
Diagnostic Test (primary test in bold)
Metachromatic leukodystrophy (250100) Krabbe leukodystrophy (245200)
AR
Frontal and diffuse
AR
Parieto-occipital predominance
Adrenoleukodystrophy (300100)
X-linked dominant
Occipital predominance
Canavan disease: aspartoacylase deficiency (271900)
AR
Diffuse pattern involving cortex
Pelizaeus-Merzbacher disease: proteolipid protein 1 (312080; allelic to SPG2)
X-linked; females are more likely to manifest in families with more mildly affected males
Diffuse, involving brainstem
Arylsulfatase A assay; ARSA mutations Galactocerebrosidase assay; galactosylceramidase gene mutations Very long-chain fatty acid assay; ABCD1 mutation testing Urinary N-acetylaspartylglutamate (requires mass spectrometry); ASPA gene mutations Genetic diagnosis by PLP1 analysis
Cockayne syndrome (216400)
AR
Diffuse; basal ganglia calcification
UV sensitivity assay
Presentation See text See text
See text
Often Ashkenazi Jewish; presents at 35 months with developmental delay, hypotonia, head lag, and macrocephaly Onset in infancy with nystagmus, hypotonia, cognitive impairment, with progression to spasticity, dystonia, and ataxia; often survival to adulthood Short stature, typical facies Continued
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Disease Gene (OMIM)
Inheritance
White Matter Involvement on Cerebral MR*
Diagnostic Test (primary test in bold)
Alexander disease: glial fibrillary acidic protein (203450). Leukoencephalopathy with vanishing white matter: translation initiation factor eIF2B (603896)
Usually de novo dominant mutations
Frontal (with periventricular T1 hyperintensity)
AR
T2-weighted hyperintensity replaced by cystic lesions
Pathology shows Rosenthal fibers; GFAP mutations (research) No assay; MRI often diagnostic: genetically heterogeneous
Sudanophilic leukodystrophy (272100)
?
Heterogeneous: pathological diagnosis
Presentation Infantile macrocephaly; progressive spasticity and dementia Onset usually in childhood with ataxia. Progressive but exacerbations caused by stresses; survival until adulthood Exclude ALD and PelizaeusMerzbacher disease
*MR is more sensitive than CT imaging. Imaging may not be characteristic during the first 2 years (period of myelin maturation). CT may be required if calcification suspected. Other disorders with prominent cerebral white matter abnormalities on MR brain scans: CADASIL, homocysteinuria, mitochondrial disease (MNGIE, MELAS), cerebrotendinous xanthomatosis, Refsum’s disease, phenylketonuria, congenital muscular dystrophy, and non-genetic diseases (MS, post-encephalitic, radiation-induced, etc.)
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Table 7.1 Leukodystrophies—cont’d
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Metachromatic Leukodystrophy (MLD; OMIM 250100) MLD is autosomal recessive and is usually caused by deficiency of arylsulfatase A, which is usually, but not always, caused by mutations in the arylsulfatase A (ARSA) gene on chromosome 22q13.31. It can manifest at almost any age, with adult onset being least common. In the typical form early development is normal, but in the second year of life onset is with motor symptoms, rigidity, mental deterioration, and sometime seizures. A demyelinating neuropathy causes reduced tendon reflexes. In late-onset forms the onset may be with behavioral or psychiatric symptoms, with motor symptoms only appearing later. Investigations MR brain scan shows characteristic changes of a diffuse and usually symmetrical demyelination, which may initially be confined to the periventricular areas. On suspicion of the diagnosis, arylsulfatase A activity can be measured in leukocytes or cultured skin fibroblasts. Beware of pseudodeficiency, which is relatively common in the population (1015%), but is not associated with disease. It is therefore necessary to corroborate the diagnosis by identifying metachromatic granules in urine, by showing metachromasia in a nerve biopsy or by metabolic studies of fibroblasts. Nerve conduction studies show a demyelinating neuropathy and CSF protein is high. Many different mutations have been found in the ARSA gene, the two commonest accounting for half of mutant alleles. Several polymorphisms have also been described. Pathophysiology The defective enzyme is a lysosomal hydrolase. Deficiency causes accumulation of galactosphingosulfatides that are strongly metachromatic and doubly refractile in polarized light. Accumulations are found in the white matter of the central nervous system, in the kidney, and in the urinary sediment. Multiple sulfatase deficiency (Austin disease; OMIM 272200) can also result in arylsulfatase A deficiency, along with other enzyme deficiencies. This gives rise to a phenotype suggestive of both MLD and mucopolysaccharidosis, which may include icthyosis and coarsened facial features. Rarely, mutations in the arylsulfatase activator protein (prosaposin; OMIM 176801) can cause earlyonset forms of the disease. Prognosis Typically, disease with onset before 30 months results in a fatal outcome before 510 years of age. Later-onset disease follows a slower course but leads to disability and eventually a fatal outcome. Adult-onset disease, presenting with mental changes, may have a course over several decades. Treatment There is no proven treatment. Bone marrow transplantation may delay progression in some cases.
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Genetic Advice Because of the poor prognosis, parents who have had a previous child with MLD may request prenatal testing. The arylsulfatase A-deficient forms of MLD can be diagnosed prenatally using cells obtained either by amniocentesis or by chorionic villus sampling. Enzymatic analysis using synthetic substrates is usually adequate, if it can be established that the pseudodeficiency gene is not present. The cerebroside sulfate loading test can be used if there is a possibility of a low enzyme level due to pseudodeficiency. Prenatal testing can be performed on a genetic basis if the familial mutations have been identified. Carrier frequency is approximately 1/150.
Krabbe Disease (OMIM 245200) Krabbe disease is an autosomal recessive leukodystrophy caused by mutations in the galactosylceramidase gene on chromosome 14q31. The majority (90%) of patients appear normal in early infancy but prior to 6 months show irritability, developmental delay, and spasticity. Rapid progression leads to death in a decerebrate state at an average of 13 months. The remaining 10% of patients have onset between 6 months and adulthood. Late-onset cases usually present with unsteadiness or spastic paraparesis. Rarely a peripheral neuropathy may be the initial feature.
Investigation MR brain scan shows white matter involvement symmetrically, and particularly in the periventricular parieto-occipital regions. The changes may be subtle in milder, late-onset cases. Biochemical diagnosis is by measuring galactosylceramidase activity (GALC: 05% of normal) in leukocytes isolated from whole heparinized blood or cultured skin fibroblasts. Carrier testing by measurement of galactosylceramidase activity in leukocytes or cultured skin fibroblasts is unreliable due to the wide range of enzymatic activity observed in carriers and non-carriers. Genetic investigation is feasible after the diagnosis has been made biochemically to facilitate identification of heterozygotes and to allow genetic prenatal testing. Five common mutations account for approximately 60% of mutant alleles. Pathophysiology Deficiency of GALC impairs cleavage of the galactose moiety from galactosylceramide. This leads to accumulation of galactosylceramide within multinucleated macrophages of the white matter, forming globoid cells. Psychosine, a metabolite of galactosylceramide, also accumulates and is toxic to oligodendroglia. This ultimately results in damage to the white matter of both peripheral and central nervous systems.
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Prognosis Whereas the average age of death of infantile-onset cases is 13 months, later-onset cases vary in prognosis, even within families, and prediction at onset is difficult. Treatment There is no specific treatment of symptomatic infants. Presymptomatic infantile patients and later-onset patients have been given bone marrow transplants, with apparent slowing of progression. The long-term outcome is not known. Genetics Counseling is for an autosomal recessive disorder. Prenatal testing can be performed genetically or biochemically. In biochemical prenatal diagnosis, it is wise to measure galactosylceramidase activity in the parents, to exclude a low activity associated with the heterozygote state, which might otherwise result in a heterozygote fetus being thought to be affected.
Adrenoleukodystrophy and Adrenomyeloneuropathy (ALD/AMN; OMIM 300100) ALD/AMN is an X-linked disorder due to mutations in the ATP-binding cassette (subfamily D, member 1) gene (ABCD1) on chromosome Xq28. It can have different presentations even within the same family. ALD/AMN refers to a spectrum of disease, from predominantly cerebral manifestations (ALD) to AMN predominantly affecting the spinal cord and peripheral nerves: Childhood cerebral adrenoleukodystrophy (ALD). Presenting in boys (average age 7 years). Signs of attention deficit disorder followed by behavioral disturbance, dementia, visual loss, and incoordination. Adrenal failure may precede or follow neurological symptoms. Adolescent or adult-onset ALD. Older male children or male adults with adrenomyeloneuropathy (AMN), typically with progressive spastic paraparesis, sphincter disturbances, and axonal neuropathy with variable adrenal failure (70% of cases) and cognitive manifestations (45%). This is the commonest form. Males with adrenocortical failure (most will go on to develop neurological features). Adult females with AMN features described above, but without adrenocortical impairment. Other features of ALD/AMN include thinning of scalp hair. Occasionally ataxia is prominent and the presentation resembles that of a spinocerebellar ataxia. Overt or subclinical hypogonadism is common. Up to one half of all female heterozygotes show neurological symptoms resembling those of AMN. The onset is usually in the fourth decade, symptoms
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are milder, and the progression is slower than in male patients with AMN. Very rarely, females develop rapidly progressive cerebral demyelination. Adrenocortical dysfunction in female carriers has been reported, but is usually normal. Scanty scalp hair can also be found in heterozygotes. Clinical Hints ALD/AMN may present as progressive spasticity resembling hereditary spastic paraplegia. ALD/AMN may present as progressive ataxia resembling a spinocerebellar ataxia. All males with ALD/AMN should have periodic assessment of adrenocortical function.
Investigations In most patients with ALD, cerebral MRI typically shows extensive demyelination in the occipital periventricular white matter, and lesser abnormalities in about one half of AMN patients. Nerve conduction studies show an axonal neuropathy. All male patients should have adrenocortical function measured. Assay of very long-chain fatty acids (VLCFAs) in blood in males is diagnostic. Abnormalities are found in 99% of males and 85% of female heterozygotes. The assay measures plasma concentrations of C26:0 and the C24:0/ C22:0 and C26:0/C22:0 ratios. Skin fibroblast culture and assay is more sensitive and is used for confirmation of diagnosis in males, but remains normal in 510% of female heterozygotes. More than 450 different mutations have been identified in the ABCD1 gene and genetic analysis is not used routinely in diagnosis. However, genetic investigation is feasible after the diagnosis has been made biochemically to facilitate identification of heterozygotes and to allow genetic prenatal testing. Pathophysiology Pathogenesis is incompletely understood. The ABCD1 gene is a member of the ABC transporter superfamily and is located in peroxisomal membranes. ALD/ AMN is likely to arise from failure of transport across peroxisomal membranes, which, among other effects, disturbs VLCFA metabolism. ALD is known to invoke a large inflammatory reaction within the brain. It may involve two steps; first a degradation of myelin due to its instability caused by an excess of VLCFAs, followed by an inflammatory reaction that destroys the myelin. Prognosis Prognosis differs according to presentation. Childhood ALD results in severe disability and then in death between 1 and 10 years after onset. Later onset ALD also has a poor prognosis. AMN has a variable course, often with slow progression over decades. At worst it may lead to disability and death in middle life, especially if cerebral involvement develops. Unrecognized adrenocortical deficiency can also be fatal.
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Treatment Adrenocortical insufficiency should be monitored periodically and treated if necessary. The results of dietary treatment with supplements (Lorenzo’s oil) so far have been disappointing, although studies indicate it may delay symptoms in neurologically asymptomatic patients. Bone marrow transplants have been shown to stabilize or improve neurological function in selected patients. Genetic Advice Counseling is for an X-linked disorder with significant manifestation in females. It is important to know that within a family there may be wide variability in onset and severity. The same family may contain members with mild AMN phenotypes as well as others with a severe ALD phenotype. Asymptomatic boys at risk may be identified through genetic testing so that early treatment of problems such as adrenocortical failure is facilitated. Prenatal testing is possible for pregnancies of carrier women. The risk of having an affected male is 25% (or 50% if the fetus is known to be male). The usual procedure is to first determine fetal sex through a karyotype of fetal cells obtained by chorionic villus sampling (CVS) or amniocentesis. If the fetus is male, then further genetic or biochemical analysis to determine its disease status may be indicated. Rare false-negative biochemical testing for VLCFA has been reported.
MULTIPLE SCLEROSIS (MS; OMIM 126200) Multiple sclerosis may have onset at almost any age but is usually a disease of young adults, with first symptoms typically appearing between ages 20 and 40. Three percent of patients have onset before 18; and approximately 10% after the age of 50. Typically the disease starts with episodes (relapses) of neurological dysfunction affecting the spinal cord, brainstem, cerebral hemispheres, or optic nerves. Usually each episode at least partially remits, but eventually permanent neurological impairment is established, with most patients then experiencing progression in disability. In about 10% of cases, the disease is progressive from onset. Traditionally, MS has been thought of as an inflammatory disorder that affects CNS myelin, but it is now clear that axonal damage is also sustained. The white matter of the brain and spinal cord are predominantly affected. The most commonly used diagnostic test is the MR brain scan. This shows characteristic changes in cerebral white matter in over 90% of patients, although corroboration by clinical findings or other investigations is necessary, especially in older patients. The etiology of MS is likely to be heterogeneous. Genetic, environmental, and immune factors are all likely to contribute. The prevalence of MS varies by gender, geography, and ethnic background. Females are affected about twice as commonly as males. High-risk areas include northern and central Europe, northern USA and Canada, parts of the former Soviet Union, southeastern Australia, and New Zealand. In any geographic region, higher latitudes have greater prevalence. Ethnic background plays a major role in susceptibility. For example, MS is very rare in black South Africans and uncommon in Asians.
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Table 7.2 MS: Risks to Siblings and Children of Affected Individuals
Approximate Risk (%) General population First-degree relative Dizygotic twin Second-degree relative Third-degree relative Monozygotic twin Adopted first-degree relative Half sibling Offspring of conjugal MS
Relative Risk to General Population
0.2 35 35 1 1 38 0.2 1.3 29.5
% Predicted Genetic Sharing with the Proband
1 1525 1525 5 5 190 1 6.5 147.5
0 50 50 25 12.5 100 0 25 50
Modified from Sadovnick AD, Dircks A, & Ebers GC (1999). Genetic counseling in multiple sclerosis: risks to sibs and children of affected individuals. Clin Genet, 56,118122, with kind permission of Blackwell Publishing. The data refer to lifetime risks appropriate for a northern European population living in a temperate climate
Genetic susceptibility has been studied at length and single high-risk predisposing genes are unlikely to play a role. Even monozygotic twins are usually discordant. An association with major histocompatibility complex (MHC) alleles DR15 and DQ6 (each of which have multiple variants) has been shown in population studies, but the association is too weak to be useful in genetic counseling. Systematic genome-wide searches have not identified other major susceptibility genes to date.
Genetic Advice in Multiple Sclerosis Depending on the amount of genetic ancestry shared, family members of patients with MS have an increased risk of developing MS. Table 7.2 gives guidance to the approximate risk derived from epidemiological studies. The risks given will require adjustment depending on the age of the relative being considered. The median age of onset is approximately 30 years. Genetic risks are greater if the proband has early-onset disease. Risks are also greater if
Table 7.3 MS: Risks for Brothers and Sisters where Sibling and/or Parent is Affected, Adjusted for Age of Onset and Parental Status Risk (SE)% for Brothers Age of Onset in Proband <20 2130 3140 >40
One Parent with MS 12.7 (9.6) -
Risk (SE)% for Sisters
No Parent with MS 2.7 1.2 1.6 0.5
(2.1) (0.5) (0.6) (0.4)
One Parent with MS 50.0 (25.0) 15.3 (10.3) 7.3 (5.0) -
No Parent with MS 7.7 3.5 2.5 1.4
(2.8) (0.7) (0.6) (0.6)
SE = standard error Tables 7.2 and 7.3 modified from Sadovnick AD, Dircks A & Ebers GC (1999). Genetic counseling in multiple sclerosis: risks to sibs and children of affected individuals. Clin Genet, 56, 118122, with kind permission of Blackwell Publishing
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Table 7.4 Genetic Conditions that can Mimic MS Clinically CADASIL (Chapter 13)
Late-onset leukodystrophies (see text) ALD/AMN (see text) Episodic and other ataxias (Chapter 6) Hereditary spastic paraplegias (Chapter 10) Familial cavernous hemangioma (Chapter 9) Acute intermittent porphyria (Chapter 11)
MR brain scan appearance may be similar; investigation to exclude this possibility may be necessary Autosomal recessive X-linked Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant
more than one relative is affected. Table 7.3 can be used for predicting risks to siblings allowing for age of onset of proband and for parental MS status. Rare families exist where inheritance appears to be autosomal dominant. Care should be taken to exclude the autosomal dominant conditions in the differential diagnosis of MS (see Table 7.4). To date, no high-risk genes have been identified in MS and thus these rare apparent dominant families could be suitable for genetic research. Leber’s hereditary neuropathy may cause an MS-like illness that may satisfy current diagnostic criteria for MS (Harding’s syndrome). Typically patients are female and most commonly carry the mtDNA 11778 mutation. Symptoms usually include significant visual loss.
BIBLIOGRAPHY www.geneclinics.org Sadovnick AD, Dircks A & Ebers GC (1999). Genetic counseling in multiple sclerosis: risks to sibs and children of affected individuals. Clin Genet, 56, 118122.
Chapter 8 Movement Disorders Thomas T. Warner
INTRODUCTION Movement disorders are defined as disturbances of the nervous system in which there is either an excess (hyperkinesia) or paucity (hypokinesia) of voluntary or automatic movements, not associated with weakness or spasticity. At a practical level they can be simply divided into parkinsonism and the dyskinesias. Even to the trained neurologist, the terminology and diagnosis can be confusing. The diagnosis is usually clinical, but the difficulties can arise when classifying the movements. Chorea can be difficult to distinguish from myoclonus, dystonia from athetosis, tics from stereotypies, and so on. Many of the movement disorders have a genetic basis and so it is vital that the correct clinical diagnosis is made to allow appropriate genetic advice and testing. Most movement disorders are associated with abnormalities of basal ganglia function. These are the group of gray matter nuclei that lie deep within the brain, comprising the caudate nucleus and putamen (known as the striatum, which also includes the nucleus accumbens of the limbic system), the pallidum (made up of lateral and medial parts, the latter including the substantia nigra pars reticulata), the subthalamic nucleus, and the main pigmented part of the substantia nigra, known as the pars compacta. There are some exceptions to this general rule. Myoclonus and many forms of tremor do not appear to be directly related to basal ganglia pathology. In addition, the anatomical origin of tics is not known, although the basal ganglia and limbic structures have been implicated. The following sections will describe a pragmatic approach to the clinical diagnosis and investigation of the movement disorders. Although there are roughly equal numbers of patients with parkinsonism and dyskinesia, there are far more genetic causes of dyskinesia than parkinsonism and these will be described first, with particular emphasis on Huntington’s disease.
DYSKINETIC MOVEMENT DISORDERS The most critical question when assessing a dyskinesia is to determine the category of the involuntary movement, e.g., chorea, dystonia, myoclonus, 102
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tremor, and so on. The rhythmicity, speed, duration, pattern, and induction (e.g., action, exercise, or stimulus induced) of the movements are important, as are the complexity of the movements, whether they can be suppressed by volition or sensory tricks, and whether the movements are accompanied by sensations such as restlessness. In addition, the body parts involved must be determined.
Chorea Chorea refers to involuntary, irregular, purposeless, non-rhythmic, abrupt, unsustained movements that flow from one body part to another. Classic choreiform movements are seen in Huntington’s disease, in which the brief and rapid movements are irregular and occur randomly in time. When choreiform movements are infrequent, they appear as isolated small-amplitude, brief movements, slower than myoclonus, but sometimes indistinguishable. When chorea is more pronounced, the movements occur almost continually, presenting as a pattern of involuntary movements flowing from one site to another. Random choreic movements can be partially suppressed, and the patient can often disguise them by incorporating them into semipurposeful movements.
Huntington’s Disease (OMIM 143100) Huntington’s disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by motor disturbances (usually chorea) plus variable emotional, behavioral, or psychiatric abnormalities, leading to dementia. It is regarded as a prototype neurogenetic disease stimulating the development of protocols for genetic counseling, and presymptomatic and prenatal testing of autosomal dominant diseases. HD has a prevalence of 47 per 100,000 with some regional variation, probably due to local founder effects. This relatively low figure hides the far greater number of family members at risk of developing HD. The disease can be a source of great fear and burden within families as its late onset and variable presentation mean that an affected individual has often had children before HD develops. Clinical Features HD can become clinically evident from early childhood to late adulthood, although the peak age of onset is around the age of 40 years, with about 25% of individuals displaying first symptoms after the age of 50. Around twothirds present with neurological manifestations, whilst the other third present with psychiatric or behavioral symptoms. It is classically associated with progressive emotional, cognitive, and motor disturbances. Early, relatively subtle symptoms may precede outright disease by several years and include mild personality changes, forgetfulness and distractibility, clumsiness, and gradual development of brief fidgety movements of the distal extremities. As time
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passes the chorea, which is present in over 90% of individuals, becomes more evident, affecting the limbs, trunk, and face. Movements flow into one another and appear slower and more writhing. Other movement disorders can develop, including bradykinesia, rigidity, and dystonia. Gait is affected and can be almost dance-like and disjointed. In advanced disease there is also postural instability, motor impersistence (patients often drop objects), poor tongue and diaphragm control, dysphagia, and dysarthria. Characteristic oculomotor abnormalities, with impersistence of gaze, difficulty initiating saccades, and slow and hypometric saccades, can be seen in up to 75% of symptomatic individuals. Emotional and behavioral problems may develop with time, including irritability, impulsiveness, lack of self-control, and loss of interest. Psychiatric disturbances such as anxiety, depression, agitation, obsessive-compulsive disorders, and hostile outbursts and psychosis are common. Suicide occurs in up to 12% of individuals. These behavioral problems are associated with declining cognitive function with increasing difficulty in memory retrieval, concentrating, and absorbing new information, and impaired judgment and ability to plan and execute purposeful movements (apraxia). Juvenile HD accounts for around 10% of cases. It has onset before 20 years and a characteristic phenotype with more aggressive course. Cognitive decline is more apparent and rapidly progressive. The motor abnormalities take the form of rigidity and bradykinesia rather than chorea. The terms akinetic-rigid HD or Westphal variant have been used. Epileptic seizures and myoclonus, which are rarely seen in adult-onset HD, are more common. Differential Diagnosis and Investigations The presence of chorea and cognitive changes in an individual with a family history compatible with autosomal dominant inheritance strongly suggests HD. The diagnosis can be confirmed by direct genetic analysis after appropriate counseling. Patients should be given information about HD and the implications that a positive test will have on both themselves and their family. The presence of chorea alone with no family history prompts other investigations, although frequently this leads to a diagnosis of HD. Most patients diagnosed as senile or benign hereditary chorea prior to the identification of the HD gene subsequently have been shown to carry the HD expansion. The differential diagnosis and suggested investigations for an individual with chorea are presented in Table 8.1. In practice, only Huntington disease-like 1 and 2 (HDL-1 and 2), DRPLA, choreoacanthocytosis, and neuroferritinopathy closely mimic HD. Cranial imaging in HD with CT or MRI scans may reveal bilateral atrophy of the caudate and putamen in moderately advanced cases. There may also be evidence of cortical atrophy in fronto-temporal regions with ventricular enlargement. These findings correlate with the histopathological findings of selective death of medium spiny neurons within the striatum and neuronal degeneration in the frontal and temporal lobes. In general, cranial imaging is only carried out if a symptomatic individual does not have the HD gene and there is suspicion of another neurodegenerative disorder.
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Table 8.1 Differential Diagnoses for HD and Chorea Disease (OMIM) Positive family history Huntington disease-like 1 (603218) Huntington disease-like 2 (606438) Wilson’s disease (277900) DRPLA (125370) Choreoacanthocytosis (200150)
Ataxia telangiectasia (208900)
Xeroderma pigmentosum
Spinocerebellar ataxia 17 (607136) Benign hereditary chorea (118700) No family history Sydenham’s chorea
Systemic lupus erythematosis (SLE) Polycythemia rubra vera Hyperthyroidism Hypocalcemia Drug-induced
Distinguishing Clinical Features
Investigations
AD, progressive prion disease with features that overlap HD AD, often indistinguishable from HD
Expanded octapeptide repeat in prion protein gene Expanded CTG repeat in JPH3 gene
AR, mixed movement disorder, liver disease, Kaiser-Fleischer rings AD, ataxia common, seizures and myoclonus in younger patients AR, mixed movement disorder, cognitive and affective problems, axonal neuropathy AR, ataxia, mixed movement disorder, skin and conjunctival telangiectasia, neuropathy, mental retardation
Serum copper and ceruloplasmin, 24-hr urinary copper, liver biopsy Expanded CAG repeat in gene for atrophin 1 Acanthocytes on blood film. Mutation in CHAC gene
AR, skin sensitivity to light, ataxia, chorea, deafness, mental retardation, neuropathy, seizures, spasticity AD, chorea, ataxia, dementia, and psychiatric disturbance AD, non-progressive chorea without dementia Self-limiting but can relapse, associated with b-hemolytic streptococcal infection Rash, fever, arthralgia
Raised a-fetoprotein, impaired immunity (IgA/G). Sequence analysis of ATM gene or immunoblot of ATM protein Chromosomal fragility studies. Cell complementation studies. Screening of XPA and XPC genes SCA17 gene test Mutations in thyroid transcription factor-1 (TTF1) ASOT
ANA, anti-dsDNA antibodies FBC, packed cell volume Thyroid function test Serum calcium History of exposure to drugs: amiodarone, dopaminergic agents, neuroleptics, carbamazepine, anticholinergics
Prognosis In advanced disease the combination of dementia and severe motor dysfunction leads to loss of ability to walk, communicate, and self-care. Life-threatening complications result from falls, poor nutrition, choking, and aspiration pneumonia. For adult-onset HD, the median survival time is 1518 years after onset. Juvenile HD has a more aggressive course and mean duration of 810 years. Genetics and Pathophysiology HD is caused by a mutation in a gene that is transmitted as an autosomal dominant trait with almost complete penetrance. Anticipation occurs in HD,
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with increasing severity and decreasing age of onset in successive generations. Anticipation occurs more commonly in paternal transmission of the mutated allele, with a greater proportion of cases of juvenile HD being of paternal origin. New mutations have been described, but at very low frequency, and population studies suggest the presence of founder mutations. The gene for HD (IT15) maps to the short arm of chromosome 4 and encodes the protein huntingtin. The HD gene encompasses 67 exons and contains a trinucleotide repeat (CAG) in exon 1 that is expanded in individuals with HD. The CAG repeat length is highly polymorphic in the population and normal size varies from 10 to 35 repeats, with most common alleles between 15 and 20 repeats. In HD this is expanded to 36 or more repeats (36 to 121). Huntingtin contains an extended polyglutamine tract at its amino terminus, encoded by a corresponding CAG repeat in the gene. Expansions of 40 or more repeats are associated with full penetrance of HD, whilst an individual with 3639 repeats has reduced penetrance and may not develop HD. Repeats length of 2735 repeats are referred to as intermediate alleles, as an individual with these is not at risk of developing HD but may be at risk of having a child with an allele in the abnormal range. There is some correlation between the number of repeats and age of onset of symptoms, particularly for large expansions. Individuals with adult onset of symptoms usually have an allele size that ranges from 36 to 55 repeats. Repeat sequences of 60 or greater are normally associated with juvenile HD. Expanded CAG repeats are not stable and tend to become larger from generation to generation, providing a molecular explanation for the genetic anticipation observed. This instability is greatest during spermatogenesis, leading to the paternal effect on anticipation. The protein is ubiquitously expressed and is present in neurons, although its function is unknown and the mechanisms by which mutant huntingtin causes selective death of medium spiny neurons in the striatum and cortical neurons are unknown. There is a toxic gain of function, which means that the abnormal protein interferes in some way with normal cellular functioning. The CAG repeat is translated into an expanded polyglutamine tract at the N terminus of the protein, which appears to form abnormal inclusions within the nucleus of neurons in association with other proteins. These inclusions may be the result of the cells attempting to inactivate the toxic huntingtin protein or be integral to the pathogenic mechanisms. Work in cell and animal models has implicated a number of potential mechanisms by which the expanded glutamine tract and inclusions can lead to cell death, including triggering of apoptotic pathways, altered proteosomal function, reduced transcription of other genes, and a deleterious effect on axonal transport. Treatment There is no curative treatment for HD at present, although increasing understanding of its pathogenesis and study of transgenic animals have led to optimism for therapies in the future. Drugs may be used to alleviate chorea or treat behavioral or psychiatric symptoms. Chorea should only be treated if functionally disabling and can respond to neuroleptic agents (e.g., sulpiride, haloperidol, quetiapine), benzodiazepines (clonazepam), or monoamine depleting agents such as tetrabenazine. Neuroleptic use may be complicated by the
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development of tardive dyskinesia and parkinsonism. Neuroleptics may also be used to control psychiatric symptoms such as agitation, hallucinations, or delusions. Supportive measures should also be employed. Speech therapy can aid communication and dietary advice may be needed to increase calorie intake as patients with generalized chorea may require up to 5000 calories per day. Nursing care in later stages is needed and for advanced HD residential care is often the best option. Striatal transplants for HD are currently being performed on an experimental basis and their value will become clearer in the coming years. Therapeutic trials have also commenced as the molecular pathogenesis of HD has been studied, including use of creatine, riluzole, NMDA receptor antagonists, and neurotrophic factors, amongst other agents. At present none has been demonstrated to be efficacious. Genetic Advice and Testing HD is inherited as an autosomal dominant trait with complete penetrance for CAG repeats greater than 40. Thus each child of an affected parent has a 1 in 2 chance of inheriting the disease gene. Those who do not inherit the disease gene do not develop HD and cannot pass it on to their offspring. Those who do inherit the mutated gene will develop HD, assuming they live long enough. Analysis has allowed risks to be estimated for healthy first- and second-degree relatives at risk of HD. Table 8.2 shows the risk for a healthy first-degree relative at 50% prior risk of HD carrying the HD gene at different ages. Although most individuals diagnosed with HD have an affected parent, the family history may be negative for the following reasons: 1. Failure to recognize the disorder in family members. 2. Early death of a parent before the onset of symptoms. 3. Presence of an intermediate allele (2735 CAG repeats) or a mutant allele with reduced penetrance (3639 CAG repeats) in an asymptomatic patient. 4. Late onset of the disease in the affected patient. Table 8.2 Probability of First-Degree Healthy Relative Carrying HD Gene at Different Ages Age (years)
Probability of Carrying HD Mutation (%)
20 25 30 35 40 45 50 55 60 65 70
49.6 49 47.6 45.5 42.5 37.8 31.5 24.8 22.1 12.8 6.2
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Predictive Testing. Prior to the isolation of the HD gene, linkage analysis using genetic markers in close approximation to the HD gene was used to predict the likelihood of an individual at risk from HD of having actually inherited the region of chromosome 4p from the affected parent. This testing is less precise than direct mutation analysis and required blood samples from a number of family members, both affected and unaffected. This method has been superseded by direct gene testing. For those individuals requesting predictive tests, it is critical to have confirmed the molecular diagnosis of HD in a sample from an affected relative whenever possible, as a number of dominantly inherited neurodegenerative disorders can mimic HD. Individuals at risk from HD should be given access to specialist advice about the disorder with discussion of the options of predictive and prenatal testing. Protocols for predictive testing recommend two separate interviews before testing. Those considering testing should be given sufficient information about HD, and advice regarding their potential level of risk, the limitations of genetic testing (positive results do not predict age of onset or severity of HD), and the possible implications of the results including positive, negative, and inconclusive (alleles size 3639 CAG repeats) findings. The pre-test counseling should cover the mechanism and timetable for performing the test. In addition, confidentiality concerns, possible effects on employment, insurance, and mortgages, the impact of the result on family and partners, and family planning should be discussed. The individual is also encouraged to be accompanied by a relative, partner, or close friend throughout the counseling sessions. Pre-test screening should aim to identify those individuals with or at risk from depression or other psychiatric conditions and, in some cases, it may be appropriate to postpone testing until psychiatric advice or treatment has been obtained. Follow-up is recommended regardless of the result. It is generally accepted that presymptomatic testing should not be performed in children under the age of 18. Individuals should have the right to make their own decisions on testing when they reach the age of majority. Prenatal Testing. Direct prenatal mutation analysis has unique ethical issues. It is performed by analysis of DNA extracted from chorionic villus sampling (CVS) at about 1012 weeks gestation or fetal cells obtained by amniocentesis at 1618 weeks gestation. The finding of a positive result indicates that a parent also carries the mutation. In general parents are encouraged to undergo predictive testing themselves in this situation, which will then allow direct testing for the expanded CAG repeat. In some cases, however, parents wish to determine the risk to the fetus without knowing their own risk. In these circumstances, use of linked genetic markers on chromosome 4p can be used to determine whether the fetus has inherited one of the regions of chromosome 4p from the affected grandparent. This allows the risk analysis for the fetus to be increased from 25 to 50% (to that of the at-risk parent). Termination of a pregnancy based on this risk is controversial and at-risk individuals should seek genetic counseling before pregnancy. The risks of prenatal testing should also be made clear, which include <1% risk of spontaneous abortion with CVS.
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Huntington Disease-Like 2 (HDL2; OMIM 606438) The diagnosis of HDL2 is typically made in individuals of African descent who present with clinical features of HD, but who do not have an expanded CAG repeat within the HD gene. Clinical Features HDL2 usually presents in mid-life (50 years and above) with progressive chorea, and emotional and cognitive abnormalities. A second presentation is similar to juvenile-onset HD with weight loss, and rapid development of rigidity and dystonia developing between 29 and 40 years of age. Dementia and psychiatric disturbances are common and more severe in the second form. All individuals, with the exception of one Mexican family, have been of African descent. MRI shows typical features of HD with atrophy of the caudate and cerebral cortex with sparing of the brainstem and cerebellum. Genetics HDL2 is inherited as an autosomal dominant trait and is caused by an expanded CTG repeat within the gene for Junctophilin-3 (JPH3). Normal alleles contain 628 repeats. Full-penetrance alleles contain greater than 41 repeats. The pathogenicity of alleles containing 2939 repeats is unclear but there is evidence that they are potentially mutable. Genetic advice should be given as for HD and gene testing for the JPH3 gene is available.
Dystonia The dystonias are an unusual group of movement disorders whose main feature is involuntary muscle contraction or spasm. It is defined as a syndrome characterized by sustained involuntary muscle contractions affecting one or more sites of the body which lead to abnormal postures or repetitive twisting movements. The diagnosis is invariably based on the clinical features. Dystonic movements can range from slower twisting, or athetoid, through to more rapid jerky movements. They are repetitive and rhythmic and may be accompanied by tremor. The movements tend to be aggravated by movement (action dystonia) and can be task-specific (e.g., writing). With time the movements occur with less specific movements and eventually may occur at rest or cause sustained abnormal postures. The spectrum of dystonia can range from focal dystonia affecting one specific body part, such as the neck (cervical dystonia or spasmodic torticollis), eyes (blepharospasm), hand (writer’s and other task specific cramps), or voice (laryngeal dystonia), through to severe generalized dystonia affecting the limbs, trunk, and sometimes head and neck. Dystonic muscle contractions may be relieved by tactile or proprioceptive sensory tricks known as ‘‘gestes antagonistes,’’ such as touching the chin with the hand to bring the head back to midline position in cervical dystonia. Dystonia worsens with stress or fatigue and may improve with relaxation or sleep. Once present, dystonic movements
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Table 8.3 Classification of Dystonia Age of onset Early: <28 years Late: >28 years Distribution Focal: single body part affected Neck: cervical dystonia (spasmodic torticollis) Eyelids: blepharospasm Mouth: oromandibular dystonia Larynx: laryngeal dystonia Hand or arm: writer’s cramp and other limb dystonias Segmental: two or more contiguous body parts Cranial: cranial and/or neck Axial: neck and trunk Brachial: one arm and axial; both arms and/or neck and/or trunk Crural: one leg and trunk, both legs and/or trunk Generalized: segmental crural and any other segment Multifocal: two or more non-contiguous parts Hemidystonia: ipsilateral arm and leg
persist through life, although up to 10% may experience periods of spontaneous remission (particularly cervical dystonia). Dystonia can be classified by affected body part or age of onset (Table 8.3). Those dystonias with an earlier age of onset are more likely to generalize and have a more severe course. It can also be classified by etiology: 1. Primary dystonia, where the clinical picture is of dystonia alone, sometimes with associated tremor. 2. Dystonia-plus syndromes. These refer to two specific conditions where dystonia is associated with parkinsonism (dopa-responsive dystonia and rapidonset dystoniaparkinsonism) or myoclonic jerks (dystoniamyoclonus syndrome). 3. Secondary dystonia, where there is an identifiable underlying cause (other than genetic) such as stroke or tumor of the basal ganglia, exposure to drugs (especially dopamine-blocking drugs, e.g., neuroleptics) or toxins, and so on. 4. Heredodegenerative disorders. By definition these are genetic conditions where dystonia is just one aspect of the clinical picture, for instance HD, Wilson’s disease, neuroaxonal dystrophy. These are dealt with in the section on mixed movement disorders and Chapter 16 on metabolic disorders. The following box highlights key clinical and diagnostic points when considering the etiology of a case of dystonia. Clinical Hints for Cases of Dystonia Focal primary dystonia is usually adult-onset and sporadic. Generalized primary dystonia is usually childhood-onset and genetic in origin. The presence of other neurological features and intellectual involvement alerts to secondary cause (e.g., metabolic). Hemidystonia alerts to contralateral cranial structural lesion. Never forget DRD or Wilson’s disease as they have specific treatments. Genetic tests available for DYT1 and DYT5 dystonia to confirm diagnosis.
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Table 8.4 Investigation of Dystonia Dystonia Phenotype
Investigation
Primary torsion dystonia Early onset (<28 years)
Late onset (>28 years)
Secondary dystonia
Copper studies, slit lamp examination MRI brain DYT1 gene analysis Trial of L-dopa Copper studies, slit lamp if under 50 years of age Consider MRI brain MRI spine if dystonia fixed or painful EMG if painful axial muscle spasm MRI brain/spine Nerve conduction studies Copper studies, slit lamp, and/or liver biopsy if Wilson’s disease possible Genetic test for neurodegenerative disorders (e.g., Huntington’s disease) White cell enzymes a-Fetoprotein, immunoglobulins Lactate, pyruvate, mtDNA analysis, muscle biopsy Blood film for acanthocytes Urine amino acids, organic acids, oligosaccharides Bone marrow biopsy Phenylalanine loading test, CSF pterins ERG, retinal examination
Investigations. Investigation of a case of adult-onset focal dystonia is usually not necessary as the diagnosis is clinical and a secondary cause extremely unlikely. For childhood-onset generalized dystonia it is important to look for other causes. Table 8.4 lists potential investigations. For any childhood-onset case of dystonia, especially if there is a positive family history and onset is in a limb, testing for the DYT1 gene GAG deletion should be offered. A positive test prevents unnecessary investigations and also permits genetic advice to be given. Analysis of CSF biopterins or performing a phenyalanine loading test can help diagnose dopa-responsive dystonia, but the most pragmatic way is to challenge with L-dopa. The following sections focus on the major genetic forms of dystonia, namely primary torsion dystonia and the dystonia-plus syndromes.
Primary Torsion Dystonia (PTD) Clinical Features PTD is the commonest form of dystonia and encompasses the focal dystonias as well as more severe childhood-onset generalized dystonias. The majority of adult-onset focal dystonias tend to remain localized to one body part and are usually sporadic. PTD that develops in childhood tends to spread to become generalized and is usually genetic in origin. The dystonia often starts in a limb and initially is
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only evident on use of the limb, but then can involve the trunk and other limbs. This spread can occur over months or years. The majority of these cases are familial and autosomal dominant. It has been suggested from family studies that 85% of cases of generalized PTD can be explained by the presence of an autosomal dominant gene(s). Penetrance is reduced to around 3040% and expression is variable, with some relatives only developing focal dystonia in later life. Prognosis The most common forms of dystonia are adult-onset and focal in distribution. However, up to 20% can spread to an adjacent body area (e.g., spasmodic torticollis and blepharospasm or writer’s cramp) thereby becoming segmental. Early-onset dystonia, which is usually familial, can present as focal action dystonia but tends to progress, often leading to generalized dystonia. Most primary forms of dystonia, whilst being disabling, do not shorten life expectancy. Genetics Most forms of early PTD are genetic in origin and Table 8.5 describes the genetic forms that have been identified to date. The majority have only been described in single families. The commonest genetic defect is a single GAG deletion in the DYT1 gene (OMIM 128100) which encodes the protein torsinA (OMIM 605204), leading to the loss of a glutamic acid residue in a highly conserved region near the carboxyl terminus of the protein. DYT1 dystonia is more common in the Ashkenazi Jewish population due to a founder mutation which occurred during a population bottleneck in the Middle Ages. Table 8.5 Genetic Forms of Primary Dystonia Type (OMIM)
Clinical Features
DYT1 (128100)
Limb onset, 50% cases early onset generalizes, can in non-Jews, 90% present as focal in Ashkenazi Jews Focal and generalized Spanish gypsy families and single Iranian kindred Laryngeal and Single Australian cervical, some family generalized Focal or generalized, Two Mennonite cranial, cervical or Amish families limb Focal dystonia, Single German family cervical and laryngeal Cranial or cervical, Single Italian family some generalized
DYT2 (224500)
DYT4 (128101)
DYT6 (602629)
DYT7 (602124)
DYT13 (607671)
Frequency
Age of Onset
Inheritance/Locus/ Gene
Childhood, most AD, TOR1A, protein present by 26 years torsinA Childhood to adult
AR, locus unknown
1337 years
AD, locus unknown
Mean age of onset 19 AD, DYT6, chromosome 8p21-q22 2870 years AD, DYT7, chromosome 18p Childhood to adult
AD, DYT13, chromosome 1p36
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However, in both Jewish and non-Jewish kindreds with DYT1 dystonia, haplotype analysis has shown that the same mutation has arisen independently. The DYT1 GAG deletion leads to a characteristic phenotype. The majority have onset under the age of 26 with dystonia in a limb (leg more frequently than arm). Dystonia spreads to involve other limbs or axial muscles, but only to cranial muscles in about 10% of cases. There have also been reports of familial writer’s cramp with young onset, caused by the DYT1 GAG deletion. Treatment Treatment for PTD can be difficult, especially for more severe forms. For focal and segmental PTD, botulinum toxin injections are the first line of treatment. Botulinum toxin inhibits the release of acetylcholine at the neuromuscular junction and produces temporary weakness which can provide very effective relief of symptoms for dystonic muscles. Drugs can be helpful for childhoodonset generalized dystonia and include anticholinergics, dopaminergic agents, baclofen, and benzodiazepines. All cases of early-onset dystonia should have a therapeutic trial of L-dopa, to exclude the possibility of dopa-responsive dystonia (see later). For medically refractory dystonia surgery can be offered. Recently, there has been increasing interest in the use of pallidal deep brain stimulation for severe forms of dystonia and a number of reports have shown promising results. Genetic Advice and Testing Recurrence risks for childhood-onset PTD are presented in Table 8.6. It is important to examine parents carefully before deciding whether a case is isolated or familial, due to the possibility of minor dystonic manifestations in adults. Risks are the same for males and females and recessive dystonia appears very rare. These recurrence risks were formulated from a study of 100 families with an index case of generalized PTD before the cloning of the DYT1 gene, and were based on the assumption that 25% were new mutations, one-third of non-Jewish cases had a non-genetic disorder and penetrance was 42% (Fletcher et al. 1990). Thus for a DYT1 GAG deletion positive case, although more accurate figures may be calculated, in practical terms they do not differ greatly from those in Table 8.6. Diagnostic, predictive, and prenatal testing for the DYT1 GAG deletion is available. Individuals with childhood-onset generalized PTD should be considered for testing, as should those with young-onset (<28 years) focal or segmental dystonia, especially if the dystonia involves a limb. For predictive and Table 8.6 Recurrence Risks where Index Case has Generalized PTD Risks for Clinical Disease in:
Familial case Isolated Ashkenazi Jewish case Isolated non-Jewish case
Sibs (%)
Offspring (%)
21 15 8
21 21 14
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prenatal tests it is important to realize that dystonia is a non-fatal condition and a positive result means that the individual has a 30% chance of developing some form of dystonia, which could be a mild focal form.
Dopa-Responsive Dystonia (DRD; OMIM 128230) Clinical Features DRD, first described in Japan in 1977, is a rare genetic form of dystonia characterized by the profound response to L-dopa treatment seen in most patients. Patients typically present with gait disturbance due to foot dystonia in childhood. The dystonia frequently worsens as the day goes on (diurnal variation) and is relieved by rest or sleep. Progression is variable, with some patients developing severe generalized dystonia, whilst others develop features suggestive of lower limb spasticity. Parkinsonian features such as bradykinesia and rigidity can develop in later life in some individuals, but can also be the presenting feature in adult life in a minority of cases. Occasionally DRD can present with adult-onset limb dystonia (e.g., writer’s cramp), cranial or cervical dystonia, or with signs resembling spastic paraplegia. In most cases DRD is inherited as an autosomal dominant trait with reduced penetrance. The key feature is that DRD shows a dramatic and sustained response to small doses of L-dopa, often as small as 50200 mg per day. Benefit is usually apparent within days to weeks and the motor complications of L-dopa treatment seen with Parkinson’s disease rarely develop, even with long-term treatment. Anticholinergic drugs also can be beneficial. The principal differential diagnoses for childhood DRD are of early-onset PTD, spastic paraplegia and cerebral palsy, and early-onset parkinsonism, especially when caused by mutations in the gene for parkin (see later). The last group of patients often present with dystonia and show good initial response to L-dopa. However, clues to the diagnosis come from inheritance pattern (usually autosomal recessive for parkin) and the occurrence of motor fluctuations and dyskinesias with L-dopa treatment. PET scanning with markers for presynaptic dopaminergic terminals (18F-dopa) or SPECT can also differentiate between the two conditions. The diagnosis of DRD can usually be confirmed by an excellent response to L-dopa treatment in doses slowly increasing up to 400 mg per day. A trial of L-dopa should use doses escalated to 300 mg per day for 2 months. Alternatively, detecting reduced levels of pterins in the CSF or an abnormal oral phenylalanine loading test can substantiate the diagnosis. Genetics Most cases of autosomal dominant DRD are caused by mutations within the gene for GTP cyclohydrolase 1 (OMIM 600225) on chromosome 14 (DYT5). This enzyme is needed for synthesis of tetrahydrobiopterin, a cofactor of tyrosine hydroxylase, the rate-limiting enzyme of dopamine synthesis. Numerous mutations have been identified in all five exons and genetic testing is available in specialist laboratories. This can be complex as most families have a private mutation.
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Other extremely rare forms of DRD have been reported, including autosomal recessive forms with genetic deficiency of tyrosine hydroxylase (OMIM 191290), and also defects in other enzymes involved in pterin synthesis. In these cases the phenotype is usually more severe than with the classical dominant form with childhood-onset and associated motor and cognitive delay and seizures.
Myoclonus Dystonia Syndrome (MDS; OMIM 159900) Clinical Features MDS is characterized by the presence of dystonia in combination with brief lightning-like myoclonic jerks. It usually has onset in childhood or early adolescence, with myoclonic jerks affecting the upper limbs and axial muscles (trunk and neck). The myoclonus can occur on rest and also be precipitated by action. Dystonia occurs in around two-thirds of patients, with cervical dystonia and writer’s cramps the most common forms. Occasionally dystonia affects the legs. Several reports have identified psychiatric features associated with MDS, including obsessive-compulsive disorder, panic attacks, and anxiety. Most patients note significant relief of symptoms with alcohol or benzodiazepines, and can have marked rebound of symptoms following administration of these. This can often lead to abuse of these substances. Genetics MDS is frequently inherited as an autosomal dominant trait, caused by mutations in the gene for e-sarcoglycan (OMIM 604149; DYT11), although sporadic cases also occur. Routine testing for mutations is not currently available. A further autosomal dominant locus (DYT14) has been mapped to chromosome 18 (OMIM 607195).
Rapid-Onset Dystonia Parkinsonism (RDP; OMIM 128235) Clinical Features This is a rare autosomal dominant movement disorder characterized by abrupt or subacute onset of both dystonia and parkinsonism with prominent bulbar involvement. Symptoms develop over hours to days with dystonic posturing of the limbs, bradykinesia, dysarthria, and dysphagia, postural instability, followed by little or no progression. Onset is usually in adolescence or young adulthood and the subacute extrapyramidal storm can be preceded by stable mild limb dystonia for a number of years. Potential triggers in some families include emotional trauma, extreme heat, or physical exertion. Investigations with MRI, CT, and PET imaging of the presynaptic dopamine uptake sites have been normal. In some patients reduced levels of CSF dopamine metabolites have been detected. The current assumption is that RDP is due to neuronal dysfunction rather than neurodegeneration.
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Genetics The condition is rare and only a small number of families have been described with evidence for autosomal dominant inheritance with reduced penetrance. The gene was mapped to chromosome 19q12-q13.2 (DYT12) and mutations in the gene for the Na/K-ATPase a-3 subunit (ATP1A3: OMIM 182350) have been identified in seven unrelated kindreds with RDP. This finding implicates the Na/K pump, which is crucial for maintaining the electrochemical gradient across the cell membrane, in dystonia and parkinsonism. Testing for mutations in the ATP1A3 gene is only available on a research basis.
Paroxysmal Dyskinesias This is a group of rare conditions which manifest with abnormal involuntary movements that occur episodically and are of brief duration. The abnormal movements are mixed but include dystonia, chorea, and ballism. They can be acquired or genetic in origin and between attacks the patient is normal. Paroxysmal Kinesigenic Dyskinesia (PKD; OMIM 128200) In this condition the dyskinetic movements are precipitated by sudden movement. Onset is usually in childhood, and PKD is more common in males and often familial, with autosomal dominant inheritance. Attacks consist of dystonia or choreo-dystonia induced by sudden movement, change in position or running. Often they affect one side of the body, which can alternate, and are brief, lasting seconds or occasionally minutes. Numerous attacks can occur in a day. For idiopathic or genetic forms the prognosis is good, and frequency of attacks decreases with age and often abates in adult life. A genetic locus for PKD has been mapped to chromosome 16, which may be allelic with a locus found for families with infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome; OMIM 602066), although there is also evidence for genetic heterogeneity. PKD responds well to antiepileptic drugs, particularly carbamazepine in low doses. Reports also suggest benefit with gabapentin, lamotrigine, topiramate, and levetiracetam. Paroxysmal Non-Kinesigenic Dyskinesia (PNKD; OMIM 118800) PNKD is characterized by attacks of dyskinesia which are frequently precipitated by alcohol, caffeine, stress, or fatigue. The episodes are often dystonic or choreic, have longer duration (minutes to hours), and are less frequent (13/day) than seen in PKD. There may also be longer attack-free intervals, and again males are more often affected than females. PNKD is frequently familial, with autosomal dominant inheritance, characteristically with onset in childhood and attacks diminishing in adulthood. A locus on chromosome 2q31-36 has been mapped in a number of families. Most patients with PNKD do not benefit from antiepileptic drugs but some response to clonazepam or clobazam has been reported. In general it is more difficult to treat than PKD and patients often learn to avoid precipitants.
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Paroxysmal Exercise-Induced Dyskinesia (PED) In this condition, episodes of involuntary movements occur after exercise such as walking or swimming. These usually take the form of dystonia which resolves 1015 minutes after ceasing exercise. The dystonic movements take longer to come on and last for longer than in PKD. Cold exposure may also bring on an attack. Sporadic cases have been described, but it is frequently familial with autosomal dominant inheritance. As with PNKD, the movements in PED are often difficult to treat, although some response to antiepileptic drugs has been reported. If the dystonia is unilateral and severe, stereotactic surgery may be an option. Paroxysmal Hypnogenic Dyskinesias (PHD) Paroxysmal hypnogenic dyskinesia is a term used to describe brief episodes of involuntary dystonic or ballistic limb movements that frequently occur during the night and can waken the patient from sleep. The majority of these cases, particularly familial forms, have been found to be due to mesial frontal lobe seizures, now described as autosomal dominant nocturnal frontal lobe epilepsy type 1 (OMIM 600513). To date, mutations in two genes, the a-4 subunit of neuronal acetylcholine receptor (CHRNA4; OMIM 118504) and b subunit of the nicotinic acetylcholine receptor subunit genes (CHRNB2; OMIM 118507), have been described in some families (see also Chapter 4). Secondary Paroxysmal Dyskinesias It is vital to distinguish genetic or primary forms of paroxysmal dyskinesia from secondary or symptomatic paroxysmal dyskinesias. The latter are notable for variability of onset, the presence of both kinesigenic and non-kinesigenic symptoms in some patients, the prevalence of sensory precipitants, and the reversal of symptoms if the underlying condition can be treated. The presence of other neurological symptoms and signs also points to a secondary cause. The association of PKD and PNKD with multiple sclerosis is well described. Other causes include stroke, antiphospholipid syndrome, central and peripheral nervous system trauma, HIV infection, hypo- and hyperglycemia, hypoparathyroidism, pseudohypoparathyroidism, basal ganglia calcification, and kernicterus.
Deafness-Dystonia-Optic Neuronopathy Syndrome (Mohr-Tranebjaerg Syndrome; OMIM 304700) This rare syndrome is characterized by sensorineural hearing impairment in childhood or early teens, slowly progressive dystonia and ataxia with additional pyramidal features in the teens. From the third decade visual acuity declines due to optic neuropathy, and there may also be additional neuropsychiatric and behavioral features. The condition is inherited as an X-linked recessive trait with males affected, although female carriers may have mild deafness and dystonia in later life. It occurs either as a single-gene disorder resulting from a mutation in the TIMM8A (tranlocase of inner mitochondrial membrane 8; OMIM 300356)
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gene, or as a contiguous gene deletion syndrome at Xq22, which also includes X-linked agammaglobulinemia.
Tremor Tremor is an oscillating movement affecting one or more body parts, usually the upper limbs, but can affect the legs, tongue, head, chin, or vocal cords. It is usually rhythmical and regular. It is best categorized by whether the tremor is present at rest, on maintaining a posture (arms extended), with action (such as writing) or with intention maneuvers (such as fingernose testing).
Essential Tremor (ET) ET is a postural tremor, usually of the upper limbs, and is the commonest movement disorder, with prevalence 1020 times higher than Parkinson’s disease. Prevalence estimates from different studies worldwide range from 0.4 to 3.9% for the general population, and prevalence increases with age, rising to at least 5% over 60 years of age. Clinical Features ET is a clinical diagnosis made by the presence of a postural upper limb tremor of 412 Hz. It may also produce tremor of the head, legs, voice, and jaw. Onset is in adult life and incidence increases with age. Invariably the tremor worsens with age and can be functionally disabling. The tremor can be alcohol-responsive. There are no specific investigations although it should be distinguished from enhanced physiological tremor such as that seen in hyperthyroidism. The pathogenesis of ET is uncertain but is believed to involve a central oscillatory generator involving olivo-cerebello-rubral loops which lead to release of spinal loop oscillations. The mainstay of treatment is with non-selective beta-adrenergic blocking drugs such as propranolol. Primidone or clonazepam may also be used but have sedating side effects. Genetics ET may be sporadic or familial. Up to 50% of cases report a positive family history. Families described have autosomal dominant inheritance with high or complete penetrance by 70 years of age. Recurrence risk can be estimated from a family study of index cases of ET (Louis et al. 2001), which found that 22% of first-degree relative had evidence of tremor compared with 5.6% of controls (a 5-fold greater relative risk). If onset in the proband was under the age of 50 years, the relative risk increased to 10. A significant problem in attempting to map loci for ET is accurately determining affected status, especially as physiological tremor can mimic ET. A consensus classification has been derived which defines ET as a bilateral postural/action tremor of the hands and forearms (but not rest tremor)
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which has been present for at least 3 years as a core criterion. Three ETM loci have been mapped: ETM1 (OMIM 190300) on chromosome 3q13.1 in a group of Icelandic families with ET: support for this locus comes from an independent study of the Ser9Gly polymorphism in the dopamine receptor gene 3, which maps to this interval, in 30 pedigrees with ET, demonstrating evidence of linkage. ETM2 (OMIM 602134) on chromosome 2p22-p25 in a large American family of Czech descent: this region has been further refined in an additional group of US families, and in two families sequence variants have recently been identified in a transcript for HS1-BP3 protein, although there is evidence to suggest that these may be polymorphisms. The HS1-BP3 protein is believed to bind proteins highly expressed in motor neurons and Purkinje cells and regulate Ca2+/calmodulin-dependent protein kinase activation. ETM3 (OMIM 611456) has been mapped in a large family with tremor to chromosome 6p23. Some affected individuals also had focal dystonia. Tics and Gille de la Tourette Syndrome (OMIM 137580) Tics are unwanted, highly stereotyped and repetitive behaviors which occur in short sudden bouts. They include a wide range of movements from simple motor and vocal movements (e.g., eye blinking, shoulder shrugging, head jerking, throat clearing) to coordinated patterns of sequential movements, such as hand gestures, bending, or complete utterances. The majority of tics are simple and non-genetic. Tics are exacerbated by stress and fatigue and reduced during times of concentration and to some extent are suppressible, but this leads to a build-up in inner tension relieved only by the tics. Suppressing tics invariably feels uncomfortable and frequently results in an increase in the number and severity of tics when released from active suppression. Tics often involve ocular movements, a feature not seen in other dyskinesias. If phonic or vocal tics are present it suggests the diagnosis of the one familial tic condition, Gilles de la Tourette syndrome. Clinical Features of Tourette Syndrome (TS) TS is a neuropsychiatric disorder with onset in childhood. The diagnosis is clinical and characterized by onset under 21 years with motor and vocal tics, which must have been present for at least 1 year. Males are more frequently affected than females and psychiatric features include attention deficit disorder and obsessive-compulsive behaviors (OCBs) found in 50% of individuals with TS. Both tics and OCBs include premonitory experiences such as sensations (tics) or thoughts (OCBs) that precede involuntary repetitive movements (tics) or behaviors (OCBs). Performance of the tic or compulsion terminates the premonitory symptoms, albeit temporarily. Genetics TS has a strong heritable component, with a high percentage of TS patients having an affected first-degree relative. Affected males are more likely to have
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tics and attention deficit disorder whilst females are more likely to have OCBs. The risk of developing TS is greater if there are two affected first-degree relatives rather than one, and relatives of female index cases are at greater risk for being affected than the relatives of male patients. Recurrence risk rates vary according to the study and population, with lower rates in Japan. However, the risk for a first-degree relative of a TS patient of developing TS has been estimated at 915%, and 1520% for developing any form of tic. Twin studies have demonstrated high concordance rates in monozygotic but not dizygotic twins. Families with individuals with TS have been reported and segregation analyses in these have shown that TS is inherited as an autosomal dominant trait with incomplete and sex-specific penetrance. Thus TS genetics are complex, with evidence to support polygenic inheritance, and linkage data point to several potential susceptibility loci. Recently, a sequence variant on chromosome 13 was found to be associated with TS in a child. This was an inversion and the gene encoding Slit and Trk-like 1 (SLITRK1; OMIM 609678), a member of a family implicated in neurite outgrowth, was close to one of the breakpoints. Among 174 unrelated subjects with TS, two mutations in the gene were identified in three unrelated individuals, but no mutations found at this locus in 3600 control chromosomes. Both mutations were predicted to produce a haploinsufficiency of SLITRK1 protein, and in cell cultures the mutations reduced neuronal dendritic growth. Management Treatment with dopamine receptor blockers, such as haloperidol and pimozide, is most effective at suppressing tics, but some patients prefer not to take drugs. Serotonin-uptake inhibitors can be used to treat obsessive-compulsive symptoms.
Myoclonus Myoclonus is defined as sudden, abrupt, involuntary, jerk-like contractions of a muscle or muscle group, arising in the central nervous system. Most genetic disorders have other neurological (e.g., seizures, ataxia) or systemic features, in addition to myoclonus. They are predominantly metabolic or mitochondrial disorders and are described in Chapters 14 and 16. The autosomal recessive neurodegenerative disorder Unvericht-Lundborg disease, which has prominent myoclonus in addition to seizures, is described in Chapter 6.
HYPOKINETIC MOVEMENT DISORDERS Parkinsonism Parkinsonian syndromes are characterized by decreased amplitude and slowness of movement (bradykinesia). Parkinsonism is a syndrome manifested by the presence of bradykinesia and/or tremor at rest, plus at least one of the following features: rigidity, flexed posture of neck, trunk and limbs, loss of
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postural reflexes, freezing, or motor blocks. Idiopathic Parkinson’s disease is the commonest form of parkinsonism and diagnostic criteria also include a beneficial response to L-dopa therapy. The other forms of secondary or parkinson’s-plus syndromes do not have a significant genetic etiology and will not be considered further.
Parkinson’s Disease (OMIM 168600) Clinical Features Idiopathic Parkinson’s disease is the commonest form of parkinsonism, and is a progressive neurodegenerative disorder. The cardinal features are tremor, bradykinesia, and rigidity, usually with asymmetric onset. Asymmetrical tremor of a limb which is present at rest and attenuates on action is often the first symptom. Alternatively onset may be with slowness in movement or shuffling gait. Difficulty turning in bed is often an early symptom. Bradykinesia presents as masked facies, decreased blinking, soft speech, drooling of saliva due to reduced spontaneous swallowing, difficulty with manual dexterity including micrographia, and shuffling gait with decreased arm swing. The limbs can feel heavy and stiff due to rigidity, which is defined as the increased resistance to passive movement. As the disease progresses the patient assumes a flexed posture and begins to lose balance, with a tendency to fall due to loss of postural reflexes. The freezing phenomenon, or motor block, develops often with start hesitation, but later can become extremely disabling with unpredictable periods of immobility. Dementia occurs in about 10% of patients, but more common is bradyphrenia, or slowness of thought processes. The age of onset of PD is usually above 50 years, but younger patients can be affected. Onset before 20 years does not preclude a diagnosis of PD, but juvenile parkinsonism should alert to other conditions such as Wilson’s disease and Westphal variant of Huntington’s disease. The younger the age of onset, the more likely it is that there is a significant genetic component to the disease. The disease is more common in men than women, with a male:female ratio of 3:2. PD is a common condition and the incidence in the USA is estimated at 20 new cases per 100,000 population per year, with a prevalence of 187 cases per 100,000 population. Investigation and Differential Diagnosis Investigation of a case of PD is determined by the presentation. A 65-yearold patient with the cardinal features of PD and L-dopa responsiveness does not require further tests. In contrast, an early age of onset plus additional neurological features would lead to further tests to look for a symptomatic or hereditary cause. Table 8.7 lists common causes of secondary parkinsonism, and Table 8.8 shows the parkinson’s-plus syndromes which much be considered in the differential diagnosis of PD. The presence of symmetrical signs of parkinsonism, early autonomic or cognitive involvement, or severe axial
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Table 8.7 Causes of Secondary or Symptomatic Parkinsonism Cause
Clinical Features
Examples
Drugs
May be associated with tardive dyskinesias Psychomotor retardation
Dopamine-blocking drugs (e.g., neuroleptics), tetrabenazine Encephalitis lethargica Manganese, carbon monoxide, cyanide, MPTP
Postencephalitic Toxins Diffuse cerebrovascular disease Normal-pressure hydrocephalus
Gait (marche a petit pas), lower limb parkinsonism Shuffling gait, bladder disturbance, cognitive features
Other cerebral insults
Basal ganglia tumor, head trauma
rigidity and impaired postural reflexes should alert to the possibility of alternative diagnoses to PD. Key investigations include MRI of the brain and copper studies, with further tests guided by the phenotype. The diagnosis of PD can be supported by 18F-dopa positron emission or SPECT scanning or DAT scans, which can show asymmetric reduction of ligand uptake in PD. Pathophysiology The primary pathological hallmark of PD is degeneration of the nigrostriatal dopaminergic pathway, which, in depleting the brain of dopamine, produces the abnormal motor activity. Other brain areas are involved, including the locus ceruleus, raphe nuclei, and nucleus basalis of Meynert. The pathological diagnosis of PD also requires the presence of Lewy bodies, which are eosinophilic cytoplasmic inclusion bodies, found in all affected brain areas. They consist of a number of proteins, of which a-synuclein is a major component. Genetics of PD The cause of almost all cases of PD is unknown. The majority of cases of PD appear sporadic, although are likely to be multifactorial in origin. Familial PD is very rare. For an isolated case of PD the critical factor in assessing genetic risk to relatives is the age of onset in the proband. The earlier the age of onset, the greater is the the role of genetic factors. One study has shown that risk to siblings of an isolated case of PD varies with age of onset, being around 1 in 12 when the Table 8.8 Parkinson’s-Plus Syndromes Syndrome
Additional Clinical Features
Progressive supranuclear palsy Multiple system atrophy Cortical Lewy body disease Cortico-basal degeneration Heredo-degenerative disorders
Supranuclear gaze palsy, axial rigidity, frontal lobe dementia Cerebellar, autonomic (early bladder involvement, impotence), pyramidal signs Nocturnal hallucinations, confusion, dementia Apraxia, alien limb phenomenon Wilson’s disease (liver involvement), Huntington’s disease (chorea and cognitive involvement), neuraxonal degeneration (other movement disorders, e.g., dystonia, dementia) Alzheimer’s disease (temporal and parietal lobe cognitive features)
Dementia syndromes
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age of onset is between 35 and 45 years, 1 in 20 between 45 and 55, 1 in 26 for 55 to 65 years, and 1 in 71 for above 65 years. These figures may be an overestimate as another study found no difference between siblings and controls. Data from twin studies have been conflicting, with a number showing low concordance in both monozygotic and dizygotic twins. Again the age of onset is important and in a study of twins registered in the USA for World War II, a high risk ratio for concordance was found in monozygotic versus dizygotic twins with onset of PD before 50 years. For those with onset after 50 years the study could not identify any genetic component (Tanner et al. 1999). An extensive analysis of PD patients in Iceland using the genealogic database found that PD patients were significantly more related to each other than subjects in matched groups of controls, even for those with onset after 50 years. The risk ratio for PD was 6.7 for sibs, 3.2 for offspring, and 2.7 for nephews and nieces of patients with lateonset PD (Sveinbjornsdottir et al. 2000). A number of families with PD exhibiting Mendelian inheritance have been reported. At present, 13 PARK loci have been identified and are listed in Table 8.9. Genes have been cloned for PARK 1, 2, 5, 6, 7, and 8 and are discussed below. PARK1 (OMIM 168601). This was identified in the largest PD kindred reported, the Contursi family, including more than 60 affected individuals with Table 8.9 The PARK Genes Locus (OMIM)
Inheritance
Locus
Gene
No. of Families
PARK1 (168601)
AD
4q21-q23
a-Synuclein (SNCA)
PARK2 (602544) PARK3 (602404) PARK4 (605543)
AR AR AD
PARK5 (191342)
AD
6q25.2-q27 Parkin 2p13 ? 4p ? triplication of SNCA 4p14 UCH-L1
PARK6 (605909)
AR
1p36-35
PINK1
PARK7 (606324)
AR
1p36
DJ-1
PARK8 (607060)
AD
12q12
LRRK2
PARK9 (606693)
AR
1p36
?
PARK10 (606852)
1p32
?
PARK11 (607688)
2q36-q37
?
PARK12 (300557)
Xq21-q25
?
PARK13 (610297) ?AD
2p12
HTRA2
Early onset, rapid progression, L-dopa-responsive >60 Juvenile onset, dystonia 6 Late-onset PD 1 Early onset, dementia, postural tremor 1 Tremor dominant, L-dopa-responsive <30 Early onset, slow progression prominent tremor, L-dopa-responsive <20 Early onset, benign course, dystonia, L-dopa-responsive 1% sporadic, Middle-age onset, 3% familial cases L-dopa-responsive 1 Pyramidal features, supranuclear gaze palsy, dementia Susceptibility locus for late-onset parkinsonism Susceptibility locus for late-onset parkinsonism Susceptibility locus for late-onset parkinsonism 4 PD patients G399S heterozygote mutation detected <10
Clinical Features
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autosomal dominant inheritance. Age of onset was young (mean 46 years) with a low frequency of tremor and rapid disease progression, but L-dopa was effective. Linkage to markers on chromosome 4q21-q23 was identified. Further analysis identified a mutation in exon 4 of the gene encoding a-synuclein. The missense mutation results in an alanine to threonine substitution at codon 53 (A53T), which was also found in affected members of three Greek families with earlyonset autosomal dominant PD. A second mutation (A30P) was later found in a small German family with PD, and a third (E46K) in a family with parkinsonism and Lewy body dementia. Mutations have not been identified in many other families or sporadic cases. The precise pathogenesis of a-synuclein PD is unknown but mutant protein appears to act via a gain of function mechanism, supported by the fact that genomic multiplication of the gene is associated with a familial form of PD (PARK4). Mutant a-synuclein forms aggregate in cells and is also a component of Lewy bodies, suggesting a possible toxic role. PARK2 (OMIM 602544). This is a more common cause of PD and was first identified in Japanese families with AR young-onset parkinsonism. Subsequently, a range of deletions and point mutations in the gene encoding parkin have been identified. Community-based studies suggest that nearly 50% of all familial cases with early onset (<45 years), as well as a significant proportion of apparently sporadic cases, are due to homozygous or compound heterozygous PARK2 mutations. Only a very small proportion of later-onset cases have mutations in the parkin gene. Parkin functions as an E3 ubiquitin ligase involved in the ubiquitin-proteasome pathway which degrades and recycles unwanted proteins. PARK4 (OMIM 605543). Initial linkage analysis in a family with AD PD with young onset (mean age 34 years) whose phenotype ranged from typical PD to dementia with Lewy bodies suggested linkage to markers on chromosome 4p15. Re-analysis found a haplotype segregating with PD encompassing 26 genes, including the a-synuclein gene. A whole gene triplication of the a-synuclein gene was found. Carriers of this triplication are predicted to have four functional copies of a-synuclein, and it was suggested that PD results is the result of a dosage effect of wild-type a-synuclein. These findings are also consistent with data from case-control association studies, as common variability within the a-synuclein promoter has been associated with increased expression and increased risk of sporadic PD. PARK5 (191342). A single dominant mutation in the gene encoding ubiquitin C-terminal hydrolase-L1 (UCH-L1) was found in two affected members of a German PD family with onset in the sixth decade. The Ile93Met mutation decreases the enzyme’s activity, which is also involved in the ubiquitin-proteasome pathway. Susceptibility to late-onset sporadic PD has been shown to be associated with Ser18Tyr polymorphism. PARK6 (605909). The PARK6 locus was mapped to chromosome 1p36 in a large consanguineous Sicilian PD family with AR PD. It was subsequently shown that homozygous recessive and compound heterozygote mutations in the PINK1 gene account for 12% of early-onset cases. The gene encodes
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PTEN-induced putative kinase-1 (PINK1), which is a mitochondrial protein ubiquitously expressed, especially in the brain. Mutations appear to act by a loss of function mechanism which may lead to impaired phosphorylation of its target mitochondrial protein. PARK7 (606324). A number of different mutations affecting the gene encoding DJ-1, a homodimeric, multifunctional protein, have been linked to an AR form of PD. Deletions and missense mutations have been identified, but are rare and found in <1% of early-onset parkinsonism. The function of this protein, and hence the mechanism of pathogenesis, is unknown, but it also has mitochondrial localization. PARK8 (607060). The PARK8 locus was originally mapped as an autosomal dominant trait in a Japanese family with asymmetrical, L-dopa-responsive, late-onset PD. Subsequently, numerous amino-acid substitution mutations have been identified in the gene for leucine-rich repeat kinase 2 (LLRK2). The Gly2019Ser mutation leads to the most frequent substitution in Causcasians, typically explaining <2% of cases of sporadic PD, and 5% of familial parkinsonism. In Ashkenazi Jews and North African Arabs this figure is higher, possibly <30%. The LLRK2 gene encodes the protein named dardarin, whose function and role in PD pathogenesis is unclear. Management Treatment. It is beyond the scope of this book to describe in detail the treatment of PD, which involves use of dopamine agonists or L-dopa therapy, in conjunction with other drugs and occasionally functional neurosurgery. Supportive therapy with physiotherapy, occupational therapy, and speech therapy is important. Genetic Advice and Testing. Studies of recurrence risks for relatives of probands with isolated PD are discussed in the section above. Whilst the studies provide conflicting data, a pragmatic approach is that the overall risk to siblings of an isolated case of PD is only mildly increased if disease onset is above the age of 50 years. From the Icelandic study (Sveinsbjonsdottir et al. 2000), the siblings of an individual with PD had a 3.4% risk of developing PD, and offspring 1.6%, compared with a population prevalence of about 0.5%. Other studies have suggested that for onset under 50 years, the risk to siblings is in the region of 510%, with higher risks for earlier onset (e.g., under 40 years). For autosomal dominant pedigrees standard recurrence risks should be given. The role of a-synuclein mutations appears relatively minor, as does that for UCH-L1. For families with AR inheritance and early-onset PD, it is estimated that parkin mutations may be responsible for up to 50% of cases. Parkin may be responsible for most apparently sporadic cases of PD with onset under 20 years. Mutation screening for parkin is currently the only service test available, but mutation screening in the LLRK2, PINK1, DJ-1, and a-synuclein genes is performed in research laboratories.
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MIXED MOVEMENT DISORDERS There are a group of neurological disorders, usually with underlying neurodegenerative basis, which can present with movement disorder in addition to other neurological and systemic features. Frequently, they can lead to a combination of hyper- and hypokinetic movement disorders, and this should alert the clinician to the underlying diagnoses and to search for other features. Disorders producing a combination of movement disorders are often metabolic in origin, with childhood onset and systemic features, and are covered in Chapter 17. The more common disorders, often with adult onset, are covered below.
Disorders of Metal Metabolism Wilson’s Disease (Hepatolenticular Degeneration; OMIM 277900) Introduction. Wilson’s disease is a disorder of copper metabolism that presents with liver, neurological, or psychiatric disturbances, or a combination of these. It is vital to consider and detect cases as it is potentially treatable with copper-chelating agents. The prevalence of Wilson’s disease is estimated at 1 in 30,000 in most populations, with a higher prevalence in China and Japan. Clinical Features. Wilson’s disease can present from the age of 3 years onwards up to 50 years. Around 40% of cases present with liver disease, 40% with neurological symptoms, and 20% with psychiatric disturbance. Hepatic disease commonly presents in childhood and young adulthood as a self-limiting hepatitis-like illness with recurrent jaundice, although fulminant hepatic failure has also been reported. Neurological presentation includes movement disorders including tremor, ataxia, and chorea through to rigid dystonia and Parkinsonism. Pseudobulbar involvement with dysarthria, drooling, and dysphagia are more common in older individuals. The psychiatric disorders are variable and depression is common. There can be a slowly progressive personality disorder with anxiety and affective changes and gradual intellectual deterioration. Other clinical features include Kayser-Fleischer rings (see under Investigations), sunflower cataracts, hemolytic anemia, renal involvement, arthritis, and involvement of other systems, including pancreatitis, cardiomyopathy, and endocrine disorders. Investigations. In any individual suspected of having Wilson’s disease, slit lamp examination of the cornea for Kayser-Fleischer rings is vital. These are found in up to 85% of individuals with liver disease and 90% of those with neurological manifestations, and result from copper deposition in the Descemet membrane of the cornea. MRI abnormalities in the basal ganglia can also be seen (Fig. 8.1). Diagnosis can also be confirmed by finding low concentrations of serum ceruloplasmin and high urinary copper. If the diagnosis remains in doubt then it is necessary to perform a liver biopsy looking for increased hepatic copper concentration.
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Figure 8.1. T2-weighted MR brain scan in Wilson’s disease showing abnormal signal in the basal ganglia.
Molecular genetic testing is important where copper studies are equivocal. It is also important for determining genetic status of ‘‘at-risk’’ siblings. Mutations in the ATP7B gene can be identified and over 200 mutations have been found. Testing is available on a clinical basis and usually involves screening for a panel of more common mutations, including H1069Q, which accounts for 30 to 45% of Wilson’s disease alleles in a mixed European population, and R778L, which is relatively frequent in the Asian population. Where no mutation can be identified then sequence analysis is available on a limited basis. In the British population, screening of exons 8, 14, and 18 accounts for 60% of the alleles with mutations, and exons 8 and 12 account for a similar percentage in the Chinese population. Occasionally, linkage analysis with markers on chromosome 13 is performed when no mutation can be identified, which can be useful for early diagnosis for ‘‘at-risk’’ siblings and prenatal testing. Differential Diagnosis. For the neurological presentation, it is important to consider other causes of Parkinsonism and dystonia, including neurodegenerative diseases such as Huntington’s disease, spinocerebellar ataxia, DRPLA and Niemann-Pick disease Type C, the last of which can also be associated with liver disease. Pathophysiology. Wilson’s disease is caused by an autosomal recessive mutation in the copper-transporting ATPase (ATP7B; OMIM 606882) on chromosome 13q. The protein product is an intracellular transmembrane copper transporter which plays an important role in incorporating copper into
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ceruloplasmin, and moving copper out of the liver cells into bile. When it malfunctions, tissue damage occurs due to copper accumulation. Mutations that completely prevent function of the gene produce a more severe phenotype than certain missense mutations. The most severe mutations result in symptoms before the age of 12, frequently with liver disease. Prognosis. Treatment with copper-chelating agents can reduce symptoms in affected individuals, although death can occur with progressive disease, particularly with liver failure. For presymptomatic individuals at risk, early treatment and careful surveillance can lead to a normal life span. Management. Treatment with copper-chelating agents should be started as soon as possible in individuals with symptomatic Wilson’s disease. For those siblings of probands who are presymptomatic, it should be started prior to onset of symptoms and treatment is life-long. Copper-chelating agents (penicillamine or trientine) increase urinary excretion of copper and are first-line treatments for Wilson’s disease. Oral zinc in high doses is also used as it interferes with absorption of copper from the gastrointestinal tract. Zinc therapy is most effective after initial decoppering with a chelating agent. It should not be used at the same time as a chelator. Discontinuation of all treatment can lead to hepatic decompensation. Antioxidants are used, and in addition restriction of foods with a very high copper content is recommended. In severe cases, orthotopic liver transplantation is reserved for individuals who fail to respond to medical therapy. Genetic Advice. Wilson’s disease is inherited in an autosomal recessive manner and siblings of an affected individual have a 25% chance of having the condition. Carriers do not develop clinical manifestations. For offspring of an individual with Wilson’s disease, given that the carrier rate in the general population is 1 in 90, the likelihood that an affected individual would have an affected child is 1 in 180. It is recommended that ceruloplasmin concentration should be checked in the offspring of a Wilson’s disease-affected parent at around the age of 1 year. Genetic testing is available and is useful both diagnostically and to detect presymptomatic individuals and carriers. Carrier testing is not usually of clinical importance except in cases of consanguinity or in populations with high disease prevalence. Prenatal diagnosis is controversial as Wilson’s disease is a treatable condition. Careful counseling is required in this situation. Neuroferritinopathy (OMIM 606159) Introduction. Neuroferritinopathy is an autosomal dominant condition with progressive onset of dystonia or chorea and cognitive deficits. It is relatively rare and fewer than 50 cases have been described to date. Clinical Features. Neuroferritinopathy typically presents in adult life (mean age 40 years), although it has been described with onset in teenage years. Typically presenting with chorea or dystonia, it has a progressive course although limb involvement can be asymmetric. There have been reports of
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Parkinsonism and cerebellar ataxia. With time, orofacial dystonia develops, affecting speech, but eye movements are preserved. A progressive frontal and subcortical cognitive decline is also noted. Dysphasia develops and can become a serious problem. Investigations. The most useful investigation is an MRI of the brain, which shows evidence of iron storage, sometimes associated with cystic change, in the basal ganglia, particularly the caudate, globus pallidus, and putamen. At post-mortem there is characteristic basal ganglia cavitation, iron and ferritin deposition, and accompanying neuronal loss. Serum ferritin may be low. Molecular genetic testing is only available on a research basis for mutations within the ferritin light-chain gene (FTL; OMIM 134790). Differential Diagnosis. The differential diagnosis in both sporadic and familial cases should be with other dominantly inherited conditions with dystonia and/or chorea, which include Huntington’s disease, spinocerebellar ataxia type 17, DRPLA, choreoacanthocytosis, and DYT1 dystonia. These can be distinguished by cerebral imaging and appropriate genetic testing. Autosomal recessive diseases which can mimic neuroferritinopathy include Parkin-type juvenile-onset Parkinson’s disease, Niemann-Pick type C and pantothenate kinase-associated neurodegeneration (PKAN). The last of these can have similar changes on MRI with iron deposition in the basal ganglia. Treatment. No treatments have been shown to influence the course of neuroferritinopathy. The movement disorders are resistant to most drug treatments although botulinum toxin can help with painful focal dystonia. Supportive treatment with dietary assessment, speech and language therapy, and physiotherapy involvement is helpful. Current treatments under evaluation include venesection and iron chelation. Genetic Counseling. Neuroferritinopathy is inherited as an autosomal dominant trait with almost complete penetrance and counseling should be given appropriately. Genetic testing of the FTL gene on chromosome 9q is only available on a research basis. Pantothenate Kinase-Associated Neurodegeneration (PKAN; OMIM 234200) Introduction. PKAN is another form of neurodegeneration with brain iron accumulation leading to typical MRI findings. It is a rare autosomal recessive condition with estimated prevalence of 13 per million, which suggests a carrier frequency of one in 275300. The majority of these cases have mutations in the pantothenate kinase 2 gene (PANK2; OMIM 606157). Clinical Features. Typical PKAN presents with onset in the first decade of dystonia, rigidity, and sometimes chorea, which progresses rapidly. Cranial and limb dystonia is common, often leading to dysarthria and trauma to the tongue. Corticospinal tract involvement is common, leading to spasticity.
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Pigmentary retinopathy occurs in around two-thirds of cases with night blindness and progressive peripheral field loss. Intellectual involvement is variable. Motor symptoms progress, leading to loss of walking after 1015 years. Atypical PKAN has later onset (first three decades) presenting with speech difficulties (dysarthria, palilalia), psychiatric features (personality change, depression, emotional lability) and sometimes motor and verbal tics. Progression is slower and motor features develop later and loss of walking can take up to 40 years. Retinopathy is rare. The HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration; OMIM 607236), which has a similar phenotype, is also part of the PKAN spectrum as mutations have been identified in the PANK2 gene in families studied. Investigations. MRI of the brain typically shows the ‘‘eye of the tiger’’ sign on T2-weighted images, with a central region of hyperintensity in the globus pallidus, surrounded by a rim of hypointensity. Genetics. PKAN is an autosomal recessive disorder and appropriate risks should be given. Genetic analysis for mutations in the PANK2 gene is available for diagnostic and carrier testing.
Lysosomal Storage Disorders This is a large group of disorders including the gangliosidoses, neuronal ceroid lipofuscinosis (Batten disease), and fucosidosis, all described in Chapter 16. It also incorporates the leukodystrophies (Chapter 7), Niemann-Pick disease type C (Chapter 16), and Pelizaeus-Merzbacher disease. All have systemic features but can also present with movement disorders. They have been described in the chapters indicated with the exception of the following. Niemann-Pick Disease Type C (NPC; OMIM 257220) NPC typically presents in infants with liver disease, and pulmonary disease, hypotonia and developmental delay (Chapter 16). It can also have onset in childhood or early adulthood with ataxia, vertical supranuclear gaze palsy, dementia, dystonia, and seizures. Pelizaeus-Merzbacher Disease (PMD; OMIM 312080) This X-linked childhood dysmyelinating disorder is described in Chapter 7. Presentation is usually with nystagmus and hypotonia and later development of spasticity and ataxia. Movement disorders with dystonia and chorea are described.
Disorders of Purine Metabolism The most important of these is Lesch-Nyhan syndrome.
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Lesch-Nyhan Syndrome (OMIM 300322) Lesch-Nyhan syndrome is characterized by neurological dysfunction, cognitive and behavioral disturbances, and uric acid overproduction. It is an X-linked disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Male infants present in the first year of life with hypotonia and developmental delay. Infants usually do not gain the ability to walk and develop extrapyramidal features including dystonia, chorea, and opisthotonus as well as spasticity. Cognitive and behavioral disturbances emerge between two and three years of age. Persistent self-injurious behavior is a hallmark of the disease (biting fingers, lips, cheeks, banging head). The hyperuricemia can lead to uric acid crystals with calculi in the kidneys, ureter, or bladder, and also to gouty arthritis. Diagnosis can be confirmed by detecting a raised urate:creatinine ratio in blood and detecting reduced HPRT activity in blood or cultured fibroblasts/ lymphoblasts. Genetic advice is for an X-linked disorder. Molecular genetic testing of the HPRT1 gene is clinically available to identify mutations in males diagnosed with the condition, and also to determine carrier status in at-risk females. Prenatal testing is available.
Trinucleotide Repeat Disorders Dentatorubro-Pallidoluysian Atrophy (DRPLA; OMIM 125370) DRPLA is a rare autosomal dominant neurodegenerative disorder caused by expansion of a CAG repeat in the DRPLA gene, leading to an expanded polyglutamine tract in the protein. Onset is from childhood to 60 years, with mean age of onset of 30 years. Cardinal clinical features are of ataxia, chorea, dystonia, parkinsonism plus additional myoclonus, seizures, and cognitive change. Clinical Features. The clinical phenotype is largely determined by age of onset. Onset before 20 years of age is associated with a progressive myoclonus epilepsy phenotype with myoclonus, seizures, ataxia, and progressive intellectual decline. Seizures are less frequent with increasing age of onset and rare with onset over 40 years. Individuals with onset over 20 years typically develop cerebellar ataxia, chorea and dystonia, dementia, and psychiatric disturbances. Parkinsonism has been seen in late disease. The movement disorders and cognitive change can mask ataxia and thus DRPLA can mimic Huntington’s disease. The other main differential diagnoses are the spinocerebellar ataxias for adult-onset DRPLA and a number of conditions with ataxia, myoclonus, and seizures for younger onset (see Chapter 6). Prognosis is similar to that for HD. There are no specific investigations for DRPLA other than genetic testing. In longstanding cases of adult-onset DRPLA, diffuse high-intensity areas in deep white matter can be seen on cranial MRI.
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Genetics. DRPLA is inherited as an autosomal dominant trait. As with other CAG repeat disorders DRPLA exhibits anticipation. The normal-sized allele repeats are between 6 and 35 CAG repeats, and for affected individuals 4893 repeats have been described. Onset before 21 years is associated with median CAG repeat length of 68, whereas this is 63 repeats for those with onset after 40 years. The DRPLA gene (OMIM 607462) is located on chromosome 12p13.3 and encodes the protein atrophin 1. As with other CAG repeat disorders the truncated form of the protein appears involved in its pathogenesis and perinuclear and intranuclear inclusions are found in neurons in DRPLA (see Chapter 2). Genetic advice is for an autosomal dominant disorder with high penetrance. Genetic testing is available following a similar protocol for HD. De novo mutations have been described. Spinocerebellar Ataxias (SCAs) A number of the SCAs (e.g., SCA3, SCA17) can produce a variety of movement disorders, particularly dystonia, chorea, and occasionally parkinsonism. These are described in Chapter 6.
Other Degenerative Processes A variety of neurodegenerative disorders are associated with movement disorders. These include disorders with associated ataxia, such as ataxia telangiectasia, and ataxia with vitamin E deficiency (see Chapter 6). Another condition with a varied presentation is choreoacanthocytosis, described below. Choreoacanthocytosis (OMIM 200150) Introduction. Choreoacanthocytosis is an autosomal recessive condition characterized by a progressive movement disorder, myopathy, cognitive and behavioral changes, and acanthocytosis of red blood cells. Choreoacanthocytosis usually develops in adult life with a mean age of onset of 35 years. It runs a chronic progressive course and leads to progressive disability with reduced life expectancy. The movement disorder most frequently seen is chorea, but some individuals can present with Parkinsonism. Dystonia is also common and affects the oromandibular region and tongue, which leads to dysarthria and dysphagia. Tongue and lip biting are characteristic. Involuntary vocalizations (vocal tics) are present in around two-thirds of patients. Changes in personality and behavior occur in around two-thirds of patients. These can resemble patterns of a frontal lobe syndrome with apathy, depression, bradyphrenia, and emotional instability. Cognitive deterioration is also common. Seizures, usually generalized tonic-clonic, are observed in up to 50% of patients and can be the presenting feature. Myopathy and axonal neuropathy are also features and result in progressive distal muscle wasting and weakness. Differential Diagnosis. There is a wide range of differential diagnoses because of the many manifestations of choreoacanthocytosis. These include the
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McLeod syndrome, which has similar movement disorders, but has a specific laboratory feature with absence of red blood cell antigen kell. Other diagnoses include abetalipoproteinemia, pantothenate kinase-associated neurodegeneration (PKAN), HARP syndrome, Lesch-Nyhan syndrome, Wilson’s disease, Huntington’s disease, and other disorders including DRPLA. Investigations. Acanthocytes are found in the blood of patients in a variable proportion of between 5 and 50% of red cell populations. These need to be specifically looked for in a fresh blood sample fixed with heparinized saline or phosphatebuffered saline. There is an increased concentration of muscle creatine phosphokinase (CK) in the majority of patients. CT or MRI of the brain can reveal atrophy of the caudate nucleus often with increased T2 signal in the caudate and putamen on MRI. Electrophysiology shows evidence of a sensory axonal neuropathy with normal conduction velocity and EMG often reveals neurogenic changes. Molecular genetic testing for the CHAC gene is only available on a research basis and is described below. Prognosis. Life expectancy is reduced. In case reports the age range at death is between 28 and 60 years. Management. There is no specific treatment for choreoacanthocytosis. Supportive treatment with physiotherapy, occupational therapy, and splints can be helpful and use of dopamine-blocking agents for the hyperkinetic movement disorders can sometimes be of benefit. Botulinum toxin may reduce the orofaciolingual dystonia. Genetic Advice. Choreoacanthocytosis is inherited in an autosomal recessive manner and counseling should be given appropriately. The gene CHAC has been mapped to chromosome 9q21 and the gene product named chorein. The gene is large, spanning 73 exons, and at present there is no clinical testing available, either diagnostically or prenatally. Research testing is available on a limited basis. Little is known about the function of chorein, but Vps13, chorein’s yeast homologue, is required for intracellular trafficking of certain trans-Golgi network (TGN) proteins. Some families with similarities to choreoacanthocytosis and apparent autosomal dominant transmission have been reported. At present, it is not known whether these disorders are linked to the CHAC locus.
MOVEMENT DISORDERS RELATED TO SLEEP Narcolepsy Clinical Features Narcolepsy is a common cause of excessive daytime sleepiness. It is equally frequent in males and females, and around two-thirds of cases are sporadic. Onset is between the ages of 15 and 30 and it affects approximately 1 in 2000 individuals.
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Narcolepsy is characterized by excessive daytime sleepiness, disrupted nocturnal sleep, rapid eye movement (REM) sleep occurring at the onset of sleep, and cataplexy (a sudden loss of skeletal muscle tone) in response to strong emotional stimuli (e.g., laughter, anger, joking). The presence of cataplexy is distinctive for narcolepsy. Sleep paralysis (an inability to move, usually on wakening) and hypnogogic hallucinations (vivid and often frightening visual or auditory hallucinations at sleep onset) are also associated with the disease, but occur more variably. A combination of excessive daytime sleepiness and cataplexy is essential for a definite diagnosis of narcolepsy. Diagnosis is on clinical grounds but can be confirmed by EEG correlates during a multiple sleep latency test showing fast passage into REM sleep within 10 minutes of sleep onset. Genetics and Pathogenesis Most cases are sporadic, but the risk of the disorder for first-degree relatives is 12%, a 10-fold increase compared with the general population. One-third of monozygotic twins are concordant for narcolepsy. Therefore, narcolepsy is a multifactorial disorder, with contribution from both genetic and environmental factors. A genetic susceptibility factor has been found in the human leukocyte antigen class II region: HLA-DRB*1501-DQB1*0602 haplotype (OMIM 604305). Current theories suggest that narcolepsy is an autoimmune disorder which may lead to selective destruction of a subset of neurons in the lateral hypothalamus. This area is rich in neurons containing two neuropeptides, hypocretin 1 and 2 (orexin A and B), which project to most nuclei involved in regulation of sleep and wakefulness. In support of this are animal models with narcolepsy caused by targeting hypocretin-containing neurons, the finding of low levels of CSF hypocretin 1 in 90% of narcoleptics, and one case with a mutation in the gene for hypocretin (see below). Familial cases of narcolepsy are rare and those described tend to be autosomal dominant. Three genetic loci have been mapped in such families: Narcolepsy 1 (OMIM 161400). A mutation in the gene for hypocretin (OMIM 602358) on chromosome 17q 21 has been demonstrated in one patient with narcolepsy. Narcolepsy 2 (OMIM 605841). A genome-wide linkage study in eight Japanese families with 21 DR2-positive patients with narcolepsy mapped a locus to chromosome 4p13-q21. Narcolepsy 3 (OMIM 609039). A large French family with autosomal dominant inheritance was used to map this locus to chromosome 21q 11.2. A recent large genome-wide analysis in Japan found further evidence of a susceptibility locus in the HLA region, but also a possible area of linkage disequilibrium on chromosome 21q22.3 for a resistance gene. Treatment Narcolepsy is typically treated with amphetamine-like substances, and more recently with modafenil. Cataplexy has been treated with antidepressants
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(usually tricyclic such as impiramine, protriptyline). Sodium oxybate, which may act through GABA receptors, can help with fragmented nocturnal sleep, cataplexy, and narcolepsy.
Restless Legs Syndrome (RLS; OMIM 102300) Clinical Features RLS is a neurological disorder characterized by an almost irresistible urge to move the limbs which is most often, but not necessarily, accompanied by uncomfortable sensations in the legs. The symptoms are evoked by rest and are worse in the evening and at night and the upper limbs may occasionally be involved. The prevalence of RLS in the general population is between 5 and 10% and women are affected twice as often as men. The four essential diagnostic criteria are: 1. an urge to move the legs, usually accompanied by unpleasant sensations; 2. the urge to move or the sensations beginning or worsening during periods of rest or inactivity such as sitting and lying; 3. the urge to move or unpleasant sensations partially or totally being relieved by movement such as walking or stretching, at least for as long as the activity continues; 4. the urge to move or unpleasant sensations becoming worse in the evening or night or only occurring in the evening or at night. The diagnosis is also supported by a positive response to dopaminergic medication (e.g., L-dopa, dopamine agonists), which can be effective treatments, the occurrence of periodic limb movements in sleep, and a positive family history. RLS can be familial or sporadic. In the latter group it can be associated with a number of different conditions, including iron deficiency anemia, pregnancy, renal failure, peripheral neuropathy, and hypothyroidism. In some cases, treatment of the associated condition leads to resolution of RLS. Genetics Clinical surveys suggests 4090% of patients have a positive family history. Segregation analysis suggests an autosomal dominant mode of inheritance in patients with early age of onset. The majority of cases appear to be sporadic, but affected families have been described and a number of RLS genetic loci have been mapped. Family studies have suggested predominantly autosomal dominant inheritance in these individuals. Several loci for RLS have been reported: RLS1 (OMIM 102300): autosomal recessive locus on chromosome 12q12-21. RLS2 (OMIM 608831): autosomal dominant locus on chromosome 14q13-21. RLS3 (OMIM 610438): autosomal dominant locus on chromosome 9p24-22. RLS4 (OMIM 610439): susceptibility locus identified in South Tyrolean population mapping to 2q33.
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RLS5 (OMIM 611242): antosomal dominant locus on chromosome 20p13. RLS6 (OMIM 611185): susceptibility locus in population study identified for two single-nucleotide polymorphisms in the BTBD9 gene on chromosome 6p.
BIBLIOGRAPHY Farrer M (2006). Genetics of Parkinson’s disease: paradigm shifts and future prospects, Nat Rev Genet, 7, 306318. www.geneclinics.org www.wemove.org
REFERENCES Fletcher NA, Harding AE & Marsden CD (1990). A genetic study of idiopathic torsion dystonia in the UK. Brain, 113, 379395. Louis ED, Ford B, Frucht S, Barnes LF, X-Tang M & Ottman R (2001). Risk of tremor and impairment from tremor in relatives of patients with essential tremor: a community based family study. Ann Neurol, 49, 761769. Sveinbjornsdottir S, Hicks AA, Jonsson T, et al. (2000). Familial aggregation of Parkinson’s disease in Iceland. N Engl J Med, 343, 17651770. Tanner CM, Ottman R, Goldman SM, et al. (1999). Parkinson’s disease in twins: an etiologic study. JAMA, 281, 341346.
Chapter 9 Cerebrovascular Disease Thomas T. Warner
INTRODUCTION Stroke is defined as sudden loss of neurological function lasting longer than 24 hours due to interruption of cerebral blood supply. It is the second leading cause of death in the world, and the commonest cause of acquired disability in adults. The incidence of stroke is rising with increasing life expectancy. Cerebral infarction is the underlying pathogenic mechanism responsible for approximately 80% of first strokes; 10% are secondary to intracranial hemorrhage and 5% secondary to subarachnoid hemorrhage. The cause of stroke may remain undetermined in up to 5% of cases. Infarction or hemorrhage can be determined by cranial imaging, with either CT or MRI, and this is an essential investigation of all stroke patients. Cerebral infarction may arise secondary to large artery atherosclerosis, intracranial small artery occlusion, cardiac embolism or other processes (e.g., arterial dissection, prothrombotic states). Epidemiological studies involving twins, siblings, and families have found evidence of a genetic influence on stroke. From a clinical standpoint, it is important to differentiate single-gene disorders that cause stroke, from a polygenic, multifactorial genetic predisposition to stroke. The first part of this chapter will focus on single-gene disorders associated with stroke. The second part reviews genetic factors that are important in the pathogenesis of common ischemic stroke, including data from candidate gene and linkage studies.
SINGLE-GENE DISORDERS ASSOCIATED WITH STROKE Monogenic disorders are uncommon and are responsible for a minority of cases of stroke, often with younger onset. In any young patient who presents with a stroke or transient ischemic attack (TIA), a potential genetic cause should be considered, and Table 9.1 lists clinical features that should be elicited. A number of conditions in which stroke occurs are inherited in a classic 137
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Table 9.1 Genetic Causes to Consider in an Individual with Stroke/TIA (to be read in conjunction with Table 9.2) Clinical Feature
Consider Diagnosis
Previous or family history of stroke Previous or family history of thrombosis Previous or family history of heart disease History of migraine (with aura) Cognitive impairment Skin lesions Epilepsy Eye abnormality
Any genetic cause in Table 9.2 Prothrombotic disorder Cardioembolic disorder CADASIL, FHM, CCM, HHT, MELAS (Chapter 14) CADASIL, amyloid angiopathies (Chapter 3), MELAS HHT, Fabry’s disease (Chapter 11) CCM, CADASIL, HHT, MELAS Collagen disorder (e.g., Marfan’s), macular edema, and retinal microangiopathy (HERNS)
CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalophy; CCM, familial cerebral cavernous malformations; FHM, familial hemiplegic migraine; HHT, hereditary hemorrhagic telangiectasia; HERNS, hereditary endotheliopathy with retinopathy, nephropathy, and stroke; MELAS, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes.
Mendelian pattern. In many, stroke is only part of the phenotype, but in some it is the prominent or sole clinical manifestation. These conditions should be considered in the differential diagnosis of any young stroke patient, or a middle-aged stroke patient without usual risk factors, especially if there is a positive family history. Table 9.2 lists these disorders, classified according to the pathogenesis and etiology of the stroke. Some of these conditions are discussed in more detail below. A detailed description of cardiac, hematological, or collagen vascular disorders and hyperlipidemias is beyond the brief of this chapter, and because they rarely present to a neurogenetic service will not be discussed further.
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; OMIM 125310) CADASIL is a systemic non-amyloid, non-atherosclerotic vasculopathy with preferential involvement of small arterioles and arteries of the brain, which is inherited as an autosomal dominant trait. It is the most common single-gene disorder leading to ischemic stroke in adults. Clinical Features CADASIL is characterized by migraine, cerebrovascular disease progressing to dementia, and diffuse white matter lesions and subcortical infarcts on imaging of the brain. Around 40% of patients have migraine, usually with aura, which may be the first manifestation of the condition and often occurs before TIAs or stroke. More than 80% of patients with CADASIL have TIAs or stroke at an early age, with a mean age of onset of 45 years. These usually take the form of recurrent lacunar infarcts affecting the white matter and deep gray matter nuclei, but more diffuse chronic ischemic changes also occur which lead to
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Table 9.2 Single-Gene Disorders Leading to Stroke Mechanism Ischemic Stroke Small vessel
Large vessel
Large and small arteries
Cardioembolic
Prothrombotic
Arterial dissection
Mitochondrial Channelopathies Hemorrhagic Stroke Arterial bleed
Arteriovenous bleed
Condition
Gene/Locus
OMIM
CADASIL CARASIL HERNS Hereditary cerebral hemorrhage with amyloidosis Dutch type Dyslipidemias Moyamoya disease Pseudoxanthoma elasticum
NOTCH 3 Unknown 3p21.1-21.3 Amyloid b precursor protein; cystatin C Various 3p24.2-26, 17q25, 8q23 ABCC6
125310 600142 192315 609065
Fabry’s disease
a-Galactosidase A
Homocysteinuria
Cystathione b-synthase; methylenetetrahydrofolate reductase Hemoglobin S and SC Various 17q23-24
603174 236250 603903
Endoglin and ALK1
187300
Protein C gene Protein S gene Antithrombin III gene Factor V Leiden mutation Unknown Collagen type III gene Fibrillin-1 gene Unknown Mitochondrial DNA mutations CACNA1A gene
176860 176880 107300 227400 107320 130050 154700 135580 540000 141500
Sickle-cell disease Cardiomyopathies Familial atrial myxoma Familial dysrythmias Hereditary hemorrhagic telangiectasia Protein C deficiency Protein S deficiency Antithrombin III deficiency Activated protein C resistance Familial anticardiolipin syndrome Ehlers-Danlos syndrome IV Marfan’s syndrome Fibromuscular dysplasia MELAS Familial hemiplegic migraine Autosomal dominant amyloid angiopathies Familial intracranial berry aneurysms Familial cerebral cavernous hemangiomas
252350 264800 177850 301500
255960
104760 105800 CCM1 (KRIT1), CCM2 7p15-13, CCM3 (PDCD10) 3q25.2-27
116860
cognitive decline. The cognitive decline can begin as early as 35 years and progresses, so that most affected individuals have severe cognitive impairment after the age of 65. Typically, this is a subcortical type of dementia with memory disturbance, bradyphrenia, and loss of initiative. Approximately one-third of patients have psychiatric disturbance, which can vary from personality changes to severe depression. Depression may also precede the onset of TIAs or stroke. Whilst it is uncertain whether the psychiatric
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symptoms are primary or secondary to the underlying microangiopathy, or reactive in response to stroke, it is clear that psychiatric symptoms can be the presentation of CADASIL. Less common features include epilepsy, which has been reported in up to 10% of patients, and an acute reversible encephalopathy. There is also evidence of a sensorimotor peripheral neuropathy (with both axonal and demyelinating features) in some patients. The major differential diagnoses for CADASIL are those which can produce similar symptoms and MRI changes. These include multiple sclerosis (MS), Binswanger’s disease, and primary cerebral angiitis. These are sporadic disorders and the presence of a family history compatible with autosomal dominant inheritance favors a diagnosis of CADASIL. The presence of hypertension is more common in Binswanger’s encephalopathy. Involvement of the spinal cord or optic nerve does not occur in CADASIL and makes a diagnosis of MS much more likely, whereas peripheral nerve involvement favors CADASIL. CSF analysis for oligoclonal bands can be useful if there is still doubt about MS. These are present in the majority of MS patients and negative in CADASIL. Investigations. The key investigation for CADASIL is an MRI of the brain, which always demonstrates white matter abnormalities. Diffuse periventricular and deep white matter lesions are often associated with small lacunar infarcts involving the white matter, basal ganglia, and brainstem. The external capsules and temporal lobes are also often affected. Confluent involvement of the anterior temporal pole is a useful radiological sign as it is rare in sporadic cerebral small vessel disease, but is present in over 90% of patients with CADASIL. Another useful, but less sensitive, indicator of CADASIL is involvement of the external capsule. The leukoencephalopathy is often detectable on MRI prior to symptom development, and absence of white matter changes on an MRI in an individual over 35 years of age usually excludes CADASIL. Figure 9.1 shows a typical MRI scan from a patient with CADASIL. A skin biopsy can be used to confirm the diagnosis by electron microscopy of the arterioles. The highly specific characteristic finding is of granular osmiophilic inclusions adjacent to smooth muscle cells of small arteries, but requires very careful examination by an experienced pathologist and estimates of sensitivity of this test vary from 50 to 90%. CADASIL can also be confirmed by molecular genetic testing as more than 90% of patients have mutations in the NOTCH3 gene (chromosome 19p13.213.1). Most are caused by missense mutations which lead to gain or loss of cysteine residues. Screening of the five (of 33) exons with the highest mutation frequencies (3, 4, 11, 18, and 19) detects mutations in 87% of patients with skin-biopsy confirmed CADASIL. Screening of the remaining exons detects an additional 6% of mutations. In general, genetic analysis is performed to confirm diagnosis in those individuals in whom CADASIL is suspected, and who have an abnormal MRI. Pathophysiology Most mutations in NOTCH3 lead to loss of cysteine residues in one of the epidermal growth factor-like domains. Members of the NOTCH gene family
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Figure 9.1. T2-weighted MRI scan of brain of patient with CADASIL showing typical anterior temporal white matter changes.
encode evolutionarily conserved transmembrane receptors which are important in determining cell fate during development. Mutated NOTCH3 may lead to conformational changes due to disruption of disulfide bonding of the cysteine residues and may lead to aberrant cell signaling. Management There is no evidence from randomized controlled trials as to the optimal management of patients with CADASIL. Most patients are empirically treated with antiplatelet therapy for secondary stroke prevention, usually with aspirin, or with aspirin and dipridamole despite the absence of evidence of benefit. Supportive care for the affected individuals and families is helpful. Genetic Advice CADASIL is inherited as an autosomal dominant trait with almost complete penetrance, but expression varies in age of onset, severity, and progression. Most individuals with CADASIL have an affected parent, although family history can be apparently negative due to early parental death, lack of recognition of the phenotype (e.g., migraine, dementia), or late onset in a parent. Occasionally, a de novo mutation occurs. Presymptomatic and prenatal testing are available if a NOTCH3 mutation has been detected in an affected relative, using protocols similar to those for Huntington’s disease.
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Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL or Maeda Syndrome; OMIM 600142) A rare syndrome similar to CADASIL, but with apparent recessive inheritance, has been reported in a small number of Japanese kindreds. Migraine is less prominent and there may be associated extracerebral features, including alopecia, thin skin, and pronounced degenerative spine disease. Histopathology has shown intense arteriosclerosis without evidence of granular osmiophilic inclusions. No genetic locus has been identified.
Familial Cerebral Cavernous Malformations (CCM; MIM 116860) CCMs are dilated vascular sinusoids lined by an endothelial layer without normal intervening brain parenchyma or mature vessel wall elements, that can range in diameter from a few millimeters to several centimeters. Their thin walls, lack of subendothelial support, and abnormal basal lamina predispose to recurrent microhemorrhage. Slow flow of blood also promotes thrombosis. Familial CCM (FCCM) is an autosomal dominant disorder characterized by multiple cerebral vascular abnormalities that may lead to neurological deficits including cerebral hemorrhage, seizures, and headache. The diagnosis of FCCM requires the presence of multiple CCM identified by MRI scanning or histopathology in at least two family members. FCCM has been linked to three genetic loci (CCM13) and testing is available for CCM1. Sporadic CCMs are generally single, and a patient with multiple CCMs is likely to be familial, as in <75% of such cases other family members with lesions are identified on screening. FCCM is most frequently seen in Hispanic Americans, although non-Hispanic families have also been identified. Clinical Features Up to 25% of individuals with CCM remain asymptomatic throughout their lives. The majority of symptomatic patients with CCM present in adult life between the second and fifth decades, although childhood onset has been described. CCMs are dynamic and studies suggest that new lesions appear at a rate of 0.20.4 lesions per year. Around 80% of the lesions are supratentorial, although infratentorial lesions are more likely to be symptomatic, especially if they affect the brainstem. Patients most often present with seizures (4070%), focal neurological deficits (3550%), non-specific headaches (1030%) or cerebral hemorrhage. CCMs hemorrhage at a rate of 0.62% per lesion-year, or 413% per patient-year in familial cases. Occasionally this can be fatal. Cutaneous capillary venous malformations and retinal hemangiomas have occasionally been reported in families. The major differential diagnosis is multiple sporadic CCM, although multiple lesions are more common in the familial form of CCM. Other differential diagnoses include von Hippel-Lindau disease, hereditary hemorrhagic telangiectasia, and blue rubber bleb syndrome.
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Figure 9.2. T2-weighted MRI scan of the brain showing multiple cavernomas of the left occipital and frontal lobes and right temporal horn.
Investigations The key investigation is MRI scanning of the brain. The characteristic lesion on T2-weighted imaging is of mixed signal intensity with a central reticulated core surrounded by a dark ring which represents hemosiderin deposition from previous hemorrhage. Figure 9.2 shows typical MRI features of a cavernoma, which has been described as looking like ‘‘popcorn.’’ Cerebral angiography is negative with CCM. Management The major treatment issue is control of seizures. Usually this is with anticonvulsant drugs. Occasionally, cavernomas associated with intractable seizures require surgical removal. Surgical treatment may be considered in the acute situation for hemorrhage producing mass effect within the brain or for those with recurrent bleeds. However, patients should be informed that if one cavernoma is successfully removed, complications could still arise from additional cavernomas or new lesions may even develop.
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Genetic Advice FCCM is inherited in an autosomal dominant trait and patients should receive counseling with appropriate risks. Parents of a proband can be screened by MRI of the brain. The incidence of de novo germline mutations is unknown but has been described. The validity of screening family members of a proband with multiple CCMs is debatable, as asymptomatic CCMs are rarely treated. Three genetic loci have been identified for FCCM. Around 40% of families show linkage to the CCM1 locus on chromosome 7q21-q22 (MIM 604214). A single mutation in the CCM1 gene has been identified in about 70% of Hispanic families (1363C>T), and testing for this single mutation is available clinically. The CCM1 protein product, Krit1, has unknown function, although may act as a tumor suppressor gene. All mutations identified to date appear to act via loss of function. Approximately 20% of FCCM patients are linked to the CCM2 locus (chromosome 7p15-p13, MIM 603284) and 40% to the CCM3 locus (3q25.2-q27, MIM 603285). The genes have been identified recently and testing is available on a research basis.
Homocysteinuria (OMIM 603174) Several autosomal dominant and recessive enzyme deficiencies lead to increased plasma and urine homocystine levels and increased plasma methionine, although the commonest biochemical deficit is absence of cystathione b-synthase, which catalyses the conversion of homocysteine into cystathione. The full phenotype includes mental retardation, ectopia lentis, skeletal deformities, and thromboembolic cerebrovascular events. Individuals with cystathione b-synthase deficiency can be divided into those who respond to treatment with the coenzyme precursor pyridoxine (B6), and non-responders having a more severe phenotype. Thromboembolism is the most frequent cause of morbidity, with B6-responders having a thromboembolism of 0.08 events per year untreated and 0.04 treated. For non-responders the rate is 0.1 events per year untreated, and 0.06 treated. Treatment for B6-responders is a methionine-low diet and 100500 mg of pyridoxine per day. For non-responders, folate and vitamin B12 are also given. The cystathione b-synthase gene maps to chromosome 21q22.3 and homocysteinuria usually occurs in individuals homozygous for mutations. Most disease alleles appear in exons 3 and 8 of the gene. The I278T and A114V are common mutations in pyridoxine responders, whilst the G307S and A1224C mutations occur more commonly in Northern Europeans who are unresponsive to pyridoxine.
Familial Hemiplegic Migraine (FHM; OMIM 141500) FHM is a subtype of migraine with aura. It is included in this chapter as occasionally it can lead to an ischemic stroke. In addition, the hemiplegia can be misdiagnosed as a stroke unless the diagnosis of FHM is considered.
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Clinical Features The diagnosis of FHM depends on the clinical features and the presence of a family history. Migraine with aura is an idiopathic, recurring condition of neurological symptoms which can be localized to either the cerebral cortex or brainstem. The aura develops over 520 minutes and lasts less than 60 minutes and includes visual disturbance (fortification spectrum, scotoma, photopsia), hemisensory loss, and dysphasia. Headache, nausea, and vomiting usually follow the aura, immediately or after a period of less than an hour, and can last for 4 to 72 hours. Occasionally, headache can be completely absent. FHM usually has onset in the first or second decade and the number of FHM attacks tends to decrease with age. Hemiparesis (weakness of at least one limb) must occur, usually in association with at least one other symptom in the aura. Dysphasia can occur and there can also be confusion and impairment of consciousness. The neurological deficit can be prolonged in FHM, often hours to days, and may outlast the migrainous headache. Cerebral infarction is a rare complication. In FHM, a defining feature is the presence of other affected family members. The mode of inheritance is autosomal dominant with high penetrance. Some families with hemiplegic migraine are distinctive due to the presence of cerebellar signs ranging from nystagmus to progressive, lateonset ataxia. In these families linkage to a locus on chromosome 19 is found (see later). A single affected individual with migraine and hemiparetic aura may or may not have other family members with typical migraine. It is unclear how much overlap exists in the genetic basis of FHM and typical migraine. The spontaneous mutation rate for hemiplegic migraine, however, appears low. Investigations and Differential Diagnosis. In a case of FHM with definite involvement of other family members, the diagnosis is clear and investigations are limited to cranial imaging, usually with MRI. Other inherited disorders associated with migrainous headache that may include hemiplegic aura are mitochondrial disease (MELAS, MERRF), CADASIL, hereditary hemorrhagic telangiectasia, familial cerebral cavernous malformation, and hereditary cerebral amyloid angiopathy (Table 9.1). More extensive investigation may be needed for apparent sporadic cases, particularly to exclude the potential of stroke. If an infarct is present on imaging, further investigations to identify the cause or risk factors should be undertaken. Three FHM genetic loci have been identified. Approximately 50% of families show linkage to 19p13 (FHM1; OMIM 601011), including all families with FHM and ataxia. A number of mutations in the a-1 subunit of a neural voltage-dependent P/Q-type calcium-channel gene (CACNA1A) have been identified in these patients. The mutated forms of the protein appear to affect the pore or voltage sensor parts of the ion channel. An expanded CAG repeat in this gene is responsible for SCA6 (see Chapter 6), but has never been shown to cause FHM. Other mutations in this gene can cause episodic ataxia type 2.
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Linkage analysis has identified two additional loci: 1q21-q23 (FHM2; OMIM 602481) and 1q25-q31. The FHM2 gene encodes the a-2 subunit of the sodium/potassium pump (ATP1A2), but has only been described in a small number of families. Seizures have been reported in affected individuals due to mutations in this gene. Management Treatment. For all FHM types a trial of standard migraine prophylactic drugs should be undertaken (propranolol, calcium-channel blockers, tricyclic antidepressants) if the attacks are frequent. For FHM1, acetazolamide can be effective in preventing episodes. In general, vasoconstricting drugs should be avoided due to potential risk of precipitating a stroke. Cerebral angiography may also be hazardous. Prognosis. FHM is a relatively benign disorder. The main complications are the rare occurrence of stroke, and the late development of mild ataxia in FHM1-linked families. Genetic Advice In most cases of FHM, the trait is inherited in an autosomal dominant manner and appropriate risks should be given. Fifty percent of FHM families, and >90% of those with FHM and ataxia, show linkage to the FHM1 locus. T666M is the most common mutation, and limited mutation and sequence analysis is available for clinical testing. Sequence analysis for other mutations is limited by the large size (47 exons) of the gene.
Hereditary Hemorrhagic Telangiectasia (HHT; OMIM 187300) HHT is an autosomal dominant vascular dysplasia, with prevalence of 1/10,000, which leads to telangiectases and arteriovenous malformations of the skin, mucosa, and viscera. Epistaxis and gastrointestinal bleeding are the major complications of mucosal involvement. Visceral involvement includes that of the lungs, liver, and brain. Cerebral AVMs occur in 10% of individuals with HHT and can manifest with hemorrhage, migraine, or seizures. The majority of neurological morbidity, however, is the result of paradoxical emboli via pulmonary arteriovenous malformations, which are present in 40% of patients. These can lead to cerebral infarction or abscess formation. The most frequent form of HHT maps to chromosome 9q34.1, although there is evidence for genetic heterogeneity. Mutations within the gene encoding endoglin, a transforming growth factor-beta binding protein, have been identified in families with 9q34.1-linked HHT. Prevention of stroke by screening for large pulmonary AVMs is very important, either by formal angiography, or in recent years with CT or MRI angiography. Large AVMs can be closed by embolization or endovascular coiling. This reduces the risk of paradoxical emboli, and also the risk of heart failure.
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Familial Intracranial Berry Aneurysm (OMIM 105800) There have been reports of families with berry aneurysms or subarachnoid hemorrhage (SAH), usually showing autosomal dominant inheritance. In addition, there have been a number of studies to estimate the risk to first-degree relatives of an individual with an aneurysmal SAH. A comprehensive study in 1999 prospectively screened over 600 first-degree relatives of 160 patients with sporadic SAH with magnetic resonance angiography (Magnetic Resonance Angiography Study Group 1999). Aneurysms were found in 4% of firstdegree relatives. Surgery was performed in the majority, but the resulting slight increase in life expectancy that this imparted was offset by postoperative complications. The conclusion was that a screening program was not warranted as the majority of aneursysms are small and do not rupture. A more recent study in Scotland found a 4.7% lifetime risk of SAH in first-degree relatives of a patient with SAH, and this figure increased if two first-degree relatives were affected (Teasdale et al. 2005). At present, for individuals where there is a clear family history of aneurysmal SAH, screening with MRA is recommended, with repeat MRA after intervals of 510 years. The guidelines are not definitive as endovascular treatment of anerurysms appears to have lower morbidity and mortality than surgery, and screening with CT angiography may become more sensitive than MRA. The screening situation is clearer for individuals with autosomal dominant polycystic kidney disease (ADPCKD; OMIM 173900) who have multiple renal and hepatic cysts, diverticulosis, cardiac valvular defects, and intracranial aneurysms. The prevalence of intracranial aneurysms in ADPCKD patients is 510%, and they have a higher risk of rupture than sporadic aneurysms. It should be noted, however, that despite the high mortality of ruptured intracranial aneurysms, hypertensive intracerebral hemorrhage is a more common cause of cerebrovascular mortality in these patients. In the general population, a number of genetic linkage studies have reported positive findings for various genetic regions and putative candidate genes, although no causative mutations have been identified.
Moyamoya Disease (OMIM 252350) Moyamoya disease is a rare cause of ischemic stroke in children and juveniles, and of subarachnoid hemorrhage in adults. The term is used to describe the characteristic findings on cerebral angiography with bilateral intracranial carotid artery occlusion with associated telangiectatic vessels in the circle of Willis, particularly in the basal ganglia. A high incidence of Moyamoya is found in Asia, predominantly in Japan. The name is Japanese, and said to describe little puffs of smoke, which resemble the angiographic changes of the vessels. Clinically, children present with stroke, especially hemiplegia, but can also have epilepsy. In adulthood, presentation is more often with subarachnoid hemorrhage. Most cases appear sporadic, and approximately 10% are familial, with around 75% occurring in sibs and 25% in a parent and offspring, although
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the true familial rate may be higher and this reflects the fact that diagnosis is made with angiography. Three genetic loci have been mapped (MYMY1, 3p26p24.2, OMIM 252350; MYMY2, 17q25, OMIM 607151; MYMY3, 8q23, OMIM 608796), but no gene has been cloned. Due to the fact that Moyamoya disease appears to be inherited in recessive or dominant modes, genetic risks are hard to predict, unless there is a clear family history.
GENETIC RISK FACTORS FOR ISCHEMIC STROKE The cause of most common strokes is multifactorial and involves both genetic variants and environmental factors. Studies in families have estimated that the relative risk of stroke to a first-degree relative of a patient who has had a stroke is between 1.5 and 2.5. Such a risk is low at an individual level and does not have major practical clinical implications, particularly when compared with established risk factors such as hypertension, diabetes, elevated lipids, smoking, and alcohol. However, at a population level, this slight increase in the risk of stroke is important due to the high incidence of ischemic stroke. Numerous studies have attempted to identify genetic polymorphisms and candidate genes which may be responsible for increased genetic risk. It is beyond the brief of this book to list these studies, particularly as genetic association studies can be methodologically flawed and positive findings have been difficult to replicate. None of the potential associations reported to date has led to definitive testing for stroke risk factors.
Stroke Susceptibility Locus (STRK1; OMIM 606799) A recent development in understanding stroke genetics has been the identification of a potential susceptibility locus (STRK1). A genome-wide screen on 179 pedigrees with at least two members with ischemic stroke in Iceland identified evidence for linkage to chromosome 5q12 with a multipoint allele-sharing LOD score of 4.40. One difficulty with this study is that all types of ischemic stroke were used, including thrombotic, embolic large, and small vessel, making the cohort a pathophysiologically heterogeneous group. A 20 cM region was physically and genetically mapped and the strongest association with stroke was found for the gene encoding phosphodiesterase 4D (PDE4D, OMIM 600129), especially for carotid and cardiogenic stroke. PDE4D is a regulator of cyclic AMP levels, and is proposed to control the level of smooth muscle proliferation and immune function in vessels, thereby leading to increased or decreased atherosclerosis and hence ischemic stroke risk. Another gene identified which appeared to be associated with increased risk of stroke (and myocardial infarct) was ALOX5AP on chromosome 13q, which codes for arachidonate-5-lipoxygenase activating protein (OMIM 603700). For both the PDE4D and ALOX5AP potential susceptibility loci, no causative mutations have been identified and subsequent association studies have provided both positive and negative results.
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BIBLIOGRAPHY www.geneclinics.org Majersik J & Skalabrim E (2006). Single-gene stroke disorders. Semin Neurol, 26, 3348.
REFERENCES Magnetic Resonance Angiography in Relatives of Patients with Subarachnoid Hemorrhage Study Group (1999). Risks and benefits of screening for intracranial aneurysms in first degree relatives of patients with sporadic SAH. N Engl J Med, 341, 13441350. Teasdale GM, Wardlow J, White P, Murray G, Teasdale E, Easton V & Cooper D (2005). Scottish aneurysm study group. The familial risk of subarachnoid haemorrhage. Brain, 12, 16771685.
Chapter 10 Motor Neuron Diseases Thomas T. Warner
INTRODUCTION Motor neuron diseases are a heterogeneous group of disorders characterized pathologically by death of motor neuron cells. They can be sporadic or genetic and are classified clinically according to whether they involve upper or lower motor neurons, or both. Upper motor neuron involvement leads to positive neurological features including spasticity, brisk reflexes, clonus, and extensor plantar responses, as well as negative features such as weakness and loss of dexterity. Spasticity is defined as the velocity-dependent increase in muscle tone as assessed by passive movement of the limbs. The term is used to define the stiffness and other features seen due to damage to descending motor pathways in the central nervous system. This damage, frequently in the spinal cord, leads to abnormal hyperexcitability of the tonic stretch reflex. In practical terms the patient with spastic legs complains of difficulty walking, stiffness or heaviness of the legs, weakness, fatigue, and reduced exercise tolerance. They may also have cramps or ‘‘bounciness’’ of the legs due to spontaneous clonus. Lower motor neuron loss, on the other hand, leads to muscle wasting with fasciculation, weakness, and reduced or loss of reflexes. A clinical classification of motor neuron diseases is outlined in Table 10.1, along with important differential diagnoses.
DISORDERS OF LOWER MOTOR NEURONS Table 10.2 lists the major genetic disorders affecting lower motor neurons, which are dominated by the spinal muscular atrophies. Spinal Muscular Atrophy (SMA) SMA is characterized by degeneration and loss of the anterior horn cells in the spinal cord and sometimes in the brainstem nuclei, resulting in symmetrical 150
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Table 10.1 Clinical Classification and Differential Diagnoses for Motor Neuron Diseases Important Treatable Differential Diagnosis
Clinical Classification Lower Motor Neuron Disorders Spinal muscular atrophy Spinobulbar muscular atrophy Hereditary motor neuropathies
Upper Motor Neuron Disorders Primary lateral sclerosis Hereditary spastic paraplegia Mixed Upper and Lower Motor Neuron Disorders Amyotrophic lateral sclerosis Complicated HSP/hereditary motor neuropathy
Investigations
Multifocal motor neuropathy with conduction block, pure motor chronic inflammatory demyelinating neuropathy, toxic neuropathies, myasthenia gravis
EMG/nerve conduction studies, genetic tests (e.g., SMA, SBMA)
Spinal cord compression, multiple sclerosis, adrenoleukodystrophy, vitamin B12 deficiency
MRI scan of brain and spine, CSF analysis, blood tests: vitamin B12, white cell enzymes, genetic tests
Compressive myeloradiculopathy, HIV infection, paraneoplastic syndromes, arteriovenous dural fistula
MRI spine, HIV serology, CSF analysis
muscle weakness and atrophy which is progressive. It is predominantly a disorder of newborns and infants, although the clinical spectrum extends to onset in young adults. SMA is the second most common lethal autosomal recessive disorder after cystic fibrosis and with prevalence of approximately 1 in 6000 live births, and carrier frequency of around 1 in 50. Prior to clarification of the molecular genetic basis to SMA, it was classified into discrete subtypes. It is now clear, however, that the phenotype of SMA associated with pathogenic mutations in the survival of motor neuron (SMN1) gene spans a continuum without clear delineation of subtypes. The subtypes based on age of onset do still have clinical use, particularly for prognosis and management.
Table 10.2 Lower Motor Neuron Diseases Disorder
OMIM
Inheritance
Location
Gene
Spinal muscular atrophy Spinal muscular atrophy (adult onset) Spinobulbar muscular atrophy GM2 gangliosidosis Hereditary motor neuronopathy 2 Hereditary motor neuronopathy 5
253300
AR
5q11.2-13.3
158590
AD
12q24
Survival of motor neuron (SMN) Unknown
313200
XL
Xq21-22
Androgen receptor
272800 158590
AD AD
15q11.2-13.3 12q24
600361
AD
7p and 11q
Hexosaminidase A Small heat shock proteins B1 and B8 Glycyl tRNA synthetase (7p) and BSCL2 (11q)
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Table 10.3 Differential Diagnosis for SMA Spinal Muscular Atrophy SMA I
SMA II
SMA III
SMA IV
Differential Diagnosis Causes of floppy child: Chromosomal disorders Prader-Willi Peroxisomal disorders (hepatosplenomegaly, hearing loss, retinopathy) Infantile acid maltase deficiency (cardiomegaly) Myopathy: nemaline, central core Congenital myotonia Congenital muscular dystrophy As for SMA I Motor neuropathies (e.g., multifocal motor neuropathy with conduction block) Muscular dystrophies (e.g., Duchenne) Congenital myopathies Metabolic myopathies Motor neuropathies Consider ALS with only lower motor neuron signs
Tests to Consider in Addition to EMG
Karyotype, muscle biopsy, very longchain fatty acids and phytanic acid, fibroblast assays
EMG/NCS EMG/NCS, muscle biopsy
Clinical Features Prenatal onset of SMA is associated with reduced fetal movements and polyhydramnios, often with breech presentation. Neonates have severe weakness, joint contractures, facial diplegia, and ophthalmoplegia and require ventilatory support from birth. Where there are joint contractures affecting at least two regions of the body it is sometimes referred to as arthrogryposis multiplex congenital-SMA. Death usually occurs from respiratory failure in the first month of life. The clinical classification by age of onset is listed below. Table 10.3 shows differential diagnoses that should be considered, and Table 10.4 lists rarer forms of SMA and motor neuropathies. SMA I (acute SMA; Werdnig-Hoffmann disease; OMIM 253300). In this group onset is before 6 months of age. Proximal symmetric muscle weakness, lack of motor development and poor muscle tone are the major clinical manifestations. The key feature is that children do not achieve the ability to sit unaided. Facial and oculomotor muscles are spared, but feeding is poor. Death due to respiratory failure occurs before the age of 2 years. SMA II (intermediate SMA; OMIM 253550). This follows a more benign course with the child being able to sit but never gaining the ability to walk unaided. The onset of proximal weakness is before 18 months and survival is beyond 4 years.
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Table 10.4 Hereditary Motor Neuropathies and Other Forms of SMA Disorder (Overlap Syndromes)
OMIM
Distal HMN-I (dominant SMA)
606595
Distal HMN-II (scapuloperoneal SMA, CMT2F)
158590, 608014
Distal HMN-III
Distal HMN-IV
SMA with respiratory distress (SMARD)/ HMN-VI
604320, 600502
Distal HMN-V (CMT2D)
600794, 601472, 600287
Distal HMN-VB (Silver syndrome, SPG17)
600794, 270685, 606158
Distal HMN-VII
158580
Distal HMN-VII (distal spinal and bulbar muscular atrophy) Congenital distal SMA
607641, 601143
600175
Fazio-Londe disease
211500
Inheritance and Clinical Features AD, juvenile onset with distal weakness and wasting AD, adult onset with distal wasting and weakness AR, early adult onset, slow progressive weakness/wasting AR, juvenile onset, severe muscle wasting, diaphragmatic paralysis AR, severe distal muscle wasting and diaphragm involvement AD, upper limb predominance, occasionally pyramidal signs AD, prominent hand muscle wasting, mild to severe lower limb spasticity AD, adult onset with vocal cord paralysis AD, adult onset with vocal fold paralysis and facial weakness AD, congenital nonprogressive HMN with contractures AR, lower cranial nerves involved, onset 2nd decade, death in 5 years
Locus/Gene Unknown
Small heat shock proteins B8 on 12q24.3, and B1 on 7q11-q21 for CMT2F 11q13
11q13
SMARD I: immunoglobulin m-binding protein 2 gene, 11q13.2-q13.4 7p15, glycyl tRNA synthetase (GARS) gene 11q12-q14, BSCL2 gene
2q14 2p13, dynactin gene
12q23-q24
Unknown
SMA III (Kugelberg-Welander disease; OMIM 253400). Proximal weakness occurs after 2 years of age and the child gains the ability to walk until the weakness progresses. Survival into adulthood is common. SMA IV (OMIM 271150). This is a more controversial entity and has been defined as having onset after the age of 30 years. By definition, motor milestones are normal, the condition is slowly progressive and lifespan is usually normal.
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Investigations Prior to the availability of genetic testing, investigations would include neurophysiological studies, biochemical tests for metabolic diseases, and muscle biopsy. These are unnecessary if a child presents with a typical clinical picture and has a positive genetic test for the SMN1 gene (see below). EMG reveals denervation and diminished motor neuron action potential. Spontaneous motor unit activity is a feature of SMA, especially type I. Muscle biopsy reveals evidence of denervation (group atrophy of type 1 and 2 muscle fibers and variation in fiber size) with no other structural abnormalities, storage material, or dystrophic changes. Genetics and Pathophysiology SMA is linked to chromosome 5q13 in more than 95% of patients, where there is a large inverted duplication of a 500-kb element. Within this region is the SMA determining gene, the survival of motor neuron (SMN) gene, which is also duplicated and both copies expressed. The two SMN genes are highly homologous and only differ at 5 base-pairs. These differences (in exons 7 and 8) are used to distinguish the telomeric (SMN1) from centromeric (SMN2) copy in DNA analysis. SMA of all types is associated with homozygous mutation (invariably deletions) of the SMN1 gene. The centromeric SMN2 cannot compensate for SMN1 deletion because the sequence difference in exon 7 leads to exon skipping. Approximately 95% of individuals with SMA caused by mutations of SMN1 are homozygous for deletions which can be detected by a PCR-RFLP assay which tests for deletion of exon 7 and 8. This is used for diagnostic and prenatal testing. About 5% of cases are compound heterozygotes for exon 7 deletion of SMN1 and small intragenic mutations, of which the most frequent are the Y272C missense and 813ins/dup11 frameshift mutations in exon 6. These are not always detectable in current DNA testing protocols. Thus, the presence of two exon 7 deleted SMN1 alleles in a symptomatic individual is diagnostic for SMA, and the presence of only one is supportive of the diagnosis. Carrier detection in SMA relies on quantitative SMN1 gene dosage analysis. A PCR-based dosage assay determines the number of SMN1 gene copies to allow carrier detection. There are, however, a number of limitations to carrier detection using this test: 1. Technical limitations: a. Some carriers have two SMN1 gene copies on one chromosome and so deletion of the copy on the other chromosome is not detected by a dosage test. b. Some carriers have one normal copy and a subtle intragenic SMN1 mutation of the other copy. 2. Interpretation limitations: a. De novo mutations can occur in 2% of patients with SMA, meaning that only one parent is a carrier. The SMN protein is a 38-kDa polypeptide that is ubiquitously expressed, but is present in high levels in spinal motor neurons. SMN appears
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to be required for pre-mRNA splicing in the nucleus, and also assembly of spliceosomal small nuclear ribonuclear proteins in the cytoplasm. It has been suggested that mutant SMN leads to an impaired capacity of motor neurons to produce specific mRNAs which become deficient in proteins necessary for growth and function of these cells, leading to their death. Prognosis The prognosis for the various forms of SMA varies widely and is discussed above. Management The management of SMA involves supportive and preventive strategies. Physiotherapy and occupational therapy are used to promote and maintain gross motor function and fine motor skills. Respiratory function should be monitored with forced vital capacity. Supportive measures with non-invasive ventilation can be used successfully for SMA II and III, as long as there is sufficient orofacial muscle strength. Long-term ventilatory support for children with SMA1 is usually not considered. Early discussion with the family about the management of respiratory failure and, where appropriate, ‘‘do not resuscitate’’ status is helpful. Attention to nutritional status and to orthopedic complications, such as corrective spinal surgery for scoliosis, is important. Experimental approaches which may be of value in the future include attempts to up-regulate expression of SMN2 gene to increase the amount of transcribed SMN protein, and viral delivery of the SMN1 gene to motor neurons. Genetic Advice SMA is inherited as an autosomal recessive trait and approximately 98% of parents of an affected child are asymptomatic obligate heterozygotes with disease-causing mutations of the SMN1 gene. About 2% of parents are not carriers as their child has a de novo disease-causing mutation. Standard risks are given to unaffected siblings of a proband with SMA for an autosomal recessive disorder. Only patients with milder forms of SMA are likely to reproduce and all of their offspring will be carriers. Dosage testing for carrier detection may be considered in parents of a single child with SMA in whom the diagnosis has been confirmed with direct DNA testing. There are limitations in interpretation in that a de novo mutation can occur in up to 2% of individuals, and 4% of the population can have two SMN1 genes on a single chromosome. This means that approximately 6% of parents of a single child affected with SMA have normal results of SMN dosage testing. Thus, the finding of normal SMN1 dosage in a parent significantly reduces, but does not eliminate, the risk of the parent being a carrier for SMA. Further study by linkage analysis including other family members may allow clarification of these two situations, since documentation of a de novo mutation in the child reduces the couple’s risk of having additional affected children.
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For parents of a deceased child with SMA in whom DNA testing was not performed, carrier detection can be performed, although the interpretation can be difficult as discussed above. Carrier testing is also performed in at-risk relatives of a patient with SMA who is homozygous for exon-7 deleted SMN1 or unrelated partners of known SMN1 deletion carriers. Prenatal testing is possible for fetuses at 25% risk, when the disease-causing SMN1 mutations in both parents are known.
X-Linked Spino-Bulbar Muscular Atrophy (SBMA; OMIM 313200) SBMA, or Kennedy’s disease, is an X-linked lower motor neuron disease affecting proximal limb and bulbar muscles, associated with mild androgen insensitivity. Clinical Features SBMA is a relatively rare disorder, with estimated prevalence of 1 in 40,000, but is particularly common in some regions of Japan and western Finland due to a founder effect. It only affects males and has onset of weakness usually between 15 and 50 (mean 27) years of age, although symptoms of muscle pain, exhaustion, and gynecomastia may be noted in adolescence. Common symptoms are of slowly progressive proximal and bulbar weakness and atrophy with fasciculations, particularly affecting the facial muscles and tongue. Additional features include signs of androgen insensitivity, including gynecomastia (Fig. 10.1), testicular atrophy, and infertility, as well as diabetes mellitus, tremor, and subclinical sensory neuropathy or neuronopathy. Heterozygous females can have mild manifestations in later life. Muscle cramps are common, and around 20% have fasciculations and tongue atrophy by their sixties. Tables 10.1 and 10.2 document conditions that can lead to progressive muscular weakness and mimic SBMA. Occasionally it can be confused with ALS, although an X-linked inheritance pattern, absence of upper motor
Figure 10.1. Individual with SBMA demonstrating gynecomastia.
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neuron signs, much slower progression and features such as tremor, gynecomastia, and sensory involvement should allow SBMA to be distinguished in most cases. Other specific conditions that affect the bulbar musculature but should be clinically distinguishable include Fazio-Londe syndrome (OMIM 211500), which can be autosomal recessive or dominant and produces a progressive bulbar palsy of childhood. Brown-Vialetto-van Laere syndrome (OMIM 211530) can be either autosomal recessive or dominant, although most cases are sporadic. Onset is usually in the second decade with slowly progressive bulbar palsy and sensory-neural deafness. The Worster-Drought syndrome (OMIM 185480) is a congenital pseudobulbar palsy presenting in childhood and usually associated with limb spasticity, dysphasia (expressive>receptive), and learning difficulties. Investigation Creatine kinase levels are often elevated and EMG demonstrates a neurogenic pattern with chronic partial denervation and reinnervation. Nerve conduction studies show reduced sural sensory action potentials in up to 80% of cases with reduced or absent posterior tibial somatosensory evoked potentials. The diagnostic test of choice is DNA analysis for an expanded CAG repeat in the first exon of the androgen receptor gene which maps to chromosome Xq11-q12. The number of CAG repeats within the gene is 11 to 35 in normal subjects, but expands from 38 to 62 in patients. The clinical significance of alleles of 35, 36, and 37 CAG repeats varies from laboratory as different techniques are used and the results should be treated with caution. As with other CAG repeat disorders, there is a correlation between increasing CAG repeat size and disease severity: people with longer expansions have earlier age of onset of weakness and more rapid progression. Muscle biopsy is unnecessary in the context of genetic confirmation: it shows neurogenic changes with or without myopathic features. Pathophysiology In autopsy cases the findings are of marked depletion of lower motor neurons throughout all spinal segments and in the brainstem motor nuclei except the third, fourth, and sixth cranial nerves. In common with other CAG repeat disorders, it is believed that the polyglutamine repeat in the androgen receptor protein confers a toxic gain of function. The hallmark of CAG repeat pathology, the neuronal intranuclear inclusion, is found in neurons (see Chapter 1). Evidence suggests that accumulation of mutant protein causes dysfunction of nuclear transcriptional regulatory proteins which leads to cell death. In SBMA this may be a ligand (androgen) dependent process. Prognosis The weakness slowly progresses, sometimes necessitating use of a wheelchair, although lifespan is usually unaffected. Most patients eventually have some dysarthria and dysphagia, which becomes life-threatening in around 10% of elderly patients.
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Management Supportive and preventive treatment is important, with physiotherapy and rehabilitation approaches. The use of orthoses and walking aids can be helpful. Speech and language therapy and dietetic input is important and, where dysphagia is severe, a percutaneous endoscopic gastrostomy should be considered. There is no convincing evidence that androgen or anti-androgen therapy is effective in SBMA. Genetic Advice Genetic advice should be based on that for an X-linked recessive disorder. The incidence of de novo mutations is unknown, but the mother of a male proband is likely to be a heterozygote. Carrier testing is available after appropriate counseling. Prenatal testing for pregnancies of women known to be carriers of an expanded allele can be performed by chorionic villous sampling, although careful counseling is required.
Hereditary Motor Neuropathies (HMN) The hereditary motor neuropathies are a heterogeneous group of disorders which have clinical overlap with SMA and hereditary spastic paraplegia (HSP). The pathological process occurs in the motor neuron cell body in the ventral horn. They can present mimicking classic or distal SMA, typically with progressive weakness and wasting of extensor muscles of the toes and feet, with later involvement of distal upper limb muscles. Foot deformity is a common feature. Additional features are present in ‘‘complicated’’ distal HMN, including predominant hand involvement, vocal cord paralysis, diaphragm paralysis, and pyramidal tract signs. The original classification was clinical and dependent on age of onset, distribution of weakness and wasting (distal or proximal), mode of inheritance, and presence of additional features. With identification of genetic loci and genes, the classification has become more blurred, with overlap with forms of SMA or HSP. Most cases have autosomal dominant inheritance, which helps distinguish them from classical SMA, and it is likely that the cases of dominant distal SMA and HMN are the same entity. Table 10.4 describes the various forms of HMN and SMA and their overlap with other LMN disorders.
DISORDERS OF BOTH UPPER AND LOWER MOTOR NEURONS Amyotrophic Lateral Sclerosis (ALS) or Motor Neuron Disease ALS is a progressive neurodegenerative disorder involving both upper and lower motor neurons with prevalence of 46 per 100,000 population. Lower motor neuron degeneration in the spinal cord leads to muscle wasting, weakness, fasciculation, cramps, and hyporeflexia. Upper motor neurons in the motor cortex send their axons via the corticospinal tracts and degeneration of these
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leads to increased muscle tone, hypereflexia, and extensor plantars. Most forms appear sporadic, with familial forms comprising a minority of cases. Clinical Features The diagnostic criteria for ALS include the presence of upper and lower motor neuron degeneration with progressive phenotype in the absence of evidence to indicate other disorders. The typical presentation is with asymmetric weakness and wasting in the limbs associated with evidence of corticospinal tract damage which comes on insidiously over months. Disease often begins in one limb with either foot drop or wasting of intrinsic hand muscles. Fasciculations are often prominent in affected muscles. It can present with a combination of bulbar and corticobulbar symptoms dysphagia, dysarthria, tongue wasting, and clumsiness. Regardless of site of onset, wasting and weakness eventually affect other muscles, although extraocular muscles and sphincter function are spared. The mean age of onset for sporadic ALS is 56 years. Familial ALS (FALS) is clinically identical to ALS, but has an earlier mean age of onset of 46 years. FALS consititutes around 10% of all cases of ALS. Autosomal dominant, recessive and X-linked modes of inheritance have been described and the monogenic forms of FALS are listed in Table 10.5, along with the genetic loci and genes. The familial forms are discussed below. A number of conditions should be considered in the differential diagnosis, including spondylotic myeloradiculopathy, myasthenia, tumors (meningeal, brainstem), multifocal motor neuropathy, postpoliomyelitis syndrome, endocrinopathies (hyperparathyroid and hyperthyroid states), paraneoplastic syndromes, lead intoxication, and infections (Table 10.1). Investigations There is no specific test for ALS, which remains a clinical diagnosis. The main purpose of investigation is to exclude potentially treatable alternative diagnoses and resolve diagnostic uncertainty. If clinical signs are restricted to the limbs it is compulsory to perform an MRI to detect possible spinal cord and nerve root compression. For a pure upper motor neuron syndrome, MRI of the entire neuraxis may be required. High-quality neurophysiology is essential to support the diagnosis, or exclude alternatives (e.g., multifocal motor neuropathy with conduction block). At best these studies are confirmatory, not diagnostic. Typically in ALS, motor and sensory nerve studies are normal and electromyography reveals diffuse fibrillation and fasciculation. Pathophysiology The pathology of ALS includes loss of motor neurons in the spinal ventral horns, most brainstem motor nuclei and motor cortex. Histology shows ubiquinated inclusions in lower motor neurons and axonal swellings that are thought to contain disarrayed neurofilaments. The exact mechanism underlying selective motor neuron degeneration is unclear but there is evidence to implicate many potential factors, including oxidative damage, excitotoxicity,
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Table 10.5 Monogenic Forms of ALS Locus
Inheritance
OMIM
Clinical Features
Gene/Mutation
ALS1 (21q22)
AD (AR)
105400
Typical ALS
ALS2 (2q33-q34)
AR
205100
ALS3 (18q21) ALS4 (9q34)
AD AD
606640 602433
Young-onset ALS, long survival, juvenile PLS, AR HSP, infantile ascending HSP Typical adult-onset ALS Juvenile slowly progressive ALS
ALS5 (15q12-q21)
AR
602099
Superoxide dismutase 1 (147450), missense common in AD ALSIN (606352), deletions cause truncated protein Unknown Senataxin gene (608465), missense mutations Unknown
ALS6 (16q12) ALS7 (20ptel-p13) ALS8 (20q13.33)
AD AD AD
608030 608031 608627
ALS X (Xp11-q12) FTDP (17q)
X-linked dominant AD
600274
Frontotemporal dementia, parkinsonism +/ ALS
ALS-FTD (9q21)
AD
105550
Frontotemporal dementia and ALS
Similar to ALS2 except does not involve face and bulbar muscles Adult-onset FALS Adult-onset FALS Adult-onset ALS, predominant lower motor neuron
Adult onset
Unknown Unknown Vesicle-associated membrane protein/ synaptobrevinassociated membrane protein B (VAPB) (605704) Unknown Microtubuleassociated protein tau (157140) (splicing mutations) Unknown
ALS, amyotrophic lateral sclerosis; PLS, primary lateral sclerosis; HSP, hereditary spastic paraplegia; FALS, familial ALS; FTD, frontotemporal dementia; FTDP, frontotemporal dementia with parkinsonism
apoptosis, abnormal neurofilament function, defects in axonal transport, aberrant protein processing and degradation, increased inflammation, and mitochondrial dysfunction. Study of those genes which, when mutated, can lead to ALS suggests a number of mechanisms which result from abnormal interaction between proteins, which not only leads to loss of function of those proteins, but more importantly to gain of function, e.g., toxic effect on neurons. Increasingly, potential susceptibility genes are being reported for sporadic ALS, and it is likely that in most cases a complex interplay between genetic and environmental factors is causal. Genetics of ALS A number of genetic loci, with dominant, recessive, and X-linked patterns of inheritance, have been associated with familial ALS and associated ALS syndromes (Table 10.5). Autosomal dominant inheritance is the most common pattern.
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ALS1 (SOD1). Mutations in the gene for SOD1 are found in approximately 20% of families with FALS. Most are missense point mutations, although there are nonsense mutations, deletions, and insertions. The clinical features of patients with SOD1 ALS are usually indistinguishable from those of patients without the mutation, although onset with monomelic leg weakness suggests SOD1 FALS. Age of onset is, on average, 10 years earlier than sporadic ALS and 3.5 years earlier than non-SOD1 FALS. Approximately 3% of patients with no family history of ALS have SOD1 mutations. Inheritance is generally autosomal dominant and penetrance may be incomplete (90% by 70 years) and complicated by age dependence. The most common mutation is in exon 1, Ala4Val, which is associated with a rapid onset and progression, whilst His46Arg is linked with later onset and slower progression. In Sweden and Finland, recessive inheritance is recognized for the D90A SOD1 mutation (which causes AD FALS in other populations) where there is a common founder haplotype, suggesting that there is a linked cisacting protective factor that makes this mutation recessive in this specific genetic background. The gene encodes the protein zinc-copper superoxide dismutase 1, but it is unclear how mutations lead to motor neuron cell death. Most mutations affect subunit folding or ability of the protein to form a dimer, although some influence the copper binding site. A number of hypotheses have been put forward, including excitotoxic cell damage, toxic gain of function, or predisposition of neurofilament deposition in the cell. Other ALS Genes. These are listed in Table 10.5 and generally they relate to small numbers of families and there are no available genetic tests for the genes. Despite an increasing number of loci and genes being identified, the majority of cases of FALS do not have identifiable genetic loci. ALS2 encodes the protein alsin, which has been implicated in three autosomal recessive upper motor neuron disorders of childhood; ALS2, juvenile primary lateral sclerosis (PLS), and infantile-onset ascending spastic paralysis. Onset is usually in the first 10 years of life (mean 6.5) and very slowly progressive, such that individuals can still be ambulant at 40 years of age. Loci have been mapped for ALS38, but their significance for the majority of patients is unclear. The ALS4 locus was originally mapped in a large family with juvenile-onset autosomal dominant ALS. The unusual feature was normal life-expectancy. Subsequently other AD juvenile-onset ALS families have been identified and mutations found in the senataxin (SETX) gene. Interestingly, recessive loss-of-function mutations are associated with a separate condition, ataxia-oculomotor apraxia type 2 (see Chapter 6). The phenotypic differences between these disorders and distinct pattern of inheritance suggests that dominant ALS4 mutations cause a toxic gain of function, resulting in a motor neuron specific phenotype. ALS8 was described in a number of Brazilian families with AD FALS with onset 2555 years. Bulbar involvement was common, but progression was slow. The same missense mutation (Pro56Ser) in the gene for vesicle-associated membrane protein B (VAPB) was identified in all families.
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Table 10.6 Potential Susceptibility Genes for Developing ALS Protein
Gene (OMIM)
Localization
Variant
Association
Neurofilament heavy chain Vascular endothelial growth factor Survival of motor neuron 1 Survival of motor neuron 2 Apolipoprotein E Glutamate transporter Glutamate receptor Ciliary neurotrophic factor Angiogenin
NEFH (162230)
22q12
Deletions
Sporadic
VEGF (192240)
6p12
Promoter SNPs
Sporadic
SMN1 (600354)
5q12.2-q13.3
Copy number
Sporadic
SMN2 (601627)
5q12.2-q13.3
Copy number
Sporadic
APOE (107741) EAAT2 (600300) GLUR2 (138247) CNTF (118945)
19q13.2 11p13-p12 4q32-q33 11q12.2
e4 genotype Decreased expression Altered RNA editing Null allele
Sporadic Familial, sporadic Sporadic Familial
ANG (105850)
14q11.2
Familial, sporadic
HFE (235200)
6p21.3
SNPs and missense mutations SNPs
SPG4 (182601)
2p22-p21
Duplication mutation
Sporadic
Hemochromatosis gene Spastin
Sporadic
A small number of families have been reported where typical features of frontotemporal dementia cosegregate with ALS. The features of FTD are described in Chapter 3. Five families with AD ALS-FTD were mapped to chromosome 9q21. Within any family around 75% of those with ALS develop FTD. Mean age of onset is 54 years and the disease course rapid (34 years). Sporadic ALS and Susceptibility Genes. Considering that mutations in ALS genes occur in patients with familial as well as some cases of sporadic ALS, probably more than 10% of ALS can be explained by the multiple autosomal dominant and recessive forms. Most of the remaining cases of sporadic ALS are thought to result in interaction of susceptibility genes and environmental factors. A considerable research thrust has been to identify these susceptibility genes and Table 10.6 lists those thought to potentially contribute to the development of ALS. A recent development has been the finding of mutations within the gene for angiogenin (ANG) segregating with familial and sporadic ALS. ANG is similar to another gene implicated in ALS (vascular endothelial cell growth factor, VEGF), both of which are potent mediators of new blood vessel formation, and this supports the role for hypoxia-inducible genes in motor neuron degeneration. It should be noted that, at present, none of those listed can be used practically in the genetic diagnosis of ALS. Prognosis ALS is usually relentlessly progressive and around 50% of patients are dead 23 years after diagnosis. However, 20% are alive at 5 years, and 5% at 10 years. The prognosis is generally worse if the onset of disease is bulbar
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and there is early evidence of respiratory involvement. A predominantly lower motor neuron picture is generally more slowly progressive. Of the familial forms, those associated with SOD1 mutations have similar prognosis to sporadic ALS. Families linked to the ALS2, 4, and 5 loci appear to have much longer survival, despite earlier age of onset. Management Patients with all forms of ALS have complex treatment needs which are best addressed by a multidisciplinary team. This should include a physiotherapist to advise on mobility, postural support, and prevention of contractures; a speech and language therapist to assess swallowing and provide communication aids; an occupational therapist to provide aids to maintain function (e.g., wheelchair); a dietician to advise on maintaining weight and enteric feeding where necessary. Patient support groups also provide invaluable advice and psychological support. As for SMA, particular care should be taken to monitor swallowing and respiratory function (with FVC) as patients can benefit from enteric feeding and non-invasive ventilatory support. The only drug licensed for use in ALS is riluzole, which is thought to act via glutamate inhibition. Clinical trials have shown mild slowing of disease progression. Liver function should be monitored. Genetic Advice Advice will depend on the mode of inheritance. A rare kindred with X-linked dominant ALS has been described. Autosomal dominant forms of FALS are the most prevalent. SOD1 mutations are the only DNA tests widely available for (AD) FALS. When SOD1 mutations are detected within a family, most genetic centers use a protocol similar to Huntington’s disease for predictive testing. Prenatal tests can also be offered but may be complicated by the need to test an asymptomatic at-risk parent first.
PURE UPPER MOTOR NEURON SYNDROMES A common presentation in the neurology clinic is of a patient with spastic paraplegia. A wide range of diagnoses must be considered but the main neurogenetic cause is hereditary spastic paraplegia (HSP). Other causes include cerebral palsy (CP) and primary lateral sclerosis.
Hereditary Spastic Paraplegia HSP is a clinically and genetically heterogeneous group of conditions characterized by the presence of lower limb spasticity and weakness. There have been few epidemiological studies of HSP, but prevalence is estimated at 10 cases per 100,000 population in Europe. HSP can have onset from childhood through to the fifth or sixth decades. It can be divided into pure (uncomplicated) or complicated HSP depending on the presence of other neurological features in addition
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to spastic paraparesis. The key diagnostic clinical findings are of lower limb spasticity, hyperreflexia with extensor plantar responses and pyramidal weakness of the lower limbs. A number of other features have also been described under the rubric of pure HSP and include mild sensory abnormalities of the lower limbs (e.g., reduced vibration sense), urinary symptoms, pes cavus, and mild to moderate cognitive decline. Cranial nerves are almost never involved in HSP. Complicated HSPs comprise a large number of conditions in which spasticity is accompanied by other features such as muscle wasting (amyotrophy), optic atrophy, pigmentary retinopathy, mental retardation, extrapyramidal disease, ataxia, dementia, deafness, icthyosis, peripheral neuropathy, and epilepsy. Table 10.7 lists the recognized forms of complicated HSP. These forms are often autosomal recessive and are rare, so the finding of additional neurological features with spastic paraplegia should alert to other possible diagnoses. Clinical Features The onset of HSP can be from early childhood through to adulthood with insidious development of leg stiffness and/or abnormal wear of the shoes. In HSP there often appears to be relative preservation of power despite dramatically increased tone in the legs. The important clues to the cause of spastic paraplegia are the age and nature of onset, progression of symptoms, the family history, and Table 10.7 Complicated Forms of HSP Associated Feature
Disease
Inheritance
Clinical Features
Amyotrophy
Resembling HMN
AD
Silver syndrome SPG17 Troyer syndrome SPG20
AD AR
Charlevoix-Saguenay Ataxia Extrapyramidal features Mental retardation
AR AR AD AR
Retinal degeneration Optic atrophy Sensory neuropathy Icthyosis
AR AR/AD AR/AD AR
Mild paraparesis with distal wasting Marked wasting, small muscles Distal wasting, spastic tetraparesis, choreoathetosis, short stature in Amish people Similar to Troyer in Quebec Dysarthria, ataxia upper limbs Chorea, rigidity, dystonia Usually with spastic quadriparesis Pigmentary retinal changes Optic atrophy, dysarthria Trophic ulcers and deformities Skin changes plus mental retardation All seizure types reported within families Exaggerated startle response Dysarthria and limb ataxia, dementia, retinal degeneration, and amyotrophy Cataracts, gastro-esophageal reflux, amyotrophy Dementia, dystonia, dysarthria in Amish people
Sjogren-Larsson
Epilepsy Hyperekplexia Others
AR/AD
Kjellin syndrome SPG15
AD AR
SPG9
AD
Mast syndrome SPG21
AR
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the presence of other clinical features. Onset in the first years of life with delayed motor milestones points more towards cerebral palsy (CP), which usually leads to a static clinical picture. It is helpful to ask about athletic ability in childhood, as poor performance or lack of interest in sport may indicate a longstanding motor disability. There is a high incidence of urinary symptoms in HSP, reported in <40% of cases, but this is rarely marked in early disease. Differential Diagnosis The differential diagnoses according to age of onset are listed in Table 10.8. Some of the complicated early forms of HSP, however, such as the SjogrenLarsson and Kjellin syndromes, may mimic CP in early childhood and specific features of these should be sought (see later). In young-onset cases, spinal dysraphism may need to be excluded in the type of HSP presenting with peroneal muscle atrophy if the upper limbs are spared. The presence of pyramidal signs in this form should also help distinguish from hereditary motor and sensory neuropathies and distal spinal muscular atrophy. Spastic paraplegia developing over the age of 20 years is a fairly frequent clinical problem in neurological practice. It is likely that a significant proportion of cases of undiagnosed paraplegia are of genetic origin and detailed family investigations are critical. This is particularly important for adultonset cases as asymptomatic affected individuals have been described in some families. The presence of a slowly progressive gait disorder with relatively little in the way of sensory symptoms and signs favors HSP. Sudden onset of spasticity favors a vascular or inflammatory cause and in these cases there is frequently more marked weakness. Similarly spinal cord compression usually
Table 10.8 Differential Diagnoses in Spastic Paraplegia Childhood onset:
Adult onset:
Diplegic cerebral palsy Structural: Chiari malformation, atlanto-axial subluxation Hereditary spastic paraplegia Leukodystrophy: e.g., Krabbe’s Metabolic: arginase deficiency, abetalipoproteinemia Dopa-responsive dystonia Infection: myelitis Cervical spine degenerative disease Multiple sclerosis Motor neuron disease Neoplasm: primary/secondary tumor, parasagittal meningioma Dural arteriovenous malformation Chiari malformation Adrenoleukodystrophy Hereditary spastic paraplegia Spinocerebellar ataxias Vitamin deficiency: B12 and E Lathyrism Dopa-responsive dystonia Infection: syphilis, HTLV1, HIV
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Clinical Hints for Distinguishing HSP from Other Diagnoses Age of onset: HSP has onset usually > 5 years of age (frequently as adolescent or young adult), CP usually < 5 years, acquired causes of spastic paraplegia often adult Progression: HSP has very slowly progressive spastic paraparesis, CP usually non-progressive, acquired causes more aggressive Clinical: Complicated HSP is often autosomal recessive, pure HSP dominant Neurological features that alert to alternative diagnosis: * weakness greater than spasticity * prominent sensory signs or level * upper limb weakness or amyotrophy * asymmetry of signs * pain * prominent ataxia * peripheral neuropathy * extrapyramidal signs * retinal pigmentation * cranial nerve involvement
has a more aggressive progression than HSP in association with sensory symptoms and signs plus spinal or referred pain. A family history compatible with autosomal dominant transmission in the context of adult onset spastic paraplegia is almost always due to HSP. However, HSP can show autosomal dominant, recessive, and X-linked inheritance. For the apparently sporadic case of spastic paraplegia, HSP is a diagnosis of exclusion. Multiple sclerosis, cervical spondylotic myelopathy, cord compression (e.g., thoracic meningioma), and vitamin B12 deficiency must be excluded in cases of ‘‘pure’’ HSP. Cases of HSP with evidence of wasting of small hand muscles should be distinguished from cervical spondylotic radiculomyelopathy, compressive foramen magnum lesions, and motor neuron disease. The above box lists useful clinical hints to help distinguish HSP from CP and other causes of spastic legs. Investigations The diagnosis of pure HSP in a family in which several members have typical clinical features presents few difficulties. For a case where there is no reliable or verifiable family history further investigation is required. Table 10.9 lists potential investigations. Age of onset (Table 10.8) and clinical presentation will determine the extent of tests, particularly for complicated cases in childhood where metabolic conditions need to be excluded. For an isolated case with young adult onset, MRI scanning of brain and cervical and thoracic cord is particularly important to exclude the main differential diagnoses. In addition, blood investigations (vitamin B12, very longchain fatty acids, serology where appropriate) may be required. In cases of HSP, the most common MRI abnormality is thinning of the cervical and thoracic spinal cord. Studies in dominant HSP kindreds have also suggested that there is loss of volume of the corpus callosum and a higher incidence of cerebral white matter lesions. In most cases of pure HSP, nerve conduction studies and EMG are normal. Central motor conduction times
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Table 10.9 Investigation of Spastic Paraplegia MRI brain, spinal cord CSF examination EMG and nerve conduction studies Evoked potentials Very long-chain fatty acids White cell enzymes Plasma amino acids Serum lipoprotein analysis Vitamin B12/E Serum serology Neuro-ophthalmological evaluation
have been reported to be delayed or unrecordable from the lower limbs and lower limb somatosensory evoked potentials small. CSF analysis is usually normal in HSP. The mapping and cloning of HSP genes has led to specific molecular genetic tests which will allow more focused investigation of potential cases of HSP. Pathophysiology The main neuropathological finding in HSP is axonal degeneration of the terminal portions of the long descending (corticospinal tracts) and ascending (dorsal columns) pathways in the spinal cord. There have also been reports of degeneration of the spinocerebellar tracts and loss of Betz cells in layer V of the motor cortex. Any pathophysiological mechanism must explain why the brunt of the disease falls upon the longest neurons in the spinal cord. The current hypothesis is that the different mutant proteins disrupt axonal transport of macromolecules and organelles, which predominantly affects the distal parts of these neurons. This has come from study of a number of genes. For instance the KIF5A (SPG10) gene encodes a kinesin heavy chain which is an integral part of the motor protein involved in antegrade axonal transport. Spastin (SPG4) appears to play a key role in the dynamics of microtubule turnover, which make up the intracellular cytoskeleton, along which axonal transport occurs. Atlastin (SPG3A) is a dynamin involved in vesicular transport, and in transgenic mouse models mutant paraplegin (SPG7) and proteolipoprotein (SPG1) appear to disrupt axonal transport. Genetic Subtypes of HSP HSP can be inherited as an autosomal dominant or recessive or X-linked recessive trait and a number of genetic loci (SPG) have been mapped. Autosomal dominant HSP is the most prevalent form and represents around 70% of cases. Most cases of pure HSP are autosomal dominant, whilst complicated forms tend to be autosomal recessive (Table 10.7). For practical purposes HSP can be divided according to mode of inheritance and presence or absence of ‘‘complicating’’ features.
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Table 10.10 Pure AD HSP Locus Name (OMIM)
Locus
Gene
Protein
SPG3A (182600) SPG4 (182601) SPG6 (600363)
14q11-q21 2p22-p21 15q11.1
SPG3A SPG4 NIPA1
Atlastin Spastin Non-imprinted PraderWilli/Angelman syndrome
SPG8 (603563) SPG10 (604187) SPG12 (604805) SPG13 (605280) SPG19 (607152) SPG31 (610250)
8q23-q24 12q13 19q13 2q33.1 9q33-q34 2p12
Unknown KIF5A Unknown HSPD1 Unknown REEP1
Neuronal kinesin heavy chain 60-kDa heat shock protein Receptor expression-enhancing protein 1
Relative Frequency (% or no. of families) 9% 45% 10 families
1 family <5 families 3 families 1 family 1 family <8%
Autosomal Dominant Pure HSP Prior to gene mapping and isolation, a simple clinical classification was that of Harding (1981), who divided families according to age of onset. The larger group of cases with onset below 35 years was called type I, and later-onset patients type II. Type II patients appeared to have a more severe form of HSP with greater weakness, sensory loss, and urinary symptoms. Whilst this clinical classification has now been superseded by the identification of SPG loci and genes, it still has practical use for genetic and clinical counseling. Table 10.10 lists the genetic forms of pure AD HSP, which are the most prevalent forms of HSP. The commonest of these are discussed below. SPG4 HSP. The locus on chromosome 2p22-p23 (SPG4) is the most important and accounts for around 45% of AD HSP kindreds. The gene encodes the protein spastin and has 17 exons spanning about 90 kb. Most pedigrees with spastin mutations have pure HSP, with onset from childhood to old age (typical age of onset 2635 years). SPG4 HSP cannot be reliably differentiated from other forms of AD HSP by clinical features alone. Cognitive impairment, dementia, and epilepsy have been reported in some kindreds. No genotype/phenotype correlations have been reported and the severity and age of onset can vary markedly even within one family, suggesting the effect of modifying genes or environmental factors. The function of spastin is unknown, but it is a member of a group of proteins known as the ATPases Associated with diverse cellular Activities (AAA). These AAA proteins act in various cellular functions, including cellcycle regulation, protein degradation, organelle biogenesis, and vesiclemediated protein function. Mutations within the spastin gene that have been identified include missense, nonsense, and splice site mutations in various exons which usually lead to major amino acid sequence changes in the AAA domain or truncation of the protein. This implies that there is a loss of function and a threshold level required of spastin to maintain axonal integrity.
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Table 10.11 Autosomal Dominant Complicated HSP Locus Name (OMIM)
Locus
Gene
SPG9 (601162)
10q23.3-q24.1
Unknown
SPG17 (270685)
11q12-q14
SPG17
SPG29 (609727)
1p31.1-p21.1
Unknown
Protein
Clinical Features
BSCL2
Cataracts, gastro-esophageal reflux, motor neuronopathy Distal amyotrophy, Silver syndrome (overlap with HMNV) Sensorineural hearing loss, hiatus hernia
SPG3A HSP. SPG3 locus on chromosome 14q11.2-q24.3 was initially identified in five families. The gene has been isolated and a number of missense mutations identified. The phenotype is of pure HSP with relatively young age of onset (usually <10 years of age) and a relatively benign course. Most individuals with SPG3 HSP remain ambulant. It has been estimated to cause approximately 10% of AD HSP. The protein encoded has been named atlastin and is a member of the dynamin protein family, which again has very diverse cellular functions, from vesicle and receptor recycling and trafficking to mitochondrial maintenance and distribution. SPG31 HSP. The recently cloned SPG31 gene encodes the mitochondrial protein REEP1. Mutations have been found in <8% of patients with pure AD HSP. Autosomal Dominant Complicated HSP (Table 10.11) SPG17 (Silver syndrome). Silver syndrome is characterized by HSP plus amyotrophy of the small muscles of the hands and feet with onset usually in the second to fourth decades. The gene was mapped in a number of families to 11q12-q14 and is allelic to HMNV (see section on HMN). Mutations were identified in the BSCL2 gene, which also causes the autosomal recessive condition Berardinelli-Seip congenital lipodystrophy. The gene codes for the endoplasmic reticulum protein seipin, whose function is unknown. Autosomal Recessive Pure HSP Table 10.12 lists the loci described for autosomal recessive uncomplicated HSP, which have mainly been described in single kindreds only. Recently, the SPG5A locus has been cloned and mutations found in the gene for cytochrome P450-7B1, involved in cholesterol degradation. Table 10.12 Autosomal Recessive Pure HSP Locus Name (OMIM)
Locus
Age of onset
Number of Families
SPG5A (270800) SPG24 (607584) SPG27 (609041) SPG28 (609340)
8p12-q13 13q14 10q22.1-q24.1 14q21.3-q22.3
Onset 120 years 15 years 2545 years 615 years
<10 1 1 1
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Table 10.13 Autosomal Recessive Complicated HSP Locus Name (OMIM)
Locus (protein)
Clinical Features
SPG7 (607259)
SPG14 (605229) SPG15 (270700)
16q24.3 (paraplegin) 15q13-q15 (spatacsin) 3q27-q28 14q22-q24
SPG20 (275900)
13q12.3 (spartin)
SPG21 (248900)
15q21-q22 (maspardin)
SPG23 (270750)
1q24-q32
SPG25 (608220) SPG26 (609195)
6q23.3-q24.1 12p11.1-q14
SPG30 (610357)
2q37.3
Onset 2040 years, cerebellar features, dysarthria, axonal neuropathy, optic atrophy Onset 420 years, mental retardation, agenesis of corpus callosum Mental retardation, motor neuropathy Retinal degeneration, mental retardation (Kjellin syndrome) Amish, onset in childhood, short stature, learning difficulties, distal amyotrophy, dysarthria (Troyer syndrome) Cognitive decline, mute. MRI atrophy corpus callosum, cerebellum and white matter changes (Mast syndrome) Abnormal skin and hair pigmentation, axonal neuropathy Spinal pain and disk herniation Dysarthria, distal amyotrophy, mild intellectual impairment Sensory neuropathy, mild cerebellar signs
SPG11 (604360)
Autosomal Recessive Complicated HSP The large number of genetic loci identified are listed in Table 10.13. Most are described in single families only, apart from SPG7. SPG7 HSP. Mutations in the SPG7 gene leads to a complicated form of AR HSP with additional neurological features of ataxia, dysarthria, optic disk pallor, and axonal neuropathy. Onset is between 20 and 40 years of age, leading to progressive disability. The gene encodes paraplegin, a mitochondrial ATPase protein. In some patients histochemical abnormalities on muscle biopsy (ragged red fibers) have been described, although this is not a consistent feature. It has been suggested that SPG7 HSP accounts for 510% of AR HSP. SPG11 HSP. Mutations in the gene encoding spatacsin appear to be a relatively common cause of AR complicated HSP. SPG20 and SPG21. These two complicated forms of AR HSP were identified in members of the Old Order Amish family. A single mutation in SPG20 (1110delA) which codes for the protein spartin causes Troyer syndrome, whilst a mutation in SPG21 coding for the protein maspardin leads to Mast syndrome. Both are due to a founder mutation in this population. X-linked HSP Despite X-linked recessive HSP being very rare, its molecular basis is best understood (Table 10.14). Families with both pure and complicated HSP have been linked to SPG1 and SPG2.
Number of Families >20 35 1 <10 1
1
2 1 1 1
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Table 10.14 X-Linked HSP Locus Name (OMIM)
Locus
Gene Product
SPG1 (303350) SPG2 (312920) SPG16 (300266) SPG22 (300523)
Xq28 Xq22 Xq11.2-12.3 Xq13.2
Neural cell adhesion molecule L1 (L1CAM) Myelin proteolipid protein Unknown Monocarboxylate transporter 8
SPG1. Mutations in the gene encoding the L1 cell adhesion molecule (L1CAM) at Xq28 are responsible for a complicated form of HSP with mental retardation and absence of the extensor pollicis muscle. L1CAM is a transmembrane glycoprotein expressed mainly in neurons and Schwann cells and appears to play an important part in the development of the nervous system. Different mutations within the gene also cause the MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, X-linked hydrocephalus, and X-linked agenesis of the corpus callosum. SPG2. Mutations within the proteolipoprotein gene at Xq21-q22 have been found in a family with pure HSP and also complicated forms. Mutations (usually duplications) of this gene also give rise to the dysmyelinating condition Pelizaeus-Merzbacher disease (PMD), which is characterized by congenital hypotonia, psychomotor deterioration, and progressive pyramidal, dystonic, and cerebellar signs. Death usually occurs in infancy or childhood. The variation in phenotype between PMD and SPG2-linked HSP is thought to arise from the differential effect that mutations can have on the two isoforms of the protein product, proteolipid protein (PLP), and DM-20. SPG16. A third X-linked locus has been mapped to Xq11.2 in one family with a complicated form of HSP. Onset was in the first months of life with delayed motor milestones, spasticity, and nystagmus. Additional features were of severe mental retardation, apahasia, facial hypotonia, and maxillary hypoplasia. Both the PLP and L1CAM genes were excluded. SPG22. SPG22 has been used to describe the Allan-Herndon-Dudley syndrome, which could represent a complicated form of HSP presenting in infancy and childhood with hypotonia, weakness, and developmental delay. Cognitive development is severely delayed and hypotonia gives way to spasticity. Limbs develop dystonic posturing and ataxia becomes apparent. Abnormal thyroid function is frequently found. A number of families have been described with mutations in the MCT-8 gene, which is believed to be essential for tri-iodothyronine uptake in central neurons during development. Genetic Advice Autosomal Dominant HSP. Recurrence risks for an autosomal dominant condition with high penetrance should be given. Molecular genetic testing is available for SPG4 (spastin), SPG3A (atlastin), SPG6 (NIPA1), and SPG31
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(REEP1) for families with pure HSP. Other testing (e.g., SPG13 and SPG17) may be available on a research basis. A common counseling scenario for HSP is the unaffected relative in a family with AD HSP of unknown genotype. Many of the data concerning recurrence risks in families with HSP come from the work of Harding, who constructed a cumulative frequency curve for age of onset for type I AD HSP (i.e., age of onset <35 years) (Harding 1981). From this it was calculated that for a clinically normal offspring of an affected parent with HSP there was a 24% chance of having the disease gene at 20 years of age, 22% by 25 years, 19% by 30 years, 13% by 35 years, 11% by 40 years, and 9% by 45 years. For offspring of patients with type II HSP, the genetic risks remain high throughout the reproductive period by virtue of the late onset of disease. Penetrance for AD HSP is very high, although for SPG4 non-penetrance has been reported. However, many cases of apparent non-penetrance are due to asymptomatic individuals who have positive clinical signs on examination. The commonest cause of AD HSP is mutation of the spastin gene (SPG4). Over 150 mutations have been identified in all of the 17 exons except exon 4, which is frequently spliced out. Most are missense, nonsense, or splice site mutations which lead to a truncated or malfunctioning protein. Autosomal Recessive HSP. When considering recessive inheritance of HSP it is important to examine the parents. If this is not possible, then the empirical risks to children of affected individuals who have asymptomatic parents but affected siblings can be calculated. In Harding’s study the proportion of asymptomatic cases over the age of 20 was 16%. Therefore, the chance of two or more affected siblings having an affected asymptomatic parent is about 1 in 6. The risks to the offspring of affected siblings are therefore approximately 1 in 12. Again these risks only apply to families in whom the onset of HSP is under 35 years of age. Mutation analysis is available for SPG5A (CYP7B1), SPG7 (paraplegin), and SPG11 (spatacsin) as a research protocol. AR HSP often has a complicated phenotype and can be more severe than AD HSP. Problems arise for those complicated forms of HSP where both AD and AR inheritance have been described. This occurs in patients with paraplegia and optic atrophy and dysarthria, with sensory neuropathy and with extrapyramidal features. Spastic Paraplegia with no Family History. Counseling single cases of progressive spastic paraplegia is difficult. Some cases are probably non-genetic, whilst some are undoubtedly autosomal recessive. Others may be new dominant mutations, although the proportion of fresh mutants in dominant HSP is thought to be small as the condition is relatively benign and biological fitness is not impaired. A detailed family history and sometimes examination of relatives is helpful, as is the presence of other neurological features. Testing for mutations in spastin (SPG4) should be considered as mutations have been detected in <10% of apparently sporadic cases of pure HSP. X-linked recessive pure HSP is very rare so a singleton affected male is unlikely to have this form of HSP. In those few families reported with X-linked HSP, obligate female carriers have been reported to have normal
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examination findings, although it is possible that at a later stage they may develop signs of spasticity. In appropriate X-linked families, it may be possible to undertake predictive testing using linkage analysis or mutation detection. Prognosis The prognosis in HSP is very variable and depends mainly on the underlying genetic abnormality. For instance, SPG3A HSP has onset in childhood but only progresses very slowly and most adults remain ambulant. However, many of the recessive complicated forms of HSP have a more aggressive course and are more disabling, not least due to the additional neurological features that are present. There is also significant phenotypic heterogeneity and affected individuals with SPG4 HSP can have a quite varied clinical course even within the same family. Management There is no disease-modifying therapy currently available for HSP. Physiotherapy is important with the aim of maximizing function and preventing complications such as contractures. Antispasticity drugs such as baclofen, tizanidine, and to a lesser extent diazepam and dantrolene, can be helpful, as can botulinum toxin injections into specific muscles. Footdrop can be helped by orthoses. Occasionally surgery is required to release contractures or tendons. Early referral to continence advisory clinics is helpful to deal with urinary problems.
Cerebral Palsy (CP) Cerebral palsy is due to motor pathway damage occurring before birth. The pathology is permanent and so the spastic weakness is non-progressive, which can help to distinguish it from early-onset HSP. The disabilities produced interfere with normal motor development and there may be complicating neurological or mental features (e.g., learning difficulties, epilepsy, visual impairment, hearing loss, speech, and behavioral disorders). Traditionally, most cases of CP are thought to be environmental, related to preterm hypoxia and ischemia. There is increasing evidence, however, that the majority of cases of CP do not arise in labor, but as the result of earlier events. Taken as a whole, the recurrence risk for a sibling of a patient with CP is 12%. Certain forms of CP, however, appear to have a higher risk of a genetic component, notably symmetrical spastic paraplegia and ataxic and athetoid CP. If there are no identifiable external factors such as prematurity, small size for gestational age, multiple pregnancy, and kernicterus, then there is a higher recurrence risk for siblings. Spastic (diplegic) CP is the most common subtype and it is the symmetrical subtypes that appear to have the greatest genetic basis. Studies of cases of symmetrical spastic diplegia or quadriplegia with normal birth histories have suggested that the recurrence risk from this form of CP was about 1 in 9.
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This represents either autosomal recessive inheritance or possibly a new dominant mutation. To date two spastic CP gene loci have been identified. A consanguineous family with symmetrical spastic CP was studied and homozygosity analysis mapped a locus to chromosome 2q21-31, and in another recessive family the gene was mapped to chromosome 9p12-q12.
Primary Lateral Sclerosis A small percentage of ALS patients never develop lower motor neuron symptoms, or only very late in the course of the illness. The term primary lateral sclerosis (PLS) has been used to describe this condition, which is considered to be part of the ALS spectrum. Patients develop symmetrical spastic tetraparesis with pseudobulbar palsy (brisk jaw jerk, stiff slow tongue, and spastic dysarthria). Males are more commonly affected and the survival is longer than with ALS. PLS is rare and accounts for around 1% of cases. Juvenile PLS can be inherited due to mutations in ALS2 locus (see Table 10.5).
BIBLIOGRAPHY Gros-Louis F, Gaspar C & Rouleau GA (2006). Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta, 1762 (11-12), 956972. Irobi J, De Jonghe P & Timmerman V (2004). Molecular genetics of distal hereditary neuropathies. Hum Mol Genet 13, 195202. Kunst CB (2004). Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet 75, 933947. Soderblom C & Blackstone C (2006). Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias. Pharmacol Ther 109, 4256.
REFERENCE Harding AE (1981). Hereditary ‘‘pure’’ spastic paraplegia: a clinical and genetic study of 22 families. J Neurol Neurosurg Psychiatry 44, 871883.
Chapter 11 Neuropathies Simon R. Hammans
INTRODUCTION One of the commonest genetic problems in the neurology clinic is an inherited neuropathy. While some disorders, known as the Charcot-Marie-Tooth diseases, have a peripheral neuropathy as the foremost manifestation, others have additional central nervous system features. In others the peripheral neuropathy may be only part of a syndromic diagnosis with non-neurological manifestations.
Clinical Features Neuropathies usually affect the longest peripheral nerves and so distal motor and sensory function (i.e., to the feet and hands) is normally affected earlier and more prominently. In the context of a known family history the diagnosis of a genetic neuropathy may be straightforward. It can be more problematic in the case of a negative or obscure family history. Important distinguishing features in history and examination are indicated in Table 11.1. Careful examination should include inspection of the muscles of the hands and feet for wasting. Orthopedic deformities of the feet should be noted, as well as scoliosis or hip dysplasia. Palpable or visible nerve enlargement may be present. Both genetic and acquired neuropathies may have a particular anatomic distribution, but also often particularly affect one part of the peripheral nervous system. The motor or sensory nerves may be exclusively or predominantly affected. A sensory neuropathy may predominantly affect small fibers (pain and temperature) or other modalities such as proprioception and vibration sense.
Investigations Simple blood tests may be helpful in excluding causes of an acquired neuropathy such as diabetes, B12 deficiency, paraproteinemia, or renal or liver disease. 175
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Table 11.1 Clinical Features of Genetic Neuropathies Features Favoring a Genetic Etiology
Features Favoring a Non-Genetic Etiology
Onset prior to 20 years
Late or rapid onset
Static or slow progression
Progressive or relapsing
Symmetrical, uniform distribution
Focal distribution
No positive sensory symptoms Family history
Paraesthesias and other positive symptoms Known causes of neuropathy: e.g., diabetes, drugs, alcohol, paraprotein, malignancy
Foot deformity (pes cavus)
On nerve conduction studies no conduction block, symmetrical reduction in nerve conduction velocities (if demyelinating)
Conduction block, focal nerve involvement
Exceptions Porphyrias, familial amyloid polyneuropathies Hereditary neuropathy with liability to pressure palsies Hereditary neuropathy with liability to pressure palsies. CMT1X
Indicates an early-onset neuropathy which is usually, but not always, genetic Hereditary neuropathy with liability to pressure palsies
Nerve Conduction Studies (NCS) NCS are an invaluable investigation of neuropathy and are regarded as an extension of the clinical examination. The neurophysiologist can confirm the existence of a neuropathy and quantify sensory and motor nerve amplitudes and velocities. As indicated in Table 11.1, nerve conduction studies may give a clear indication of the likelihood of a genetic neuropathy, which will usually be uniform in distribution and not show conduction block. Further, NCS indicate whether there is significant slowing of nerve conduction velocity. This is important in the classification of neuropathy and will often guide further molecular genetic investigation. A slow conduction velocity indicates a demyelinating neuropathy, whereas evidence of a neuropathy from diminished sensory and motor nerve action potentials, without slowing, indicates an axonal neuropathy. An arbitrary demarcation is taken as a median nerve motor conduction velocity of 38 m/s. A severe axonal neuropathy will also decrease conduction velocity as the fastest nerve fibers are affected, but will not usually decrease conduction velocity below 38 m/s. The presence of intermediate conduction velocities in some neuropathies, and the ability of some genetic defects (e.g., in the P0 gene) to cause either form, complicates an otherwise useful distinction. Genetic Molecular Analysis Genetic molecular analysis is increasingly used in investigation of peripheral nerve disease. Normally, nerve conduction studies guide the use of molecular tests, but in certain clinical contexts molecular analysis may be used first.
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B
Figure 11.1. Resin sections of sural nerve biopsies stained with thiamine and acridine orange. Bar = 10 mm. (A) Control nerve from 29-year-old female showing normal fiber size distribution. (B) Amyloid neuropathy showing large extracellular deposit of amyloid with very few myelinated nerve fibers remaining. Continued
Nerve Biopsy Nerve biopsy is not a routine investigation but may occasionally be required. Examples of its diagnostic use include familial amyloid polyneuropathy and giant axonal neuropathy. A small sensory nerve such as the sural nerve is usually selected (Fig. 11.1).
CHARCOT-MARIE-TOOTH DISEASE (CMT) The CMT diseases, also known as the hereditary motor and sensory neuropathies (HMSNs), are a heterogeneous group of genetic disorders of the peripheral nerves. Prevalence is estimated to be 3040 per 100,000. Clinically, CMT presents with distal muscle wasting and weakness, impaired sensation, and reduced or absent reflexes. Onset and severity can vary from disabling disease in infancy to asymptomatic disease in adulthood. Classification of the CMTs has moved from a clinical and neurophysiologically based system towards a genetic classification. Because the genetic basis for some neuropathies is unknown, the genetic classification is incomplete.
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D
Figure 11.1. cont’d (C) HMSN 1a: myelinated fibers surrounded by reduplicated Schwann cell processes (‘‘onion bulbs’’), with some loss of myelinated fibers. (D) HNPP: the myelinated fiber population is slightly reduced, and many have inappropriately thin myelin indicating remyelination. There are also some thick myelinated fibers showing tomaculous where the sheath is locally abnormally thickened.
The initial division of CMTs is into type 1 (demyelinating) and type 2 (axonal) as indicated by nerve conduction velocity. However, intermediate velocities prevent a clear-cut division in all cases and recognition of intermediate forms of CMT is acknowledged. The first subdivision of type 1 and 2 CMT is usually made on the basis of the mode of inheritance: dominant, recessive, or X-linked. Unfortunately, terminology varies, particularly in the rarer recessive forms, with some authors using CMT4 to denote all recessive forms, while others refer to autosomal recessive forms of CMT1 and 2. Furthermore, the ever-expanding list of causative genes complicates a genetic classification (Table 11.2).
Autosomal Dominant Demyelinating CMT (CMT1): PMP-22 and P0 This is the most common form of CMT, accounting for about half of all CMT. CMT1 associated with duplications or mutations of PMP-22 is termed CMT1A; CMT1 caused by mutations in the myelin protein zero (P0, MPZ) is termed CMT1B. CMT1A and B are not distinguishable on clinical examination.
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Table 11.2 Charcot-Marie-Tooth Diseases Designation (OMIM number)
Inheritance (frequency)
Gene
Demyelinating Charcot-Marie-Tooth type 1 autosomal dominant (CMT1/HMSN 1) CMT1A (118220) AD (40%)
CMTIB (118200) CMT1C (601098)
AD (5%) AD (1%)
CMT1D (607678)
AD
Charcot-Marie-Tooth type 1 X-linked (CMTX) CMT1X (302800) X-linked semidominant (15%)
98% have duplication 17p11.2-12 (PMP-22) and 2% have point mutation in PMP-22 P0 protein Lipopolysaccharide-induced tumor necrosis factor-a factor (LITAF) Early growth response 2 gene (EGR2; 10q21-q22) Gap junction protein beta 1 (GJB1; Xq13.1)
Dejerine-Sottas disease (HMSNIII) DSD (145900)
AD/AR
Point mutations in PMP-22, P0, EGR2, periaxin, and others
Congenital hypomyelinating neuropathy CHN (605253)
AD/AR
Point mutations in PMP-22, P0, EGR2
Hereditary neuropathy with liability to pressure palsies HNPP (162500) AD
Charcot-Marie-Tooth type 1 autosomal recessive (CMT1 AR) CMT1 ARA or CMT4A (214400) AR
CMT1 ARB1 or CMT4B1 (601382)
AR
CMT1 ARB2 or CMT4B2 (604563) CMT1 ARC or CMT4C (601596)
AR AR
CMT1 ARD or CMT4D (+hearing loss) or HMSNL (601455) CMT4E CMT1 ARE or CCFDN (604168)
AR
CMT1 ARF or CMT4F (605260) CMT1 ARG or HMSNR (605285)
AR AR
AR/AD AR
85% have deletion 17p11.2-12 (PMP-22), some have point mutation in PMP-22 Ganglioside-induced differentiation-associated protein 1 (GDA P1) Myotubularin-related protein-2 (MTMR2) SET binding factor 2 (SBF2) KIAA1985; prominent scoliosis; not rare N-myc downstream-regulated gene 1 (NDRG1) EGR2 allelic CMT1D Congenital cataracts, facial dysmorphism, and neuropathy syndrome (CCFDN 18q23-qter) Periaxin (19q13.1-13.3) 10q23.2 Continued
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Table 11.2 Charcot-Marie-Tooth Diseases—cont’d Designation (OMIM number)
Inheritance (frequency)
Gene
Axonal Charcot-Marie-Tooth type 2 autosomal dominant (CMT2/HMSN II) CMT2A (118210) AD (9% of CMT2)
CMT2B (600882) CMT2C (606071)
AD AD
CMT2D (601472)
AD
CMT2E (162280)
AD
CMT2F (606595) CMT2
AD AD
Mitofusin 2 (MFN2) (also kinesin family member 1B (KIF1B) similar locus, rare, especially Japan) RAB7 (distal ulceration) Vocal cord and diaphragm involvement (12q23-q24) Glycyl tRNA synthetase (GARS protein); hand weakness early and prominent Neurofilament light chain (NF-L; 8p21) HSPB1 P0
Charcot-Marie-Tooth type 2 X-linked CMT2X
X-linked
Xq24-q26
Charcot-Marie-Tooth type 2 autosomal recessive (CMT2 AR) CMT2 ARA AR
Lamin A/C (1q21.2)
Other autosomal recessive CMT2 families have been described but are rare and so far inconsistently classified Entities representing more than 5% of CMT are shown in bold
Clinical Features Most patients with autosomal dominant CMT1 present in the first decade of life, less commonly in the second decade, or later. Later presentation is usually due to mild or overlooked symptoms or signs. Presentation is commonly with foot drop or foot deformity. Slowly progressive distal wasting and weakness, areflexia, distal sensory loss, and foot deformity (pes cavus) are usually present (Figs. 11.2 and 11.3). Gene carriers nearly always have signs of the disease by the age of 20, and nerve conduction studies are usually decisive if signs are equivocal. Minimal disease is evident from foot deformity, difficulty in walking on the heels, or ankle hyporeflexia. Wasting of extensor digitorum brevis may also be a useful sign (this muscle is a toe extensor situated on the dorsum of the foot). Slow progression of the condition is usual, with more severe weakness and wasting peripherally and including the intrinsic hand muscles, and later involvement of more proximal muscles. Demyelination causes enlargement of peripheral nerves, which may be detectable clinically (e.g., the ulnar nerve at the elbow). Roussy-Levy syndrome refers to a combination of demyelinating neuropathy and a postural tremor. It can be caused by PMP-22 duplications or P0 mutations and can be thought of as a phenotypic variant of CMT1.
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Table 11.3 Investigation of Neuropathy (not all are relevant to all patients) Investigation
Neuropathy
Full history, examination, and neurophysiology Full drug and occupational history Full family evaluation, including examination of relatives Glucose including glucose tolerance test if necessary Full blood count, B12 Alcohol history, liver function tests Autoantibodies Protein electrophoresis Search for malignancy. Antineuronal antibodies Nerve biopsy
Toxic neuropathy (axonal or demyelinating) CMT Diabetic neuropathy B12 deficiency Alcoholic neuropathy Immune-mediated neuropathies Paraproteinemic neuropathy (often demyelinating) Paraneoplastic neuropathy May help confirm inflammatory, toxic, or genetic causes
Investigations Without a clear family history, clinical investigation should be directed at excluding a non-genetic cause. Chronic inflammatory demyelinating neuropathies and paraproteinemic neuropathy cause slowing of nerve conduction and therefore require specific exclusion (see also Table 11.3). In CMT1, nerve conduction studies show reduced or absent sensory nerve action potentials and global and symmetrical reduction in the nerve conduction velocities. The median nerve motor conduction velocity is less than 38 m/s, typically between 10 and 30 m/s. After the patient has been classified clinically and neurophysiologically as having CMT1, molecular diagnosis should be attempted by the following strategy, depending on availability and clinical necessity. 1. Screen for the chromosome 17p duplication in all patients (irrespective of presence or absence of family history) as this is the commonest cause of CMT1. 2. If there is no evidence of male-to-male transmission screen for GJB1 mutations. 3. Screen for P0 and PMP-22 mutations. 4. Further testing should usually follow specialist referral, but screening for EGR2 and LITAF mutations may be considered. CMT1A is the single commonest form of CMT, accounting for approximately 40% of all CMT and 80% of CMT1. Accordingly, genetic analysis of 17p may be used as a first investigation of a genetic neuropathy if molecular testing is readily available, or if this genetic cause has been established in other members of the family. Different myelin protein zero (P0) mutations (CMT1B) can give rise to different phenotypes. Such patients may fall into two phenotypic groups, either early-onset demyelinating neuropathy with manifestations before walking, or with late-onset (adult) neuropathy with only moderately slow nerve conduction. P0 mutations only occasionally cause the classic CMT1 phenotype.
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GJB1 mutations can cause a demyelinating neuropathy (CMT1X), which is described separately. Although X-linked, females may have a significant neuropathy and GJB1 mutations account for a significant proportion of disease previously thought to be autosomal dominant. Pathophysiology CMT1A is defined by an abnormality of the PMP-22 gene on chromosome 17p. In 98% of CMT1A a segmental duplication of one chromosome including the PMP gene is present, giving, in total, three copies of the gene. New mutations account for approximately one-fifth of cases and are usually of paternal origin caused by unequal crossing-over of homologous chromosome 17 regions. A small minority of cases are due to point mutations within the PMP-22 gene. Rarely, a deletion of PMP-22, normally giving rise to a phenotype of HNPP, can cause a CMT1 type neuropathy. The normal function of PMP-22 is unknown, and it accounts for less than 5% of peripheral myelin protein. The presence of an extra copy of the PMP-22 gene causes overexpression of the protein, causing an early excess of myelin production. Slowing of conduction is present by 2 years of age. The precise mechanism for abnormal myelination is unknown. In CMT1A there is considerable variability in expression and clinical severity despite the same genetic defect. This is unexplained and is presumably due to other genetic or environmental factors. Some variability may be explained by a higher frequency of superimposed inflammatory neuropathy than would be expected by coincidence. The P0 protein accounts for 50% of peripheral nerve protein and is thought to be involved in homophilic linkages between adjacent myelin lamellae. Prognosis Disability in CMT is very slowly progressive. While distal leg weakness causes worsening foot drop and difficulties in walking, only rarely is weakness sufficient to confine patients to a wheelchair (<5%). Early onset and low conduction velocities are correlated with more severe disease. As the disease progresses, increasing weakness and wasting of the hand and distal arm muscles cause disability. Proximal weakness is uncommon. Treatment There is no specific treatment for CMT neuropathies that affects the disease process. In a few patients an unexpected worsening of neuropathy should prompt consideration of an inflammatory component and immunomodulatory treatment. CMT patients may be particularly sensitive to drugs known to cause neuropathy such as vincristine. Otherwise, treatment is supportive and best performed using a multidisciplinary team. Patients are often helped by orthotic advice. Ankle-foot orthoses and/or special shoes can help foot drop. Careful use of surgery to correct foot deformity may be necessary. Occupational therapists can provide advice to enhance independence.
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Genetic Counseling In most CMT1 patients, an autosomal dominant family history is present together with a recognized PMP-22 duplication or a P0 or PMP-22 mutation, allowing appropriate genetic advice. Apparent sporadic disease is more likely to be due to unrecognized disease in a parent or a new mutation than recessive disease. As the 17p duplication is inherited in a dominant fashion, sporadic CMT1A due to a duplication will cause a recurrence risk of 50% in offspring. PMP-22 or P0 point mutations usually indicate autosomal dominant inheritance but some mutations can cause recessive disease. For reasons explained in Chapter 2, presymptomatic testing of children is discouraged, but confirmatory diagnostic testing is often performed in the context of early symptoms. Prenatal testing is possible but seldom requested in the context of a disease that does not typically shorten lifespan or affect intellect. The variability in CMT1A even between family members complicates genetic advice.
X-Linked Charcot-Marie-Tooth Disease The clinical presentation of CMT1X is indistinguishable from CMT1 or CMT 2. Males have a more severe phenotype and earlier onset than females, but this may not be immediately apparent or discernible in small families, and inheritance can appear to be autosomal dominant. In practice, CMT1X can only be definitively excluded on clinical grounds if male-to-male transmission occurs within the family. Males usually have nerve conduction velocities in the demyelinating range, but females may have nerve conduction velocities in the axonal range. Neurophysiology of a single patient may indicate a classification of CMT1 or CMT2 depending on the sex of the patient. Nerve conduction velocities may be asymmetric or less uniform than seen in CMT1. A few families with CMT1X have hearing loss and abnormal auditory evoked potentials. Transient CNS abnormalities with abnormalities on MR brain scans have been described in CMT1X patients. Clinical Hints Beware of CMT1X neuropathy masquerading as autosomal dominant disease. Beware of CMT1X appearing patchy and masquerading as chronic inflammatory demyelinating polyneuropathy. CMT1X may have CNS manifestations.
CMT1X is due to mutations located in any part of the GJB1 gene (also known as connexin-32). The protein has some homologies to PMP-22 with four transmembrane domains and is thought to form intracellular gap junctions between the folds of Schwann cell cytoplasm. Genetic advice is given as appropriate to an X-linked dominant disorder. For treatment refer to CMT1. Other rare X-linked recessive neuropathies have been reported, including CMT2X, which also causes deafness and mental retardation.
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Dejerine-Sottas Disease (DSD) and Congenital Hypomyelinating Neuropathies (CHN) DSD and CHN are severe, early-onset demyelinating neuropathies. On clinical and pathological grounds they were thought to be distinct disorders. They show very slow conduction velocities (often <12 m/s). These disorders are usually caused by new point mutations in the genes that cause CMT1 (PMP-22 and P0). Mutations in EGR2 can also give rise to these phenotypes. Point mutations in these three genes can exist in the heterozygous or homozygous states, allowing either form of inheritance. For example, homozygous PMP22 duplications can give rise to a DSD phenotype. The fact that CMT1, DSD, and CHN are caused by mutations in the same three genes suggests that DSD and CHN can be thought of as severe variants of CMT, either dominant or recessive.
Autosomal Recessive Demyelinating CMT (CMT1 AR or CMT4) The genetic investigation of the recessive forms of CMT is a fast-moving field and is subject to a variable and evolving classification. At the time of writing there are more than ten loci if one includes the fact that PMP-22, P0, and EGR2 mutations may be recessive. These are detailed in Table 11.2. All are rare and most have specific ethnic associations, which may suggest the molecular diagnosis.
Charcot-Marie-Tooth Type 2 (CMT2) CMT2 refers to the autosomal dominant axonal form of CMT. CMT2 accounts for 3040% of all CMT. Clinical Features Clinically CMT2 is difficult to distinguish from CMT1, and classification requires nerve conduction studies. Motor nerve conduction velocity may be a little less than normal but above the arbitrary value of 38 m/s in the median nerve. On average, CMT2 has later onset than CMT1, typically with onset in the second decade, and sometimes later. The tremor seen as part of the Roussy-Levy syndrome is not a feature of CMT2. Enlarged nerves are not found. Studies have shown a high incidence of restless leg syndrome, which is not a feature of CMT1. Skeletal deformity is less frequent in CMT2, except in the ulcero-mutilating form, CMT2B. Investigations Axonal neuropathies have many non-genetic causes, including diabetes, drugs, vitamin deficiencies, malignancies, and sporadic idiopathic axonal neuropathy. Unless there is a clear family history, extensive investigation may be necessary to establish a genetic cause (Table 11.3). Rarely, CMT2 syndromes may have additional clinical features that point to a likely diagnosis, as indicated in Table 11.2. Recently described mutations in the mitochondrial fusion protein mitofusin 2 (MFN2) gene
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appear to account for approximately 20% of CMT2 patients. So far, no other single gene appears to account for a substantial proportion of CMT2. The strategy of investigation by genetic analysis is dependent on availability, and is not currently routinely performed in the context of CMT2. However, if this is clinically necessary, the following strategy may be followed: 1. Depending on availability consider studying MFN2 first. 2. In the absence of male-to-male transmission, and especially if an axonal neuropathy is found in a female proband, GJB1 should be screened. 3. P0 can manifest as an axonal neuropathy and should be analyzed next. 4. Depending on availability it may be worth studying NF-L, but most axonal neuropathies will remain undiagnosed at the genetic level. 5. In the ulcero-mutilating form of CMT2, consider studying RAB7. Treatment See CMT1 Genetic Advice The commonest situation is advising patients about recurrence risks without knowing the gene or mutation responsible. This requires full family studies to determine the mode of inheritance, bearing in mind that CMT2 is capable of being asymptomatic in adulthood. Examination findings are made more secure by neurophysiological confirmation. Depending on availability, the genetic analysis above may be indicated. Recurrence risks can then be estimated and will often depend on the evidence provided by family evaluation. Autosomal recessive forms of axonal CMT are rare and are summarized in Table 11.2.
Hereditary Neuropathy with Liability to Pressure Palsies (HNPP; OMIM 162500) HNPP is an autosomal dominant disorder characterized by recurrent episodes of peripheral nerve palsies. Clinical Features Onset is typically in early adulthood, but presentations as early as 3 years may be observed; other gene carriers have no symptoms in adulthood. Each episode is of acute onset, usually painless, and may follow mild trauma or compression. In half of the episodes there is complete recovery over days, weeks, or months, but others result in partial recovery causing some patients to develop permanent deficit, which can coalesce to cause a more generalized neuropathy. Lesions are most likely to develop at usual sites of nerve compression. These include the peroneal nerve at the head of the fibula, causing foot drop, the ulnar nerve at the elbow, the median nerve at the wrist, and the radial nerve in the spiral groove of the humerus. Brachial plexopathies may also occur (less
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Figure 11.2. Hand muscle atrophy in an individual with Charcot-Marie-Tooth disease.
painful than experienced in hereditary brachial plexus neuropathy). Less frequently facial nerve and vocal cord palsies are observed. One-fifth of patients have pes cavus (Fig. 11.3). Tendon reflexes may be normal, reduced, or absent, particularly at the ankle. Some patients have features suggestive of a progressive generalized neuropathy with few or no focal features and resemble CMT1.
Figure 11.3. Pes cavus in hereditary neuropathy with liability to pressure palsies.
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Clinical Hints Consider HNPP in the context of: Recurrent entrapment neuropathies Nerve conduction studies performed for an entrapment neuropathy showing other abnormalities or a generalized neuropathy Any undiagnosed demyelinating neuropathy (may resemble chronic inflammatory demyelinating polyneuropathy) A test for CMT1A showing a PMP-22 deletion rather than a duplication. Differential diagnosis includes: Recurrent pressure palsies occurring secondary to diabetes mellitus Hereditary recurrent brachial plexopathy (if the brachial plexus is predominantly involved and the episodes are painful) Multifocal neuropathy caused by vasculitis (usually more acute and painful).
Investigations If the diagnosis is clinically likely then analysis of the PMP region on chromosome 17p might be performed first. The PMP-22 deletion accounts for approximately 85% of cases. Some of the remaining patients have PMP-22 point mutations (usually nonsense or frameshift mutations). In practice, the diagnosis is often made in the context of nerve conduction studies requested to confirm an entrapment neuropathy. Rather than a single nerve lesion, sensory nerve action potentials are diffusely reduced, and minor slowing of conduction velocities may be observed. There is more slowing in distal nerves with prolonged distal motor latencies observed most commonly in the median, peroneal, and ulnar nerves and less commonly in the tibial and more proximal muscles. Neurophysiology is usually abnormal even in asymptomatic carriers of the deletion. Nerve biopsy is now seldom needed for diagnosis. It shows sausagelike focal thickening and folding of the myelin sheath with segmental demyelination. HNPP is sometimes referred to as tomaculous neuropathy (tomaculum = sausage: Latin), although tomacula on nerve biopsy are not specific for HNPP. Pathophysiology In most cases HNPP is caused by a 1.5 Mb deletion of 17p11.2 encompassing the PMP-22 gene. The deletion corresponds to the identical region that is duplicated to cause CMT1A. PMP-22 expression is reduced in nerves in HNPP. New mutations are usually caused by unequal crossing-over of the region in chromosome 17 as discussed in the context of CMT1A. HNPP has also been described in association with particular mutations in PMP-22. Prognosis Long-term prognosis is variable. Commonly patients do accrue neurological deficit, most frequently foot drop, but severe disability appears uncommon.
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Treatment No treatment is known to alter the course of the disease. It is wise to warn patients to avoid trauma which may precipitate episodes. Prolonged kneeling, sitting with legs crossed, and resting arms on elbows should be avoided. As with CMT, ankle-foot orthoses may be required for foot drop. Surgical decompression of nerves is controversial. Carpal tunnel release is not clearly of benefit and ulnar nerve transposition may produce poor results, whereas other patients experience benefit. There are no study data to guide practice. Genetic Advice HNPP is autosomal dominant. There is variability in severity even between family members.
Hereditary Brachial Plexus Neuropathy (HBPN; OMIM 162100) This rare condition is often considered in the differential diagnosis of HNPP and is therefore considered here. Hereditary brachial plexus neuropathy is an autosomal dominant disorder with attacks of unilateral or asymmetrical pain leading to weakness, atrophy, and sensory alterations of the shoulder girdle and upper limb muscles. The symptoms, distribution of neurological findings, and course of the attacks are probably not distinguishable from sporadic (idiopathic) brachial plexus neuropathy (also known as neuralgic amyotrophy or ParsonageTurner syndrome). The neurological deficit is thought to arise from a localized inflammation in the nerves of the brachial plexus. HBPN differs from the sporadic variety in the following ways:
Family history Recurrent attacks Attacks follow parturition, trauma, or stress Minor dysmorphic features in some families (hypotelorism, epicanthic folds, short stature, syndactyly).
Although HNPP can affect the brachial plexus, it can be distinguished from HBPN by less associated pain, other more peripheral nerve lesions, a more generalized neuropathy, and by molecular genetic investigation. In general, HBPN has a benign prognosis with good recovery after attacks, little evidence of a generalized neuropathy, and a tendency for the attacks to lessen. Some families with HBPN have been shown to harbor mutations in the septin 9 gene on chromosome 17q25, but families not linked to this locus have also been reported. There is no proven treatment.
Hereditary Sensory and Autonomic Neuropathy Overall the HSN and HSANs can be considered rare, although founder effects can cause higher incidences in some populations. Inheritance and clinical features differ; a thorough assessment may lead to a clinical diagnosis (Table 11.4).
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Table 11.4 The Hereditary Sensory Neuropathies HSN (OMIM)
Gene
Inheritance
Features
HSN1/HSAN1 (162400)
Serine palmitoyltransferase, long-chain base subunit 1 (SPTLC1) HSN2
AD (English/Australian)
Small fiber loss; acromutilation; onset in early adulthood Early onset; acromutilation; slow or non-progressive Neonatal onset; pain and temperature sensation absent, sweating normal; autonomic crises; absent fungiform tongue papillae; usually fatal (50% at 30 years) Congenital insensitivity to pain; hyperpyrexic episodes; self-mutilation; absent lacrimation and sweating; corneal ulceration; mental retardation; no sweating
HSN2/HSAN2 (201300) HSAN3 (Riley-Day; 223900)
HSAN4 (256800)
AR
Inhibitor of k light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP)
AR (Ashkenazi Jewish)
TRKA/NGF receptor
AR (Israeli/Bedouins)
Other HSN/HSAN have been described but are mostly confined to single families
Clinical Features HSN1 (also known as HSAN1) is a rare, autosomal dominant sensory neuropathy and presents in the second decade or later. Slow progression of pain and temperature loss leads to ulceration and eventual mutilation of the toes, feet, and sometimes hands. Spontaneous pain, often lancinating in character, may be a feature; vibration sense is typically preserved. Other forms of similar sensory neuropathies exist (e.g., HSN2: Table 11.4); CMT2B (RAB7) should be considered in the differential diagnosis. In CMT2B, spontaneous pain is less prominent, all modalities of sensation are similarly affected, and the hands usually only mildly affected. Nerve conduction studies show an axonal neuropathy. Riley-Day syndrome (HSAN3, familial dysautonomia) should be suspected in a child of eastern European Jewish extraction with breech delivery, meconium staining, poor suck, hypotonia, or hypothermia. Absence of fungiform papillae of the tongue and absent tendon reflexes further suggests the diagnosis. Intradermal histamine and intraocular pilocarpine tests are abnormal. A single mutation in the IKBKAP gene accounts for 99.5% of disease alleles and allows an easy genetic diagnosis. Treatment and Genetic Advice Appropriate precautions to delay trauma, ulceration, and mutilation are advised, but in most HSANs complications are inevitable. Amputations are likely. Specific problems require expert advice. Prenatal diagnosis may be required and is usually made possible by identification of the causative mutation.
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Familial Amyloid Polyneuropathies (FAPs) These autosomal dominant disorders are clinically and genetically heterogeneous. They can affect many organs but a generalized sensory and autonomic neuropathy is often the presenting problem. The amyloidoses are caused by mutations in one of three genes: transthyretin, apolipoprotein A-1, or gelsolin. These are all serum proteins and the mutations cause conformational changes resulting in the deposit of insoluble protein fibrils in the extracellular matrix. Clinical Features Onset is in adulthood. A typical presentation is with a sensory polyneuropathy with prominent pain, temperature, and autonomic involvement, and less prominent motor involvement. Other presentations include carpal tunnel syndrome, autonomic insufficiency, restrictive cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. Other phenotypes are characterized by nephropathy, gastric ulcers, cranial nerve dysfunction, and corneal lattice dystrophy. Rarely, involvement of the leptomeningeal or cerebral structures dominates the clinical picture. Investigations Amyloid neuropathy is usually diagnosed on nerve biopsy. Immunocytochemistry can sometimes identify the protein responsible. Diagnosis is more straightforward if FAP is already identified in a relative. Recognition of the ethnic and clinical associations of the different mutations may make analysis easier or allow direct genetic diagnosis. Examples include the common transthyretin Val30Met mutation in Portuguese, Swedish, and Japanese patients. Particular presentations may also be recognized, such as the upper limb and carpal tunnel syndrome associated with transthyretin Ser77Tyr and the gelsolin mutations in Finnish patients causing facial paresis and corneal lattice dystrophy. Caution is required in sporadic cases because not all amyloid neuropathy is genetic. Non-genetic amyloid polyneuropathy is usually caused by deposition of immunoglobulin light chain associated with a paraprotein, myeloma, or lymphoma (primary amyloidosis). Secondary amyloidoses caused by chronic inflammatory conditions rarely cause a neuropathy. Management Transthyretin in synthesized in the liver. Liver transplantation is an established treatment. Transplantation arrests or retards further progression of the neuropathy. Established neuropathy or cardiomyopathy appears not to improve. Timing of transplantation is difficult and requires specialist input. Genetic Advice Advice is as appropriate for autosomal dominant disorder. For some of the more severe variants, prenatal diagnosis may be desired. Some mutations have incomplete penetrance.
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Table 11.5 Genetically Determined Neuropathies Associated with CNS and Non-Neurological Manifestations.
Adrenomyeloneuropathy Metachromatic leukodystrophy Krabbe’s leukodystrophy Mitochondrial disease MNGIE Friedreich’s ataxia Autosomal dominant cerebellar ataxias Most other genetic ataxias including abetalipoproteinemia, ataxia telangiectasia, cerebrotendinous xanthomatosis Chorea-acanthocytosis Neuraxonal dystrophy Leigh’s syndrome Carbohydrate-deficient glycoprotein syndrome Tangier disease Fabry’s disease Refsum’s disease Porphyria
Demyelinating (D) or Axonal (A)
Major CNS/Other Features
A D D Mostly A D A (sensory) A
Spasticity, ataxia Leukodystrophy Leukodystrophy Various Ophthalmoplegia, GI symptoms Ataxia Ataxia
A
Ataxia
A A
Movement disorders, epilepsy Loss of mental and motor milestones Ataxia and other features Ataxia, mental retardation
A or sometimes D D A A (painful) D A, mostly motor or autonomic
Facial weakness, organomegaly Deafness, strokes, and other systems involved Ataxia, deafness, retinopathy Psychiatric, dementia, seizures
GENETICALLY DETERMINED NEUROPATHIES ASSOCIATED WITH CNS AND NON-NEUROLOGICAL MANIFESTATIONS Neuropathies may be a prominent or minor feature of many disorders also affecting the CNS and other systems. These disorders are described elsewhere in this book but are tabulated for convenience (Table 11.5).
NEUROPATHIES ASSOCIATED WITH METABOLIC DEFECTS Tangier Disease (OMIM 205400) Tangier disease is a rare autosomal recessive multisystem disorder caused by mutations in the ATP binding cassette transporter (ABC1) on chromosome 9q31. Onset can be in any decade of life. Approximately one-third of patients have a neurological presentation with a slowly progressive sensory neuropathy particularly affecting pain and temperature. Facial diplegia, hand muscle wasting, and mononeuropathies are frequent. The diagnosis can often be made from the appearance of enlarged lymph nodes, liver, and spleen, and orange tonsils. There is a high incidence of coronary artery disease.
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Blood tests show hypocholesterolemia, reduced or absent high-density lipoproteins (HDL), high triglycerides, thrombocytopenia, and reticulocytosis. Neurophysiology shows a patchy neuropathy with both axonal and demyelinating features. There is no specific treatment.
a-Galactosidase A Deficiency (Fabry’s disease; OMIM 301500) Fabry’s disease is caused by mutations in the a-galactosidase A gene on chromosome Xq22. Clinical Features Males present in late childhood with burning pain in the palms and soles, precipitated by stress, alcohol, exercise, or heat. The diagnosis is commonly overlooked initially. The pain may come in attacks (Fabry crises) or may be chronic. A neuropathy affecting small fibers (pain, temperature, and autonomic) develops. Deafness, premature strokes, cardiomyopathy, gastrointestinal symptoms, and renal failure are variable but inexorably contribute to morbidity. Corneal opacities, dysmorphic facies, and a characteristic rash may allow a clinical diagnosis. The rash appears in late teenage years, commonly most evident between the umbilicus and knees and consists of small (up to 5 mm) raised venous lesions (angiokeratomas). Female heterozygotes have later-onset, milder disease but may experience pain, fatigue, skin lesions, and ocular manifestations. An increased incidence of cerebrovascular, renal, and cardiac disease is observed, but later than in males. Investigations Diagnosis in males is by measuring a-galactosidase A enzyme levels in plasma, leukocytes, or in fibroblast cultures. Enzyme levels may be in or near the normal range in female heterozygotes. Urine sediment contains cells with birefringent lipid globules termed ‘‘Maltese crosses.’’ Mutations can be sought in the a-galactosidase A gene, which contains seven exons. Most families have private mutations. Prognosis Typically there is cardiological, neurological, or renal decline from the fourth decade, leading to a median survival of 50 years, with death most commonly due to complications of renal failure or cerebrovascular disease. Lesser manifestations in female heterozygotes lead to a better prognosis, but on average longevity is decreasedby 1015 years. The impact of newtreatments on prognosis is not yet clear. Management Infusion of the deficient enzyme has resulted in clinical improvement in symptoms of pain, and stabilization of renal and cardiac manifestations. Although studies
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continue, the prospects look encouraging. Gene therapy is also being explored. Pain sometimes responds to gabapentin or carbamazepine. A multidisciplinary approach including renal, cardiac, and neurological specialists is required. Genetic advice is that appropriate to an X-linked disorder with significant manifestations in females.
Refsum’s Disease (OMIM 266500) Refsum’s disease is a rare autosomal recessive disorder caused by mutations in the phytanoyl-CoA hydroxylase (PHYH) gene on chromosome 10pter-p11.2. Onset is typically with night blindness (retinitis pigmentosa) between the age of 5 and 20. A demyelinating neuropathy causing distal weakness progresses at a variable rate (sometimes over weeks or following a relapsing course). Anosmia, deafness and ataxia are features. Ichthyosis and skeletal abnormalities are present (short fourth metatarsal, epiphyseal dysplasia, syndactyly). Heart involvement may lead to cardiac failure. Investigation Elevation of serum phytanic acid is diagnostic. Nerve conduction shows very slow velocities. Elevated CSF protein, abnormal electroretinogram, and abnormal nerve biopsy are typical. Treatment Treatment is dietary restriction of foods containing phytanic acid such as meat, fish, and dairy products. Plasmapheresis is sometimes used. Genetic counseling is as appropriate for a rare recessive disorder. Infantile onset variants of Refsum’s disease (OMIM 266510) are caused by recessive mutations in peroxin-1 or peroxin-2 genes.
Porphyrias Porphyrins and porphyrinogens are intermediates in heme synthesis. Each porphyria corresponds to an enzyme defect; four types of porphyria cause neurological symptoms manifest in recurrent acute attacks. Although caused by different enzyme defects the three commonest all are autosomal dominant, an exception to the general rule that disorders of metabolism are recessive. They have neurological features in common. Acute attacks Provoked by drugs, hormones, infections, low carbohydrate intake Start after puberty or later First sign is usually abdominal pain, followed by constipation, urinary retention, hypertension, and autonomic features
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The neuropathy is predominantly proximal and axonal (hence knee reflexes may be absent yet ankle reflexes present), motor, and may be severe, causing respiratory failure; weakness may start in one limb or be more diffuse and take days or weeks to evolve; the presentation may resemble Guillain-Barre syndrome Sensory loss is mild and distal, but pain may be prominent Autonomic involvement, facial weakness, and dysphagia CNS changes include psychosis, depression, and seizures May cause urine to turn red on standing (due to oxidation of porphobilinogen) Nerve conduction studies show diminished amplitudes but no demyelination.
Acute Intermittent Porphyria (AIP; OMIM 176000) AIP is due to mutations in the porphobilinogen deaminase gene. In most populations it is the most common acute porphyria. Although there is a prevalence of approximately 5/100,000, the disease may remain latent unless provoked by the above factors. AIP does not have skin manifestations. Variegate Porphyria (VP; OMIM 176200) VP is due to mutations in the gene for protoporphyrinogen oxidase on chromosome 1q22. It is thought to be less common than AIP, except for a high incidence in South Africans. Acute attacks occur with variable skin manifestations, including hyperpigmentation and hypertrichosis in sun-exposed areas. Coproporphyria (CP; OMIM 121300) CP is due to mutations in the gene for coproporphyrinogen oxidase on chromosome 3q12. Photosensitivity is occasionally present. Psychiatric features may be the only manifestation. Delta-Aminolevulinic Acid Dehydratase Deficiency (ALA Dehydratase-Deficient Porphyria; OMIM 125270) This autosomal recessive porphyria is very rare, and usually presents with an infantile hepatic disorder but may have an associated neuropathy. Investigations The key to diagnosis is suspicion of the disease. During a suspected attack the urine should be screened for porphyrin precursors, delta-aminolevulinic acid (ALA), and porphobilinogen (PBG), which are always present in an acute neurovisceral attack. At other times most patients with latent AIP and some with latent coproporphyria and VP will have elevated levels. Abnormal urine screens should be verified by quantitative measures of urine ALA, PBG, and porphyrins. Most elevated urine porphyrins on screening tests are false positives, due to rises in coproporphyrin excretion seen with acute illness, liver disease, or
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alcohol excess. Increased levels of porphyrins in the urine and stool demonstrate the diagnosis of coproporphyria or VP. Between attacks, erythrocyte PBG deaminase is about 50% of normal in most patients with AIP, but is not fully specific or sensitive. Analysis of the porphobilinogen deaminase gene for mutations may be required but most families have private mutations. Clinical Hint ALA and PBG are always present in the urine in a neurovisceral attack. Their absence effectively excludes porphyria as a cause of the attack.
Prognosis Attacks of porphyria are rarely fatal because of better recognition and treatment. Avoidance of precipitants may prevent attacks and the neurological prognosis is good. Treatment In acute attacks the precipitating factors should be removed where possible (particularly sulfonamide or barbiturate drugs). Infusions of a heme preparation are helpful in severe attacks, and should be given as soon as possible after confirmation by urinary PBG. The formulation of the heme preparation differs between countries. A high-carbohydrate diet should be taken if possible, an intravenous glucose infusion if not. Treatment of seizures is difficult because some anticonvulsants are known to exacerbate attacks and others are not proven to be safe. Gabapentin and sodium valproate have been suggested if prophylaxis is necessary. Benzodiazepines may be required in status epilepticus, but convulsions normally improve as the attack resolves. Genetics The three common ‘‘neurological’’ porphyrias are all autosomal dominant. Deltaaminolevulinic acid dehydratase deficiency is rare but is autosomal recessive. Because porphyrias may be latent and never manifest, gene carriers may not be recognized. In screening relatives for AIP both erythrocyte PBG deaminase and urinary PBG should be measured, since neither is an entirely reliable screening test. The identification of a porphobilinogen deaminase mutation allows more certain testing. In giving advice it should be remembered that most people who carry the AIP gene who inherit this trait never develop symptoms. The penetrance of the other acute porphyrias is also incomplete.
Giant Axonal Neuropathy (GAN; OMIM 256850) GAN is an autosomal recessive disorder caused by mutations in the gigaxonin gene on 16q24. Onset is mostly in the first decade (typically at 3 years) with
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a clumsy gait as the first symptom. There is a motor and sensory neuropathy predominantly affecting the legs. Facial weakness and dysarthria are common. CNS features also include ataxia, nystagmus, optic neuropathy, upgoing plantar responses, and mental retardation. Tightly curled hair, long curly eyelashes, high forehead, and short stature also suggest the diagnosis. Nerve conduction studies confirm an axonal neuropathy. Nerve biopsy shows axonal loss and axonal swellings. Ultrastructurally, axons are greatly enlarged and packed with masses of tightly woven neurofilaments. Prognosis is variable. Most patients are chair-bound or dead by the third decade, but with slower progression in some. Genetic advice is that appropriate for a rare recessive disorder.
BIBLIOGRAPHY www.geneclinics.org Isitt J (2006). Charcot-Marie-Tooth Disease: A practical guide, CMT United Kingdom. Reilly MM (2007). Sorting out the inherited neuropathies. Prac Neurol, 7(2), 93105.
Chapter 12 Muscle Disease Simon R. Hammans
INTRODUCTION This chapter describes genetically determined disorders of skeletal (or voluntary) muscle. Muscle function can be impaired by disorders of other parts of the nervous system including the anterior horn cell, motor nerve, metabolic factors, or the neuromuscular junction, but this chapter is concerned with primary diseases of muscle. The diagnostic approach to muscle diseases is very dependent on the clinical assessment. On some occasions the diagnosis can be made with near certainty after taking a history and performing a clinical examination, where other presentations may require a systematic application of blood tests, neurophysiology, genetic analysis, and/or histochemical and immunocytochemical studies of a muscle biopsy. Muscle disease therefore requires careful application of clinical techniques, to minimize unnecessary use of invasive and expensive investigations.
Clinical Features The key points in clinical assessment are: History Onset of disease * Motor milestones * Athletic performance at school, etc. Rate of progression Distribution of symptoms at onset, e.g., difficulty in tiptoeing, dysphagia, etc. Variation or episodic nature of weakness/stiffness/cramps Family history * Ethnic origin 197
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Research any investigations into family members even if performed elsewhere (with appropriate consent) * Consider asking to see other family members Presence of additional symptoms * Myoglobinuria * Pain or cramps on exercise * Myotonia * Cardiac, respiratory, GI, endocrine, CNS features. *
Examination General examination * Frontal balding, deafness, retinopathy, cardiac signs, etc. Muscle hypertrophy, atrophy, and contractures Fasciculations Fatigability Careful record of distribution of weakness, particularly * External ocular movements * Facial weakness * Periscapular weakness * Truncal, neck, or abdominal weakness * Respiratory weakness Lying and sitting vital capacity * Bulbar weakness Test dysphagia by observing a drink of water. Common myopathies diagnosable from clinical assessment include myotonic dystrophy, Duchenne muscular dystrophy, oculopharyngeal muscular dystrophy, and facioscapulohumeral dystrophy. These can sometimes be followed by genetic confirmation without recourse to neurophysiology or biopsy.
Investigations A creatine kinase (CK) assay in blood is often a very useful investigation, which may help detect the presence of muscle pathology in subclinical disease. It is not specific to muscle disease and may be elevated up to 5-times the upper limit of normal (5 ULN) or occasionally more in amyotrophic lateral sclerosis or other causes of neurogenic atrophy; 23 ULN may occasionally be seen in normal subjects, particularly physically fit males if they are of greater than average muscle bulk, or following vigorous exercise. The CK may also help in specific diagnosis. A very high CK (10100 ULN) may suggest a dystrophinopathy, or a dysferlinopathy, depending on clinical features. In the context of a limb girdle syndrome it can help narrow the differential diagnosis. Neurophysiology can be overused in muscle disease. A good rule is to define the question being asked of the neurophysiologist. A neuropathy may be in the differential diagnosis and this can usually be confirmed or excluded with
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confidence by nerve conduction studies. If the origin of muscle weakness is unclear, then electromyography (EMG) can usually differentiate between neurogenic and myogenic weakness. EMG can also detect or confirm myotonia, which may be very useful. Specific techniques are useful in investigating channelopathies and are described in Chapter 13. Neurophysiology is less useful at detecting subclinical disease with certainty. In the presence of clinical evidence of myopathy it is unlikely to usefully refine the differential diagnosis and the patient might reasonably be spared the investigation. Muscle biopsy is not always required to make a diagnosis in muscle disease. However, it is a useful investigation if clinical assessment has not guided the clinician to a likely diagnosis that can be confirmed by molecular genetic analysis. In congenital myopathies biopsy may provide a diagnosis on morphological appearance alone. In the metabolic myopathies the diagnosis can be made by appropriate histochemical reactions. In muscular dystrophies the biopsy can be subjected to an increasingly large number of immunocytochemical reactions directed against known sarcolemmal and sarcomeric proteins. This often then permits a directed approach to subsequent genetic analysis. Figure 12.1 shows schematically the location and disease associations of some of these proteins.
Classification of Myopathies The elucidation of the genetic basis of inherited myopathies has challenged existing notions of classification. Particularly difficult is the wide phenotype often seen with mutations within the same gene. Striking examples include defects of the lamin A/C gene, which can produce phenotypes which are primarily neuropathic, myopathic, cardiological, and others, including a lipoatrophy syndrome. Myotilin mutations produce a myopathic phenotype, but the phenotype varies between limb girdle dystrophy, distal myopathy, and myofibrillar myopathy. Although the classification used here is clinically based, there is considerable overlap and diagnosis of some myopathies often requires some lateral thinking.
THE CONGENITAL MYOPATHIES AND MYOFIBRILLAR MYOPATHIES The term ‘‘congenital myopathy’’ refers to a useful but slightly ill-defined concept. It implies a disorder that generally presents with muscle weakness at birth and follows a non-progressive course. This definition is usually widened to include disorders with weakness evident in the first few years of life and following a static or slowly progressive course. Some patients are not diagnosed until adult life. Only a minority of patients with congenital weakness will have primary muscle disease (Table 12.1). Ultimately these disorders will be classified genetically.
Central Core Disease (CCD; OMIM 117000) Central core disease may present as a congenital myopathy but also as a limb girdle syndrome typically with teenage onset, or may be asymptomatic.
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Laminin 2 Congenital MD
Basal lamina Bethlem myopathy Collagen VI
δ
an
Dystroglycans
α
α
β Sarcoglycans LGMD2D LGMD2E SPN LGMD2C LGMD2F
β
LGMD2B
LGMD1C Dysferlin
γ
ε
lyc Big
Caveolin 3
Extracellular space
Sarcolemma Intracellular space Dystrophin Duchenne/Becker MD
S
LGMD2J
Titin
Actin
Telethonin
LGMD2G
NO
TRIM32
tilin
Syntrophins
LGMD2A LGMD1A FKRP
Nucleus
β1
Dystrobrevin
Calpain 3
Myo
α1
LGMD2H
LGMD2I
Emerin EDMD Lamin A/C LGMD1B
Figure 12.1. Location and disease associations of some sarcolemmal and sarcomeric proteins.
Importantly, it may also confer susceptibility to malignant hyperthermia and thus may present as a crisis precipitated by general anesthesia. Clinical Features In early-onset disease decreased fetal movements may be noticed. Affected children may be hypotonic with proximal weakness often more obvious in the legs. Facial weakness may be present. Sometimes the diagnosis may be prompted by recognition of congenital hip dislocation, scoliosis, or foot deformity. The weakness may become apparent in teenage years with
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Table 12.1 Differential Diagnosis of Early-Onset Muscle Weakness Category
Examples
Comments
CNS disorders
Cerebral palsy
Congenital myopathies
Central core disease; myofibrillar myopathies Merosin-deficient CMD Myotonic dystrophy, FSH dystrophy
CNS disorders are the commonest cause of hypotonia in infancy Congenital weakness with little progression Usually severe course May be diagnosed by DNA analysis
Congenital muscular dystrophy Early-onset ‘‘adult’’ muscle disorders Spinal muscular atrophy Myasthenic syndromes Neuropathies Metabolic myopathies
Neonatal transient myasthenia, congenital myasthenia Dejerine-Sottas neuropathy, hypomyelinating neuropathy Acid maltase, debranching enzyme, branching enzyme, carnitine deficiency, mitochondrial myopathies
May be diagnosed by DNA analysis; see Chapter 10 See this chapter See Chapter 11 See Chapter 13
CCD presenting as a limb girdle syndrome. Occasionally the disease may be recognized after a family member presents with malignant hyperthermia. Whenever the onset, the disease follows a static or very slowly progressive course. Investigations CK may be normal or modestly raised. The diagnosis is usually made on muscle biopsy, with characteristic central cores best seen in histochemistry for oxidative enzymes. These appearances are not completely specific, with similar appearances seen in association with other muscle diseases (e.g., myopathies caused by mutations in MYH7, SEPN1). CCD has a complex relationship with multiminicore disease, with some evidence that the appearance of cores varies or evolves. Genetic Advice Inheritance is usually autosomal dominant. In most cases CCD is due to mutations in ryanodine receptor gene (RYR1). Within this gene, some mutations cause CCD, some malignant hyperthermia (MH), and some both. About onethird of CCD patients are MH-susceptible. When CCD has been identified patients and first-degree relatives require evaluation for MH susceptibility. In practice this requires explanation of the risks of general anesthesia and recommendation of muscle biopsy at an approved center for in vitro contracture testing. Rarely core diseases are associated with recessive RYR1 mutations, often with multicores seen on biopsy.
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Myotubular Myopathy (MTM; OMIM 310400) Myotubular myopathy is also known as centronuclear myopathy. The commonest form is X-linked, due to mutations in myotubularin (Xq27.3-q28). It is usually defined by the characteristic muscle biopsy appearance, but this is increasingly supplemented by molecular genetic investigation. Usually the homogeneous X-linked form is known as myotubular myopathy. The term centronuclear myopathy usually refers to the heterogeneous autosomal forms of lesser severity. Clinical Features In the X-linked form, weakness is usually evident at birth, with severe hypotonia and weakness with respiratory failure often requiring mechanical ventilation. Clinical clues include birth length greater than the 90th percentile, large head circumference with or without hydrocephalus, narrow, elongated face, and slender, long digits. Non-muscle problems such as kidney stones, liver hemorrhage, and a vitamin K-responding bleeding diathesis require careful surveillance. Family history may indicate X-linked inheritance with related females having sons with infantile death. Diagnosis without family history may be problematic. Exclusion of other causes of neonatal weakness is important. Neonatal myotonic dystrophy should be specifically excluded by genetic analysis. Muscle biopsy may support the diagnosis on morphological grounds. Interpretation should be cautious since similar findings may be produced by autosomal forms of MTM or by congenital myotonic dystrophy. Immunocytochemical diagnostic techniques are being evaluated and will be of potential value in diagnosis of sporadic cases and in detecting heterozygotes. Mutational analysis of the MTM1 gene is performed in specialist centers but is hindered by the distribution of mutations throughout the gene. Typically, mutations can be found in 8085% of suspected males. If tissue from a deceased male is not available then the mother can be tested. Autosomal dominant (OMIM 160150) MTM is caused by mutations found in MYH6 and dynamin 2. Recessive MTM (OMIM 255200) is less common. They both present with limb weakness and variable ophthalmoplegia, and ptosis with facial or scapular weakness. Dominant disease is often later-onset and of lesser severity than X-linked disease, with recessive disease presenting with intermediate onset and severity. Prognosis In X-linked MTM the respiratory problems may lead to death in infancy. Survivors show no progression in muscle weakness with indications that the prognosis may not be as grave as previously thought. A small minority of female heterozygotes may show manifestations that range from asymptomatic facial weakness to more disabling muscle weakness qualitatively similar to affected males. Genetics In X-linked MTM identification of a causative mutation allows carrier detection and prenatal testing if desired. Counseling is as for X-linked disease with awareness of the potential problems of germline mosaicism.
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Table 12.2 Myofibrillar Myopathies Gene
Clinical Presentation
ZASP mutations (OMIM Proximal and/or distal weakness, some 605906); autosomal dominant with cardiac or neuropathic involvement; some show dominant inheritance Desmin mutations (OMIM Distal myopathy progressing to more 601419); autosomal dominant proximal weakness and sometimes to respiratory failure; cardiac involvement common aB-crystallin mutations (OMIM Slowly progressive weakness involving 608810); autosomal dominant face, bulbar, distal, and proximal muscles; cardiac involvement may lead to sudden death; cataracts, intestinal malabsorbtion Myosin heavy chain IIa Congenital joint contractures which (OMIM 605637); autosomal improve, external ophthalmoplegia, dominant progressive proximal weakness
Muscle Pathology Myotilin, desmin, vimentin, nestin and other proteins accumulate in muscle fibers Similar to above
Similar to above
Variable rimmed vacuoles
See also Table 12.3. Myotilin and telethonin defects may present as myofibrillar myopathies see limb girdle dystrophies Table 12.7 and 12.8.
Myofibrillar Myopathies and Defects of Internal Cytoskeletal Genes Improvements in immunostaining have elucidated a genetically heterogeneous group of muscle diseases termed myofibrillar myopathies. They have morphological features in common, including disintegration of the Z-disk and myofibrils, with abnormal accumulation of multiple proteins. Myofibrillar proteins represent the largest constituents of the muscle fiber, but myopathies secondary to genetic defects appear relatively rare. Mutations in ZASP, myotilin, and desmin account for approximately half of cases. They may have distinct clinical presentations, which can include cardiomyopathy, distal myopathy, or neuropathy, but diagnosis is usually suggested by muscle biopsy. The classification of these disorders is not firmly established but brief details are given in Table 12.2. Some related disorders manifest as rod myopathies and are listed in Table 12.3.
Nemaline Rod Myopathies These are clinically and genetically heterogeneous disorders that are often termed ‘‘rod’’ myopathies. Onset may be congenital, or in childhood or adulthood. Congenital-onset patients present with weakness and hypotonia. Severe cases may show arthrogryposis or cardiac or CNS involvement. Late-onset cases may present with truncal weakness or respiratory failure. These clinically disparate disorders are unified by a non-progressive course, and often by involvement of the respiratory muscles. On muscle biopsy the rods are seen on the Gomori trichrome stain, where they appear as dark red-blue structures. Electron microscopy shows electron-dense structures emanating from Z-lines. The rods are probably generated by a common mechanism of contractile dysfunction.
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Table 12.3 Genetic Defects Causing Rod Myopathies Gene
Inheritance
Onset
Other Features
Respiratory Failure
a-Tropomyosin 3 (TPM3)
Dominant (OMIM 609284) Recessive Recessive (OMIM 256030)
515 years
achalasia
Usually
Birth Birth
Death in childhood Dysmorphic
Dominant (OMIM 102610)
Variable
Recessive Recessive (OMIM 605355) Dominant (OMIM 609285)
Early Infancy
Some new dominant mutations may follow lethal course Usually severe course Contractures; usually lethal Rare
Nebulin
a-Actin (ACTA1; skeletal muscle)
Troponin T1 b-Tropomyosin (TPM2) Other forms not characterized
Infancy/childhood Any
May improve after initial respirator dependence Yes, may be indolent
Yes Yes Some
Consider cardiac or respiratory involvement
The histological appearance is common to several genetic defects summarized in Table 12.3.
Other Congenital Myopathies Other patients may have histological findings that define other congenital myopathies. These are rare, and histological features are sometimes not sufficiently specific to define a disease entity. Genetic data are increasingly defining entities within this group (e.g., SEPN1 mutations in multiminicore myopathy). Further genetically defined entities will emerge from this group and allow definition of clinical features, prognosis, and inheritance to aid management and genetic advice. Examples include fingerprint body myopathy, reducing body myopathies, multiminicore disease, and congenital fiber type disproportion.
THE MUSCULAR DYSTROPHIES Myotonic Dystrophy (DM1; OMIM 160900) Myotonic dystrophy is the commonest adult genetic neuromuscular disease. A study in Wales estimated a prevalence of 510/100,000, with similar frequencies affecting other Western populations. It is a multisystem disorder that is capable of presenting at any age to almost any medical specialty (Table 12.4). Myotonic dystrophy is usually caused by a triplet repeat expansion in the DM1 gene. Proximal myotonic myopathy (PROMM) was described as a separate clinical entity, but its genetic basis is identical to DM2, the second myotonic dystrophy locus, and it will be referred to as DM2. DM2 may be clinically indistinguishable from myotonic dystrophy.
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Table 12.4 Multisystem Features of Myotonic Dystrophy System
Problems
Management
Eyes
Cataract extraction
Cardiac
Cataracts (multiple, posterior, subcapsular); retinal degeneration Learning difficulties (non progressive); apathy; somnolence; depression Dysphagia (pharyngeal or esophageal); constipation; anal sphincter dysfunction; cholelithiasis Conduction defects
Endocrine Respiratory
Hypogonadism; insulin resistance Sleep apnea; hypoventilation; aspiration
CNS Gastrointestinal
Results of trials of stimulant drugs awaited Speech therapy assessment; laxatives
Annual ECG; cardiological opinion (pacemaker, antiarrhythmic drugs) Usually do not require treatment Full assessment, nocturnal nasal ventilation sometimes required
Congenital myotonic dystrophy may be caused by DM1 (but not DM2). It presents with neonatal respiratory failure leading to motor delay and mental retardation. Prenatal problems may be suspected with reduced fetal movements, polyhydramnios, and talipes. Characteristically facial weakness, hypotonia, and feeding difficulties are present. Myotonia is not evident until later. Early presentation is usually followed by a severe clinical course. Onset in childhood is often with prominent myotonia and learning difficulties, but is comparable with the classic ‘‘adult’’ presentation. Onset in adolescence or adulthood is typically with muscle weakness and myotonia. However, many patients are uncomplaining and these symptoms may be ignored by patient or doctor. Thus the presenting symptom may be with dysphagia, cataracts, or abdominal symptoms. Unless myotonic dystrophy is kept in mind the characteristic diagnostic physical signs may be missed. In late adulthood, presentation may be with minimal disease, usually with premature cataracts with absent or mild myotonia and muscle weakness. The distribution of muscle weakness is often diagnostic. The facial appearance with frontal balding, mild ptosis, and atrophy of temporalis and masseter is distinctive. The sternomastoids are wasted and weak, even when limb weakness is relatively mild. Unlike most myopathies limb weakness is distal as well as proximal, typically causing wrist weakness and foot drop. Bulbar weakness can cause a dysarthria with a nasal quality. Myotonia can be elicited by requesting rapid finger extension from a tight grip. Percussion myotonia is less constant but elicited by tapping the thenar eminence with a reflex hammer to cause adduction and slow relaxation of the thumb.
Clinical Hints: Myotonic Dystrophy Clinical diagnosis is usually easy, if you remember to consider it. Facial appearance, neck flexor weakness, and grip myotonia are the most useful diagnostic signs. Regular review is necessary, including ECG. DM2/PROMM is clinically similar except for the absence of congenital onset.
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Investigations In suspected cases, diagnosis can be established genetically by analysis of the triplet repeat number in the DMPK gene (Table 12.5). A negative test should prompt clinical review. If myotonic dystrophy remains likely the DM2 locus should be investigated. A diagnostic genetic result makes EMG and muscle biopsy unnecessary. Ultrasound evidence of polyhydramnios or reduced fetal movements in the second and third trimester may raise suspicion of congenital disease. Genetics Myotonic dystrophy (DM1) is caused by an expanded CTG repeat in a noncoding part of the DMPK gene (chromosomal locus 19q13). The diagnosis is made by direct analysis of the repeat (Table 12.5). Inheritance is autosomal dominant. The repeat size is unstable and may change between parent and child. Usually, but not always, children have a larger repeat than their parent, giving rise to the phenomenon of anticipation (with more severe disease in offspring corresponding to a larger repeat number). Congenitally affected infants usually have inherited myotonic dystrophy from their mothers, although rarely the congenital form is transmitted from the father. Congenital myotonic dystrophy is seldom transmitted from minimally affected parents, although disease in a mother may not be diagnosed until after the birth of a congenitally affected child. Presymptomatic testing differs in several ways from the protocols used in Huntington’s disease. Examination of at-risk adults may well show diagnostic signs of the disease. Conversely, a normal examination considerably reduces the risk of finding a triplet repeat expansion. Unusually, an expansion may be found in a clinically normal adult, but is unlikely to lead to severe manifestations. Thus the initial clinical assessment may provide more data than molecular genetic testing. Nevertheless, an approach to normal at-risk young adults desiring presymptomatic testing should be based on the protocols suggested for Huntington’s disease. Prenatal testing requires careful counseling bearing in mind the variability of the disorder. Because of the imperfect correlation between repeat number and
Table 12.5 Clinical Correlate of Repeats at the DM1 Locus (note overlap in repeat number) DMPK repeats
Phenotype
537 3849 50150 1001500
Normal Premutation No symptoms, cataracts, mild muscle symptoms Classic adult phenotype
2301800 10004000
Childhood onset Congenital onset
In the mid range of repeats, correlation between repeat number and phenotype is poor
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phenotype great caution is required if the decision to terminate is made on the repeat number. However, a large repeat number does indicate likely congenital or severe disease. Reduced fetal movement or polyhydramnios on ultrasound scanning may also indicate congenital disease. Pathophysiology DM1 and DM2 are considered examples of RNA diseases. The untranslated transcripts appear to exert similar effects independent of their chromosomal position. One mechanism appears to be interference with alternative splicing of several genes implicated in the production of the phenotype. Prognosis Longevity is reduced in myotonic dystrophy patients. Adult-onset disease is compatible with a normal lifespan, but studies have shown mortality typically between 50 and 60 years of age, milder variants to 60+ years, while childhoodonset disease led to a mean age at death of 45. Congenitally affected patients may die of respiratory problems in the neonatal period, but otherwise will typically improve and survive to early adulthood. The high mortality is largely due to respiratory problems and cardiovascular diseases. One study showed that half of all patients were at least partly chair-bound in the year prior to their death. Management Patients with myotonic dystrophy benefit from regular review by a physician with knowledge of the disorder. Explanation of potential problems in anesthesia is necessary. Informing the surgeon or anesthetist of the diagnosis prior to the anesthetic allows precautions to minimize these risks. Patients should know the importance of cardiac symptoms (such as syncope), which require prompt cardiological assessment. In the absence of cardiological symptoms, an annual ECG to screen for the development of heart block is prudent. Cardiac manifestations may be the presenting feature of myotonic dystrophy, but usually accompany other signs of the disease. No specific treatment can aid muscle weakness, but referral to a multidisciplinary team may aid function and independence. Symptoms from other organs may not be volunteered (see Table 12.4). An annual review with a questionnaire may be useful, routinely asking about dysphagia, cardiac symptoms, and somnolence as well as checking for cataracts, muscle symptoms and myotonia, ECG, and vital capacity. Review frequently reveals the need for specialist help from other disciplines, such as gastroenterologists, cardiologists, respiratory physicians, and others. Myotonia can be treated, but is often less problematic than weakness, and many patients prefer to avoid antimyotonic treatment. In the presence of pronounced myotonia a trial of treatment can be offered. No clear evidence of relative therapeutic effect of different drugs is available. Phenytoin does not block AV conduction and this drug is commonly used in this situation.
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Myotonic Dystrophy Type 2 (DM2/PROMM; OMIM 600109) The phenotype of DM2 is similar to DM1, and on an individual basis usually cannot be distinguished with confidence. DM2 is usually diagnosed genetically following negative DM1 analysis in a suggestive phenotype. DM2 is caused by a CCTG repeat expansion (mean approximately 5000 repeats) in the first intron of the zinc finger protein 9 (ZNF9) gene. The normal allele has 104176 repeats. DM2 seems to be most prevalent in patients of northern European origin (with the exception of the UK). Anticipation is less marked in DM2 and congenital onset has not yet been reported, with onset later than 8 years and usually in early adulthood. The long-term prognosis may be more benign than DM1 because of fewer problems with dysphagia, hypersomnia, cardiac, and respiratory complications.
Dystrophinopathies (Including Duchenne and Becker Muscular Dystrophy; OMIM 310200) This disease spectrum is defined genetically by abnormalities affecting the dystrophin gene on Xp21.2 (Table 12.6). Clinical Features In dystrophinopathies the family history may disclose X-linked inheritance. Duchenne muscular dystrophy (DMD) presents before 5 years of age with progressive symmetrical proximal weakness, often with calf hypertrophy (Fig. 12.2) and very high CK levels. Leg weakness and exaggerated lordosis is most obvious, but arm weakness is present if sought. Evidence of learning difficulties or cardiomyopathy may be present. Gower’s phenomenon, in which boys use their hands to climb up their legs to gain the standing posture, is an expression of hip extensor weakness. Loss of unassisted walking occurs before 13 years. A dilated cardiomyopathy is often a cause of morbidity, and becomes apparent between 10 and 18 years of age. In Becker muscular dystrophy (BMD) onset is usually after 7 years of age with a similar distribution of weakness, which is slowly progressive with loss of walking between 16 and old age, depending on severity. Some patients have predominant weakness in the quadriceps. Patients with loss of walking between 13 and 16 years have a dystrophinopathy of intermediate severity. Cardiomyopathy is more variable in BMD than DMD, and may be out of Table 12.6 Dystrophinopathy Phenotypes Phenotype
Description
Duchenne muscular dystrophy Becker muscular dystrophy Cramp-hyperCKemia syndrome Cardiomyopathy Asymptomatic hyperCKemia Manifesting heterozygotes
Defined as losing ability to walk before age 13 years Loss of walking after 16 years Myalgia and cramps, often on exercise Minimal or no skeletal muscle weakness Raised CK but no symptoms Some female heterozygotes
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Figure 12.2. Calf hypertrophy in Becker muscular dystrophy.
proportion to skeletal muscle involvement. It is the most common cause of death. In all dystrophinopathies muscle cramps are common and are useful diagnostically. Cramp-hyperCKemia syndrome has onset of cramps in childhood with normal or near normal strength and CK values 10100-times normal. Cramps are usually exercise-related. Manifesting Female Carriers Hoogerwaard et al. (1999a) found 19% of DMD heterozygotes (carriers) and 14% of BMD heterozygotes developed weakness, with a further 5% troubled by cramps. Muscle weakness is often atypical of DMD, with the distribution being proximal, but asymmetric. Arms may be affected more than legs. Onset is after 16 years of age. Although studies have found that about half of DMD/ BMD carriers have some abnormality on ECG or echocardiogram, Hoogerwaard et al. (1999b) found only 8% of DMD heterozygotes developed a dilated cardiomyopathy, and none of the BMD heterozygotes.
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Investigations Dystrophinopathies characteristically caused a raised CK typically greater than 10-times normal in DMD and greater than 5-times normal in BMD. As the disease advances the CK may decline. If the clinical picture is suggestive of dystrophinopathy, EMG is usually unnecessary. Molecular genetic analysis is usually performed prior to biopsy, and may render biopsy unnecessary. Most laboratories perform a multiplex deletion screen that detects nearly all deletions, which in total account for two-thirds of molecular genetic defects in DMD/BMD. In boys without deletions detected by this method, small deletions, insertions, or single base changes may be responsible. These are often detectable by further study and may be sought before or after muscle biopsy, depending on the clinical situation and availability. If genetic analysis does not identify a mutation a muscle biopsy is necessary. Immunocytochemistry can detect the absence or deficiency of dystrophin, and Western blot studies can be performed if necessary. Immunocytochemistry of other muscle proteins can follow if a dystrophinopathy is excluded. Manifesting heterozygotes should have chromosomal studies to exclude Turner syndrome or chromosomal rearrangements. If the diagnosis is unclear it may be necessary to biopsy muscle. Heterozygotes exhibit a patchwork pattern of dystrophin reflecting X-inactivation. Pathophysiology The dystrophin gene is huge, comprising 79 exons. Dystrophin is localized to the subsarcolemmal region in skeletal and cardiac muscle, forming part of the link between intracellular cytoskeleton and the extracellular matrix. It is also expressed in some neurons. There are specific genotypephenotype correlations. One of the most obvious is that usually, but not always, frame-shift mutations are likely to result in DMD phenotypes whereas in-frame mutations and deletions result in BMD. Recognized subgroups of mutations are correlated with disproportionately severe or mild phenotypes and with certain variant phenotypes such as those with myalgia with little weakness. Other subgroups of mutations may be associated with prominent cardiomyopathy, or with prominent mental retardation. Prognosis DMD patients are wheelchair-bound before the age of 13, and all develop cardiomyopathy by the age of 18. Few patients reach 30 years because of respiratory and cardiac complications. Respiratory prognosis is worsened by the severity of scoliosis. BMD is less stereotyped but cardiomyopathy remains a significant cause of morbidity and mean survival is the middle of the fifth decade. Mental retardation is seen in DMD, with a mean IQ of 88, but is uncommon in BMD. Treatment Trials of gene therapy continue but have not yet proved clinical benefit. Lowdose steroids prolong the ability to walk and reduce complications such as
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respiratory involvement and scoliosis. The most commonly reported side effects of steroid treatment in DMD are weight gain, behavioral problems, and reduction in bone mineral density. Use of these drugs requires careful follow-up, with prophylaxis and treatment of side effects. Timing of therapy and steroid dosage regimen remains controversial. Optimal management of DMD requires a skilled multidisciplinary team. The poor prognosis makes difficult emotional demands of the family, which should not be overlooked. The practical aspects are summarized as: Physiotherapy to maintain mobility and prevent contractures Expert orthotic advice including seating Monitoring of scoliosis with intervention when necessary Weight control Surveillance for cardiomyopathy and appropriate treatment (including heterozygotes) Surveillance of respiratory function with incremental respiratory support * Airway clearance therapy * Use of nocturnal/non-invasive ventilation * Tracheostomy.
Similar management is required for BMD patients, although scoliosis and respiratory problems are less prominent, and steroids are not used. Genetic Advice The dystrophinopathies are inherited in an X-linked recessive manner. A full family history is important (e.g., evidence of a dystrophinopathy in a male cousin may significantly alter the analysis of the family). Advice can be enhanced and refined if the causative mutation is known. Genetic analysis is best performed on leukocyte DNA from an affected male, although technical advances are making analysis of heterozygote DNA easier. The commonest situation is one where the diagnosis of a dystrophinopathy has been made in a male child, and the following steps are taken. 1. The first step is to establish the genetic status of the mother of the proband. If there is another affected family member in the maternal line then she will be an obligate carrier. 2. If she has two or more affected sons then the mother has a germline mutation or has germline mosaicism. 3. If the proband is the only affected family member then the mother and other female relatives may be carriers. Approximately two-thirds of mothers of males with DMD and no family history of DMD are carriers. The mother may have a germline mutation, somatic mosaicism, or germline mosaicism. In most cases the dystrophin mutation can be identified in the proband. The absence of the mutation in the mother’s blood does not exclude somatic or germline mosaicism and there remains a risk of transmission of the mutation to further offspring. In the absence of a known mutation then linkage studies within the family may be helpful. Further discussion of X-linked inheritance
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is in Chapter 2. Genetic counseling of dystrophinopathies is described further in www.geneclinics.org and van Essen et al. (1997). Genetic studies may identify female heterozygotes who require further explanation of possible manifestations and recurrence risks.
LIMB GIRDLE MUSCULAR DYSTROPHY SYNDROMES (LGMD) The LGMDs have in common a progressive weakness, usually of the proximal limb muscles. In general, they do not have prominent manifestations in facial, external ocular, or distal muscles, nor any episodic manifestations to suggest a channelopathy or metabolic myopathy. The majority of LGMDs show recessive inheritance. Historically it has proved difficult to subclassify the LGMDs on clinical grounds. However, genetic advances have proved the heterogeneity of the LGMDs. The ability to make a genetic diagnosis has allowed a more certain clinical analysis by using distribution of weakness and clinical course to establish a genotype phenotype correspondence.
Autosomal Dominant LGMD Autosomal dominant LGMDs are less common than autosomal recessive LGMDs and are summarized in Table 12.7. Bethlem myopathy is distinctive clinically, and other AD-LGMDs have clinical features which may guide diagnosis.
Autosomal Recessive LGMD (Table 12.8) The sarcoglycanopathies are diseases with defects of the sarcoglycan complex. As might be predicted, they have some clinical features in common, although Table 12.7 Autosomal Dominant LGMDs Gene
Features
Investigations
1A: Myotilin (OMIM 159000)
Uncommon; nasal dysarthria; benign prognosis
1B: Lamin A/C (OMIM 159001) 1C: Caveolin; allelic to rippling muscle disease and familial hyperCKemia (OMIM 601253) Bethlem myopathy (OMIM 158810 several loci)
Atrioventricular block; slow progression beginning with legs CK: 425 normal
Biopsy shows rimmed vacuoles; immunochemistry or genetic analysis possible Genetic analysis (see also Emery Dreifuss MD2) Immunocytochemistry and Western blotting shows reduced caveolin-3
Onset at any age from infancy onwards; widespread contractures including fingers; some joints hypermobile; slow progression of weakness in adulthood
Mutations in collagen VI alpha 1, 2 or 3 genes; genetic analysis difficult
CK is normal or mildly raised in all AD-LGMDs except for caveolinopathy. Other AD-LGMDs have been described (1D, 1E) but currently appear rare.
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Table 12.8 Recessive LGMD LGMD Designation: Protein
Specific Clinical Features in addition to Limb Girdle Weakness
2A: Calpain-3
Proximal legs, rectus abdominus, scapular winging; relative sparing of hip abduction and quadriceps Weak gastrocnemius with early inability to walk on toes; legs worse than arms Duchenne-like, quadriceps spared
2B: Dysferlin
2C: g-Sarcoglycan 2D: a-Sarcoglycan 2E: b-Sarcoglycan
Prominent leg weakness, scapular winging, calf hypertrophy Variable severity; enlarged calves
2F: d-Sarcoglycan
Dilated cardiomyopathy
2G: Telethonin
Foot drop; cardiac involvement
2H: TRIM32 (tripartiteProximal leg weakness, neck motif containing gene 32) weakness, slow progression 2I: FKRP Tongue and calf hypertrophy, cramps
CK and Muscle Pathology CK: 780; absence of calpain-3 on immunoblotting CK: 10100 (usually nearer 100). Immunocytochemistry shows absence of dysferlin CK: very high. Immunocytochemistry shows absence of all sarcoglycans CK: 10100. Immunocytochemistry shows absent a-sarcoglycan CK: 10100. Immunocytochemistry shows absence of all sarcoglycans CK: 1050. Immunocytochemistry shows absence of all sarcoglycans (may be some g-sarcoglycan) CK: 330. Rimmed vacuoles on muscle biopsy. Immunocytochemistry shows absent telethonin CK: 125 Reduced staining for a-dystroglycan and a2-laminin
with great variability in severity. Typically they present in childhood with lower limb weakness, but later onset is well recognized. Calf hypertrophy and scapular winging are common. Unlike dystrophinopathies, there is equal involvement of quadriceps and hamstrings and less frequent cardiac and intellectual impairment. Together, they account for 1020% of LGMDs, but represent a much higher proportion of families with severe childhood-onset disease and a lower proportion in families with later onset. Relative frequency of the four disease genes is alpha>beta>gamma>delta in a ratio of approximately 8:4:2:1. Clinical Hints: LGMD Dystrophinopathy may present as a limb girdle syndrome a genetic diagnosis can sometimes be made prior to biopsy. In the presence of contractures or cardiac manifestations consider lamin A/C disease. LGMD2I is a common cause of adult onset LGMD and direct genetic testing may be feasible. Otherwise limb girdle syndromes usually require a muscle biopsy and immunocytochemistry to make a specific diagnosis.
Calpainopathy may account for approximately 2030% of patients with LGMD, and may be clinically distinguishable from the sarcoglycanopathies. Muscular atrophy in the posterior leg compartments with early pelvic girdle involvement is seen. There is relative sparing of the hip abductors, with scapular winging and abdominal laxity. Contractures are also seen, most commonly
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of the Achilles tendon. Patients often adopt a wide-based stance with lordosis and abdominal laxity evident. The characteristically high CK and early weakness of ankle plantar-flexion may allow the clinical diagnosis of dysferlinopathy. There is relative preservation of upper limb strength at presentation. It accounts for approximately 510% of LGMDs overall, but a higher proportion of adult-onset cases. LGMD2I has proved the commonest LGMD in many populations, with variable age of onset and severity. Calf and/or tongue hypertrophy and cardiorespiratory involvement may be evident. Approach to Diagnosis in LGMD A full clinical assessment is required, which may give clues to the molecular diagnosis (Table 12.9). Dominant inheritance raises the possibility of facioscapulohumeral dystrophy (FSHD), which may be overlooked if facial weakness is absent or subtle. FSHD should be specifically excluded either clinically or by genetic analysis. Inheritance compatible with an X-linked pattern including a sporadic male or female patient or male siblings requires exclusion of a dystrophinopathy. CK levels may help refine the differential diagnosis. It is often possible to clinically predict a molecular diagnosis, but further assessment does usually necessitate muscle biopsy with full analysis using immunocytochemistry. Because of the frequency of LGMD2I, and the presence of a common mutation (C826A), it may be practical to screen for this mutation prior to muscle biopsy in a patient with a compatible phenotype. Otherwise a muscle biopsy is usually required to direct further analysis. Muscle biopsy analysis is a specialist service requiring expertise in application of immunocytochemical techniques and their interpretation. A primary defect (e.g., of a dystrophin or a sarcoglycan) can cause secondary defects in other proteins and cautious analysis is required. Most protein defects can be detected by use of the appropriate antibodies on the biopsy but diagnosis of calpainopathies currently requires an immunoblot to identify absence of calpain-3. Analysis of the muscle biopsy can lead to an indication of the primary defect, or narrow the differential diagnosis. Genetic analysis and direct detection of the mutation is the final proof of diagnosis. Currently, in all centers, a substantial minority of patients defy precise genetic diagnosis. Table 12.9 Clinical Clues to Diagnosis in LGMD Clinical Clues
Suggested Diagnosis
Calf hypertrophy, childhood onset Early difficulty in tiptoe walking, very high CK, and late teenage onset Atrophic muscles, scapular winging, preservation of hip abduction Calf hypertrophy, high CK, some have cardiac or respiratory involvement Dominant history
Sarcoglycanopathy Dysferlinopathy Calpainopathy LGMD2I (commonest adult-onset LGMD in some populations) Exclude FSHD, myotonic dystrophy, lamin A/C
Always consider whether pedigree allows possibility of X-linked inheritance (dystrophinopathy).
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Treatment Treatment follows the guidelines stated in the section on dystrophinopathies, adapted for the severity and distribution of the weakness. Steroids are sometimes used but proof of efficacy is lacking. Limb Girdle Muscular Dystrophy When the genetic diagnosis is known: More precise advice on recurrence risk, prognosis, and surveillance for cardiac and respiratory complications can be given. Be aware that some dystrophies predict specific complications. For example: In lamin A/C disease, specialist cardiac management is mandatory, including consideration of implantable defibrillators, etc. LGMD2I requires respiratory and cardiac assessments. In the absence of a precise diagnosis: Review patients regularly for new clinical features. Gain consent for storage of DNA to allow future genetic analysis. Regular cardiac and respiratory surveillance for possible manifestations.
Genetic Advice When a specific mutation has been found, specific advice can be given. Advising a family in the absence of a known mutation is more difficult. Uncertainties regarding the specificity of protein-based testing of patient muscle biopsies make accurate genetic counseling difficult when based purely on immunostaining of muscle biopsy. It may be possible to deduce the mode of inheritance from the family history and the results of investigations, although this may not be possible in a small family with few affected members. In the absence of a definite genetic diagnosis it is unwise to assume recessive inheritance.
Facioscapulohumeral Dystrophy (FSHD; OMIM 158900) Definition Currently FSHD is defined clinically. Improvement in the specificity of molecular genetic finding of a deleted 4q35 fragment may ultimately allow a genetic definition. Clinical Features Onset of the disease may be at any age but typically is in the second decade. Facial or shoulder girdle muscles are affected first. Facial weakness affecting orbicularis oculi and oris is present in nearly all patients, but may be subtle. Extraocular, masticatory, pharyngeal, and lingual muscles are not affected.
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Figure 12.3. Asymmetrical elevation of scapulae and lower facial weakness in facioscapulohumeral dystrophy.
Scapular fixators are prominently involved, with the pectoralis muscles also involved early in the disease course. Asymmetrical involvement is usual, usually affecting the right side first. Inheritance is autosomal dominant and diagnosis is made more straightforward if a family history is evident. Early symptoms reported include sleeping with the eyes open, difficulty whistling, or scapular winging. Arm abduction may be limited by poor scapular fixation despite preservation of deltoids (Fig. 12.3). Shoulder weakness is the most common presenting complaint. Biceps is usually weaker than triceps; wrist extensors are involved later. Leg involvement is variable. The commonest initial leg manifestation is foot drop due to peroneal muscle weakness. Pelvifemoral weakness may sometimes precede peroneal weakness and proximal weakness is present in about half of patients as the disease progresses. Clinical Hints Ask about sleeping with eyes open and ability to whistle, blow up balloons, or suck through straw. Facial weakness is often asymptomatic and can be overlooked; test closure of eyes and pursing of lips. Abduction of the arm causes scapular elevation as well as winging, often observable from the front. Ask patient to walk on heels with toes clear of the ground to test ankle dorsiflexion. Observe the umbilicus when the head is raised from pillow. Lower abdominal muscle weakness causes a move upwards (Beevor’s sign).
Asymptomatic high-tone hearing loss is common in FSHD of childhood or teenage onset, but not in adult-onset patients. Careful retinal examination shows vascular abnormalities in about half of patients, but this rarely causes visual symptoms. Onset before 5 years represents a small proportion of cases, but is associated with more severe weakness, retinal, and hearing problems, and in some cases, learning difficulties and epilepsy. Asymptomatic parents should be examined before assuming that a family history is absent. Genetic analysis is often helpful in confirming a diagnosis made by clinical examination.
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Genetics More than 95% of patients with FSHD have identifiable alterations in the subtelomeric region of 4q35. The deletions occur in a 3.3-kb repeat termed D4Z4. Normal alleles have between 10 and 100 copies of D4Z4, while FSHD patients have between one and eight copies. A homologous configuration in chromosome 10q can complicate analysis, but a double endonuclease digestion technique cuts the 10q fragment to allow better analysis of 4q35. In practice, normal alleles have digestion fragments larger than 38 kb, and almost all abnormal alleles are 34 kb or smaller, leaving some fragments in the intermediate range of unclear significance. Up to 5% of suspected FSHD patients do not have a small fragment. This may be due to an undetected translocation, technical difficulties, or genetic heterogeneity. Translocations between 4q35 and 10q26 occur relatively frequently, even among normal controls. The size of the 4q35 deletion has a correlation with the phenotype, with larger deletions and small fragments being correlated with more severe disease, and, in the extreme case, infantile-onset disease. Male gene carriers are more often symptomatic than females. By age 30, 95% of males and 69% of females manifest with the disease. In some 80% of cases there is a family history consistent with dominant inheritance, with the remainder being sporadic cases. This may arise as a new mutation in the proband or be caused by somatic mosaicism in an asymptomatic parent, more often the mother. Mosaic males typically have a mild FSH phenotype, whereas mosaic females are often detected because they are non-manifesting mothers of de novo cases. Large deletions are usually new mutations. Investigations The creatine kinase level is normal or mildly elevated (<5-times normal). With a suspected diagnosis of FSHD the first investigation is genetic analysis of the 4q35 locus. With a family history, suggestive phenotype and a double digest fragment of <35 kb the diagnosis is secure. An intermediate fragment of 3538 kb is consistent with the diagnosis but the phenotype needs to be considered carefully. This may represent milder, later-onset disease. Because some typical families have normal fragments and are not linked to 4q35 another locus is presumed to account for a small number of families. With equivocal genetic findings it may be necessary to proceed to neurophysiological investigations and muscle biopsy to define the condition further and exclude other conditions which can provide a similar phenotype (Table 12.10). Table 12.10 FSHD: Other Conditions with Prominent Periscapular Involvement Calpainopathies Sarcoglycanopathies (especially LGMD2E) EDMD Lamin A/C deficiency Other scapuloperoneal syndromes
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Pathophysiology Because no genes are expressed in the region of the 4q35 deletion, the pathogenesis of FSHD is unclear. The most popular hypothesis invokes the phenomenon of position effect variegation. It is proposed that a deletion of the D4Z4 repeat alters the organization of heterochromatin and euchromatin. Genes adjacent to the region may thus have aberrant expression. Prognosis Muscle involvement tends to progress caudally, with facial weakness before arms and then legs. Progression is slow with apparent periods of static weakness. For most patients life expectancy is normal and only a minority (approximately 20%) progress to loss of ambulation. Although cardiac involvement with atrial tachyarrhythmias has been reported it is uncommon. Bulbar function is preserved and, although respiratory involvement may be detected, it is rarely problematic. Management Prednisolone has been used in FSHD, but any benefits are short-lived. Anabolic steroids improve muscle mass but have not been shown to improve function. Surgical fixation of scapulae to the chest produces improvement in arm abduction, which may be overtaken as weakness becomes more generalized. Referral for physiotherapy and occupational therapy assessment may be helpful. Genetic Advice Inheritance is autosomal dominant. Note that penetrance is not complete (see above). Each offspring of an affected individual has a 50% chance of inheriting the gene. Sporadic cases may be caused by a new gene mutation, but two other possibilities exist. First, a parent (more often the mother) may carry a nonpenetrant deletion, and genetic analysis of parents’ blood may be indicated to exclude this possibility. Second, it is also possible that germline mosaicism is present in a parent. Absence of a mutation in parental leukocyte DNA does not, therefore, exclude the risk of another affected child. The degree of risk associated with germline mosaicism is currently unknown. Physicians will encounter this situation rarely because parents have often completed a family by the time the diagnosis is established in a previous child. It has been observed that large deletions causing congenital and severe variants of FSHD are often due to new mutations with no disease apparent in the parents, falsely suggesting autosomal recessive disease.
Scapuloperoneal Syndromes (OMIM 181430, 181400, 309660) Scapuloperoneal syndromes are diagnosed on clinical grounds; they are less common than FSHD but represent an important differential diagnosis now
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being clarified by the contribution of genetic analysis. Most reports are of single families, usually with dominant inheritance. Neuropathic etiology is suggested in some families. While facial weakness is an early feature of FSHD, it is absent or mild in the scapuloperoneal syndromes. Because some families with proven FSHD have variable facial weakness, genetic analysis of 4q35 in scapuloperoneal syndromes is prudent; there are some reports of small deletions at 4q35 causing scapuloperoneal weakness without facial weakness.
Oculopharyngeal Muscular Dystrophy (OPMD; OMIM 164300) Definition OPMD is a distinctive clinical disorder, but since discovery of the gene the disorder is defined genetically by the presence of a triplet expansion of the polyadenylate binding protein nuclear 1 gene PABPN1 (previously called polyadenylation binding protein 2, PABP2). Clinical Features OPMD can be autosomal dominant or recessive, with dominant inheritance much more common. Onset is insidious and hard to date, but in dominantly inherited disease is usually between 40 and 70 years. The commonest presenting feature is ptosis, but mild dysphagia may precede ptosis or coincide. Early dysphagia can be suspected if slower eating and avoidance of dry foods is reported. Limb weakness develops later in the disease course. It is proximal and may be more evident in the legs. It is slowly progressive and is often mild but in more severe, early-onset individuals the weakness may be sufficient to prevent walking later in the course of the disease. Ptosis is slowly progressive and often asymmetrical. Ophthalmoplegia may not be present at onset and is always less obvious than the ptosis. Upward gaze is most often affected. Ophthalmoplegia remains partial, and complete ophthalmoplegia should suggest another diagnosis. Dysphagia is progressive and may lead to aspiration of food or liquid into the lungs, often associated with coughing after eating. A suggested test for dysphagia is to time the drinking of 80 ml of cold water. Greater than 7 seconds is considered abnormal. Further bulbar failure is accompanied by facial weakness and dysphonia. Clinical Hints: Differential Diagnosis Late-onset myasthenia often presents with oculobulbar weakness. Fatigable weakness is a clue. Other investigations may be necessary. Prominent ophthalmoplegia is unusual and suggests mitochondrial myopathy. Amyotrophic lateral sclerosis, polymyositis, and inclusion body myositis may cause dysphagia but not ptosis. Myotonic dystrophy can usually be distinguished on clinical grounds. Family photographs may provide evidence of ptosis in previous generations.
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Investigations In the presence of an autosomal dominant history and typical findings the diagnosis can be made on clinical grounds, but it may be prudent to seek genetic confirmation. Sporadic cases prompt consideration of myasthenia, mitochondrial myopathy, and other alternatives. Creatine kinase is normal or mildly elevated. Genetic confirmation is mandatory in the absence of a family history. Further investigations to firmly exclude the treatable alternative of myasthenia may be required. Most series of OPMD show small numbers of families that do not have the PABPN1 expansion. These families require careful assessment and full investigation including muscle biopsy. OPMD due to the PABPN1 expansion has the characteristic findings on muscle biopsy of rimmed vacuoles with nuclear tubular filaments. Pathophysiology The causative mutation accounting for nearly all families with OPMD is a triplet expansion in the polyadenylate binding protein nuclear 1 gene (PABPN1; 14q11.2-q13). Nearly all (98% or more) of control alleles have six GCG repeats. Eight repeats or more causes dominant OPMD. The commonest expansion is to a total of 9 or 10 repeats, with 13 repeats being the largest number observed so far. There is a weak correlation between repeat number and age of onset. Seven repeats on the second allele may give a more severe phenotype than a second allele with the more common six repeats. Recessive disease is caused by a homozygous expansion of seven repeats, which appears rare outside Quebec. This is explained by the 2% allele frequency of seven repeats in French-Canadians, probably higher than elsewhere. Unlike some triplet expansions, the PABPN1 expansion is very stable. Analyses of large OPMD families show that expansion or contraction of the repeat during meiosis is an extremely rare event. Mutated PABPN1 is able to induce nuclear protein aggregation and form filamentous nuclear inclusions, which are the pathological hallmarks of OPMD. Within muscle the nuclear protein aggregation is potentially toxic and may cause cell death. Prognosis Slow progression of ptosis and dysphagia can be expected. Limb weakness is evident later but also progresses slowly. A minority of patients will become wheelchair-bound, which may partly be predicted by the appearance of leg weakness before the age of 60. Management Ptosis surgery is indicated when the eyelids begin to interfere with vision. There are different surgical techniques available and management by an oculoplastic specialist is advisable, particularly as facial weakness may cause potential problems with eye closure. Progressive dysphagia and dysphonia requires referral to a speech therapist. When symptoms cause sufficient difficulty they can be improved by
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cricopharyngeal myotomy, which partially alleviates symptoms. Alternative approaches include pharyngeal dilatation using a balloon or bougie. Some patients with dysphagia despite intervention require alternative routes of feeding, most commonly percutaneous endoscopic gastrostomy (PEG) to allow direct tube feeding to the stomach or duodenum. Genetic Advice Advice depends on genetic findings. In the presence of a single repeat of eight or more triplets, genetic advice is that of a late-onset autosomal dominant disorder of high penetrance. Predictive testing of asymptomatic offspring is sometimes desired. A rare situation is the discovery of a homozygous expansion of seven repeats in the context of sporadic or autosomal inheritance, requiring advice along the lines of a late-onset recessive disorder.
Emery-Dreifuss Muscular Dystrophy (EDMD or EDMD1; OMIM 310300) Classic Emery-Dreifuss muscular dystrophy refers to an X-linked disorder defined clinically. A similar phenotype can result from the lamin A/C gene on chromosome 1q21.2 (EDMD2), which is described separately. Clinical Features Onset is usually before 20 years. Muscle weakness is slowly progressive, initially affecting biceps and triceps with scapular winging. Peroneal and other muscles may be affected, usually with wasting of the calf muscles. Contractures are a prominent feature and often involve the Achilles tendons, elbow, and spine (causing limitation of neck flexion) at presentation. Cardiac involvement causes conduction defects or other evidence of a cardiomyopathy. Ten to twenty percent of female heterozygotes may manifest with conduction defects or weakness. Investigations Creatine kinase is mildly elevated, usually less than 10-times normal. Muscle biopsy shows myopathic changes with some endomysial fibrosis. The diagnosis is made by use of an immunostain against emerin, the gene product. This stains nuclei in normal muscle but not in EDMD muscle. Deficiency can also be demonstrated in skin or leukocytes. Mutations may be demonstrated in the emerin gene but are often unique to each family, and the diagnosis is usually made by immunostaining. Pathophysiology The emerin protein is attached to the inner nuclear membrane and nuclear lamina. It is present in muscle, nerve, skin, and cardiac tissue. It interacts with lamins. Pathogenic mutations usually cause absence of emerin.
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Prognosis Muscle weakness is often moderate and contractures may cause as many problems. Weakness is slowly progressive, but ambulation is usually preserved until late in the disease. Cardiac involvement is always present and most patients require a permanent pacemaker prior to 30 years of age. Some patients develop myocardial dysfunction later in the disease course, sometimes with atrial dysrhythmias. Treatment The cardiac manifestations require specialist management. Patients may benefit from treatment of contractures, particularly Achilles tendon lengthening.
Emery-Dreifuss Muscular Dystrophy 2 (EDMD2; OMIM 181350, 604929) Mutations in the lamin A/C gene can cause several distinct phenotypes, apart from EDMD2. Phenotypes Associated with Mutations in the Lamin A/C Gene
EDMD2 Limb girdle muscular dystrophy 1B Autosomal dominant dilated cardiomyopathy with A-V block (CMD1A) Quadriceps myopathy Charcot-Marie-Tooth 2A Familial partial lipodystrophy Others.
EDMD2 is clinically similar to EDMD1 but differs in the following respects:
Isolated cardiac involvement may occur Cardiomyopathy is more severe and may cause ventricular fibrillation Biceps weakness may be more severe Early-onset variants may have a more severe course.
Pathophysiology The lamin A and C proteins are located at the inner nuclear membrane and are associated with emerin. The two proteins are products of alternate splicing of the 30 end of the same gene. As well as causing the different phenotypes, mutations may act as dominant or recessive mutations causing EDMD2. Prognosis This is variable, with more severe variants heralded by earlier onset. Longevity often is dependent on the severity of cardiac involvement.
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Table 12.11 Distal Myopathies Designation: Prevalent Population
Inheritance Linkage/Gene
CK
Onset, Muscles of Predisposition
Welander (OMIM 604454): Swedish Udd (OMIM 600334) Laing (OMIM 160500): German, Australian Nonaka (OMIM 600737): Iranian, Japanese Miyoshi (OMIM 254130)
Dominant 2p13
N/slight "
>40 yr, hands
Dominant titin Dominant MYH7
N/slight " up to 3
Recessive GNE gene Recessive dysferlin (allelic to LGMD2B)
" up to 10
>35 yr, tibial 125 yr, tibial, neck flexors >20 yr, tibial
10100
>20 yr, calf
Muscle Biopsy Sometimes vacuoles Vacuoles Sometimes vacuoles Vacuoles Myopathic, reduced dysferlin
Distal onset may also be associated with other myopathies, including myotonic dystrophy, myotilinopathy, desminopathy, zaspopathy, debranching enzyme, and phosphorylase b kinase deficiency.
Genetic Advice Genetic advice is difficult because of the different modes of inheritance; X-linked EDMD requires exclusion. Family history may help to define inheritance. Sporadic cases may represent recessive disease, but may also be caused by a new dominant lamin A/C mutation. Genetic analysis of the lamin A/C gene is increasingly available. Identification of the causative mutation may allow more confident prediction of recurrence risks.
DISTAL MYOPATHIES Most primary muscle diseases predominantly affect proximal muscles. Less commonly the distal muscles of the arms or legs are affected early in the disease course, but often with relative preservation of intrinsic hand and foot muscles. Myotonic dystrophy often affects distal muscles as well as the characteristic involvement of face and sternomastoids. Clinical diagnosis of distal myopathies is often possible with distinctive onset, CK levels and association with particular ethnic groups (Table 12.11). Muscle biopsy showing vacuolar change can often lead to designation as an inherited inclusion body myopathy.
CONGENITAL MUSCULAR DYSTROPHIES The term congenital muscular dystrophy (CMD) refers to a group of genetic disorders with muscle present at birth. Affected babies appear floppy, with contractures and muscle weakness. In comparison with the congenital myopathies the weakness is more severe, and it is more likely that serum CK is raised and muscle biopsy will show dystrophic change.
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Table 12.12 Non-Syndromic Congenital Muscular Dystrophies Disease
Frequency
Mutation
Merosin-deficient CMD (OMIM 156225) Partial merosin deficiency
50% of CMD Rare
CMD with integrin a-7 mutations (OMIM 600536) CMD with early spine rigidity (OMIM 602771)
Rare Rare
CMD with muscle hypertrophy and normal CNS (MDC1C; OMIM 606596)
Rare
Ullrich CMD
Unknown
Laminin a2 chain Few reports of laminin a2 chain mutations Integrin a-7 mutations Selenoprotein N, 1 (SEPN1) Fukutin-related protein (FKRP) allelic with LGMD2I COL6 genes
Congenital muscular dystrophies are non-syndromic (Table 12.12; muscle disease only) or syndromic, when other organs (in particular brain and eye) are involved. Most reports of syndromic CMD come from Japan (Fukuyama CMD) and Finland (Santavuori CMD). Walker-Warburg syndrome has a worldwide distribution but may be allelic to Fukuyama CMD. Clinical Hints Immunostaining of the muscle biopsy is the first step towards molecular characterization of CMD. Merosin-positive CMD is genetically heterogeneous and its genetic basis is currently being elucidated. In general, merosin-positive CMD is less severe than merosin-negative CMD; ambulation is usually achieved.
Merosin (Laminin a2 Chain)-Deficient CMD This is defined by deficiency of laminin a2 protein caused by mutation of the gene at chromosome 6q22. Clinical Features and Prognosis Laminin-a2-deficient CMD presents as a non-syndromic CMD as described above. Weakness is present from birth and is severe, symmetric, and includes facial weakness and neck extensors. It is non-progressive. With the most common severe form the child is never able to walk. Contractures progress with age. Intelligence is usually normal, with approximately 20% of patients developing epilepsy. A neuropathy is usually present but is not clinically evident in the context of severe muscle weakness. Partial merosin deficiency causes later onset and milder disability. Investigations Creatine kinase is markedly raised from birth. Magnetic resonance brain scans show increased signal in white matter on T2-weighted images by 6 months of age.
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Muscle biopsy at birth shows marked inflammation, which evolves into a more typical dystrophic picture. The diagnosis is made by laminin-a2 immunostaining; staining is absent from the muscle fiber surface. Skin biopsy and chorionic villus samples show diagnostic deficiency also. With a typical clinical picture and MRI and immunostaining abnormalities, nearly all patients have laminin-a2 gene mutations. As there are no common mutations, genetic analysis is not a commonly used diagnostic test. Mutations are found less frequently in the context of partial deficiency. Pathophysiology This disease is caused by mutations in the laminin-a2 gene. It is situated on 6q2 and is large and complex with 64 exons. Laminin-a2 is a major component of the basal lamina and interacts with the components of the muscle membrane cytoskeleton, including dystrophin and vinculin/integrin. Although the MRI shows dramatic abnormalities, CNS abnormalities are not prominent and the signal change is thought to represent abnormal water distribution in the brain secondary to alteration in the bloodbrain barrier. Treatment Treatment includes consideration of respiratory support and prevention of scoliosis. Genetic Advice Inheritance is autosomal recessive. If the laminin-a2 mutations are known prenatal testing can be performed genetically. Alternatively, chorionic villus samples may be analyzed for the presence of laminin-a2 immunostaining.
Syndromic Congenital Muscular Dystrophy Syndromic congenital muscular dystrophy includes three groups of diseases referred to as muscle-eye-brain disorders (Table 12.13). The most prominent brain manifestation is cobblestone lissencephaly. These disorders include Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS). The muscular dystrophy seems to be most severe in FCMD. Congenital anomalies of the eyes occur in both MEB and WWS. The brain malformations are the most severe in WWS and the least severe in FCMD. In each case inheritance is autosomal recessive.
Congenital Absence or Weakness of Muscles Congenital absence of muscles may affect unimportant muscles such as palmaris longus, but also more important muscles such as the pectoral muscles (Table 12.14).
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Table 12.13 Syndromes with Cobblestone Lissencephaly: Clinical Characteristics (all autosomal recessive)
Syndrome FCMD (OMIM 253800)
MEB (Santavuori; OMIM 253280)
WWS (OMIM 236670)
Brain and Birth Occipital Frontal Circumference (OFC) Moderate cobblestone lissencephaly, normal OFC Severe cobblestone lissencephaly, normal or large OFC due to hydrocephalus Very severe cobblestone lissencephaly; small, normal, or large OFC due to hydrocephalus
Eye
Gene
Normal or minor anomalies
Fukutin (9q31-q33)
Anterior chamber dysgenesis, retinal dysplasia
POMGnT1; O-linked mannose b1,2-Nacetylglucosaminyltransferase
Microophthalmia or bupthalmos, anterior chamber dysgenesis, retinal dysplasia, or other
POMT1; O-mannosyltransferase 1; some families linked to 9q31
Table 12.14 Congenital Absence or Weakness of Muscles Absent Muscle
Other abnormalities
Pectoral (Poland syndrome) (OMIM 173800)
Variable including ipsilateral hand Usually sporadic abnormalities, and other muscles and craniofacial abnormalities Absence of other muscles, radius, Autosomal dominant; human contractures, cardiac septal defects transcription (TBX5)
Holt-Oram syndrome (OMIM 142900); thenar muscles, trapezius Prune belly syndrome (abdominal Variable genito-urinary, anal, and muscles) (OMIM 100100) cardiac problems Diaphragm (OMIM 222400, 306950) Palmaris longus (OMIM 167600) Finger and thumb extensors
Inheritance
Autosomal recessive or dominant Autosomal recessive or X-linked Autosomal dominant with incomplete penetrance Autosomal recessive
CONGENITAL MYASTHENIC SYNDROMES The congenital myasthenic syndromes (CMS) are a heterogeneous collection of genetically determined defects of neuromuscular transmission (Table 12.15). Whereas there are clinical, neurophysiological, and genetic differences between the disorders they can be generically identified by common characteristic features:
Usually neonatal or childhood onset Often with oculobulbar distribution Fatiguable weakness Affected relatives Decrement of the muscle action potential on low frequency stimulation Absence of acetylcholine receptor and calcium channel antibodies.
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Table 12.15 The Congenital Myasthenic Syndromes Syndrome
Gene
Syndromes with decreased AChR stimulation Reduced expression Rapsyn mutations of AChRs (OMIM 601592) (commonest type)
AChR mutations* e most common
CMG with episodic apnea (OMIM 254210)
Choline acetyltransferase (ChAT)
Fast-channel syndromes
Mutations in acetylcholine receptor a, e and other subunits*
Syndromes with AChR overstimulation Mutations in Slow acetylcholine acetylcholine receptor channel receptor a, b, d, syndromes (OMIM and e subunits* 601462)
Endplate AChE deficiency (OMIM 603033)
Collagen-tailed AChE Co1Q
Presentation
Inheritance
Treatment
Prenatal onset with arthrogryposis; early respiratory crises with improvement Neonatal onset; marked ptosis and ophthalmoplegia
AR
Good response to AChE inhibitors and 3,4diaminopyridine
AR
Partial response to AChE inhibitors and 3,4diaminopyridine Pyridostigmine; apnea monitor
Neonatal onset with improving bulbar and respiratory weakness; episodic apnea Variable
Variable presentation includes adult onset with forearm extensor and scapular weakness and wasting Early onset severe oculobulbar and generalized weakness
AR
AR
Variable response to AChE inhibitors and 3,4diaminopyridine
AD
No response to AChE inhibitors; open channel blockers (quinidine, fluoxetine) helpful
AR
No response to AChE inhibitors; ephedrine may be helpful
*AChR subunit mutations have varying functional effects and may result in congenital myasthenic syndromes characterized by AChR deficiency, fast-channel, kinetic defects, or low-affinity syndromes.
None of the first four features is invariable. For example, some slow-channel syndromes can present in adult life with finger and wrist weakness, and neurophysiological signs may not always be present in all muscles. Investigations Conventional muscle biopsy is often normal or non-diagnostic in CMS. Neurophysiological testing is useful. Repetitive nerve stimulation at 2 Hz typically causes a decrement. A decrement is not invariable (it is absent in myasthenia with episodic apnea when asymptomatic). An edrophonium test is usually positive, although the response may be weak. Acetylcholinesterase (AChE) inhibitors may produce benefit. However, endplate AChE deficiency and slow-channel syndrome can be thought as producing excessive endplate stimulation and a repetitive muscle potential to a single stimulus is seen. Similarly, no response to AChEs occurs in these two conditions.
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BIBLIOGRAPHY www.neuro.wustl.edu/neuromuscular/ www.geneclinics.org Engel AG (2004). Myology. McGraw-Hill Professional. Harper PS (2001). Myotonic dystrophy. Major Problems in Neurology Vol. 37, 3rd Edition. Saunders.
REFERENCES www.geneclinics.org Hoogerwaard EM, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF, Leschot NJ, Van Essen AJ, Brunner HG, van der Wouw PA, Wilde AA & de Visser M (1999a). Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort study, Lancet, 353, 21162119. Hoogerwaard EM, van der Wouw PA, Wilde AA, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF, Van Essen AJ, Leschot NJ & de Visser M (1999b). Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy, Neuromuscul Disord, 9, 347351. Van Essen AJ, Kneppers AL, van der Hout AH, Scheffer H, Ginjaar IB, ten Kate LP, van Ommen GJ, Buys CH & Bakker E (1997). The clinical and molecular genetic approach to Duchenne and Becker muscular dystrophy: an updated protocol. J Med Genet, 34, 805812.
Chapter 13 Muscle Channelopathies and Metabolic Myopathies Simon R. Hammans
CHANNELOPATHIES Introduction Membrane ion channels are a fundamental feature of excitable cells such as muscle and neurons. Disorders of ion channels are termed channelopathies and are increasingly recognized as important causes of muscle and neurological disease. Channelopathies causing CNS dysfunction such as ataxia and epilepsy are described in Chapters 4 and 6. In muscle, channelopathies may cause paroxysmal weakness or myotonia, although fixed weakness is also observed. The disorders can be defined clinically or genetically. The genetic classification is shown in Table 13.1. The disorders are discussed by clinical presentation.
Periodic Paralyses Although the periodic paralyses vary clinically and molecularly, they have some features in common. The commonest clinical pattern is an attack of reversible flaccid paralysis. Frequency of attacks is highly variable. Weakness may range from temporary and mild weakness of an isolated muscle group (often starting in proximal legs) to generalized paralysis of the trunk and limbs. The muscles most likely to escape involvement are the eyes, face, tongue, pharynx, larynx, diaphragm, and sphincters, but occasionally even these may be involved. In the attack, tendon reflexes are reduced in proportion to weakness, and compound muscle action potentials are similarly diminished. Consciousness is preserved. Serum potassium may be high or low and this traditionally determines the form of periodic paralysis (PP). Not all hypokalemic muscle weakness is genetic, and a full clinical assessment may identify other causes of hypokalemia. Specifically, thyroid status should be tested. 229
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Table 13.1 Muscle Channelopathies Genetic Classification Channel
Gene
Phenotype
Inheritance
Calcium
CACNA1S a1-subunit
Autosomal dominant
Sodium
RYR SCN4A a-subunit
Chloride
CLCN1
Potassium
KCNJ2
HypoPP Malignant hyperthermia Malignant hyperthermia Paramyotonia congenita HyperPP K+-sensitive myotonia HypoPP Myotonia congenita (Thomsen) Myotonia congenita (Becker) Andersen syndrome
Commonest phenotypes in bold.
Differential Diagnosis of Periodic Paralysis
Hypokalemic periodic paralysis (hypoPP) Hyperkalemic periodic paralysis (hyperPP) Andersen syndrome Thyrotoxic periodic paralysis Hypokalemia secondary to diet, or renal or digestive loss.
Hypokalemic Periodic Paralysis (HypoPP; OMIM 170400) Clinical Features The attacks commence between 1 and 20 years of age, are maximal between 15 and 35 years and then decline with age. Typically, attacks begin in the early morning after the known triggers of physical activity or a carbohydrate-rich meal on the preceding day. Strength usually improves during the day but weakness occasionally lasts 23 days. Surgery or glucose infusion may also provoke an attack. In some patients, repeated reversible attacks over years evolve into a slowly progressive fixed muscle weakness predominantly in the lower limbs. In a few patients, the attacks are not prominent and the disease resembles a progressive myopathy. Investigations During and after attacks serum CK may be raised. Potassium is characteristically reduced during the attack to between 0.9 and 3.0 mM; measurement is necessary to define the disorder. EMG during the attack may show myopathic change, and between attacks if there is fixed weakness. Myotonia is not seen, and if present suggests paramyotonia/hyperPP. McManis et al. (1986) described a standardized neurophysiological exercise, performed between attacks (see Table 13.2). It is useful in determining the likelihood of a periodic paralysis, although does not differentiate between
Autosomal Autosomal Autosomal Autosomal Autosomal Autosomal Autosomal Autosomal
dominant dominant dominant dominant dominant dominant recessive dominant
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Table 13.2 The McManis Test The compound action potential (CMAP) is measured in the hypothenar muscles. The muscles are exercised maximally for 15-second bursts followed by 5-second rest periods for 25 minutes. In controls CMAP amplitude increases immediately after exercise by less than 27% and then decreases less than 30% 5 minutes after the exercise test. In periodic paralysis the CMAP increases after exercise by >35% and subsequently a successive drop in amplitude by >27%. A positive test provides support for a diagnosis of PP although does not differentiate between the types.
hyperPP and hypoPP. In patients with a fixed myopathy, muscle biopsy is abnormal, with characteristic vacuolar change as well as other myopathic changes. Tubular aggregates are sometimes evident, although these are not a specific finding. Fournier et al. (2004) describe EMG characteristics of muscle channelopathies in more detail which may help guide genetic analysis. Depending on availability, genetic analysis may be requested early in investigation after suspicion of hypoPP. Improved neurophysiological and genetic analysis has decreased the use of provocation testing. Such tests provoke hypokalemia utilizing glucose with or without insulin, and should be avoided if possible. HypoPP is most commonly due to mutations in the gene for the L-type calcium channel (CACNA1S), with the R528H and R1239H mutations accounting for 3060% of probands. HypoPP due to mutations in this gene is termed type 1. A further 10% have mutations in the sodium channel gene (SCN4A) designated hypoPP type 2. A few families have further private mutations in these genes, and a few more in the potassium channel KCNE3. This leaves a significant number of families without known mutations. Pathophysiology Mutations in the calcium channel gene are thought to enhance inactivation of the calcium channel, causing a defect in the control of the resting muscle potential and depolarization of the muscle membrane during attacks. Prognosis Penetrance, age of onset, muscle histology, response to treatment and prognosis appear to depend on the causative mutation. In women, penetrance is reduced to 5070% in the common CACNA1S mutations. Penetrance appears variable in different SCN4A mutations. Overall, more than 90% of males express symptoms. Onset of symptoms is on average 23 years younger in females. It is also earlier in the context of the R1239H CACNA1S mutation than for patients with the R528H and R672H mutations. Evolution of permanent weakness occurs in 2530% of patients, often in middle age. It predominantly affects proximal leg muscles. It may occur in CACNA1S and SCN4A patients. Successful treatment to reduce episodic weakness is not known to affect prognosis.
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Treatment Paralytic Crisis. Treatment is by oral or intravenous infusion of potassium. Serum potassium is not directly related to muscle strength and normalization of potassium may precede return of full strength by hours. Hypokalemia and potassium treatments may both promote cardiac arrhythmias and serum potassium and cardiac rhythm should be monitored during and after correction of potassium. If patients have significant paralysis and can swallow, potassium is given orally, if there are no contraindications. Recommended doses vary but typically an adult dose of 20 mmol is given every 15 to 30 minutes to a total of four doses, with adjustment dependent on serum potassium. No sugar should be given and supplementation should cease when serum potassium returns to the normal range, even if weakness persists. Intravenous potassium may be given if oral treatment is not possible, diluted in mannitol rather than glucose or sodium chloride. The concentration of potassium in intravenous fluid must not exceed 40 mmol/L, and be given no faster than 20 mmol/h and 200250 mmol/day. Prevention. Diet adjusted to reduce sodium and carbohydrate and enhance potassium intake Potassium supplementation Acetazolamide started at 125 mg/day and titrated upwards as necessary. (Warn about risk of nephrolithiasis, and maintain fluid intake) Dichlorphenamide, spironolactone, or triamterene are alternatives. The strategy for prevention may be influenced by genotype; CACNA1S mutations may predict a response to acetazolamide, which is less likely in SCN4A patients. Malignant Hyperthermia (MH). Mutations in CACNA1S and SCN4A genes may be associated with hypoPP, MH, or both. Because periodic paralysis patients are at theoretical risk of MH, all PP patients should be warned about risk of MH and (unless an in vitro contracture test proves normal) triggering anesthetics should be avoided. HypoPP patients also are at risk of paralytic attacks being triggered by anesthetics. Genetic Advice HypoPP is autosomal dominant with reduced penetrance in females. It is important to advise the family about the disorder, and specifically about potential anesthetic complications.
Hyperkalemic Periodic Paralysis (HyperPP; OMIM 170500: and PMC; OMIM 168300) Like hypoPP, hyperPP is characterized by episodes of reversible flaccid muscle weakness. It is possible to clinically differentiate the two disorders. Normokalemic PP is less well defined but evidence suggests that it may also
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be related to sodium channel dysfunction and may be allied to hyperPP. Paramyotonia congenita is considered here because it has features in common with hyperPP and is caused by mutations in the same gene. Potassium-aggravated myotonia (PAM) relates to a spectrum of rarer disorders that differ symptomatically but are also sodium channel disorders (myotonia fluctuans, myotonia permanens, acetazolamide-responsive myotonia). In hyperPP (in contrast to hypoPP) there is often earlier onset, usually in the first decade. Attacks are usually shorter (1560 minutes). Flaccid limb weakness is typical, but weakness may also include eye, throat, and trunk muscles. Attacks are associated with high serum potassium (typically >5 mM). Although hyperkalemia may cause changes in the ECG, cardiac, and respiratory problems usually do not occur in attacks. A large proportion of subjects with hyperPP develop progressive proximal weakness. Whereas clinical myotonia suggests the allelic disorder paramyotonia congenita (PMC), 5075% of patients with hyperPP have subclinical myotonia revealed on EMG. Rest, particularly following exercise, often provokes attacks. Both hyperPP and PMC are caused by mutations in a sodium channel gene (SCN4A).
Paramyotonia Congenita (PMC) Paramyotonia refers to paradoxical myotonia, where the myotonia increases with exercise. PMC particularly affects the face, neck, and arms. It is markedly worsened by cold. Family members may recognize facial stiffness in infancy on cold exposure or even in enthusiastic baptism! In clinical examination, it is important to provoke myotonia by repeated contraction. Repeated forceful grip may worsen myotonia after a few contractions. Repeated forceful eyelid closure characteristically may cause increasing difficulty in eye opening. Some patients experience episodic weakness, and it may be difficult to know whether this is the stiffness of paramyotonia, or paralysis from a PP phenomenon. Diagnosis and Investigations In hyperPP, CK may be normal or mildly raised. The McManis test (Table 13.2) is abnormal in 7080% of cases of PP, but does not differentiate between the different forms of PP. However, a typical clinical picture and family history together with the presence of myotonia clinically or electrically will often clarify the diagnosis of hyperPP. Often genetic analysis is performed at an early stage as just two SCN4A mutations account for the majority of families. It may therefore be possible to avoid provocative testing, in which exercise or an oral potassium load is used to precipitate symptoms. In PMC EMG may show myotonia, but this is sometimes absent at room temperatures. Cooling may precipitate myotonia initially, but may precipitate paralysis and disappearance of myotonia. A cold immersion EMG protocol for myotonia and paramyotonia congenita has been proposed and can provide substantial evidence for PMC (Streib 1987). Genetic analysis of the SCN4A gene is usually confirmatory.
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Pathophysiology Mutations in the SCN4A gene may cause hyperPP, PMC, or potassium-aggravated myotonia. All mutations result in impaired fast inactivation of the sodium channel. This abnormal gain of function is consistent with the dominant inheritance observed in all these disorders. HyperPP mutations give rise to a small residual current that fails to inactivate at positive membrane potentials. Impaired membrane repolarization causes extracellular potassium accumulation. This instability may explain both the episodic nature of hyperPP and the associated hyperkalemia. Mutations seen in paramyotonia congenita alter the rate and voltage-dependence of inactivation, resulting in the characteristic repetitive discharges. Prognosis Typically, in hyperPP, attacks increase with age until the age of 50, and decline thereafter. Many older patients develop a fixed myopathy. As geneticclinical correlations emerge it has become clear that prognosis and phenotype is related to the particular mutation in SCN4A. The Thr704Met mutation is commonly causative of permanent weakness, while the Met1592Val mutation is not associated with permanent weakness. Treatment Many attacks are brief and do not need treatment. Patients may discover whether carbohydrate ingestion or gentle exercise may abort attacks. Inhalation of salbutamol may also help attacks. Prophylaxis of weakness can be achieved with dichlorphenamide, acetazolamide, or thiazide diuretics. Mexiletine is probably the most effective treatment of paramyotonia, but will not prevent weakness. Malignant hyperthermia may also be associated with mutations in SCN4A. Although mutations associated with hyperPP and PMC may not characteristically cause MH, patients are at theoretical risk of MH, and all such patients should be warned about risk of MH and (unless an in vitro contracture test proves normal) triggering anesthetics should be avoided.
ANDERSEN SYNDROME (OMIM 170390) Andersen syndrome refers to a triad of periodic paralysis, dysmorphic features and cardiac rhythm abnormalities. It is caused by mutations in the potassium channel KCNJ2 gene. It is substantially rarer than hypoPP. Diagnosis Not all patients have all three elements of the diagnostic triad. Inheritance is autosomal dominant and a family history of sudden death may be obtained. Dysmorphic changes include short stature, scoliosis, tapered curved fingers and a facial appearance of hypertelorism (wide-set eyes), micrognathia, low-set ears
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and a broad forehead. Facial appearance allows a clinical diagnosis. There may be evidence of varying forms of ventricular ectopy, which may be asymptomatic or manifest as palpitatations, syncope, or sudden death. On ECG, a prolonged QU interval or large-amplitude U wave may be more sensitive than the QTc interval, which overlaps with the upper limit of normal. Serum potassium may be high, low, or normal during an attack. Causative mutations are within the KCNJ2 gene. Muscle biopsy may show tubular aggregates. Management Oral potassium has a variable effect but may improve weakness in patients with low potassium. Because of the potential fatal cardiac problems, specialist cardiac assessment is indicated. Counseling is that of an autosomal dominant condition allowing for intrafamilial variability with partial manifestations in some family members. Clinical Hint Remember to consider Andersen syndrome in periodic paralyses: recognition could prevent cardiac death.
MYOTONIA CONGENITA (MC; OMIM 160800) Both the dominant (Thomsen) and the recessive (Becker) forms of myotonia congenita are caused by mutations in the muscle chloride gene (CLCN1). Diagnosis The dominant and recessive forms share characteristics. Generalized myotonia is observed with onset in the first decade of life. The muscle stiffness is caused by a failure of muscle relaxation, which is most pronounced when muscle activity follows a period of rest. The myotonia increases for three or four contractions and then disappears. The myotonia is often followed by transient weakness. There are no episodes of long-lasting weakness. Muscle hypertrophy is usual. The myotonia may be most prominent in the legs. Worsening of myotonia on cooling is reported by some patients with MC, but is not apparent objectively. Marked cold sensitivity is more suggestive of paramyotonia congenita (Table 13.3). Recessive MC is often more severe and shows more muscle hypertrophy than the dominant form. Investigations CK may be slightly elevated. EMG detects myotonia, even in early childhood. Myotonia declines after a period of maximal contraction, but no effect of cooling is observed. Genetic analysis of CLCN1 may detect mutations. Some act as dominant mutations, some recessive and some may act as either.
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Table 13.3 Clinical Differences between Myotonia Congenita and Paramyotonia Congenita MC
PMC More prominent with each contraction
Site
May increase for 34 contractions, then improves Generalized, particularly legs
Provocation Weakness
After rest Transient after myotonia
Myotonia
Face, upper limbs Particularly eyelid opening after repeated forced closure Cold Common, may overlap with hyperPP
Some families clinically classified as MC harbor SCN4A mutations, demonstrating the phenotypic overlap of channelopathies. Pathophysiology MC is usually caused by mutations in the CLCN1 gene. Over 50 mutations have been described worldwide (mostly recessive), but some families do not carry identifiable mutations, implying genetic heterogeneity. Mutations interfere with the tetramer formation of the chloride channel, resulting in reduction of chloride conductance. This causes increased membrane depolarization and spontaneous triggering of action potentials. Prognosis Myotonia may be static or become more prominent into adulthood. MC is not associated with muscle weakness or cardiorespiratory symptoms and longevity is not affected. Malignant hyperthermia has occasionally been described in MC. Treatment Myotonia may be treated with mexiletine or other agents. Genetic Advice Examination of parents is prudent if there is no family history to establish the mode of inheritance. Genetic analysis may further clarify the likely inheritance pattern, as some mutations are characteristically dominant or recessive. Penetrance in dominant mutations is thought to be approximately 90%.
Other Disorders with Myotonia and Cramps The commonest myotonic disorder is myotonic dystrophy (Chapter 12). Less common disorders are listed in Table 13.4.
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Table 13.4 Other Disorders with Myotonia and Cramps Disorder
Gene, Inheritance
Main Features
Schwartz-Jampel syndrome (OMIM 255800) Brody disease (OMIM 601003)
Perlecan, recessive
Marked early onset myotonia; bone dysplasia Cramps and myalgias after exercise affecting limbs, face Wave-like rippling of muscle evoked by stretch; raised CK, cramps, electrically silent
Rippling muscle disease (OMIM 600332, 606072)
Ca2+ ATPase (ATP2A1), recessive 2 loci RMD-1: chromosome 1q41, dominant; RMD-2: caveolin-3 mutations, dominant
MALIGNANT HYPERTHERMIA Malignant hyperthermia (MH) denotes an inherited abnormal response to anesthesia (inhalational agents, succinylcholine) characterized by skeletal muscle rigidity and hypermetabolism. Skeletal muscle damage and cardiovascular impairment may ensue with fatal results if untreated. Some patients with MH have lesser episodes induced by exercise in hot conditions, infections, alcohol, and neuroleptic drugs. Recognition of the diagnosis in a proband requires appropriate counseling and investigation of family members. An in vitro contracture test aids diagnosis, and can be used to determine the susceptibility of asymptomatic relatives of patients with an established diagnosis. The test requires fresh muscle and is performed at designated centers. The commonest identified cause for MH is a mutation in the ryanodine receptor gene (RYR1), accounting for approximately 25% of MH patients and 50% of established MH families. MH is allelic to central core disease. Currently, because of uncertain phenotypes associated with mutations in the RYR1 gene and others, the in vitro contracture test remains central in diagnosis. Other genetic causes are listed in Table 13.5. King-Denborough syndrome is associated with muscle weakness and skeletal features resembling Noonan syndrome. If there is doubt about susceptibility to MH, then the patient should be regarded as MH-susceptible and triggering agents avoided. Table 13.5 Genetic Causes of Malignant Hyperthermia Gene
Allelic Disorders
Ryanodine receptor (RYR1) Sodium channel SCN4A Calcium channel CACNA2D1 Unknown (3q13.1) Calcium channel CACNA1S Unknown (5p) King-Denborough syndrome
Central core disease HyperPP
HypoPP
In addition MH has been inconstantly associated with dystrophinopathies, myotonic dystrophy, myotonia congenita, Schwartz-Jampel syndrome, Satoyoshi syndrome.
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Table 13.6 Glycogen Storage Myopathies Enzyme
Additional Features
Diagnosis
Usually presenting with exercise intolerance/cramps Myophosphorylase (OMIM 232600)
See text
Phosphofructokinase (OMIM 232800)
Similar to McArdle’s disease
Phosphorylase b kinase (OMIM 311870, 261750)
X-linked or recessive several forms; weakness may be distal
Phosphoglycerate kinase (OMIM 311800)
May have mental retardation/seizures; X-linked
Phosphoglycerate mutase (OMIM 261670) Lactate dehydrogenase (OMIM 150000)
High CK; abnormal ILT; glycogen storage on muscle biopsy; genetic analysis for common mutations High CK; abnormal ILT; bilirubin and urate may be elevated; hemolytic anemia; glycogen storage on muscle biopsy Raised CK, urate; abnormal ILT; mild glycogen storage on muscle biopsy; low enzyme levels in muscle Abnormal ILT; normal muscle biopsy High CK; ILT: partial response High CK; abnormal ILT; low serum LDH
Usually presenting with fixed and progressive weakness Acid maltase deficiency (OMIM Infantile onset with cardiac and liver 232300) involvement; adult onset with axial and proximal muscle weakness; respiratory involvement often leads to respiratory failure Branching enzyme (OMIM 232500) Debrancher (OMIM 232400)
Triosephosphate isomerase (OMIM190450)
CK usually very high; muscle biopsy shows glycogen present in lysosomal vacuoles; leukocytes may demonstrate glycogen; enzyme deficiency can be demonstrated in muscle; normal ILT Polyglucosan bodies seen
Congenital, systemic, and myopathic forms Usually abnormal ILT; abnormal Infants present with hypoglycemia, ECG; glycogen storage in muscle cardiac or liver dysfunction; adults present with proximal weakness and distal leg weakness; possible respiratory, cardiac, and peripheral nerve involvement Systemic disease fatal in infancy
ILT, ischemic lactate test.
METABOLIC MYOPATHIES Metabolic myopathies largely fall into one of three groups: glycogen storage disorders, lipid disorders and mitochondrial myopathies. Mitochondrial myopathies are described in Chapter 16.
Glycogen Storage Myopathies Glycogenoses present with exercise-induced discomfort, cramps, or myoglobinuria, or as a fixed weakness (see Table 13.6).
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Glycogenoses presenting with exercise intolerance present often in adolescence or early adulthood with pain or cramps on exercise. This is most pronounced during exercise and usually is relieved by rest. Patients may experience the second-wind phenomenon, when persistence with submaximal exercise eventually causes relief through use of lipid oxidation rather than glycolysis. Excessive exercise is capable of causing rhabdomyolysis and myoglobinuria. Many of the glycogenoses present in infancy or childhood with systemic disease often involving the heart or liver, whereas adult presentations may be exclusively myopathic. Although Table 13.6 divides the presentations into exercise intolerance or with weakness, these may overlap. Also, a proportion of patients presenting with exercise intolerance eventually develop fixed weakness. Many glycogenoses are rare. The two commonest in clinical myology are described in more detail. Myophosphorylase Deficiency (McArdle’s Disease; OMIM 232600) Onset is usually younger than 15 years. Exercise intolerance manifesting as myalgia, stiffness, or weakness of muscle and relieved by rest is the cardinal symptom. Isometric exercises such as lifting heavy weights, or intense dynamic exercise such as walking uphill, are the most common precipitants. Many patients adapt their exercise pattern to avoid such stimuli, or to take advantage of the second-wind phenomenon described above. Whereas symptoms usually start in childhood, diagnosis is frequently not achieved until the second or third decade. Rhabdomyolysis and myoglobinuria are experienced at least once by half of patients. About half of these will experience acute renal failure. A presentation with progressive limb girdle weakness is well established, often manifesting in the sixth decade or later. In these patients even retrospective questioning about exercise intolerance may not produce a compelling account. Investigations. CK is raised in more than 90% of patients. EMG is often unhelpful, showing myopathic changes in the presence of fixed weakness. The forearm ischemic lactate test (ILT) is abnormal in more than 90% of patients (see Table 13.7), but is not specific for myophosphorylase deficiency. The diagnosis may be confirmed by muscle biopsy. The periodic acid Schiff (PAS) reaction demonstrates subsarcolemmal deposits of glycogen in all but the mildest cases. A direct reaction for the phosphorylase enzyme can be performed on the muscle section, with absence of reaction demonstrating deficiency. Enzyme assay may be performed on fresh muscle. More than 20 separate mutations have been described in the phosphorylase gene. In the USA and Europe the commonest is the Arg49Stop mutation, which may form the basis for diagnostic testing if molecular genetic analysis is available. Pathophysiology. Phosphorylase initiates glycogen breakdown by liberating glucose-1-phosphate from the outer branches of the glycogen molecule. Deficiency prevents glycogen breakdown, causing glycogen accumulation in muscle. Muscle activity requiring anaerobic glycolysis is impaired, but more important clinically is the impairment of aerobic metabolism of glucose because of a lack of substrate (impaired glycogen breakdown leads to a shortage of pyruvate and acetyl-CoA).
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Table 13.7 Protocol for the Ischemic Lactate (and Ammonia) Test 1. After an overnight fast, venous access is obtained, baseline samples are taken for lactate and ammonia assay, and the line maintained with heparinized saline. 2. A sphygmomanometer cuff is placed around the upper arm and inflated above systolic blood pressure. 3. The subject exercises the forearm by repeatedly squeezing a sphygmomanometer bulb at 1-sec intervals for 1 min under the supervision of the clinician, who notes the amount of effort applied and any subjective complaints of pain. If a cramp occurs the cuff should be released immediately to avoid the possible complication of muscle necrosis or compartment syndrome. 4. The exercise is then discontinued and the cuff remains inflated for a further minute. Thereafter the cuff is released and samples taken immediately for assay (0 min). 5. With the subject remaining at rest, further samples are taken at 2, 5, and 12 min. Interpretation Lactate normally rises at least 3-fold within 12 min of exercise and the ammonia rise usually is greater. If the lactate does not rise normally, but the ammonia rises normally, then a diagnosis of glycogen storage disease should be considered. Alcoholic myopathy may give a similar result. A rise in lactate but a flat ammonia response suggests the diagnosis of myoadenylate deaminase deficiency. A flat response to both lactate and ammonia suggests inadequate exercise or effort.
Prognosis. Approximately 30% of patients with phosphorylase deficiency go on to develop a slowly progressive weakness mainly affecting proximal muscles. Fifty percent of patients have one or more episodes of rhabdomyolysis. Half of these episodes cause acute renal failure, which subsequently will recover with appropriate supportive treatment. Treatment. Possible treatments include creatine monohydrate and high-protein diets. Regular exercise may improve exercise tolerance. Genetic Advice. Phosphorylase deficiency is autosomal recessive, but most series show an excess of males, showing that there must be non-penetrance, at least in females. Prenatal or predictive testing is unlikely to be an issue with the rare exception of early-onset severe disease. Occasional pseudodominant inheritance has been observed. Acid Maltase Deficiency (OMIM 232300) Acid maltase deficiency is caused by mutations in the acid a-1,4-glucosidase gene resulting in enzyme deficiency. Diagnosis. This disease is inherited as an autosomal recessive trait. Infantile onset gives rise to cardiac failure and liver involvement, which is usually fatal. Childhood onset causes progressive proximal and respiratory weakness usually leading to death in early adulthood. In adult-onset disease presentation is with fatigue or with proximal weakness, which may resemble polymyositis. Respiratory failure is a frequent manifestation, being a presenting feature in one-third of patients, and increasingly common as the disease progresses. Weakness is proximal, particularly in the legs. Paraspinal muscles are often weak.
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Clinical Hints Respiratory weakness in muscle disease is insidious. Screen by measuring sitting and lying vital capacity, and by a sleep study. Patients with acid maltase deficiency should be regularly screened for respiratory muscle weakness.
Investigations. Serum CK is usually very high and is abnormal in 95% of affected adults. EMG may show myopathic change and occasional myotonic discharges. Muscle biopsy shows a vacuolar myopathy. Vacuoles contain glycogen and cell debris. There is abnormal acid phosphatase staining. Acid a-1,4glucosidase activity is reduced in adult-onset disease and usually absent in childhood-onset. The biopsy is occasionally normal in adult-onset disease. A blood film stained with PAS may identify glycogen granules within lymphocytes. Pathophysiology. The disease is caused by mutations in acid a-1,4-glucosidase, which is a lysosomal protein. Many different mutations have been described. There is correlation between the level of residual enzyme activity and severity of disease, age of onset, and location of the mutations. Unlike most other storage diseases, utilization of glycogen or glucose is not impaired. Muscle damage is caused by excessive storage of undegraded material and/or impaired lysosomal activity. Prognosis. Weakness is progressive and causes increasing disability. Respiratory failure eventually becomes evident in most patients. Although there is wide variability in severity of phenotype, the presentation within families is similar. Genetic Advice. Counseling is for autosomal recessive inheritance. Carrier frequency is approximately 1%. Prenatal testing, usually in the context of early-onset disease, can be performed using genetic analysis or enzyme assay. Treatment. Enzyme replacement therapy using recombinant acid a-glucosidase has shown some promise. Trials to establish its role in therapy continue. In all patients, respiratory status should be carefully monitored to allow appropriate and timely respiratory support. Two Other Lysosomal Disorders The muscle biopsy findings of acid maltase deficiency are similar to two other myopathies, both X-linked, summarized in Table 13.8.
Lipid Myopathies Lipids are the main fuel of muscle at rest or during prolonged exercise. As indicated by Table 13.9, disorders of fatty acid metabolism have widely varying manifestations. Nevertheless, clinical presentation usually falls into three broad groups.
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Table 13.8 Two Other Lysosomal Myopathies Disease
Clinical Features
Lysosome-associated membrane protein 2 (LAMP-2) (Danon’s disease; OMIM 300257)
High CK; vacuolar X-linked but with manifestations myopathy in females; childhood onset; predominant shoulder girdle weakness; cardiomyopathy; mental retardation Onset 020 years; usually no High CK; vacuolar manifestations in females; very slow myopathy progression
X-linked myopathy with excessive autophagy (OMIM 310440)
Investigations
Table 13.9 Lipid Myopathies Deficiency
Presentation
Investigations
Systemic carnitine deficiency (OMIM 212140)
Onset <10 years; encephalopathy, cardiomyopathy, myopathy, hypoglycemia Onset childhood or later; muscle weakness +/ cardiomyopathy Multisystem presentation in infancy, see text for adult form Multisystem presentation in infancy
Lipid storage on muscle biopsy; low carnitine
Myopathic carnitine deficiency (OMIM 212160) Carnitine palmitoyltransferase II (CPT2; OMIM 600650) Carnitine-acylcarnitine translocase deficiency (OMIM 212138) Very long-chain acyl-CoA Early-onset systemic disease; adultdehydrogenase deficiency onset exercise intolerance, myogl(VLCAD; OMIM 201475) obinuria, variable hypoglycemia Trifunctional protein deficiency Infantile-onset systemic disease; or (OMIM 600890) pigmentary retinopathy, peripheral neuropathy, limb-girdle myopathy, weakness, paroxysmal myoglobinuria; hypoparathyroidism Short-chain acyl-CoA Infantile: non-ketotic hypoglycemia, dehydrogenase deficiency failure to thrive, hypotonia, (SCAD; OMIM 201470) hypertonia, seizures. Adult: chronic myopathy, variable ophthalmoplegia Short-chain hydroxyacyl-CoA Infection-induced hypoglycemia, dehydrogenase deficiency encephalopathy, cardiomyopathy; (SCHAD; OMIM 601609) recurrent rhabdomyolysis
Raised CK; lipid storage on muscle biopsy Blood acylcarnitines; genetic analysis Blood acylcarnitines
Raised CK; lipid storage on muscle biopsy, dicarboxylic aciduria, acylcarnitines Lactic acidosis, raised CK, dicarboxylic aciduria, decreased plasma carnitine
Lipid storage and decreased total carnitine in muscle; increased excretion of urinary ethylmalonic and methylsuccinic acids Myoglobinuria, ketonuria, abnormal organic acids
In infancy presentation is primarily as an encephalopathy, which may be recurrent or acute, or even as sudden infant death syndrome. There may be vomiting, coma, hepatic and cardiac impairment, hypoketotic hypoglycemia, and hyperammonemia. A primarily myopathic syndrome, which can present at any point after the neonatal period, accompanied by variable cardiomyopathy or episodes of hypoglycemia. A syndrome of recurrent rhabdomyolysis provoked by fasting, infection, or exercise.
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Accurate diagnosis is necessary; many lipid myopathies respond to dietary manipulation and supplementation. For reasons of space, further description is restricted to carnitine palmitoyltransferase II (CPT2) deficiency, which is the commonest lipid myopathy in adults and the most common identified cause of myoglobinuria. Clinical Hints Episodes of myoglobinuria may be identified by asking the patient if urine has turned the color of tea or cola. Sustained exercise may precipitate symptoms in CPT2 deficiency; in contrast to intense exercise, which may provoke symptoms of myophosphorylase deficiency. Recurrent coma with hypoglycemia or cardiac or hepatic manifestations raises suspicion of a defect of lipid metabolism. Acylcarnitine spectrometry is a useful screening test in defects of lipid metabolism.
Carnitine Palmitoyltransferase II (CPT2) Deficiency CPT2 deficiency may present neonatally or in infancy with severe systemic forms. The less severe myopathic form presents in teenage years or later, with recurrent myalgia on exercise, sometimes with myoglobinuria. Provoking events include prolonged exercise, cold, fasting or low-carbohydrate diet, infections, or valproate treatment. Muscle weakness is usually not apparent between attacks, although occasionally occurs later in the disease. Although autosomal recessive, CPT2 deficiency is more commonly recognized in males. Pathophysiology More than 20 mutations have been described in the CPT2 gene. Ser113Leu accounts for more than half of adult cases. In adult forms, there is some residual enzyme activity. Some mutations may cause manifestations in heterozygotes. The CPT2 protein transports fatty acid-CoA across the inner mitochondrial membrane. At rest, it is thought that patients are more reliant on carbohydrate metabolism, but are asymptomatic. When stressed, the defect in fatty acid metabolism causes muscle damage. Diagnosis Serum CK is normal or mildly elevated between attacks, and very high during rhabdomyolysis. Muscle biopsy is morphologically normal, although CPT activity may be reduced if measured. The best screening test is to analyze a blood spot for acylcarnitines by using tandem mass spectrometry, which usually shows a characteristic disturbance. This is non-invasive and both sensitive and specific, but not universally available. Enzyme assay may be performed on cultured fibroblasts. Fifty to sixty percent of CPT2 disease alleles carry the S113L mutation, making direct genetic analysis an alternative means of diagnosis.
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Management Episodes of muscle damage may be prevented by frequent meals with low fat and high carbohydrate. Exercise when fasting or during an infection should be avoided. A glucose infusion before and during general anesthesia may prevent an attack. Severe myoglobinuria is capable of causing acute renal failure requiring specialist management. Genetic advice appropriate to a rare recessive disorder is appropriate.
REFERENCES Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B, et al. (2004). Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol, 56, 650661. McManis PG, Lambert EH & Daube JR (1986). The exercise test in periodic paralysis. Muscle Nerve, 9(8), 704710. Streib EW (1987). Differential diagnosis of myotonic syndromes. AAEE minimonograph 27. Muscle Nerve, 10, 603615.
Chapter 14 Mitochondrial Disease Simon R. Hammans
INTRODUCTION The mitochondrion is a cellular organelle of approximately 0.51 mm diameter whose primary function is to generate ATP, the energy currency of the cell. Mitochondria contain their own genetic apparatus, about 210 copies of a circular double-stranded DNA molecule of 16,569 nucleotide pairs. Mitochondrial DNA is almost exclusively maternally inherited in mammals, as the sperm does not contribute mitochondria to the zygote. Mitochondrial DNA (mtDNA) contains little non-coding sequence. It contributes thirteen important subunits to the enzymes of the mitochondrial respiratory chain; the remaining subunits being nuclearly encoded. As each cell carries several molecules of mtDNA, it is possible for a cell, tissue, or organism to contain more than one type of mtDNA, termed heteroplasmy. Pathological mtDNA mutations may be heteroplasmic or homoplasmic. While many neurological conditions, ranging from Huntington’s disease to beriberi, involve the mitochondrion in pathophysiology, the term mitochondrial disease is usually reserved for disorders thought primarily to involve mitochondrial DNA. This includes primary mutations and deletions of mtDNA, and Mendelian disorders in which defects of nuclear genes impair mtDNA replication and function. The complexity of mitochondrial diseases can be intimidating. Mitochondrial disease can be Mendelian or maternally inherited, while the commonest mtDNA genetic abnormality (a single deletion) is usually present in only one family member. Onset can be at any age and sudden or slowly progressive. Manifestations may occur in virtually any neurological system and involve other organs. This diversity of clinical syndromes allows mitochondrial disease to appear in the differential diagnosis of almost any neurological condition, from stroke to myopathy.
Overview of Clinical Diagnosis Despite the diversity of clinical manifestations, a full clinical assessment often allows a confident diagnosis. Familiarity with the commoner presentations of 245
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Table 14.1 Clinical Syndromes within Mitochondrial Disease Syndrome Pattern
Common Neurological Manifestations
Progressive external ophthalmoplegia plus (PEO+)
Ptosis, often asymmetric; partial ophthalmoplegia
Encephalopathy
Ataxia, dementia, epilepsy, myoclonus, stroke-like episodes Often mild to moderate limb girdle weakness Consecutive subacute optic neuropathy
Myopathy LHON (Leber’s hereditary optic neuropathy) Leigh’s syndrome
Common Non-CNS Features
g
Early onset, loss of motor and verbal milestones
Maternally inherited diabetes and deafness Multisystem pediatric disease
Diabetes, deafness, mild proximal weakness, pigmentary retinopathy, lactic acidosis, short stature, cardiac conduction defects
Typically young adult male
Lactic acidosis, deafness May have no or few other features Failure to thrive, short stature, anemia, renal tubular acidosis, cardiomyopathy
mitochondrial disease is helpful (Table 14.1). Suspicion of mitochondrial disease should be heightened by the presence of typical manifestations, such as deafness, ptosis and diabetes. Further diagnostic hints are given in the box below. Historically the mitochondrial myopathies (and encephalomyopathies) have been defined by the presence of characteristic ‘‘ragged red fibers’’ on muscle biopsy stained by the modified Gomori trichrome technique. Further histochemical findings and genetic data may also be useful. Mitochondrial myopathies can often be suspected clinically, and differ in presentation from other mitochondrial diseases without ragged red fibres such as Leber’s hereditary optic neuropathy or NARP syndrome. The following commonly used clinico-pathological classification depends on clinical features as well as either genetic findings or histochemical examination of muscle.
Clinical Hints for Diagnostics in Mitochondrial Disease Mitochondrial encephalopathies rarely present as a pure syndrome. Thus an isolated progressive dementia or isolated ataxia is seldom due to mitochondrial disease. True multisystem disease is more common in children. Even severe ophthalmoplegia can be unnoticed by the patient. Patients with encephalopathy have unpredictable combinations of features. They may not easily fit the textbook concepts of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged red fibers). Neuroimaging is seldom normal in established encephalopathies and usually gives diagnostic clues.
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MITOCHONDRIAL DISEASES ASSOCIATED WITH RAGGED RED FIBERS (RRF): THE MITOCHONDRIAL ENCEPHALOMYOPATHIES Progressive External Ophthalmoplegia (PEO; OMIM 530000) PEO refers to a combination of ptosis and restriction of ocular movements. It is typically asymmetrical. Onset is insidious and usually in childhood or early adult life. It can be asymptomatic and may be advanced by the time of presentation. Although a squint may be evident the patient may not complain of diplopia. The ocular signs may resemble ocular myasthenia, although usually with less fatiguability and diurnal variation (Fig. 14.1). PEO may be an isolated feature of mitochondrial disease, but common associations are a pigmentary retinopathy or proximal weakness. PEO, retinopathy and onset earlier than 20 years (together with the presence of either heart block, elevated CSF protein, or ataxia) comprises Kearns-Sayre syndrome (KSS). The pigmentary retinopathy may be subtle and is usually distinct from the classical appearance of retinitis pigmentosa. There is a spectrum of severity between the relatively non-disabling isolated PEO, to PEO with other features, to the most severe form, KSS. The intermediate forms are often referred to as PEO+. Patients with PEO, PEO+, or KSS have diagnostic muscle biopsy appearances. The commonest genetic defect is a heteroplasmic single deletion of mtDNA present in muscle. As the deletion is usually present only at low level in blood, muscle biopsy is usually necessary for diagnosis. The deletions in PEO-KSS are usually associated with sporadic disease. However, PEO may be maternally inherited; in this situation the commonest genetic abnormality is the A3243G mutation. If patients with PEO or PEO+ remain free of any features of encephalopathy for 5 years after onset then encephalopathy rarely ensues, and the prognosis is more benign than in encephalopathic forms of mitochondrial disease. KSS, particularly with ataxia, is usually associated with significant disability.
Figure 14.1. Progressive external ophthalmoplegia. Note asymmetrical ptosis and squint.
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Mitochondrial Encephalopathies (including MELAS: Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes) Encephalopathic manifestations of mitochondrial disease are found in various combinations. The most common overall include ataxia, deafness, dementia, and seizures. Cerebellar ataxia is often progressive and associated with atrophy on imaging. Deafness is sensorineural in type and may precede other manifestations. Seizures are common and can be focal, generalized, myoclonic, or photosensitive. One dramatic, but less common, presentation is a stroke-like episode manifesting as a sudden onset of neurological deficit such as hemianopia or hemiparesis. Such episodes are often followed by seizures or even partial or complex partial status epilepticus. Imaging often shows a segmental infarct that may cross arterial territories, and is more often occipital or parietal than frontal. Mitochondrial encephalopathies that include stroke-like episodes are often labeled with the acronym MELAS (OMIM 540000). Although deafness, diabetes, or PEO may exist in isolation, it is rare that patients with mitochondrial encephalopathy present with one major neurological feature alone. For example, mitochondrial disease is often included in the differential diagnosis of young stroke or progressive ataxia, but this is made more likely by a prior history of a typical mitochondrial feature such as ptosis, deafness, or diabetes in the patient or close relative. Other common features seen in mitochondrial encephalopathy include most forms of movement disorders, ataxia, optic neuropathy, and peripheral neuropathy. Peripheral neuropathy is usually axonal in type; an exception is the demyelinating neuropathy seen in the context of MNGIE (see below). Patients do not always conform to MERRF or MELAS stereotypes and the diagnosis of mitochondrial encephalopathy is often made in the presence of varying age onset and combinations of features even within the same family. Prognosis is highly variable in mitochondrial encephalopathies and is less predictable than is typical of neurodegenerative disorders. Whereas some patients experience a steady decline, others may have static neurological status for years, irregularly punctuated by periods of rapid deterioration. Patients with mitochondrial encephalopathies have RRF on muscle biopsy. The commonest genetic defect is the heteroplasmic mtDNA A3243G mutation present in both muscle and blood. The presence of the A3243G mutation in blood makes muscle biopsy unnecessary. Otherwise, muscle biopsy can confirm mitochondrial disease by showing RRF.
Mitochondrial Encephalomyopathies: Myoclonic Epilepsy and Ragged Red Fibers (MERRF; OMIM 590060) MERRF refers to a subgroup of mitochondrial encephalopathy with the core features of myoclonus, ataxia, and seizures. Although there is an association with the mtDNA A8344G mutation, this is not invariable. Presentation is often heralded by myoclonus, followed by epilepsy and ataxia, with onset at any age. Other features of mitochondrial disease such as optic neuropathy and
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peripheral neuropathy may also be present. Some patients have cervical lipomas, appearing as soft swellings around the neck area. Much milder disease, restricted to one or two features such as deafness or myoclonus, may be present in family members. The course of MERRF is unpredictable but most patients with the core features encounter major disability. The differential diagnosis includes other causes of progressive myoclonic epilepsy (Chapter 4), which are autosomal recessive. The maternal inheritance and/or identification of other typical mitochondrial disease manifestations may make the clinical diagnosis apparent. The commonest genetic defect is the heteroplasmic mtDNA A8344G mutation present in both muscle and blood. The presence of the A8344G mutation in blood makes muscle biopsy unnecessary. Otherwise, muscle biopsy can confirm mitochondrial disease by showing RRF.
Myopathic Presentations including Exercise Intolerance, Myalgia and Myoglobinuria Some degree of limb weakness is common but not universal in patients with PEO, PEO+, or encephalomyopathies. RRF or abnormalities in oxidative enzymes apparent on muscle biopsy remain the diagnostic hallmark of these diseases irrespective of the presence of clinical evidence of myopathy. Some patients present with limb weakness alone. This is usually in a limb girdle pattern. The severity is usually mild to moderate, and is only rarely severe enough to prevent walking, in the absence of other reasons. Other patterns of weakness such as a facioscapulohumeral pattern are very unusual but have been described. Myalgia and fatigue on exercise are common features and may be the dominant presenting complaint. In particular, weakness may be absent and the diagnosis of mitochondrial disease may only be made after muscle biopsy. The biopsy may be performed to investigate symptoms of exercise intolerance, myalgia, or episodes of myoglobinuria triggered by exercise or infection. Some patients with a myopathic presentation have mutations in proteincoding genes of mtDNA, which may be suspected by the finding of cytochrome oxidase (COX) positive RRF in muscle. The mutation is often not detectable in blood, and analysis of muscle mtDNA may be required. As there are several mtDNA mutations potentially responsible, further genetic analysis is best discussed with a specialist center.
Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE; OMIM 603041) MNGIE represents a rare but distinct autosomal recessive syndrome within mitochondrial disease. Core features include PEO, gut hypomotility and a neuropathy. Nerve conduction studies often show conduction velocities within the demyelinating range. Importantly, an asymptomatic and often unsuspected leukoencephalopathy is apparent on MRI of brain. This finding in the presence of a demyelinating neuropathy can often confirm a clinical diagnosis. Presentation is usually in childhood. PEO, neuropathy or GI
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features may be apparent years before other core features are apparent. Not all cases have diagnostic features on muscle biopsy. Prognosis is poor, with patients experiencing disability from neuropathy or myopathy, and the gut problems causing weight loss. Patients usually die from complications of the gastrointestinal problems in early to mid adulthood. Most patients have RRF or COX-negative fibers on biopsy. Some patients have mtDNA deletions or depletion, secondary to the fundamental defect in thymidine phosphorylase, a nuclear encoded enzyme which ensures homeostasis of cellular nucleotide pools. Mutations can be identified in the thymidine phosphorylase gene.
Non-Neurological Features Extending the clinical assessment beyond brain, muscle, and nerve may provide clues to the diagnosis of mitochondrial disease. Significant involvement of other organs is more common in early-onset disease, especially in infancy. Diabetes mellitus is a common manifestation of mitochondrial disease. In some kindreds maternally inherited diabetes (sometimes with deafness) may be present with no other features, but is also frequent in combination with neurological presentations. Other endocrinopathies such as hyperparathyroidism are also commoner than in the general population. Maternally inherited diabetes and deafness (MIDD) is commonly caused by the mtDNA A3243G mutation. Cardiac features include heart block or cardiomyopathy. Renal involvement is rare beyond childhood and usually manifests as renal tubular acidosis. Gastrointestinal features such as pseudo-obstruction or dysphagia may occur. Pearson’s syndrome refers to the combination of transfusion-dependent sideroblastic anemia with exocrine pancreatic failure (OMIM 557000). The severity of the disease may cause early death. In survivors, the hematological features may improve but neurological features, usually corresponding to Kearns-Sayre syndrome, supervene. Pearson’s syndrome is often associated with a single heteroplasmic mtDNA deletion, often present in blood as well as muscle.
Investigation of Mitochondrial Disease (Table 14.2) Estimation of CK is not very helpful in diagnosis. Typically it is normal or mildly raised in mitochondrial encephalomyopathies. It may be more markedly elevated in mtDNA depletion syndromes. Estimation of fasting lactate in blood or CSF may show raised levels and may be useful in supporting a clinical suspicion of mitochondrial disease. Levels are more likely to be raised in blood (>3 mM) in myopathies, while CSF lactate is more likely to be raised (>1.5 mM) in encephalopathies. Exercise testing to detect raised lactate in aerobic exercise raises methodological difficulties that have led to restricted usage. Neuroradiological investigations may be useful. The non-specific (but common) changes of cerebral or cerebellar atrophy and calcification or ‘‘holes’’ in the basal ganglia may raise suspicion of mitochondrial disease. The following changes are more specific:
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Table 14.2 Investigation of Mitochondrial Disease Clinical Syndrome
First Investigation
Further Investigation
PEO
Muscle biopsy (mutations may be sought in blood if there is maternal inheritance) Analysis of blood mtDNA for A3243G and A8344G mutations Muscle biopsy
Analysis of muscle mtDNA, especially for deletions
MR brain, nerve conduction studies Analysis of blood mtDNA for 11778, 3460, and 14484 mutations MR brain, CSF lactate
Muscle biopsy; genetic analysis of thymidine phosphorylase gene If genetic analysis negative it is difficult to confirm diagnosis in absence of family history Muscle biopsy, histochemistry, and biochemistry; genetic analysis, directed by biochemical findings Further mtDNA analysis if clinically convincing
Mitochondrial encephalopathy Myopathy, including myalgic and fatigue type symptoms MNGIE LHON
Leigh’s syndrome
NARP/MILS
Analysis of blood for T8993G/C mutations
Muscle biopsy
Genetic analysis of muscle mtDNA
MELAS: stroke-like lesions in cerebral hemispheres, usually posterior, not always obeying vascular territories. Often multiple. Kearns-Sayre syndrome: signal change in central white matter on MRI. Often with basal ganglia abnormalities and atrophic changes. MNGIE: virtually all patients have an asymptomatic white matter signal change on MRI. Leigh’s syndrome: high signal symmetrically in brainstem, thalamus, and basal ganglia (see below). In most cases of mitochondrial encephalomyopathies the diagnosis is made by muscle biopsy. However, with certain features it may be appropriate to make a diagnosis by genetic analysis first. With the clinical syndromes of encephalopathy diagnosis may be made by analysis of leukocyte mtDNA for the common mutations. This is not appropriate with patients with PEO, since the commonest defect is a single mtDNA deletion, which is present only at low levels of heteroplasmy in blood, and analysis of muscle is preferred. A significant proportion of patients with any type of mitochondrial myopathy have private mtDNA mutations. Therefore, absence of the routinely tested commoner mutations does not exclude a mitochondrial myopathy, and a muscle biopsy is often helpful in making the diagnosis. Muscle Biopsy (Table 14.3) Mitochondrial abnormalities are normally distributed throughout skeletal muscle in mitochondrial encephalomyopathies, even in the absence of weakness.
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Table 14.3 Mitochondrial Disease and Muscle Biopsy Findings Mitochondrial disease usually associated with ragged red fibers Mitochondrial disease usually not associated with ragged red fibers Variable
PEO, PEO+, Kearns-Sayre syndrome; mitochondrial encephalopathies (including MERRF, MELAS); mitochondrial myopathy LHON; NARP/MILS Leigh’s syndrome; MNGIE; disease caused by POLG mutations
The quadriceps muscle is often the most convenient to biopsy. Ragged red fibers are not always well demonstrated on muscle sections with the modified Gomori trichrome (mGT) stain. The histochemical reactions for succinic dehydrogenase (SDH) and cytochrome oxidase (COX) should be performed routinely. SDH is more sensitive in identifying mitochondrial proliferation within myofibers. In some patients with mitochondrial disease, COX histochemistry may be abnormal even when mGT and SDH reactions have not identified RRF. Sequential COX and SDH histochemistry on the same section may help to highlight abnormal fibers. RRF and COX-negative fibers are found, usually in small numbers, in other muscle conditions, particularly in older patients, thus myopathological findings must always be interpreted within the clinical context.
Genetic Advice Because of the different modes of inheritance of mitochondrial disease, confirming the diagnosis with genetic testing is important for estimation of recurrence risks. For example, PEO may be inherited in a matrilineal, autosomal dominant or recessive fashion depending on the underlying genetic defect, or may be (most commonly) sporadic. Single mtDNA Deletions Single mtDNA deletions were thought to be associated with sporadic disease, but there appears to be a small risk of transmission. A multicenter study (Chinnery et al. 2004) of patients with a single mtDNA deletion determined a recurrence risk to children of affected mothers of 4% (95% CI 0.8611.54). This figure should be used for estimation of recurrence risk only when: the laboratory can exclude the condition of multiple mtDNA deletions the laboratory has excluded mtDNA duplications, which appear more likely to be inherited. To date there have been no cases of single deletions being transmitted by affected fathers. Recurrence risks in mitochondrial diseases vary widely, and depend on the underlying genetic defect.
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Inherited PEO (multiple mtDNA deletions; OMIM 157640) PEO is most commonly caused by a single heteroplasmic mtDNA deletion. A substantial minority of cases are caused by mtDNA point mutations, including the A3243G mutation, and should be advised as described below. Rarely, PEO is inherited in autosomal dominant or recessive fashion. In molecular analysis, the important distinguishing point is that in autosomal dominant or recessive PEO, muscle mtDNA analysis shows multiple deletions, rather than the single deletion observed in typical sporadic disease. This may be overlooked in an inexperienced genetic laboratory, where additional bands seen on Southern blot analysis may be mistaken for artifact. These disorders result from defects in nuclear genes involved in mtDNA maintenance and are described below. MtDNA Point Mutations MtDNA point mutations are all exclusively inherited in the maternal line. In transmission the degree of heteroplasmy (the proportion of abnormal mtDNA) may vary in either direction (individual oocytes of an affected woman will have very variable degrees of heteroplasmy). Many factors complicate prediction of genetic risk, including variation of heteroplasmy within tissues, with age, and the poor correlation of heteroplasmy with age of onset and phenotype. The two commonest mtDNA point mutations causing mitochondrial encephalopathy are the A3243G and A8344G mutations. Higher degrees of heteroplasmy in the mother are correlated with an increased risk of affected offspring, but the correlation is not strong enough to give accurate predictions. It has been suggested that the risk of affected offspring is greater with the A3243G mutation than the A8344G mutation for a given level of maternal heteroplasmy. Data are difficult to interpret since they are derived from retrospective studies of incompletely studied families, where ‘‘unaffected’’ offspring may go on to develop disease. Nevertheless, Chinnery et al. (1998) surveyed published pedigrees and give guidance to approximate recurrence risks. No cases of transmission of mtDNA point mutations by males have been described. Estimation of placental heteroplasmy as a basis of prenatal testing has been proposed. However, the correlation of the degree of heteroplasmy with clinical phenotype in mtDNA mutations is poor, and there the data are insufficient to allow confidence in prenatal prediction of phenotype (with the exception of the T8993G/C mutations; see later). Mitochondrial Myopathies Without Identified Genetic Cause The commoner mtDNA mutations (deletions, A3243G and A8344G mutations) account for 5060% of mitochondrial encephalomyopathies in most populations. Other patients may have rare or private mtDNA mutations, or nuclear mutations. Specialist laboratories may sequence part or the entire mtDNA molecule in some situations, which may help with indication of recurrence risks. In the context of a patient without an identified mutation, careful clinical assessment of the whole family may help indicate maternal or other forms of inheritance.
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MITOCHONDRIAL DISEASE WITHOUT RAGGED RED FIBERS Leigh’s Syndrome (LS; OMIM 256000) Leigh’s syndrome can be considered as the most severe manifestation of mitochondrial encephalopathy. Onset is usually in the first year but occasionally later, and rarely in adulthood. Hypotonia with loss of verbal and motor milestones is punctuated by episodes of vomiting, ataxia, and other movement disorders, and hyperventilation. Episodes may be precipitated by intercurrent infection. The disease is often fatal within 2 years of onset. Imaging of the brain is important in diagnosis, with characteristic changes of bilaterally symmetrical lesions, especially in the thalamus, basal ganglia, and brainstem regions (Fig. 14.2). The diagnosis is supported by an elevated CSF lactate. At autopsy spongiform change is seen in the described distribution. Estimation of recurrence risks in LS requires careful investigation, because autosomal recessive, dominant, maternal, and X-linked inheritance are all possible (Rahman et al. 1996). Underlying defects all have in common the ability to impair mitochondrial ATP production. In the series described by Rahman et al., 39% had undetermined cause, but further mutations in mtDNA and other respiratory chain subunits have been described since. Family history is important; evidence of disease in the maternal line may suggest a defect of mtDNA. Depending on availability of investigations, screening for the commoner mtDNA mutations (particularly T8993G/C) in blood might be done first, as
Figure 14.2. CT scan of brain of individual with adult-onset Leigh’s disease showing low density in the putamina.
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these account for approximately 18% of LS (Rahman et al. 1996). If negative, further investigation may be guided by muscle biopsy, with histochemistry and biochemical analysis of the respiratory-chain enzymes. Fibroblast culture or other body tissues may also provide material for specialized biochemical analysis including the pyruvate dehydrogenase complex. Identification of the biochemical defect directs subsequent genetic investigation. The commonest cause of cytochrome oxidase (COX; Complex IV) deficient LS is autosomal recessive mutations in the SURF-1 gene (14% of LS). COXdeficient LS has also been reported in association with mutations in mtDNA encoded COX subunits, and other nuclearly encoded genes responsible for COX subunits or assembly. Biochemical defects of Complex 1 usually signify mutations in nuclearly encoded subunits of this enzyme. Genetic analysis is available only in specialist centers. Where respiratory-chain function is normal, LS may be due to enzyme deficiency prior to the mitochondrial respiratory chain, usually in pyruvate carboxylase or within the pyruvate dehydrogenase complex (PDHC). The commonest identified defect is within the PDHC E1-a subunit, encoded on the X chromosome (10% of LS). It can cause LS in both male and female infants. Advice on recurrence risks is difficult without a genetic diagnosis, but it cannot be assumed to be autosomal recessive. Family history and biochemical diagnosis may help (Thorburn and Dahl 2001).
Leber’s Hereditary Optic Neuropathy (LHON) LHON causes subacute visual loss. Typically, the condition affects young adult males. The optic nerves are affected simultaneously (25%) or sequentially (75% of cases), resulting in visual loss. The delay is rarely more than a year. At onset there may be swollen disks with peripapillary telangiectasia, which resolve, eventually to optic atrophy. There is sparing of the peripheral vision. Progression of deterioration is variable but occurs with a median period of 4 weeks (first eye) and 6 weeks (second eye). Over 1 or 2 years there may be visual recovery, which may be modest, but occasionally restores useful vision. Unlike optic neuritis, pain on eye movement is uncommon (17%), and fluorescein angiography characteristically does not demonstrate leakage. More than 90% of patients have one of three mtDNA mutations, present in blood and usually homoplasmic. Genetic analysis has extended the recognized phenotype of LHON. Although there is an excess of males, the overall ratio is approximately 3:1 rather than the larger figures cited in earlier literature. Inheritance of the mutations is mitochondrial, i.e., strictly through the maternal line. Incomplete penetrance and the skewed sex ratio have not been adequately explained by genetic or environmental theories. The clinical characteristics of LHON vary with the genotype and these are summarized in Table 14.4. Worse prognosis is associated with the G11778A mutation. Earlier onset is associated with a better visual outcome. After onset it is rare for patients to have recurrent episodes. Some families with LHON have other features, such as dystonia, ataxia, or neuropathy. These manifestations have been described in association with
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Table 14.4 LHON: Mitochondrial Mutations G11778A Frequency Male excess Median final visual acuity
Age at onset (range)
G3460A
T14484C
76% 9% 15% 3.7:1 4.3:1 7.7:1 1/60 3/60 6/9 More likely to be associated with Note better visual MS-like illness in females prognosis 69% of cases had onset between 11 and 30 yr; range 662 yr
private mtDNA mutations and not with the three common mutations. Females with any of the three common mutations have a higher than population risk of multiple sclerosis, with visual failure usually as the most prominent feature. Such patients are otherwise indistinguishable from other patients with MS, including the finding of unmatched oligoclonal bands in CSF. Genetic Advice These mutations represent yet another situation with respect to recurrence risks. They are strictly maternally inherited. However, penetrance is much higher in males than females, with the figures being different for the three commonest mutations (Table 14.5). These are observed risks taken from the largest studies available. Calculation of risks from penetrance data is currently not feasible because of the poorly understood genetic and environmental factors. These estimates should be applied with caution. They do not take into account the effects of heteroplasmy. There is a suggestion that more than 25% of normal mtDNA in a mother might reduce the risk of her children being affected, but, as heteroplasmy is unusual, this hypothesis has not been adequately tested. Because of drift of heteroplasmy in families, it is prudent to check heteroplasmy in individuals before giving predictions. Insufficient data have been collected from G3460A families but the risks might be estimated as similar to the other mutations. Risks will be further modified by the age of the relative at risk (see Figure 1 in Harding et al. 1995).
Table 14.5 LHON: Recurrence Risks Relationship to Proband
G11778A
Brother Sister Sister’s son Sister’s daughter Male first cousin* Female first cousin* Data from
25 8 41 17 30 7 Harding et al. 1995
*Matrilineal.
Risk of Visual Loss (%) T14484C 28 5 30 3 19 4 Macmillan et al. 1998
G3460A Insufficient data
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Neuropathy, Ataxia, Retinitis Pigmentosa (NARP; OMIM 55150) Although due to an mtDNA mutation, this condition is not defined as a mitochondrial myopathy because of the absence of RRF on muscle biopsy. It is maternally inherited. Neuropathy, ataxia, and retinopathy are the cardinal features, but variable developmental delay, fits, dementia, and a sensory neuropathy may also be present. The ocular manifestations of NARP are extremely variable and range from a mild salt-and-pepper retinopathy to bull’s eye maculopathy and classic retinitis pigmentosa with bone spicule formation. Patients do not have RRF; rather, the muscle biopsy shows changes of denervation. Electroretinogram (ERG) abnormalities include small-amplitude waveform, but may be normal. In contrast to other mtDNA mutations, the severity of the disorder is reasonably well correlated to the proportion of abnormal mtDNA (heteroplasmy). High proportions may be associated with maternally inherited Leigh’s syndrome (MILS). Therefore the families of LS patients should be evaluated for features of NARP. Two mutations at mtDNA basepair 8993 have been described (T8993G and T8993C) in association with NARP/MILS. Prenatal genetic testing is generally not performed in mtDNA disorders because of uncertainty in the relationship between fetal levels of heteroplasmy and phenotype. However, the mutations T8993G and T8993C show a more even tissue distribution and the percentage levels of these two mutations do not appear to change significantly over time. Predicted recurrence risk differs between the two mutations and increases with maternal heteroplasmy (White et al. 1999). Successful prenatal molecular diagnosis has been carried out for these two mutations.
DISORDERS OF mtDNA MAINTENANCE MtDNA Depletion (OMIM 251880) These rare childhood syndromes arise because of nuclear DNA defects causing depletion in the number of mtDNA molecules. MtDNA depletion may affect muscle and/or liver (commonly), but also, heart, brain, and kidney. Affected organs show depletion of mtDNA numbers but also deficient COX histochemistry and multiple respiratory-chain defects. Early-onset disease is often rapidly fatal, with multiorgan involvement. Patients with less severe depletion may have a chronic course, particularly when the manifestations are confined to muscle. In such cases progressive muscle weakness may lead to respiratory failure. The mtDNA depletion syndromes are currently being elucidated by discovery of the responsible genes. MNGIE syndrome is associated with mtDNA depletion and mutations in the thymidine phosphorylase gene (described above). One form of the mtDNA depletions, the hepatocerebral form, results from mutation in the gene encoding mitochondrial deoxyguanosine kinase (OMIM 601465). Mutations have also been identified in mitochondrial thymidine kinase (TK2; 188250) in cases of mitochondrial DNA depletion myopathy. Although
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expression is restricted to muscle, progressive paralysis leads to quadriplegia before 3 years.
Autosomal Disease Causing mtDNA Deletions A small proportion of mitochondrial disease is caused by nuclear mutations causing secondary deletions of mtDNA. Dominant inheritance is more commonly reported than recessive inheritance. In most families, the presentation is with adult-onset PEO. Severity may vary strikingly within family members. Accompanying features vary between families and include myopathy, deafness, tremor, ataxia and neuropathy, cataracts, and affective disorders. Three causative genes have been identified to date but further unlinked families have been described. Three genes have been identified causing secondary multiple deletions: mtDNA polymerase gamma (POLG) autosomal dominant or recessive inheritance adenine nucleotide translocator 1 (ANT1; SLC25A4) autosomal dominant Twinkle (C10ORF2) autosomal dominant. POLG mutations are the most frequent cause of multiple mtDNA deletions in both dominant and recessive PEO families. The phenotype of POLG mutations is not yet fully determined. However, it is apparent that POLG mutations may be an important cause of other phenotypes, such as Alper’s syndrome, and sensory ataxia with or without clinical or histochemical features of mitochondrial myopathy.
TREATMENT FOR MITOCHONDRIAL DISEASE No treatment has been shown to alter the course of mitochondrial disease. The myopathic features and fatigue of mitochondrial myopathy sometimes subjectively improve with ubidecarone (CoQ10). A double-blind controlled trial failed to show significant benefit. The anticonvulsant sodium valproate theoretically may worsen mitochondrial function and should therefore be avoided if possible. Other drugs that theoretically impair respiratory-chain function include barbiturates, tetracyclines, and chloramphenicol. The acute deterioration associated with stroke-like episodes of mitochondrial myopathy may improve with dexamethasone treatment, although no controlled trial has been performed. Severe lactic acidosis may improve with cautious correction by a slow infusion of sodium bicarbonate. The lack of disease-modifying therapy means that supportive treatment, specifically ptosis surgery, epilepsy and diabetes treatment, cardiac pacing, cochlear implantation, etc., are the only options at present.
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REFERENCES Chinnery PF, Howell N, Lightowlers RN & Turnbull DM (1998), MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. Brain 121, 18891894. Chinnery PF, DiMauro S, Shanske S, Schon EA, Zeviani M, Mariotti C, Carrara F, Lombes A, Laforet P, Ogier H, Jaksch M, Lochmuller H, Horvath R, Deschauer M, Thorburn DR, Bindoff LA, Poulton J, Taylor RW, Matthews JN & Turnbull DM (2004). Risk of developing a mitochondrial DNA deletion disorder. Lancet, 364, 592596. Harding AE, Sweeney MG, Govan GG & Riordan-Eva P (1995). Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation. Am J Hum Genet, 57, 7786. Macmillan C, Kirkham T, Fu K, Allison V, Andermann E, Chitayat D, Fortier D, Gans M, Hare H, Quercia N, Zackon D & Shoubridge EA (1998). Pedigree analysis of French Canadian families with T14484C Leber’s hereditary optic neuropathy. Neurology, 50(2), 417422. Rahman S, Blok RB, Dahl HH, Danks DM, Kirby DM, Chow CW, Christodoulou J & Thorburn DR (1996). Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol, 39(3), 343351. Thorburn DR & Dahl HH (2001). Mitochondrial disorders: genetics, counseling, prenatal diagnosis and reproductive options. Am J Med Genet, 106, 102114. White SL, Collins VR, Wolfe R, Cleary MA, Shanske S, DiMauro S, Dahl HH & Thorburn DR (1999). Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet, 65, 474482.
Chapter 15 Tumor Predisposition Syndromes: VHL, NF1 and NF2, Tuberous Sclerosis, and Malignant CNS Tumors Diana M. Eccles
INTRODUCTION Neoplastic disease of the CNS can be due to inherited predisposition and in general should be considered when an individual presenting with a CNS neoplasm has one or more of the following: family history of similar problems unusually young onset multiple primary tumors. A careful review of potentially related medical problems in the patient and family may reveal a genetic diagnosis.
Summary of CNS Tumor Types with Possible Underlying Genetic Diagnoses All CNS tumors can occur sporadically as well as occurring as part of a familial predisposition syndrome. Table 15.1 summarizes the main CNS tumor diagnoses that occur, and gives suggestions of which genetic syndromes can be associated with each tumor type.
VON HIPPEL-LINDAU DISEASE (VHL; OMIM 193300)
Clinical Features and Family History Von Hippel-Lindau syndrome is an autosomal dominant condition with an incidence of approximately 1 in 40,000. The penetrance of disease is
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Table 15.1 CNS Tumor Types Correlated with Possible Underlying Genetic Diagnoses Tumor Type
Cell of Origin
Genetic Syndrome
Gliomas Astrocytoma (highest grade is called glioblastoma multiforme*) Ependymoma Oligodendroglioma Medulloblastoma (infratentorial) Primitive neuroectodermal tumors (PNET)
Neuroglial cells Astrocytes
Li-Fraumeni syndrome**, Turcot syndrome***, tuberous sclerosis, NF1, NF2
Meningioma Hemangioblastomas Neuromas/schwannomas CNS lymphoma
Ependymal cells Oligodendrocytes Primitive medullary cells Supratentorial primitive neuroectodermal cells Arachnoidal cap cells of the leptomeninges Blood vessels Schwann cells Lymphoid cells
Gorlin syndrome PMS2 biallelic mutations
NF2, NF1, Werner syndrome Von Hippel-Lindau disease NF2 Rare consider immunodeficiency which may be acquired or due to an inherited immunodeficiency syndrome
*Familial cases (two or more) have been described and inheritance is compatible in different descriptions with dominant or recessive. However, glioblastoma multiforme is the most common malignant CNS tumor in adults, so two cases in a family, particularly at older ages with no other clinical features to suggest a genetic diagnosis, may be due to chance or shared low-level genetic susceptibility. **Li-Fraumeni syndrome is a rare highly penetrant cancer predisposition syndrome caused by inherited mutation in the TP53 gene. The typical combination of tumors includes sarcomas, breast, CNS, lung, and adrenocortical tumors at often exceptionally young ages. ***Turcot syndrome is the combination of CNS tumors and colorectal polyps. It is likely that most of the descriptions in the literature represent a number of underlying genetic causes. In particular, mutations in mismatch repair genes inherited from both parents leading to either homozygous or compound heterozygous status for one of these genes have recently been described. There may be a family history of colorectal cancer in adults on both sides of the family (although not always). hMLH1 biallelic mutations have been described in infant siblings with glioblastoma multiforme, primitive neuroectodermal tumors (PNETs) in infant siblings with biallelic mutations in PMS2.
age-dependent, but is usually high. It predisposes to the development of benign and malignant neoplasms. The most common are: hemangiomas * retina * cerebellum * spinal cord kidneys * cysts * adenomas * carcinomas
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Table 15.2 Diagnostic Criteria for VHL A clear diagnosis can be made where there is a family history of VHL plus any of the following: retinal, spinal, or cerebellar hemangioma clear cell renal carcinoma (not renal cysts alone) pheochromocytoma pancreatic endocrine tumor endolymphatic sac tumor The diagnosis should be suspected in the following situations: multifocal or bilateral renal cell carcinoma unusually early onset of VHL-related tumor cerebellar hemangioblastoma (CH) or retinal angioma <50 years, renal cell carcinoma (RCC) <30 years family history of RCC, hemangioblastoma, or pheochromocytoma only plus another characteristic lesion The diagnosis in the absence of a family history of VHL requires: one CNS hemangioblastoma plus a second CNS hemangioblastoma (including retinal angioma) or one VHL-associated visceral tumor
pancreas (cysts, endocrine tumors) adrenal gland (pheochromocytoma) endolymphatic sac tumors epididymal cysts and cystadenomas (less common).
Diagnostic criteria for VHL are given in Table 15.2. Sometimes manifestations of the disease are only apparent after careful clinical evaluation and investigation. A careful family history may reveal information about relatives who have manifested some of the complications of VHL but where the diagnosis has not been made. For example a parent may have had an ocular lesion treated in childhood, an aunt or uncle may have had a renal tumor removed. Past medical history should include details of any previous relevant medical problems. Careful examination is required to determine any clinical manifestations of VHL disease. This includes ophthalmoscopy (particularly looking for papilledema or retinal angiomas), blood pressure measurement, abdominal examination particularly looking for renal masses, and neurological examination especially hearing, balance, or signs indicating posterior fossa or spinal lesions. Epididymal cysts in males and broad ligament papillary cystadenomas in females are associated with VHL. Retinal lesions are often the first manifestation to present although not all patients with VHL develop such lesions. The mean age at presentation of ocular hemangiomas is in the second decade, cerebellar hemangioblastomas in the third decade and renal carcinomas in the fourth decade. Further investigations in any of the above are aimed at detecting any other manifestation of VHL with a view to a clear diagnosis and early intervention.
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Genetic Testing Genetic testing, where the diagnosis is strongly suspected, will usually reveal the causative mutation (over 95% of cases have a detectable mutation in the VHL gene). The type of mutation in the gene can have a bearing on the likely expression of the gene in a carrier. For example, mutations that lead to a gross rearrangement or deletion of part of the gene are less often associated with pheochromocytoma than the more subtle missense mutations, which can be more difficult to detect. This is likely to be because of limitations of current molecular diagnostic techniques rather than genetic heterogeneity. Not finding a mutation therefore does not rule the diagnosis out whereas finding a clearly pathogenic mutation confirms the diagnosis and allows testing of other family members. Initial Investigations After Clinical Assessment Indirect fundoscopy with fluoroscein angiography should be carried out to fully investigate for retinal angiomas these are often peripheral and can be difficult to see on direct fundoscopy. 24-hour urinary adrenaline metabolites (if results are borderline a 3-day consecutive collection should be arranged). Abdominal MRI of kidneys, adrenals, and pancreas. Ultrasound is less sensitive than MRI. MRI of the CNS brain and spinal cord. Note that CT scan can be used for an initial or diagnostic work-up if MRI is not available but should not be used for routine annual screening of a patient with VHL. This is because of concerns that the radiation used might ultimately increase the rate of somatic genetic damage and therefore increase the rate of development of tumors in these individuals already susceptible to neoplasia (see surveillance recommendations below). Annual Surveillance (Affected Individuals and Those at 50% Risk) Commencing at 5 years of age: Direct and indirect ophthalmoscopy (fluoroscein angiography is not essential each year if no retinal lesions are detected at the outset but may be required for further evaluation of suspicious lesions). Blood pressure. Commencing at 1215 years: Imaging of kidneys, pancreas, and adrenals. This will usually be using MRI but in some centers MRI is limited in availability and in such situations annual abdominal ultrasound scan and 3-yearly MRI scanning may be a reasonable compromise where no renal or adrenal pathology is found. Accurate assessment of alterations in the size of solid renal lesions will require three-dimensional imaging using MRI. 24-hour urine collection for adrenaline metabolites. Imaging of CNS. Contrast enhanced MRI imaging is necessary as a baseline assessment. Although some protocols recommend annual MRI,
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it can be argued that this is unnecessary. Since no neurosurgical intervention is offered unless a patient is symptomatic it is reasonable to offer less frequent (e.g., 3-yearly) CNS imaging after a baseline assessment unless symptoms require earlier evaluation.
Pathophysiology and Treatment The von Hippel-Lindau (VHL) gene behaves like a classical tumor suppressor gene with evidence of loss of the wild-type allele and retention of the mutant allele in the tumors of affected patients. The gene is involved in oxygen tension sensing mechanisms and loss of both copies of the normal VHL gene product creates a situation that the cell interprets as chronic hypoxia. Overproduction of angiogenic peptides (particularly VEGF) ensues and the very vascular lesions seen in the CNS in VHL patients are the end result. Treatment of Lesions
Lesion: retinal angiomas CNS lesions renal lesions pheochromocytoma
Usual treatment: laser photocoagulation often possible surgical resection only if the individual is symptomatic surgery if solid and >3 cm; nephron sparing stabilization of blood pressure and surgical resection
There is no proven medical therapy to prevent tumors or treat established tumors. Trials of treatment are in progress aimed at inhibiting vascular proliferation, including antibody therapy and gene therapy. Prognosis Careful monitoring can allow early detection of associated lesions and advantageous earlier intervention (for example in retinal angiomas and renal carcinomas). Multiple renal tumors can lead to bilateral nephrectomies and subsequent dialysis or renal transplantation. The life expectancy in VHL is shortened, with a mean of 49 years. Genetic Advice It may be necessary to investigate medical records of relatives with suspicious medical histories, organize supplementary investigations and follow-up and pursue genetic testing. If a gene mutation is found then predictive testing in presymptomatic relatives including at-risk children can be offered. Annual review and surveillance as detailed above can be coordinated through a multidisciplinary team that includes expertise in genetics, neurology and urology, neurosurgery, and neuroradiology. Advice about risks to offspring and options available for prenatal diagnosis may be helpful, as outlined in Chapter 2.
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NEUROFIBROMATOSIS I (NF1; OMIM 162200) [SYNONYM VON RECKLINGHAUSEN’S DISEASE] Contrary to earlier descriptions, this genodermatosis is distinct from NF2 so these conditions will be dealt with separately. NF1 is common, with an incidence of 1 in 30004000. It usually manifests early in childhood with multiple cafe au lait patches followed by soft cutaneous swellings which are histologically neurofibromas. Diagnosis The diagnosis of NF1 is made by finding two or more diagnostic features. Diagnostic Features (In Order of Typical Age at Onset) First degree relative with proven NF1 Cafe au lait patches (>5 lesions each >5 mm in a child and >1.5 cm after puberty) Plexiform neurofibroma Optic pathway glioma Axillary or groin freckling Lisch nodules ( 2) Neurofibromas ( 2) Specific osseous lesions such as cortical thinning of long bone possibly with pseudoarthrosis or dysplasia of the sphenoid bone. Other Less Common Features Intellectual impairment Macrocephaly Short stature Scoliosis Renal artery stenosis Cerebrovascular disease Carcinoid Glioma Rhabdomyosarcoma Leukemia Neuroblastoma Other malignancy Pheochromocytoma Peripheral nerve sheath tumor (PNST).
Differential Diagnosis Most young children with multiple cafe au lait patches of the type seen in NF1 do have NF1. Cafe au lait patches should not be confused with other genetic conditions associated with pigmentary skin changes. The skin manifestations of McCune-Albright syndrome show similar pigmentary changes in some cases,
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but the border of the cafe au lait patches is more irregular than the relatively smooth-edged patches typically found in NF1. Lentigenes, associated with a number of distinct genetic syndromes, including LEOPARD syndrome, Carney complex, and Peutz-Jeghers syndrome, are darker and smaller. Segmental NF1 has been well described, with features of NF1 that affect only a small area of the body, sometimes a single dermatome but possibly including half or all of the trunk or a limb. This is due to somatic mutation in the NF1 gene during embryogenesis so that only a proportion of all somatic cells carry the NF1 mutation. Recently, children with cafe au lait patches, neurofibromas and a high frequency of hematological and CNS malignancies have been described where the underlying cause is biallelic mutation of one of the mismatch repair genes (hMLH1 or PMS2). HNPCC (hereditary non-polyposis colorectal cancer) is usually a dominantly inherited trait in which a single mutation has no childhood phenotype but a substantially increased risk of colorectal cancer and some other epithelial malignancies at young ages in adults. Inheritance of a mismatch repair gene mutation from both parents leads to this much more severe recessive phenotype presenting in childhood. This is a rare explanation for cafe au lait patches but should be considered in a new presentation, particularly if there is a family history of colorectal cancer. Surveillance From early infancy, annual review with an interested pediatrician will allow close monitoring and early intervention if complications arise with particular attention to: General developmental progress difficulties at school Visual acuity Blood pressure hypertension may be due to renal artery stenosis or pheochromocytoma Skin particularly for plexiform neurofibromas Spine for scoliosis. In adults with NF1 an annual symptom review and blood pressure check can be carried out by primary care. Referral to genetics services for advice at a time appropriate to their future reproductive plans may be helpful. Some patients will be followed by other specialists as described below. Pathophysiology The neoplastic and hyperplastic manifestations of NF1 such as neurofibromas arise as a result of abnormal cell growth and differentiation following loss of normal functioning of neurofibromin, the 250-kDa protein encoded by the NF1 gene situated on chromosome 17q11.2. One normal copy of the gene is sufficient for normal cellular growth. Inheritance of one faulty copy predisposes to subsequent loss of gene function (following loss of or mutation in the remaining normal copy). Some features, however, including intellectual impairment, arise in the heterozygous state as a result of dysregulation of Ras signaling activity.
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Management Neurofibromas can be successfully removed if a cosmetic problem but can become so numerous with increasing age that scarring from resections may become more of a problem than the original subcutaneous swelling. Plexiform neurofibromas can be removed surgically but often regrow as they are difficult to resect completely. Bony lesions need to be managed by a specialist pediatric orthopedic surgeon. Optic gliomas are usually more indolent in NF1 than their sporadic counterparts. They are best managed conservatively. Active treatment with either surgery, chemotherapy, or radiotherapy may not lead to a better outcome and should be used only when there is clear evidence of progressive disease and deterioration in vision. Treatment of progressive lesions with radiotherapy may be warranted but radiotherapy almost certainly increases the risk of future malignancy in the radiation field. Intellectual impairment may require special-needs help at school; visuospatial learning, motor coordination, and attention span are specifically and frequently impaired. Lay organizations provide a network of support workers placed within regional genetics centers, often with nursing or social work backgrounds, who can offer support to families at all stages in their diagnosis and management.
Genetic Testing The inheritance of NF1 is autosomal dominant so 50% of offspring of an affected individual would be expected to inherit the condition. In mosaic NF1 leading to segmental distribution of features, predicting involvement of the gonads and therefore the risk to offspring is difficult. Risk of transmitting the deleterious gene to offspring is generally thought to be low (<5%) but affected offspring will carry a gene mutation in every cell so will have the more usual pattern of features found in NF1. The gene for NF1 is very large, around 350,000 bases. Large deletions or rearrangements are not uncommon and point mutations may be scattered throughout the gene. Searching for mutations is therefore technically challenging and in general mutation testing is not an integral part of management in NF1. If the clinical diagnosis is secure and blood samples can be obtained from other affected and unaffected family members then, since there does not appear to be genetic heterogeneity, linkage to polymorphic markers around the NF1 locus can be used to test for affection status. If prenatal diagnostic testing is requested, either a direct mutation test (preferred option) or linkage can be used.
Prognosis NF1 penetrance is close to 100% but the manifestations of NF1 are very variable even within a family. The phenotype is likely to be influenced by other genetic factors and potentially by environmental factors although this
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is currently poorly understood. Genotypephenotype correlations are not particularly strong so empiric predictions for risks of specific manifestations in childhood are usually used. For example, around 30% or more of children with NF1 will have some learning difficulty although in only 35% is this a more severe learning disability. It is not possible to predict in advance which features (especially the less common ones) will occur. Behavioral problems including poor short-term memory and attention span are common. Expression varies widely even within the same family. Malignant peripheral nerve sheath tumors (MPNST) sometimes arising in pre-existing plexiform neurofibromas develop in around 10% of NF1 cases in their lifetime. They usually present with sudden growth and pain, often in a long-standing plexiform neurofibroma. These tend to be highly aggressive and have a poor prognosis.
NEUROFIBROMATOSIS II (NF2; OMIM 101000) Clinical Features The incidence of NF2 is 1 in 30,00040,000. A typical presentation of NF2 is with unilateral deafness due to a vestibular schwannoma, imaging revealing a second smaller lesion on the contralateral side. Bilateral vestibular schwannomas are diagnostic of NF2. Schwannomas can arise on any of the cranial nerves as well as spinal and peripheral nerves. There are a number of clinical criteria in the published literature that are aimed at determining definite or likely NF2. Table 15.3 shows the Manchester clinical diagnostic criteria for NF2, which are relatively sensitive and specific (Baser et al. 2002). Other lesions found in NF2 include meningiomas, ependymomas, astrocytomas, neurofibromas (one or two but not many). These lesions alone are insufficient to make the diagnosis of NF2. Mild features or single features which are not diagnostic for NF2 may represent mosaicism for a mutation that, if inherited by a child, may present with more severe disease. Around 2530% of patients diagnosed with NF2 with no prior family history may be mosaic for a mutation. The great majority of individuals eventually diagnosed with NF2 have developed clinical manifestations (even if these are not initially diagnostic) before 40 years of age. Table 15.3 The Manchester Clinical Diagnostic Criteria for NF2 A. Bilateral vestibular schwannomas B. First-degree family relative with NF2 AND unilateral vestibular schwannoma or first-degree family relative with NF2 and any two of*: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities C. Unilateral vestibular schwannoma and any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities D. Multiple meningiomas (two or more) and unilateral vestibular schwannoma or any two of: schwannoma, glioma, neurofibroma, cataract *‘‘Any two of ’’ refers to two individual tumors or cataract.
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Onset of lesions at younger ages is more likely to be related to a diagnosis of NF2 than later ages at onset.
Investigations Imaging Gadolinium-enhanced MRI scanning to visualize early vestibular schwannomas is a sensitive test. Eighty to ninety percent of NF2 gene carriers will have developed these lesions by 30 years of age. Thus for an adult at 50% risk of inheriting NF2 where MRI scanning and brainstem auditory evoked potentials have not revealed any pathology by 30 years of age, the residual risk that they may have inherited the mutation is 510% ([0.5 0.1 = 0.05] to [0.5 0.2 = 0.10]). This can be helpful for individuals concerned about risks to future offspring. Cases Where Further Evaluation for Possible NF2 is Indicated
Vestibular schwannoma diagnosed at less than 30 years of age Child with meningioma or Schwann cell tumor Multiple CNS tumors with no diagnosed cause Adolescent or adult with one or more neurofibromas but no family history or major features of NF1.
Investigation of a New Case of Suspected NF2 Skin examination well-circumscribed small raised slightly roughened sometimes hairy lesions are typical, a few cafe au lait patches may be seen and discrete subcutaneous swellings (schwannomas on peripheral nerves) may be found Ophthalmological examination for cataracts Audiometry and brainstem auditory evoked potentials (AEPs) Gadolinium-enhanced MRI brain scan specifically imaging of internal auditory meati (IAM). Surveillance in Known NF2 Gene Carriers and Those at 50% Risk Should be by Annual Clinical Review Starting at Age 10 Years Skin examination if genetic status unclear (50% risk) Ophthalmic examination (cataracts can be congenital or arise later in childhood) Audiometry and brainstem AEPs MRI of IAM at baseline and every two years or if any change in hearing.
Pathophysiology NF2 is caused by mutations in the gene encoding a 595 amino acid protein called merlin (or schwannomin), which is located on chromosome 22q12.2.
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NF2-associated lesions have loss of function of both copies of the gene, one inherited and the second acquired. Tumors typical of NF2, for example, vestibular schwannomas and meningiomas, also occur sporadically within the population. In sporadic tumors molecular analysis often reveals that both copies of the NF2 gene are mutated or lost but these changes are both acquired within the tumor tissue and are not present in cells elsewhere in the body.
Genetics Mutation analysis in blood DNA detects a causative mutation in around 6080% of cases and can be useful for determining who requires annual surveillance and who can be discharged from further follow-up. Genetic testing from around 10 years of age is usually offered to at-risk relatives after thorough counseling of the parents and age-appropriate counseling of the child. Some genotypephenotype correlation has been noted; large deletions and rearrangements of the gene are often but not exclusively associated with a more severe phenotype. The frequent occurrence of mosaicism in the first affected member of a family must be noted while assessing risk to other family members and in interpreting the outcome from genetic testing. Around 50% of mutations associated with NF2 arise as de novo mutations (no previous family history). The risk to children for a patient with NF2 is up to 50%. The risk of transmitting the mutation to children is less for a patient with a somatically arising mutation affecting only a proportion of tissues; this may manifest clinically as mild disease with late onset, and fewer clinical features. However, in any dominantly inherited genetic disease with mosaicism, it is not easy to discover what proportion of gonadal cells carry the mutation, so predicting offspring risk is difficult. Mutation testing identifies a causative mutation in around 60% of cases of NF2. A known mutation allows predictive testing for at-risk relatives and if requested prenatal testing. The detection rate is lower in mosaic NF2 since usually only a small proportion (if any) of blood cells carry the mutation. Fresh tumor tissue can allow a search for both somatic and inherited NF2 mutations and testing can then be offered in the next generation if the search identifies two mutations (one assumed to be inherited and the other somatic). If the mutation is not present in blood (or present only at low levels) the risk of transmitting the disease to children is less than 50%.
Treatment Early knowledge of vestibular schwannomas may help in planning hearingpreserving surgery. The ability to effectively remove vestibular schwannomas without damage to the VIIth or VIIIth cranial nerves in particular is determined partly by the position of the tumor in the internal auditory meatus and partly by the skill of the surgeon. The option to treat tumors using radiotherapy (also known as stereotactic radiosurgery or gamma knife therapy) may be considered if the tumors are less than 3 cm in size and patients are a poor surgical risk or wish to avoid surgery. This approach can arrest tumor growth and sometimes lead to tumor size regression. There is at least a hypothetical risk
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that using high-dose ionizing radiation will increase the risk of acquired genetic mutations in key tumor genes that will lead to malignant transformation. Carefully timed surgery may therefore be the best opportunity to preserve hearing or utilize some of the new technical advances such as auditory brainstem implants where loss of the nerve function is unavoidable.
SCHWANNOMATOSIS (OMIM 162091) This diagnosis can be made in an individual with two or more histologically confirmed schwannomas but who has no evidence of vestibular schwannomas. The usual presenting symptom is pain. About 30% of patients who meet the diagnostic criteria for schwannomatosis have anatomically localized lesions. Mutations in the INI1/SMARCB1 gene are present in a small proportion of patients with familial schwannomatosis (Hulsebos et al. 2007). Most cases arise sporadically although some 10% may occur in more than one family member. In the absence of any clear genetic test, the diagnosis of schwannomatosis rests at present on clinical features, and suggested criteria are set out in Table 15.4 (MacCollin et al. 2005).
TUBEROUS SCLEROSIS (TS; OMIM 191100) Clinical Features and Family History TS has an incidence of approximately 1 in 10,000. It is characterized by multisystem involvement most commonly affecting skin, CNS, heart, and kidneys. Summary of Main Clinical Features of TS Skin
Kidney Cardiac CNS Eyes Lung
Angiofibromas of face Shagreen patches Ash leaf macules Ungual fibromas Angiomyolipomas Rhabdomyomas Subependymal hamartomas; cortical tubers Retinal giant cell astrocytomas and achromatic patches Lymphangioleiomyomatosis
8090% 5060% 60% 80% 6080% Up to 50% in infancy and childhood >90% Common (rare)
Skin Lesions Angiofibromas are most prominent around the nose and mouth. Shagreen patches (with a texture like chamois leather), plaques, and hypopigmented (ash leaf) patches occur anywhere. Ungual fibromas (around the nail beds) develop later in childhood and are very common in adults.
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Table 15.4 Proposed Diagnostic Criteria for Schwannomatosis
Age
Definite Diagnosis of Schwannomatosis (specific criteria)
<30 years
Likelihood that VS may still arise, making the diagnosis NF2; diagnosis schwannomatosis is possible but cannot be definite
>30 years
2 intradermal schwannomas, histological confirmation in at least one AND No evidence of vestibular tumor on high-quality MRI AND No constitutional NF2 mutation One pathologically confirmed schwannoma and a first-degree relative with definite schwannomatosis As above
>45 years
Possible Diagnosis of Schwannomatosis (sensitive criteria) 2 intradermal schwannomas, histological confirmation in at least one AND No evidence of vestibular tumor on high-quality MRI AND No constitutional NF2 mutation
2 intradermal schwannomas, histological confirmation in at least one AND No evidence of VIIth nerve dysfunction AND No constitutional NF2 mutation Radiographic evidence of a non-vestibular schwannoma and a first-degree relative meeting criteria for definite schwannomatosis
Ophthalmic Features Retinal giant cell astrocytomas on ophthalmoscopy may occasionally be the first noted feature of the disease; achromatic patches are also sometimes seen. Visceral Lesions Cardiac rhabdomyomas may be diagnosed antenatally on ultrasound scan and should always raise the possibility of an underlying diagnosis of TS in the baby
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even if both parents appear normal. These regress through childhood and continue to regress further into adulthood. Renal angiomyolipomas often develop during later childhood and increase in size and number with increasing age until around 80% of individuals with TS will have renal manifestations (multiple cysts and/or angiomyolipomas). In the lung a rare but life-threatening complication in young women in particular is lymphangioleiomyomatosis (LAM), which presents with cough, pneumothorax, and respiratory failure. The histological appearance of the lung infiltrates is similar to renal angiomyolipomatosis and typically this condition occurs in conjunction with significant renal involvement. CNS Lesions Cortical tubers give the condition its name and in many cases lead to seizures from an early age, infantile spasms being typical; 56% of TS patients get giant cell astrocytomas. Subependymal nodules are hamartomas and usually calcify. Forty percent of children diagnosed with TS will have a degree of mental retardation, and more than 30% have autistic features; hyperactivity, emotional outbursts, and anxiety disorder are common. Summary of Investigation and Advice in a Newly Diagnosed or Suspected Case of TS 1. Full clinical evaluation of the individual:
Skin examination in UV light CNS (MRI scan) Eyes ophthalmoscopy Kidneys renal function and ultrasound scan Heart clinical examination and echocardiogram.
2. Careful clinical evaluation of both parents as for affected case. 3. If no evidence of disease in either parent, 12% risk for future children due to gonadal mosaicism. 4. Consider the utility of molecular genetic testing may be particularly relevant if the parents plan to have more children and wish to have prenatal diagnosis. 5. Refer to genetics service for advice on reproductive choices and genetic testing.
Pathophysiology Tuberous sclerosis is heterogeneous. Mutations in one of two genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3, underlie most cases of TS. The clinical manifestations of TSC2 tend to be more severe than TSC1 in general. Mutations in the TSC2 gene are more common than mutations in the TSC1 gene. The TSC2 gene product is called tuberin and the TSC1 product is hamartin. These proteins interact together in the insulin PI3 kinase pathway and via GAP signaling modulate mTOR signaling. Mutation leads
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to overactivity in this pathway and current therapeutic strategies are being investigated using drugs that target mTOR signaling.
Prognosis TS manifestations vary in severity but a large proportion of affected children have significant learning difficulties particularly in conjunction with seizures. The renal lesions are progressive with increasing age and may bleed or lead to renal failure, requiring dialysis or renal transplantation. LAM is also a progressive condition and may require lung transplantation. Unfortunately even after transplantation, recurrence of the original pathology in a similar way to metastases from malignancy can occur.
Management Cardiac rhabdomyomas often regress spontaneously with age but have been described leading to cerebral and renal embolization. Seizures respond well to vigabatrin but severe seizures unresponsive to medical treatment may require surgery to remove tubers. Renal and lung disease may become so severe as to require donor organ transplantation. Most approaches to reducing the angiofibromas of the face have been unsuccessful. Clinical trials of management of the severe clinical manifestations of TS have investigated an immunosuppressant drug (sirolimus or rapamycin) which targets mTOR signaling.
Genetic Advice The inheritance of TSC1 and TSC2 is autosomal dominant and both genes are highly penetrant 60% of patients apparently having new mutations. Where the diagnosis is clear in an individual, the risk of having an affected offspring is 50%. Absence of any disease manifestations after thorough investigation of an adult at risk of carrying a TS gene mutation would be reassuring since thorough clinical investigation will reveal clinical features in almost all adults with TS. The risk of an unaffected adult having a child with TS is low. For a clinically unaffected adult with one affected child, the risk of a second affected child is estimated to be about 12% on the basis of the possibility of underlying gonadal mosaicism in one parent. Mutation testing in an affected individual requires assessment of both TSC1 and TSC2 genes. Sensitivity for detecting mutations is around 70%. Thus up to 30% of mutations cannot be detected, probably due to the type of mutation and the technique used rather than further genetic heterogeneity for this disease. Clinical means are therefore more helpful than genetic testing in some circumstances. Genetic testing may be particularly valuable for families wishing to have prenatal diagnostic testing. Prenatal diagnosis is available only if the gene mutation can be identified in the affected family member.
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BIBLIOGRAPHY Costa RM & Silva AJ (2003). Mouse models of neurofibromatosis type I: bridging the GAP. Trends Mol Med, 9, 1923. Evans DG, Newton V, Neary W, Baser ME, Wallace A, Macleod R, et al. (2000). Use of MRI and audiological tests in presymptomatic diagnosis of type 2 neurofibromatosis (NF2). J Med Genet, 37, 944947. Kandt RS (2003). Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases. Neurol Clin, 21, 9831004. Korf BR (2001). Diagnosis and management of neurofibromatosis type 1. Curr Neurol Neurosci Rep, 1, 162167. Li Y, Corradetti MN, Inoki K & Guan KL (2004). TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem Sci, 29, 3238. Maher ER (2004). Von Hippel-Lindau disease. Curr Mol Med, 4, 833842. Narayanan V (2003). Tuberous sclerosis complex: genetics to pathogenesis. Pediatr Neurol, 29, 404409.
REFERENCES Baser ME, Friedman JM, Wallace AJ, Ramsden RT, Joe H & Evans DG (2002). Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology, 59, 17591765. Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F & Wesseling P (2007). Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet, 80(4), 805810. MacCollin M, Chiocca EA, Evans DG, Friedman JM, Horvitz R, Jaramillo D, Lev M, Mautner VF, Niimura M, Plotkin SR, Sang CN, Stemmer-Rachamimov A & Roach ES (2005). Diagnostic criteria for schwannomatosis. Neurology, 64, 18381845.
Chapter 16 Metabolic and Degenerative Disorders of Childhood Lucinda Carr
INTRODUCTION Metabolic and degenerative disorders represent a complex and challenging area of neurogenetic pediatric practice. Individual diseases are very rare but taken together the live birth prevalence is around 0.6/1000. This chapter will discuss the clinical manifestations, investigation, and management of the more common metabolic and degenerative disorders presenting in childhood. Classification of the specific metabolic and degenerative disorders of childhood is generally by cause and pathogenesis and this is the approach adopted here. However, as an approach to investigation, it can be useful to initially subdivide by age at presentation. More detailed descriptions of the conditions discussed in this chapter can be found in the books listed in the bibliography.
CLINICAL MANIFESTATIONS AND INVESTIGATION Children typically acquire motor and cognitive skills in a recognized sequence. With this ‘‘shifting baseline’’ it can be difficult to determine whether a child presenting with abnormal development is showing simple delay or more specific deviancy or regression. Confirmation of a specific diagnosis is likely to raise important but difficult genetic issues for the family, particularly the question of prenatal and presymptomatic testing. The majority of the metabolic conditions are autosomal recessive but heterozygotes may themselves be at increased risk of disease (for example, stroke in homocystinuria and malignancy in ataxia telangiectasia). The clinical manifestations of metabolic disease are protean and many are disease-specific; however, there are some general clinical features that should alert the clinician to a possible degenerative or metabolic disorder; these are summarized below: A period of normal development before the onset of symptoms/signs Loss of previously acquired skills 276
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The emergence and progression of neurological signs Marked fluctuation of symptoms/signs Intermittent episodes of encephalopathy A positive family history including unexplained fetal loss or neonatal death.
There are important caveats to this: first, here are a number of conditions which will manifest in the neonatal period where development is never normal, such as Krabbe leukodystrophy and Zellweger cerebrohepatorenal syndrome. Second, the loss of previously acquired skills is well recognized in certain conditions which are not degenerative, such as autistic regression and some epileptic syndromes, for example, Landau-Kleffner and West syndromes. Finally, even in the case of static pathology neurological signs may not emerge until early childhood, for example, the choreo-athetoid movements seen in dystonic cerebral palsy. To confirm true regression often requires a period of clinical observation alongside detailed investigations. A general approach to investigation of the child with suspected metabolic or degenerative disease is outlined below. It should be noted that there is no consensus for investigation although a range of tests might be considered. Highly specific biochemical and genetic tests are generally needed to confirm the various metabolic or degenerative conditions. Referral to a pediatrician with particular expertise in neurology or metabolic medicine is recommended. Whilst accepting that there is a very wide variability in disease phenotype, most are rather characteristic in their time of first presentation, their principal features and their temporal profile. Recognition of this can be useful in narrowing the diagnostic possibilities and focusing investigations accordingly. Furthermore, symptomatology changes with age and the clinician may find subdivision into neonatal, infantile, and childhood presentations a useful approach.
Neonatal Presentation (<28 days) The features of neonatal metabolic encephalopathy can mimic those of infection and asphyxia and so vigilance is necessary. Prompt recognition and intervention with appropriate support may significantly improve the long-term outcome: Clinical clues include:
Hypotonia Feeding difficulties Dyspnoea Lethargy or irritability Seizures Abnormal smell, especially of urine.
The main differential diagnoses would include:
Inherited disorder of amino acid and organic acid metabolism Neonatal mitochondrial encephalopathy Neonatal peroxisomal disorder Disorders of carbohydrate metabolism Disorders of biotin synthesis
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Table 16.1 Initial Investigations for Neonatal Presentation Results of Routine Laboratory Tests
Diagnosis Suggested
Confirmatory Investigation
Lactic acidosis
Mitochondrial disorder
Hyperammonemia and respiratory alkalosis Hypoglycemia and ketoacidosis
Urea cycle disorder
Raised CSF lactate; organic aciduria; biopsy of skin/muscle; neuroimaging; DNA Plasma citrulline and arginine; urinary orotic acid; DNA AA chromatography; urine OA (GC/MS); liver biopsy; enzyme analysis on liver biopsy Carnitine assay
Hypoglycemia, low ketone bodies
Aminoacidurias; organic acidurias; glycogenosis type 1; fructose1,6-phosphate deficiency Mitochondrial fatty acid oxidation disorder
AA, amino acid; OA, organic acid; GC/MS, gas chromatography/mass spectroscopy.
Pyridoxine dependency Others (lysosomal disorders, Menkes disease, etc.). Initial biochemical investigations (Table 16.1) should include:
Blood sugar Blood gas Plasma lactate Plasma ammonia.
More detailed metabolic investigations might then be indicated as below:
Amino acid (AA) chromatography (blood/urine) Organic acids by gas chromatography/mass spectroscopy (urine) Urine orotic acid Blood spot for carnitine studies Serum very long-chain fatty acids (VLCFA) including phytanic acid Bile acids and pipecolic acid (blood/urine) Serum biotinidase Enzyme analysis (leukocytes/fibroblast culture, etc.) DNA studies CSF analysis of lactate and pyruvate and AA Ultrasound (cranial/renal/cardiac, etc.) X rays (skeletal/skull) Biopsy of liver/muscle/skin/nerve/bone marrow Neuroimaging (preferably MRI) Neurophysiology (EEG, EMG, and nerve conduction studies) Ophthalmologic assessment.
Infantile Presentation Early <12 Months Clinical clues: Evidence of neurological regression
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Delay in motor development Presence of neurological signs, particularly ocular abnormalities Presence of non-neurological abnormalities, particularly visceromegaly and/or dysmorphic features. Late 1224 Months Evidence of neurological regression, particularly loss of motor function Onset of seizures with cognitive regression Acute remitting neurological episodes. A less severe presentation of the neonatal diseases listed above should be considered. In addition the differential diagnosis would now include:
Sphingolipidosis Sialidoses and sialic acid storage disorders Leukodystrophy Neuronal ceroid lipofuscinoses (Batten disease) Neuraxonal dystrophy Mucopolysaccharidoses Others.
Childhood Presentation (>3 years) The normally developing child will now have a wide neurological repertoire. The degenerative diseases can have a multisystem effect or may be more system-specific. They may be insidious in onset. A number of children with slowly progressive metabolic conditions show pre-existing developmental delay sometimes with dysmorphic features. In these children determining a progressive disorder can be very difficult. Clinical clues include: An evolving motor disorder (progressive spastic paraplegia, cerebellar ataxia, progressive dystonia, action myoclonus) Progressive peripheral neuropathy Cognitive regression and behavioral change Recurrent stroke-like episodes Episodic confusion/coma/ataxia Progressive loss of hearing or vision. Presentation with an acute encephalopathy is a classical feature of many of the neurometabolic disorders. This approach can help in focusing investigations. In the child presenting with acute encephalopathy, particular diagnoses to be considered should include:
Mitochondrial disorders, particularly fat oxidation defects Urea cycle disorders Certain amino acid disorders Certain organic acid disorders Carbohydrate disorders Others, e.g., certain vitamin disorders.
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Treatment and Management Specific treatment and management issues will be discussed for each disorder. Treatment usually comprises symptom control rather than cure. When considering the management of any pediatric case there are a number of broad issues that should always be considered: a holistic approach is imperative; namely one that encompasses the medical, social, and educational needs of the individual child and their family. To meet these needs, the resources of a multidisciplinary child development team is often required.
DISORDERS OF SUBCELLULAR ORGANELLES Lysosomal Disease Sphingolipidoses Introduction In this group of diseases the pathway for degradation of sphingolipids is disrupted, by specific enzyme deficiency or by lack of activator protein. This results in the accumulation of sphingolipid in one or more organs, particularly the brain. The sphingolipidoses are clinically and pathologically distinct. Whilst all are individually rare, together they comprise a significant proportion of pediatric degenerative disease. All the responsible genes have now been identified so that both biochemical and molecular genetic diagnoses are available. In all these conditions the mode of inheritance is autosomal recessive, with the exception of Fabry’s disease, which is X-linked recessive. Biochemical diagnosis can generally be confirmed from other (non-brain) tissues and cells, allowing prenatal diagnosis in the majority of cases. Table 16.2 summarizes the main clinical, genetic, and diagnostic features in each condition. Tay-Sachs disease is discussed in more detail below. Metachromatic, Krabbe and adrenoleukodystrophies are discussed in Chapter 7. Treatment The cloning of these genes and the use of transgenic mouse models have opened new therapeutic avenues. Substrate depletion (i.e., inhibiting glycosphingolipds) using oral miglustat (N-butylydeoxynojirimycin or OGT-918) is now licensed for the treatment of non-neuropathic Gaucher disease. Clinical trials confirmed that this treatment significantly reduced the total number of Gaucher cells and that there was significant improvement in hematological parameters and organ volumes. Enzyme supplementation is another strategy which can be effective in nonneuronopathic Gaucher disease type 1 (b-glucosidase) and in Fabry’s disease (agalside a). There is ongoing research into the use of stem cells and of gene therapy. Tay-Sachs Disease (TS; OMIM 272800) Tay-Sachs disease is the most common of the gangliosidoses, and of the GM2 gangliosidoses it represents over 90% of cases.
Table 16.2 The Sphingolipidoses Clinical Diagnosis (OMIM)
Enzyme Defect
Genetics
Diagnostic Tests
GM1 ganglioside b-galactosidase
AR; heterogeneous mutations of b-galactosidase gene on 3p21.33
Vacuolated lymphocytes; foam cells in bone marrow; low b-galactosidase in white cell enzymes
a) b-Hexosaminidase a subunit deficiency.
b) b-Hexosaminidase b subunit deficiency
a) AR; high incidence in Ashkenazi Jews; gene on chromosome 15; >100 mutations reported mutation of D1 allele (B1 variant); especially in Portuguese b) Gene on chromosome 5; >26 mutations reported
a) Low hexosaminidase A activity in white cell enzymes
b) Sandhoff disease (268800)
a) Classical with hyperacusis, psychomotor regression, spasticity, seizures, macrocephaly, cherry-red spot Extrapryamidal signs, anterior horn cell disease, dementia b) As above + hepatosplenomegaly
c) AB variant:
c) As Tay-Sachs disease
c) GM2 activator protein deficiency
c) chromosome 5; > 4 mutations reported
GM1 gangliosidosis (230500) a) Early infantile
b) Late infantile and juvenile
c) Adult
Clinical Features
a) Hypotonia, spasticity, seizures, macular cherryred spot, hepatosplenomegaly, facial and bony abnormalities b) Slower progression, systemic features uncommon c) Progressive extra pyramidal symptoms and signs, dysarthria d) As MPS 1VB
d) As MPS 1VB
a) Tay-Sachs disease (272800) Infantile presentation:
Juvenile presentation:
b) N-acetyl-glucosaminein urine; foam cells in bone marrow; low hexosaminidase A and B activity in white cell enzymes c) GM2 activator in cultured fibroblasts
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Clinical Diagnosis (OMIM) Niemann-Pick disease (257200) Type A:
Type B:
Gaucher disease (230800) Type 1: non-neuronopathic
Type 2: infantile, acute neuronopathic.
Type 3: juvenile, chronic neuronopathic Farber disease (228000)
Clinical Features
Enzyme Defect
Genetics
Diagnostic Tests
Lysosomal sphingomyelinase
AR; especially in Ashkenazi Jews (type A); chromosome 11p15.1-4; >100 mutations
Vacuolated lymphocytes foamy; histiocytes in bone marrow; low sphingomyelinase activity in white cell enzymes; DNA
b-Glucocerebrosidase; N.B. for type 1 bglucosidase used as enzyme supplementation and OGT 18 as substrate depletion
AR; gene on chromosome 1q21-q31; >150 mutations
Raised acid phosphatase (types 1 and 2); Gaucher cells in bone marrow; low glucocerebrosidase activity in white cell enzymes
Ceramidase
AR; gene on chromosome 8p21; >11 mutations
Low ceramidase activity in white cell enzymes
A: Failure to thrive, hepatosplenomegaly, psychomotor regression with hypotonia, spasticity, retinal gray or cherry-red spot B: Hepato-spenomegaly with mild/absent CNS involvement; pulmonary fibrosis
Type 1: infant to adult, hepatosplenomegaly, bony deformity Type 2: hepatosplenomegaly neck retraction, bulbar signs, rigidity and strabismus Type 3: three subtypes with/ without visceral disease Classically infantile presentation; hoarse cry, irritability, joint pain and swelling, nodules
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Table 16.2 The Sphingolipidoses—cont’d
Fabry’s disease (301500), see Chapter 11
Metachromatic leukodystrophy (250100) a) Late infantile
Multiple sulfatase deficiency (272200)
Very rare; neonatal, infantile and juvenile forms with features of MLD and MPS Infantile > 80% of cases: irritability, seizures, spasms, psychomotor regression; juvenile and adult forms with gait disturbance (HSP-like) and/or peripheral neuropathy
AR, autosomal recessive; HSP, hereditary spastic paraplegia.
a-Galactosidase; N.B. agalside a used as enzyme supplementation
X-linked recessive; gene on Xq22; >300 mutations
Low a-galactosidase activity in white cell enzymes
Arylsulfatase A
AR; gene on chromosome 22q; >63 mutations null and residual alleles account for severe to mild phenotypes; N.B. pseudodefiency of ASA is common
Formylglycine generating enzyme defect affects all 12 sulfatase enzymes
AR; gene on chromosome 3p26
MRI brain; metachromatic granules in urine; low aryl-sulfatase activity in white cell enzymes; occasionally sphingolipid activator (SAP-B) deficiency; screen urine for sulfatide Heparin sulfate in urine; sulfatase activity low in white cells
Galactosyl ceramosidase
AR; gene on chromosome 14q24-31; >65 mutations occasional pseudodeficiency
MRI brain; white cell enzymes
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Krabbe disease (globoid cell leukodystrophy) (245200)
Classic with painful crises, angiokeratoma, retinopathy, stroke, neuropathy, progressive renal and cardiac disease; atypical adult onset with cardiomegaly and proteinurea; carriers may be symptomatic a) Classical
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Clinical Features. The classic presentation of TS disease is in early infancy around 6 months of age with the loss of developmental milestones and increasing hypotonia. A prominent acoustic startle response is a notable clinical feature in the early stages of the disease. Ninety percent of children will develop a macular cherry-red spot and the majority macrocephaly. The child gradually becomes blind, unresponsive and decerebrate. A number develop seizures. Death is usually around 4 to 5 years. Later-onset, more chronic presentations are also recognized; a juvenile form with dystonia, dementia, and often a mixture of pyramidal and extrapyramidal signs and a late adult-onset form .The adult disease is again more common in Ashkenazi Jews. It presents with psychosis in up to 50% of cases and with dysarthria and tremor. This form of the disease is associated with a distinct Gly-Ser mutation or compound heterozygote which includes a classical infantile TS mutation. Investigations. The diagnosis is generally confirmed by low levels of hexosaminidase A. For prenatal screening, levels in amniotic fluid are assayed. Further DNA testing is sometimes necessary to exclude pseudodeficiency. Neuroimaging may be normal in the early stages of the disease. Later, general cortical atrophy with hyperintensity of the basal ganglia is common. Neuropathology and Genetics. Neuropathological features are closely similar in all the gangliosidoses. Ganglioside storage material distends neuronal perikarya in both the peripheral and central nervous systems. This results in meganeurites and aberrant neurite formation. Paraffin preparation washes out the ganglioside but on frozen section these neurons are strongly PAS-positive. Total gray matter ganglioside levels are 45-times normal in classic TS disease, around 80% being GM2. This is much less pronounced in the late-onset forms. Tay-Sachs is particularly common amongst Ashkenazi Jews, in whom disease incidence is around 1 in 3000. This compares with an overall incidence of around 1 in 300,000 in the general population. Carrier frequency is around 1 in 27 in the Jewish population (which is 10-times higher than non-Jewish groups). Screening within this population is now routine and has led to a dramatic reduction in the incidence of TS. Over 100 heterogeneous mutations are recognized to cause the classic disease, with the common mechanism of b-hexosaminidase a subunit mRNA being unstable or absent. In the Jewish population >98% of cases result from one of three mutations, the most common being a four-base insertion within exon 11. There are also a number of benign mutations which in compound heterozygotes can lead to a ‘‘pseudodeficiency’’ with low but asymptomatic levels of hexosaminidase A. This is very infrequent in the Jewish population but is seen in up to a third of non-Jewish carriers. Treatment. Treatment is supportive. In classical TS ganglioside accumulation in the fetus is already detectable by the second trimester so that the success of any postnatal intervention in this condition is likely to be limited.
Lysosomal Disease Mucopolysaccharidoses (MPS) In these diseases a deficiency of lysosomal glucosidase or sulfatase results in the accumulation of mucopolysaccharides or glycosaminoglycans within the
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lysosome. Nine MPS variants are described, many with eponyms, and there are further subtypes within several of these groups. They are described in Table 16.3. Clinical Features All these disorders are extremely rare and exact incidence is unclear; MPS I (Hurler disease) is probably the most common and for this disease epidemiological studies indicate rates between 1 in 76,000 and 1 in 144,000. MPS III, being the most subtle, is probably under-reported, with given rates between 1 in 73,000 and 1 in 324,000. Most types of MPS show a range of phenotypes from mild to severe. The clinical symptoms result from the abnormal storage material in mesenchymal and neuronal cells. With the exception of MPS III (Sanfillipo disease), dysmorphic features and skeletal changes often dominate the clinical picture; affected children may show coarse features, short stature, and deformity. Corneal clouding and visceral involvement including hepatosplenomegaly is often seen. Neurological manifestations vary; they may be entirely absent as in MPS IV or relatively mild, predominantly showing nerve entrapment syndromes (MPS IS, II, VI). The more severe cases have hydrocephalus, seizures, and progressive dementia (MPS IH, Hurler disease and MPS II, Hunter disease). In these children increasing obstructive airway disease and cardiac failure secondary to valvular disease are the usual cause of death, which typically occurs in mid to late childhood. In contrast, long-term survival is expected in the milder forms, such as MPS III and IV. Investigations For screening purposes, all types of MPS show vacuolated lymphocytes with inclusions. Glycosaminoglycans are excreted in urine. A skeletal survey often shows characteristic bony changes. The diagnosis is confirmed by specific enzyme and genetic studies, summarized in the Table 16.3. Enzyme assay also allows prenatal diagnosis. Neuropathology and Genetics The striking neuropathological feature is the lysosomal vacuolation of mesenchymal cells both inside and outside the CNS. This includes mural cells in cerebral and extracerebral vessels. Neurons are distended by ganglioside inclusions known as ‘‘Zebra bodies’’. In the more chronic forms of MPS, such as MPS III, additional lipopigments may accumulate resembling the curvilinear profiles seen in neuronal ceroid-liposfuscinosis. In peripheral tissues the stored material is mainly formed of dermatan and heparin sulfates, which are also excreted in the urine. Inheritance is autosomal recessive except for MPS II (Hunter disease), which is X-linked recessive. Multiple mutations are recognized, whose incidence differs within different ethnic groups. Phenotype/genotype correlation is generally poor unless there are nonsense mutations on both alleles, as often occurs in the case of MPS I; two nonsense mutations (W402X and Q70X) account for >50% of cases and are associated with the severe form of disease.
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Table 16.3 Mucopolysaccharidoses (MPS) Storage Material (also in urine)
Severe Mild
Severe Carpal tunnel syndrome
DS and HS
Mild-moderate
Severe but no corneal clouding Mild, may be lacking initially
Marked with risk of atlanto-axial dislocation
KS
Eponym
Neurological Features
MPS I (252700)
Hurler (IH) Scheie (IS; formerly MPS V) Hunter
MPS II (309900) MPS III Four subtypes AD
Sanfilippo
(252900) (252920) (252930) (252940)
Severe; behavior problems, progressive deterioration and seizures; subtypes are not clinically distinct
MPS IV A and B (253000) (253010)
Morquio
A: mild meningeal involvement B: absent
MPS VI (253200)
Moroteaux-Lamy Mild
MPS VII (253220) MPS IX (601492)
Sly
Deficient Enzyme
Gene Locus 4p16.3
DS and HS
a-L-Iduronidase; N.B. artificial enzyme supplementation available Iduronate sulfatase
Xq28
HS
A: heparan N-sulfatase
17q25.3
17q21 unknown B: a-N-acetyl12q14 glucosaminidase C: acetyl-coA;aglucosaminide acetyltransferase D: N-acetyl-glucosamine6-sulfatase A: 16q24.3
B: 3p21.33
Mild to severe
Marked with risk of cervical cord compression Mild to severe
DS and HS
N-Acetyl-galactosamine- 5q13-14 4-sulfatase (aryl sulfatase B deficiency) b-Glucuronidase 7q21.11
?
Yes
Hyaluronan
Hyaluronidase
KS, keratan sulfate; DS, dermatan sulfate; HS, heparan sulfate.
DS
A: N-acetylgalactosamine-6sulfatase B: b-galactosidase
3p21
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Osseous and Visceral Abnormalities
Disease (OMIM)
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Treatment Treatment options for MPS are expanding. Early bone marrow transplantation (<2 years) improves or at least stabilizes the systemic effects. The cognitive benefits are less clear and the results of long-term follow-up studies are still awaited. Enzyme replacement therapy with human-a-L-irudonidase (laronidase) is now approved for clinical use in MPS I patients without neuronal pathology. In animal models gene therapy has shown partial success and in vitro gene transfer using retroviral vectors can correct the cellular phenotypes.
Mucolipidoses, Sialidoses and Other Disorders of Glycoprotein Metabolism Clinical Features Clinically, many of all these diseases show Hurler-like features. All are autosomal recessive. Their principal clinical and genetic features are summarized in Table 16.4. For screening purposes all show lymphocytic vacuolation. Abnormal material is not, however, found in the urine for the mucolipidoses. Enzyme assay is needed to confirm the diagnosis. Chorionic villus tissue can be cultured to establish enzyme activity and confirm the diagnosis prenatally. In some cases, such as ML II, electron microscopy may reveal intracellular inclusions. Treatment is symptomatic in all these conditions. Mucolipidoses The five described mucolipidoses (ML) result from abnormal lysosomal enzyme phosphorylation. ML I, also known as sialidosis, presents with two subtypes: type 1 with macular cherry-red spots, seizures, and myoclonus; type 2 as short stature and mild developmental delay. ML II (I-cell disease) presents in infancy with neurodevelopmental regression accompanied by marked dysmorphism and dysostosis multiplex. ML III (pseudo-Hurler) is less severe with a later presentation. ML IV shows visual disturbance including corneal opacities. ML V predominantly affects skeletal and cardiac muscles. Also known as type II glycogenosis or Pompe disease, it results from defective acid maltase (aglucosidase) activity. All ML patients show vacuolated lymphocytes with inclusions but there are no glycosaminoglycans in urine. Skeletal survey is often informative with characteristic boney changes. White cell enzymes are abnormal but the diagnosis should be confirmed by assay of enzyme activity on cultured fibroblasts. Sialiuria Where sialic acid transport across the lysosme is defective, free sialic acid will accumulate, leading to storage disorders with normal neuraminidase activity. Particularly seen in the Finnish population (Salla disease), ataxia and psychomotor delay emerge in infancy. A more severe infantile form (infantile free sialic acid storage disease or ISSD) is recognized. Sialuria is non-lysosomal
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Table 16.4 Mucolipidoses and Sialidoses Disease Mucolipidoses ML I/sialidosis (256550) ML II (309900) ML III ML IV (252650) ML V (Pompe) (232300) Sialic acid disorders Galactosialidosis (256540) ISSD and Salla disease (269920) Sialuria (269921)
Neurological Features
Other Features
Deficient Enzyme
Gene Locus
Variable (especially type I) Progressive psychomotor retardation Psychomotor retardation In infantile forms
Variable (especially type II) Hurler-like features mild to severe
Sialidase I and neuraminidase N-Acetyl glucosaminyl1-phosphotransferase
6p21
Retinal degeneration
Mucolipin1
19p13.2-3
Skeletal and cardiac muscle
a-Glucosidase
17q25
Variable; mild to moderate, seizures, ataxia Severe to moderate
Variable; mild with angiokeratoma to severe dysplasia Severe to moderate
b-Galactosidase and neuraminidase
20q13.1
Variable
Variable
UDP-GlcNAc 2-epimerase
Hurler-like features Dysostosis multiplex
a-Mannosidase
Oligosaccharidoses a-Mannosidosis severe Psychomotor regression infantile milder juvenile forms (248500) b-Mannosidosis Variable; seizures and (248510) dementia Fucosidosis (230000)
Mild to moderate psychomotor regression
Aspartylglucosaminuria (208400) Schindler disease (609241) Severe infantile Milder juvenile
Learning difficulties
Psychomotor regression, neuraxonal dystrophy, myoclonic seizures learning difficulties
a/b 12p g16p
Sialin
Variable; b-Mannosidase Hurler-like features angiokeratoma a-Fucosidase Mild to moderate dysmorphic, dysostosis multiplex angiokeratoma Mild; Hurler-like Aspartylglucosaminidase features a-N-Acetylgalactosaminidase Angiokeratoma
with accumulation of free sialic acid in cytosol. Vacuolated lymphocytes are present and sialic acid is excreted in the urine. Oligosaccharidoses The abnormal degradation of the glycoproteins results in accumulation of oligosaccharides. To date five diseases with differing defective enzymes
19p13.2-12
4q21-25
1p34
4q34-35
22q13.1-2
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are recognized. All show a spectrum of clinical severity. Again vacuolated lymphocytes are present. Oligosaccharides are excreted in urine. White cell enzyme studies confirm the diagnosis.
Congenital Disorders of Glycosylation (CDG) Abnormalities in the synthesis of glycoproteins result in more general systemic effects since the functions of these proteins include transport and membrane receptor proteins, glycoprotein hormones, complement factors, immunoglobulins, and certain enzymes. These disorders are described by the congenital disorders of glycosylation of N-linked glycans, namely the carbohydrate-deficient glycoprotein disorders. Two main groups are described, CDG I and II; within CDG I nine subtypes (ai) are recognized and for CDG II four subtypes. Some subtypes comprise single case reports only. With the exception of CDG 1b, in which neurodevelopment appears normal, all subtypes show varying involvement and severity of neurological and systemic features. CDG Ia (OMIM 601785/212065) Clinical Features. This is the commonest condition and is particularly prevalent in the Scandinavian population, with an incidence of around 1 in 50,000. Over 300 cases have been reported in Europe. CDG Ia shows a wide clinical spectrum but classically presents in infancy with characteristic dysmorphic and neurological features. These comprise inverted nipples, abnormal fat distribution around the buttocks and joint contractures. The child shows hypotonia and developmental delay. In addition hepatic and renal dysfunction is often seen along with pericardial effusions. Most children survive this initial phase as the condition stabilizes but severe psychomotor delay persists, often with the emergence of peripheral neuropathy, seizures, stroke-like episodes, and skeletal deformity with osteopenia. Investigations. The hallmark of all these conditions is the abnormal production of glycoproteins and this is used in diagnosis. Isoelectric focusing of transferrin in blood and CSF shows replacement of the normal tetrasialotransferrin by disialotransferrin and asialotransferrin. Thyroid binding globulin and clotting factors are also abnormal. Cranial imaging usually shows progressive pontocerebelar atrophy. Pathology and Genetics. In the case of CDG Ia the cytoplasmic synthesis of guanosine diphosphate mannose is defective, which in the majority of cases is secondary to deficiency of phosphmannomutase. Pathologically most cases show olivopontine cerebellar atrophy with severe neuronal loss in these areas. In the cerebellum there is prominent loss of Purkinje cells. In addition myelin-like fibrillary inclusions are seen in Schwann cells and in hepatocytes. All CDG are autosomal recessive. The gene loci for these conditions have been identified; in the case of CDG Ia this is at 16p13.3-p13.2 and is usually due to a missense mutation R141H in the phosphomannomutase 2 gene.
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However, there is poor genotypephenotype correlation overall. Prenatal diagnosis is available for CDG Ia and IIa. Treatment. Currently there is no known effective treatment for CDG Ia. High-dose mannose has been successful in the treatment of CDG Ib which also results in defective guanosine diphospate mannose.
Peroxisomal Disorders Peroxisomes play an important role in fatty acid oxidation, in the metabolism of phytanic acid and pipecolic acid and in the synthesis of bile acids and plasmalogens. Impaired peroxisomal function results in a number of multisytem diseases, often with prominent neurological features. Group 1: Peroxisomal Biogenesis Disorders (PBD) In these conditions a mutation in one or more of the 12 peroxisomal assembly genes (PEX genes) results in a virtual absence of peroxisomes and a generalized loss of all peroxisomal function. With an overall incidence of around 1 in 50,000 live births they comprise the most severe of the peroxisomal conditions and present in the neonatal period. Clinical Features. Zellweger syndrome (ZS or cerebrohepatorenal syndrome; OMIM 214100) is the most common and severe of the PBD. The child has craniofacial dysmorphism often with short forelimbs and calcific stippling of patella and acetabula. There is profound hypotonia with static development and seizures. Atypical pigmentary retinopathy, cataracts, sensorineural hearing loss, renal cysts, and hepatomegaly are common. The affected child rarely survives beyond infancy. Neonatal adrenoleukodystrophy has milder but similar features to ZS. Clinical signs of adrenal insuffiency are rare but there is a reduced cortisol response to ACTH. Infantile Refsum’s disease produces features of both ZS and classic Refsum’s disease. The child shows some dysmorphic features with hepatomegaly, developmental delay, sensorineural deafness, and pigmentary retinopathy. Rhizomelic chondrodysplasia punctata presents as a bony dysplasia. It can be variable in expression but characteristically produces forelimb shortening with epiphyseal and extra epiphyseal calcification. Additional features include learning difficulties, cataracts, and icthyosis. Investigations. The diagnosis is suggested by elevated plasma and fibroblast very long-chain fatty acids (VLCFA). Plasma and urine bile acids are also abnormal. Red cell plasmalogen is low. It may take some months for phytanic and pristinic acid levels to increase. Neuroimaging often shows neuronal migration defects and abnormal myelination. The diagnosis is established by the clinical and biochemical features but identification of the precise genetic defect from genetic studies is important to establish carrier status and enable subsequent antenatal diagnosis.
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Pathology and Genetics. Disordered neuronal migration, with pachygyria and polymicrogyria in cerebral neocortex, is the most striking pathological finding. Subventricular and germinal matrix cysts are also common. Dysmyelination is seen in white matter, and, in cases of neonatal adrenoleukodystrophy, inflammatory demyelinative lesions. All are of autosomal recessive inheritance. The PEX genes produce peroxins which are necessary for normal targeting and importation of peroxisomal integral membrane and matrix protein. In the case of ZS there is total absence of the Pex 1p gene which is most frequently due to an insertional frameshift mutation at 7q21-22. However, several gene loci and variable mutations are described and the phenotypegenotype correlation is generally poor. Treatment. There is no recognized effective treatment. Administration of docosahexanoic acid and bile acid replacement have shown some effects in a few patients. Treatment is largely symptomatic. Group 2: Single Peroxisomal Enzyme Defects Involving -Oxidation Peroxisomes are morphologically intact but their function is defective: Pseudo PBD. Seven separate conditions are recognized with a clinical presentation similar to ZS. The commonest is a bifunctional protein deficiency. Plasma VLCFA and bile acid studies are abnormal but, in contrast to ZS, red cell plasmalogen is normal. X-linked adrenoleukodystrophy. This condition primarily affects boys and has a variable clinical phenotype even within families. Adrenoleukodystrophy has an estimated incidence of around 1 in 20,00050,000. Several mutations of Xq28 are described, all resulting in abnormal b-oxidation. There is, however, no apparent genotypephenotype correlation. This condition is discussed in detail in Chapter 7. Group 3: Single Peroxisomal Enzyme Defects Without -Oxidation Involvement Peroxisomes are present but again their function is defective: Classic Refsum’s disease presents with retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and raised CSF protein. Sensorineural deafness and icthyosis are often seen. The diagnosis is suggested by a raised plasma phytanic acid and confirmed on fibroblast culture. This is discussed in more detail in Chapter 11. Others include pseudo-rhizomelic chondrodysplasia.
DISORDERS OF AMINO ACID AND ORGANIC ACID CATABOLISM Disruption of the normal catabolism of amino acid or organic acid pathways should be considered in any child presenting with an encephalopathy and metabolic acidosis, or in the child with more general developmental delay. All are
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individually rare and only the more commonly seen are discussed here. All these disorders are autosomal recessive with the exceptions of ornithine transcarbamylase deficiency, which is X-linked, and some forms of tetrahydrobiopterin deficiency, which are autosomal dominant.
Amino Acids Disorders Presenting without Acute Encephalopathy Hyperphenylalanemia Syndromes Phenylketonuria (PKU; OMIM 261600) Phenylalanine hydroxylase is necessary for the hepatic hydroxylation of phenylalanine to tyrosine. In classic PKU enzyme activity is <1% of normal and serum levels of phenylalanine will rapidly rise once the protective effect of the placenta is removed. Clinical Features. Disease incidence is estimated to be around 1 in 10,000, but since the introduction of neonatal screening the classic disease is now rarely seen. High phenylalanine levels result in a characteristic picture of severe developmental delay and behavior problems with acquired microcephaly. Seizures may develop. Pigmentation is strikingly fair in the majority of patients and a musty odor is often noted. In atypical and mild forms there is some residual enzyme activity and serum phenylalanine levels are only modestly elevated. Investigations. Amino acid screening shows high serum phenylalanine and low tyrosine levels, and the diagnosis is confirmed by phenylalanine and tetrahydrobiopterin (BH4) loads. A significant subset of PKU patients will show partial or complete BH4 responsiveness (see treatment below). Enzyme activity is assayed by liver biopsy and confirms the diagnosis. Genetic studies are indicated to enable prenatal testing. MRI scanning of the brain demonstrates abnormal white matter in affected individuals (Fig. 16.1). Neuropathology and Genetics. Accumulation of phenylalanine in blood and CSF is associated with deficiencies of other large neutral AA, most importantly tyrosine and methionine. This results in disruption of normal brain protein synthesis, of myelin turnover and in biogenic amine neurotransmission. White matter disturbance is generally found at autopsy. Over 400 heterogeneous mutations are recognized in PKU and their prevalence differs within different ethnic groups. Mutations occur at the phenylalanine hydroxylase locus on 12q24.1 and are compound in most patients. Treatment. Unless dietary intake of phenylalanine is restricted, classic PKU will develop. However, despite neonatal detection and careful dietary control, retrospective studies have shown that IQ is still affected. Lifelong dietary restriction of phenylalanine is now recommended, since late phenylalanemia is now recognized to cause further cognitive decline and neurological features. Furthermore raised phenylalanine levels are teratogenic. If untreated, maternal hyperphenylalanemia may result in microcephaly, growth retardation, and cardiac defects.
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FIGURE 16.1. T2-weighted MR brain scan in phenylketonuria showing high signal in the periventricular white matter.
BH4 cofactor-responsive PKU is now recognized where oral BH4 will reduce or normalize serum phenylalanine levels. This is seen in up to 10% of classic PKU patients and the majority of mild PKU patients, in some cases obviating the need for restrictive diet. The molecular basis for this is poorly understood and is probably multifactorial. Tetrahydrobiopterin (BH4) Deficiency This probably accounts for around 1% of cases hyperphenylalanemia syndromes. Tetrahydrobiopterin is the cofactor for phenylalanine hydroxylase, tyrosine and tryptophan mono-oxygenases and nitric oxide synthase so that deficiencies may result in both hyperphenylalanemia and dopamine deficiency. The more severe recessive infantile form presents with progressive encephalopathy often with microcephaly and parkinsonismdystonia. Less severe dominant forms may present with a dopa-responsive dystonia (see Chapter 8). Homocystinuria (OMIM 236200) Excessive excretion of urinary homocystine may be caused by: Deficiency of cysthionine b-synthase (classic homocystinuria) Defective methylation of 5-methyltetrahydrofolate homocystine (5,10methylenetetrahydrofolate reductase deficiency)
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Defects of cobalamine and folate metabolism nutritional deficiencies of folate and B12. Clinical Features. Disease incidence is estimated around 1 in 200,000335,000. Children with cysthionine b-synthase deficiency generally show neurodevelopmental delay, often with behavior problems. Around 20% have seizures. Affected children often have a marfanoid appearance, being tall and slender, often with osteoporosis and scoliosis. Ophthalmic complications are common, ectopia lentis being a hallmark of the disease. In contrast to Marfan syndrome dislocation is typically of downward displacement. Homocystinuria is a rare but important cause of childhood ischemic stroke: a significant minority of children will develop vascular occlusion, often with severe neurological sequelae (Chapter 9). Investigation. Urine nitroprusside testing shows raised homocystine levels. Plasma amino acid levels are abnormal, with elevated methionine and homocystine and low cystine. The diagnosis is confirmed by assay of cysthionine bsynthase activity on fibroblast culture. Prenatal testing can be offered and in some countries neonatal screening of methionine levels is used. Neuropathology and Genetics. In homocystinuria the principal lesions are ischemic, as a result of thromboembolic vasculo-occlusive disease that involves arteries, veins, and dural sinuses. Mutations involve the cysthionine b-synthase gene located at 21q22.3. The majority are private missense mutations, with over 130 mutations described to date; the most prevalent being I278T (which is pyridoxine-sensitive) and G307S (which is not). The severity of disease varies even with the same genotype although the responsiveness to pyridoxine remains constant. Treatment. Treatment with pyridoxine reduces or normalizes amino acid levels in up to 50% of affected children. There is evidence that this improves cognition and delays the onset of thromboembolic events. If unresponsive to pryridoxine, a low-methionine diet with cystine and betaine supplemention should be introduced. Tyrosinemia (OMIM 276700) Clinical Features. Type 1 results from the accumulation of tyrosine and its metabolites secondary to fumarylacetoacetase deficiency. It presents in infancy with progressive hepatorenal disease, which may ultimately result in renal and hepatic failure. Acute painful crises occur associated with peripheral neuropathy (mimicking the acute porphyrias). Both the acute and chronic forms are associated with hepatic failure and hepatoma. Investigations. The diagnosis is suggested by the presence of succinylacetone and d-aminolevulinic acid in urine and serum and confirmed by enzyme assay in lymphocytes or fibroblasts. Antenatal diagnosis is possible and neonatal bloodspots can be estimated for succinylacetone levels.
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Neuropathology and Genetics. A number of mutations within the fumarylacetoacetase gene have been identified, for which there is poor genotype phenotype correlation. Treatment. Treatment with NTBC and dietary restriction of tyrosine normalizes hepatic and renal function and prevents further neurological crises.
AA Disorders Presenting with Acute Encephalopathy Branched-Chain AA Clinical Features. In these disorders, defective catabolism of branched-chain AA (leucine, isoleucine and valine) leads to the accumulation of organic acid (OA) in body fluids. Four conditions will be discussed. All may present in one of three ways: A severe progressive neonatal encephalopathy is the most common presentation; early feeding difficulties are soon followed by unexplained progressive coma associated with neurological signs and metabolic acidosis. An intermittent late-onset form with episodes of acute encephalopathy on a background of developmental delay and failure to thrive; seizures may also develop. A chronic progressive form with developmental problems as above but where neurological attacks are rare. Investigations. Diagnosis is made from the urinary excretion of OA measured by gas chromatography and mass spectroscopy. In the case of maple syrup urine disease, branched-chain AA are elevated in serum. Specific enzyme assays can then be performed from cultured fibroblasts and this confirms the diagnosis. Prenatal diagnosis with enzyme assay of amniocytes is available in these disorders. Treatment. Treatment is with dietary protein restriction with appropriate AA, mineral, and vitamin supplementation. A trial of thiamine is recommended in all cases of suspected maple syrup urine disease and of cobalamin in methylmelonic aciduria. Any intercurrent illnesses should be aggressively managed to prevent metabolic decompensation, which is likely to be generally detrimental to neurodevelopmental outcome. Despite these measures the longterm neurological outcome is generally disappointing. Maple Syrup Urine Disease (MSUD; OMIM 248600/248611/248610) MSUD is caused by defects in the branched-chain a-keto-acid dehydrogenase (BCKD) complex. It has an overall incidence of around 1 in 185,000. The accumulating keto-acids have a caramel-like aroma and this may provide a clinical clue to the diagnosis. A number of US states routinely measure plasma leucine as part of their neonatal screening program.
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MSUD is a genetically heterogeneous condition. Over 80 causative mutations have been identified to date, all involve the BCKD complex, but there is poor genotypephenotype correlation. The gene loci are located on three separate chromosomes; E1a at 19q31, E1b at 6q14, and E2 at 1p31, and these are unique for the BCKD complex. E3 is involved in other mitochondrial complexes and gives a different phenotype. It important to note that there is a rare thiamine-responsive form associated with mutations of the E2 component in the enzyme complex. Proprionic Acidemia In this condition proprionyl CoA carboxylase activity is defective. The majority of surviving children show severe extrapryamidal movement disorders with basal ganglia changes on neuroimaging. Methylmalonic Aciduria Methylmalonyl CoA mutase is defective in this condition. The neonatal encephalopathy may be accompanied by erythematous rash and hepatomegaly. A proportion of children harbor mutations at 4q31.2 and this is associated with a clinical response to cobalamin treatment in which serum methylmalonate levels are reduced with cobalamin supplementation. These children generally have a better neurological outcome than those who are non-responsive. Isovaleric Acidemia Isovaleric acidemia results from defects in isovalaryl CoA dehydrogenase leading to the accumulation of isovaleric acid, which has a cheesy odor. Plasma isovaleric acid and isovalarylglycine are grossly elevated. Thomocytopenia and neutropenia are also common. Non-Ketotic Hyperglycinemia (NKH; OMIM 238300) Defects in the glycine cleavage system (GCS) lead to the accumulation of glycine in all body fluids. It has an incidence of around 1 in 63,000 live births. Presentation is typically in the neonatal period with a severe and often fatal encephalopathy with intractable myoclonic seizures. Survivors show a continuing seizure disorder with profound developmental delay and microcephaly. A small number present later with milder symptoms and may be less severely affected. Investigations. In contrast to other neonatal encephalopathies the only biochemical marker is the elevation of glycine. Levels are disproportionately raised in CSF, often at 1030-times above the normal range. The CSF/plasma ratio is a useful marker of disease severity. Enzyme activity can be assayed from fibroblasts, or liver biopsy in the case of T-proteins; however, this is not always predictive of disease severity nor is it entirely reliable for antenatal CVS sampling. Where mutations are known DNA studies can confirm the diagnosis prenatally.
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Neuropathology and Genetics. The pathogenisis of NKH probably results from the neurotransmitter and cotransmitter action of glycine. Brain malformation, particularly callosal agenesis and dysmyelination, is an additional feature of this disease. Four components of the GCS gene are recognized, comprising 25 exons at 16q24. These encode P-, T-, H-, and L-proteins. A number of missense mutations of the T- and P-proteins have been identified as causative in NKH. The Tprotein mutations are more often seen in the milder phenotypes. Treatment. Treatment is generally disappointing. Using sodium benzoate to reduce glycine levels may improve seizure control; dextromethorphan modifies glutamate receptors and has also been reported to reduce seizures and improve developmental outcome in some cases. However, neurological outcome generally remains poor. Sulfite Oxidase Deficiency A rare disorder that typically presents with intractable seizures and dysmorphic features including ectopia lentis: the deficiency may be isolated or be associated with molybdenum cofactor deficiency. Both conditions result in a characteristic serum AA profile and low urinary sulfate and sulfite. Enzyme assay of cultured fibroblasts confirms the diagnosis. No successful treatment is currently available.
Organic Acid Disorders Presenting without Acute Encephalopathy Canavan’s Disease (OMIM 271900) This leukodystrophy is an autosomal recessive disorder caused by accumulation of N-acetylaspartic acid (NAA) secondary to mutations in the aspartoacylase gene. It has a particularly high incidence among Ashkenazi Jews. Canavan’s disease is characterized by macrocephaly, lack of head control and developmental delays by the age of 35 months, severe hypotonia, and failure to achieve independent sitting, ambulation, or speech. Hypotonia eventually changes to spasticity. Assistance with feeding becomes necessary. Life expectancy is usually into the teens. Diagnosis of Canavan’s disease in symptomatic individuals relies upon demonstration of very high concentration of NAA in the urine and finding mutations. ASPA, the gene encoding the enzyme aspartoacylase, is the only gene known to be associated with Canavan’s disease. Three common mutations account for about 99% of the disease-causing alleles in Ashkenazi Jewish persons and approximately 5055% of disease-causing alleles in non-Jewish persons. Molecular genetic testing is clinically available, primarily to persons of Ashkenazi Jewish heritage, for confirmation of the diagnosis, carrier testing, population screening, and prenatal testing.
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Treatment for Canavan’s disease is supportive and directed to providing adequate nutrition and hydration, managing infectious diseases and protecting the airway. L-2-Hydroxyglutaric
Aciduria (OMIM 236792)
The pathogenesis of this condition is poorly understood but probably involves defects of the L-2-hyroxyglutarate dehydrogenase gene located at 14q22.1. There is early-onset cerebellar ataxia with mild learning difficulties. Progression leads to severe difficulties by early adolescence. Neuroimaging shows progressive subcortical white matter changes, often with involvement of basal ganglia and cerebellum. There is accumulation of L-2 hydroxyglutaric acid in all body fluids, particularly CSF. 4-Hydroxybutyric Aciduria (OMIM 271980) g-Hydroxybutyric acid accumulates secondary to reduced succinate semialdehyde dehydrogenase activity and acts as a GABA receptor agonist. This causes mild psychomotor delay with non-progressive ataxia, hypotonia, and areflexia. Seizures are present in around 50% of cases. The gene for this enzyme is located 6p22 with multiple mutations described. Elevated g-hydroxybutyric acid levels in plasma, urine, and CSF suggest the diagnosis, which is then confirmed by white cell enzyme assay. Treatment with vigabatrin (g-vinyl GABA), which is a GABA transaminase inhibitor, may result in mild clinical improvement.
Organic Acid Disorders Presenting with Acute Encephalopathy Glutaric Aciduria Type 1 (OMIM 231670) The metabolism of lysine, hydroxylsine, and tryptophan is disrupted secondary to deficiency in glutaryl-CoA dehydrogenase, a mitochondrial enzyme. This results in the accumulation of glutaric acid and 3-hydroxyglutaric acid. Clinical Features. Macrocephaly is an important early sign but clinical presentation is usually with progressive dystonia or choreoathetosis. Both acute and chronic presentations are seen. Early encephalitic crises are seen in around 70% of cases but become infrequent after 3 years of age. More chronic forms may be mistaken for cerebral palsy. Investigation. Neuroimaging is characteristic, with frontotemporal atrophy and often subdural effusions or hematomas. This may lead to initial suspicion of child abuse. There is excessive glutaric and 3-hydroxyglutaric acid in the urine. Plasma free carnitine is reduced and glutaryl carnitine is elevated. Reduced enzyme activity is demonstrated in fibroblasts. Neuropathology and Genetics. Striatal degeneration and spongiform white matter is often seen at autopsy.
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The disorder is autosomal recessive and results from multiple mutations of the glutaryl-CoA dehydrogenase gene, located at 19p13.2, for which there is poor genotypephenotype correlation. Treatment. Treatment is with dietary restriction of lysine and tryptophan, supplemented with L-carnitine and riboflavin. Whilst this fails to improve existing neurological deficits, if started before any encephalitic crises subsequent deterioration may be averted. Supportive therapy should be given during intercurrent infections. Other causes of acute encephalopathy include: Glutaric aciduria type II, a multiple acyl-CoA dehydrogenase deficiency caused by a defect in the mitochondrial electron transfer system (OMIM 231680) Proprionic acidemia Methylmalonic aciduria: discussed above with the branched-chain AA Isovaleric acidemia: discussed above with the branched-chain AA.
UREA CYCLE DISORDERS The urea cycle is necessary for the incorporation of nitrogen into urea and for the synthesis of arginine. Urea synthesis occurs almost exclusively in the liver. In addition to urea production, the cycle plays a key role in the synthesis and degradation of arginine so that in the urea cycle disorders, with the exception of arginase deficiency, arginine becomes an essential amino acid. Hereditary disorders have been described for the six enzymatic steps (af below): (a) (b) (c) (d) (e) (f)
N-acetylglutamate synthetase deficiency (OMIM 237310) Carbomylphosphate synthetase deficiency (CPS, OMIM 237300) Ornithine transcarbamylase deficiency (OTC, OMIM 311250) Arginosuccinate synthetase deficiency (citrullinemia, OMIM 215700) Arginosuccinate lyase (arginosuccinic aciduria, OMIM 207900) Arginase deficiency (OMIM 207800).
Clinical Features. The overall incidence of the urea cycle disorders is around 1 in 8000 live births. OTC deficiency is the most common, with an incidence of around 1 in 14,000 live births. OTC is distinct from the other cycle disorders in that it is X-linked with manifest heterozygotes (see Neuropathology and genetics below). In the urea cycle disorders the majority of cases present in the neonatal period with encephalopathy, ataxia, and seizures, often with hepatomegaly. With later-onset forms, episodes of acute encephalopathy are triggered by intercurrent infection or high protein intake and occur on a background of developmental delay and failure to thrive. Children with arginosuccinic aciduria may develop brittle hair with tricorrhexis nodosa. Arginase deficiency is the exception; encephalopathy is rare and presentation is most often with progressive spastic diplegia, seizures, and learning difficulties. Thus it is easily misdiagnosed as cerebral palsy.
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Table 16.5 Investigating Urea Cycle Disorders Disorder
Plasma Ammonia
Plasma Citrulline
Urinary Orotic Acid
N-Acetylglutamate synthetase deficiency CPS OTC Citrullinemia Arginosuccinic aciduria Arginase deficiency
Elevated
Absent/trace
Present
Elevated Elevated Elevated Elevated May be normal
Absent/trace Absent/trace Markedly elevated Moderately elevated Normal/reduced
Absent Present Present Present Present
Investigations. In all these disorders the major biochemical finding is that of hyperammonemia with respiratory alkalosis and raised plasma glutamine. In arginase deficiency ammonia levels may be normal or only modestly elevated but serum arginine levels are high. Levels of plasma citrulline and urine orotic acid further help discriminate between the different urea cycle disorders and are detailed in Table 16.5. Enzyme activity is generally measured from liver biopsy or in the case of arginase deficiency from red and white cells. Where possible DNA confirmation should be obtained to establish carrier status (particularly important in OTC deficiency) and allow accurate prenatal testing if available. Other fetal investigations may include amino acid measurement in amniotic fluid and liver biopsy. Neuropathology and Genetics. Hyperammonemia results in astrocytic swelling and cerebral edema. Later, Alzheimer II astrocytes and non-specific atrophy and gliosis are characteristic. In cases of OTC deficiency severe cystic destruction of the cerebral hemispheres may result in ulegyria. All the urea cycle disorders are autosomal recessive with the exception of OTC deficiency, which is X-linked. The OTC nuclear gene is located at Xp21.1 and more than 230 mutations have been described to date, most being private to each family. Mutations can only be detected in around 78% of cases of biochemically confirmed OTC deficiency but there is a high de novo mutation rate in this condition. Whilst female heterozygotes may be asymptomatic, they can be significantly affected; this is probably largely due to the degree of X activation. Treatment. Protein restriction with arginine supplementation (except in the case of arginase deficiency) reduces the nitrogen load. Nitrogen excretion is promoted by sodium benzoate and phenylbutarate. Neurological outcome is closely related to ammonia levels but, despite these measures, is generally poor. The exception is in arginase deficiency, where, with early and strict adherence to treatment, outcome may be more favorable.
CARBOHYDRATE DISORDERS These may present with acute encephalopathy and liver failure and include: Galactosemia Hereditary fructose intolerance.
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LACTIC ACIDOSIS This is extremely variable in presentation, with multisystem and myopathic forms. The mitochondrial disorders are discussed in Chapter 14. The common causes of lactic acidosis include: Respiratory-chain disorders Pyruvate dehydrogenase deficiency Pyruvate carboxlyase deficiency.
MITOCHONDRIAL FATTY ACID B OXIDATION DEFECTS Decompensation occurs when stressed, producing encephalopathy and hypoglycemia. Diseases encompass: Carnitine defects AcylCoA deficiencies.
DISORDERS OF VITAMIN METABOLISM A number of autosomal recessive disorders of vitamin metabolism with a neurological presentation can occur and these are summarized in Table 16.6.
DEFECTS OF INTRACELLULAR CHOLESTEROL METABOLISM Smith-Lemli-Opitz Syndrome (SLOS; OMIM 270400) Mutations of the d7-sterol reductase gene disrupt the final step in cholesterol biosynthesis, resulting in low plasma cholesterol and high levels of its direct precursor, 7-dehydrocholesterol, which has a teratogenic effect. Clinical Features Disease incidence is around 1 in 30,000 live births. The affected neonate typically shows severe psychomotor retardation with characteristic dysmorphic features, including postaxial polydactyly, preaxial syndactyly, and genital anomalies. Microcephaly and developmental brain abnormalities are often seen on neuroimaging. Investigations High plasma levels of 7-dehydrocholesterol are a consistent finding. Plasma cholesterol is usually low but can be normal. Urinary bile acid excretion is abnormal. The most common abnormalities seen on neuroimaging are of callosal anomalies (hypoplasia or agenesis), cerebellar hypoplasia, or
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Table 16.6 Inherited Vitamin Defects Causing Neurological Disease Enzyme Defect
Neurological Signs
Other Features
Diagnostic Tests
Treatment
Multiple carboxylase deficiency (253260)
Holocarboxylase synthetase; biotinidase
Encephalopathy, seizures, ataxia, basal ganglia calcification, deafness, optic atrophy
Skin rash, alopecia
Lactic acidosis and ketoacidosis; organic aciduria; serum biotinidase; holocarboxylase assay in fibroblasts
High-dose biotin
a) Intrinsic factor deficiency (261000); R binding protein deficiency) b) Transcobalamin II deficiency (275350)
a) and b) With developmental delay and subacute combined degeneration
a) and b) Megaloblastic anemia; failure to thrive
c) As above with features of methylmalonic aciduria
c) Macrocytic anemia
a) and b) Low serum cobalamin, methylmalonic aciduria, homocystinuria, Shilling test, specific assays c) Methylmalonic aciduria +/ homocystinuria
Vitamin B12 a) Absorption defect b) Transport defect
c) Intracellular metabolism
Folate a) Malabsorption
a) Protein carrier defect
b) Homocystinuria variant
b) Tetrahydrofolate reductase deficiency
Pyridoxine dependency Vitamin E, ataxia with vitamin E deficiency (277460) Hartnup disease (234500)
Unknown ? selective or secondary malabsorption AA transport defect
a) Seizures, developmental delay, ataxia, cerebral calcification b) Seizures, microcephaly, developmental delay, psychosis Early seizures
a) Macrocytic anemia and failure to thrive
a) Low folate, homocystinuria
b) Thrombosis
b) Hypomethioninemia, homocystinuria
Peripheral neuropathy, ataxia, myopathy May be absent; ataxia, psychosis
Retinopathy
Eczema
Trial of pyridoxine (EEG monitoring) Vitamin E levels
Aminoaciduria; trial of nicotinamide
Trial of cobalamin for b) and c) betaine with carnitine and folate supplementation
Folate supplementation
Pyridoxine Vitamin E supplementation
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Inborn Errors
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holoprosencephaly. High levels of 7-dehydrocholesterol in amniotic fluid allow prenatal diagnosis. Neuropathology and Genetics In addition to the gross cerebral developmental anomalies, neuronal loss and heterotopias may be seen. There is often widespread demyelination seen both centrally and peripherally. The condition is autosomal recessive and due to mutations in the d7-sterol reductase gene, located at 7q32. There is variable mutation frequencies within different ethnic populations, with over 91 mutations described to date. Treatment To date, trials of treatment with cholesterol supplementation have been ineffective.
Niemann-Pick Type C (OMIM 257220) In contrast to Niemann-Pick types A and B, reduced sphingomyelinase activity can only be demonstrated from fibroblast culture. Defective intracellular esterification leads to the accumulation of free cholesterol. Clinical Features Disease incidence is around 1 in 150,000. Some cases present antenatally with fetal hydrops and up to 50% will present in the neonatal period with prolonged but selflimiting cholestatic jaundice. Neurological features ensue but vary in time of onset from infancy to late adolescence. Psychomotor regression is seen with ataxia and spasticity. Seizures and cataplexy may also occur. A supranuclear vertical gaze palsy is a hallmark of this disease. Death is in the second to third decade. Investigations The diagnosis is suggested by the presence of foam cells and sea-blue histiocytes in bone marrow and inclusions in skin biopsy. It is confirmed by demonstrating lipid trafficking defects in cultured fibroblasts and this should be followed by genotyping where possible. Prenatal testing of cultured amniocytes or DNA can be offered. Neuropathology and Genetics Lipid storage (especially sphingolipid and unesterified cholesterol) is found in liver and spleen. In the brain, glycolipid storage predominates, often with some decrease in myelin white matter. The condition is inherited as an autosomal recessive trait. Two causative genes are recognized; NPC1 on 18q11 accounts for 95% of cases and NPC2 on 14q24.3 the remaining 5%. The two genotypes are not distinguishable biochemically, both are involved in the intracellular
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trafficking of lipids but their precise functions are still not fully understood. Over 70 mutations are recognized to date. Treatment Established treatment remains symptomatic. Clinical trials of cholesterol reduction have been disappointing. More recent interest has focused on the role of gangliosides in disease pathogenesis and clinical trials of substrate depletion are currently under way with OGT-918.
Wolman Disease and Cholesterol Ester Storage Disorder (OMIM 278000) These both result from deficiency of lysosomal acid lipase which leads to the accumulation of cholesterol esters and triglycerides. CNS involvement is only seen in Wolman disease which has an early presentation. Hepatosplenomegaly, acanthocytosis and adrenal calcification are particular features of this disease.
Mevalonic Aciduria (OMIM 610377) A rare multisystem disorder of variable severity: mevalonic acid is raised and mevalonate kinase activity is reduced in cultured fibroblasts. It is associated with progressive cerebellar atrophy.
DISORDERS OF COPPER METABOLISM Wilson’s Disease See Chapter 8
Menkes Disease (OMIM 309400) A rare X-linked disease with an incidence of around 1 in 250,000 live births. Defects in a copper-transporting ATPase results in low serum copper levels with deficiency in liver and brain. There is secondary deficit of several enzymes including cytochrome c oxidase and lysine oxidase, which accounts for the bone and connective tissue and arterial abnormalities seen in this condition. Excessive copper accumulates in fibroblasts, intestinal mucosa, and renal tissues. Clinical Features Affected infants generally have a characteristic cherubic appearance with sparse, brittle hair. Hypothermia and failure to thrive are early features soon followed by resistant seizures with profound regression and hypotonia. Mean age of death is 20 months.
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Investigations Diagnosis is made from finding low serum copper and ceruloplasmin outside the neonatal period (normal neonatal levels are low so interpretation is difficult). There is increased copper uptake in cultured fibroblasts. Microscopic examination of hair may demonstrate pili torti or tricorrhexis nodosa. Skeletal survey often shows osteoporosis, vertebral scalloping, and multiple wormian bones. Neuroimaging may show abnormal intracranial arterial tortuoisity with diffuse atrophy and subdural effusion. Genetics This is an X-linked disease and the gene is located at Xq13.3 coding for a copper-transporting ATPase. A spectrum of mutations result in defective copper transport into cellular organelles. Treatment This is symptomatic. Correction of serum copper levels fails to halt neurological progression.
DISORDERS OF PURINE METABOLISM Lesch-Nyhan Syndrome See Chapter 8
MISCELLANEOUS HETERODEGENERATIVE DISORDERS Leukodystrophies See Chapter 7
Neuronal Ceroid Lipofuscinoses (NCL or Batten Disease) These disorders are now recognized as lysosomal storage disorders in which storage material accumulates in multiple tissues with cerebral cortex disproportionately affected. Unlike other lysosomal disorders clinical manifestations outside the CNS have not been reported. Their biochemical characterization is still incomplete. Eight subtypes are described, with the hypothesis that eight separate genes were involved (NCL18). The most common subtypes are: Infantile-onset (NCL1; OMIM 256730); this is rare outside Finland Classic late infantile (NCL2; OMIM 204500)
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Juvenile-onset (NCL3; OMIM 204200) Adult (Kuf) (NCL4; OMIM 204300). Rare variants are recognized:
Finnish variant late infantile (NCL5; OMIM (256731) Variant/atypical late infantile (NCL6; OMIM 601780) Turkish variant late infantile (NCL7; OMIM 610951) Northern epilepsy (NCL8; OMIM 600143).
Clinical Features The overall incidence of NCL is around 1 in 100,000 births but is around 10-fold higher in the Scandinavian population. NCL2 is the most common subtype worldwide, constituting around half the cases. In Finland, NCL1 is the most common. These different subtypes are distinguished by the age of onset, disease progression, and the pathology of the storage material. These distinguishing features are summarized in the Table 16.7 along with the genetic details. Genetics All NCL are autosomal recessive. With the exception of NCL7 and NCL4 the genes have now been cloned. There is evidence that some cases of NCL7 and NCL8 share allelic mutations at the NCL8 site at 8p23. Only the gene products for NCL1 and NCL2 have been fully characterized and appear to be involved in the Table 16.7 Neuronal Ceroid Lipofuscinoses Infantile
Classical Late Infantile
Late Infantile Variants
Juvenile
Adult
18 months to 4 years Regression, seizures
57 years
47 years
>3 years
Ataxia, visual failure, regression
Behavioral/ Visual failure (can be the cognitive sole feature for years) Slow regression Extrapyramidal signs, facial dyskinesias Death 1030 yr Prolonged Lost Normal Vacuolated Fingerprints Granular
Age at onset
818 months
Early clinical features
Autism, regression
Late clinical features
Microcephaly
Retinitis pigmentosa
Seizures
Duration VEP/ERG Lymphocytes Cytosome type
Death <5 yr Lost
Death 515 yr Giant/lost
Death 1015 yr Giant/lost
Granular
Curvilinear
Gene, product and location
CLN1, palmitoylprotein thioesterase, 11p32
Fingerprints, less curvilinear CLN2, tripeptidyl CLN5, ??, 13q21-32 peptidase1, CLN6, 15q21-23 11p15
CLN3, battinin (438 AA residue protein), 16p11-12
CLN4, ??
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lysosomal degradation of subunit c of mitochondrial ATP synthase; the others encode membrane proteins of unknown function. In around 70% of cases mutations can be identified, with over 80 described to date in NCL1, NCL2, and NCL3. Prenatal diagnosis is available where the genetic mutation has been identified and in NCL1 chorionic villi show granular inclusions. Treatment Treatment is symptomatic only.
Infantile Neuraxonal Dystrophy (Seitelberger Disease; OMIM 256600) Clinical Features Classic presentation is in infancy (mean age 15 months) with psychomotor regression, truncal hypotonia with peripheral spasticity and areflexia. The majority develop optic atrophy with nystagmus. Death is in late childhood. A late infantile or juvenile form is sometimes seen with progressive gait disturbance and myoclonic epilepsy. This is probably a different disease. Investigations Biochemical screens are normal. Neuroimaging may show cerebellar hypoplasia. Neurophysiology is the most useful investigation; after 2 years of age there are characteristic EEG changes with persistent fast activity on a slow background. Partial denervation may be seen on EMG (secondary to anterior horn cell loss) whilst nerve conduction studies are usually normal. Visual evoked potentials may be abnormal but the electroretinogram is preserved. The hallmark of the disease is the presence of spheroid axonal swelling in central, peripheral and autonomous nervous tissue. Spheroids may also be found in biopsy of conjunctiva or skin, however diffuse axonal dystrophy is also seen in Hallervorden-Spatz disease and a-N-acetylgalactosaminidase deficiency (Schindler disease) so this should not be the sole diagnostic criteria. Genetics Sporadic and autosomal recessive cases are seen but as yet there is no specific chromosome linkage and therefore genetic testing is not available. Treatment Treatment is supportive only.
Rett Syndrome (RS; OMIM 312750) It is argued that RS is probably a developmental rather than a degenerative disorder. Once thought exclusive to girls, it is now recognized due to mutation
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Table 16.8 Clinical Stages of Rett Syndrome Stage
Clinical Features
1. Early onset deceleration (618 months) 2. Rapid destructive stage (13 years)
Developmental arrest; decelerating head growth
3. Pseudostationary stage (210 years) 4. Late motor deceleration (>10 years)
Developmental regression with irritability; autistic-like features (transient); loss of language; hand stereotypies with loss of purposeful movements (persistent) Severe learning difficulties; seizures; ataxia/apraxia; progressive scoliosis (65%); respiratory disturbance (hyperventilation/bruxism/apnea) Decreasing mobility; upper and lower motoneuron signs; trophic changes of hands and feet; reduced seizures
of the methyl-CpG binding protein gene (MECP2). Recent identification of the gene has allowed reappraisal of the disease and males who fail to meet the classic clinical criteria are now being diagnosed. Clinical Features The prevalence of RS is estimated between 1 in 10,000 and 1 in 15,000 girls. A clinical diagnosis of classic or variant RS can be made from internationally agreed ‘‘necessary’’ and ‘‘supportive’’ diagnostic criteria. Clinical manifestations are rarely apparent before 6 months of age and head circumference is normal at birth. Loss of purposeful hand use and the emergence of intense persistent stereotypies are characteristic of RS. Around 70% of patients never acquire independent ambulation. Survival may be for decades. Four distinct disease stages of the disease are described in Table 16.8. Investigations Diagnosis is suggested by the clinical picture. The EEG may be characteristic in stage 3 and even before the onset of seizures it shows a paroxysmal spike wave pattern posteriorly and during sleep. No consistent neuroimaging abnormalities are reported. The diagnosis is generally confirmed by DNA testing. Genetics The MECP2 gene is sited at Xq28 and encodes a methyl-CpG binding protein. Multiple mutations have been described to date. Phenotypicgenotypic correlation is generally poor and the severity of the disease is probably related to the pattern of skewing of X inactivation. Of girls fulfilling the agreed diagnostic criteria, 8090% will show MECP2 mutations. A small proportion of RS patients who give an atypical history of early-onset seizures have been shown to carry mutations of the cyclin-dependent kinase-like 5 gene (CDKL5). Both genes are likely to regulate the dynamic expression of neuronal genes at specific sites and at certain critical stages of development. The disease is almost always sporadic.
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Treatment Treatment is supportive.
BIBLIOGRAPHY Aicardi J (1998). Diseases of the Nervous System in Childhood. 2nd ed. Clinics in Developmental Medicine. Mac Keith Press, London. Golden JA & Harding BN (Eds.) (2004). Developmental Neuropathology. International Society of Neuropathology. Lyon G, Adams RD & Kolony EH (Eds.) (1996). Neurology of Hereditary Metabolic Diseases of Children. 2nd ed. McGraw-Hill, New York. Scriver CR, Beaudet AL, Valle D, Sly WS, Childs B, Kinzler KW & Vogelstien B (Eds.) (2001). The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York.
Chapter 17 Neurological Aspects of Chromosomal Disorders Andrea H. Nemeth
INTRODUCTION This chapter addresses neurological disorders caused by chromosomal abnormalities. These may be structural or numerical. The commonest numerical disorders of autosomes resulting in liveborn children are Down syndrome (trisomy 21), Edward syndrome (trisomy 18), and Patau syndrome (trisomy 13). Numerical disorders are usually caused by non-disjunction at meiosis leading to an additional chromosome derived from one of the parents. Most numerical chromosomal disorders affecting the autosomes are lethal or cause severe phenotypes compatible with only short lifespans, often associated with severe mental retardation. In contrast, numerical abnormalities of sex chromosomes may be associated with comparatively mild phenotypes, the commonest being Turner syndrome (XO), Klinefelter syndrome (XXY), and the XYY syndrome. Structural disorders are rearrangements that may be visible at the light microscope level (cytogenetically visible) or may be more subtle (submicroscopic or ‘‘cryptic’’ rearrangements). The commonest structural abnormality is a balanced translocation, in which all or part of a chromosome is physically attached to another. In the ‘‘balanced’’ carrier there is no net loss or gain of genetic information and it is not usually associated with any phenotype (unless the breakpoint disrupts a gene) but at meiosis the chromosomes are unable to segregate normally and the resulting conceptus may gain or lose genetic information. Many of these are incompatible with life and cause recurrent miscarriage but a significant number will proceed to term with a number of mental and physical abnormalities. Other structural abnormalities include duplications, insertions, and deletions (see Chapter 1). Visible deletions involve large regions of chromosomes and numerous genes and the phenotype is caused by loss of dosage-sensitive genes. These monosomies are nearly always associated with severe physical abnormalities and mental retardation. Submicroscopic deletions are only detectable using more sophisticated laboratory techniques, such as FISH analysis (fluorescence in situ hybridization). Newer techniques such as comparative genome hybridization are 310
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likely to allow a genetic diagnosis in many children with previously undiagnosed mental and physical handicap. When several adjacent genes are involved this is known as a contiguous gene deletion syndrome. Patients often have dysmorphic features, developmental delay, behavioral abnormalities and growth defects (‘‘chromosomal phenotype’’). They are usually diagnosed in childhood and the relevant neurological features managed by a pediatrician/pediatric neurologist.
Genetic Counseling Clinical genetic advice and discussion with the laboratory are required to determine the recurrence risk to parents of an affected child. Many affected individuals do not reproduce but if this is a possibility then recurrence risk will need to be determined in each case. Counseling for specific conditions is discussed below. Both numerical and structural abnormalities can be present in mosaic form, i.e., the individual has some cells with a normal chromosome complement and some have the abnormal complement. This may lead to an ameliorated phenotype. Fragile X syndrome is a special case in which the abnormality is microscopically visible only under certain laboratory conditions and is now usually investigated by molecular genetic techniques. In all cases of chromosomal abnormality specialist clinical genetic advice is recommended.
NUMERICAL ABNORMALITIES OF AUTOSOMES The commonest are Down syndrome, Edward syndrome, and Patau syndrome. These are summarized in Table 17.1.
Down Syndrome (Trisomy 21; OMIM 190685) This is the commonest numerical abnormality of autosomes, and is strongly associated with increasing maternal age. Two percent result from a Robertsonian translocation formed by fusion of whole long arms of two acrocentric chromosomes (which have centromeres at the end), usually 21/21 or 14/21. Clinical Features (Table 17.1) The main clinical features are a distinctive dysmorphic facial appearance with a flat facial profile and upslanting palpebral fissures, developmental delay (mean IQ in children and young adults with Down syndrome is 4548) and cardiac defects in 4050%. Genetic Advice Conventional karotyping is essential to confirm the diagnosis and determine the genetic basis for the phenotype. Parental karotyping is not indicated for standard trisomy 21 but is required in cases caused by translocations or other rearrangements. If the phenotype is compatible with Down syndrome but the karyotype is
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Table 17.1 Common Numerical Chromosome Abnormalities Syndrome Down syndrome
Edward syndrome
Patau syndrome
Clinical Features Antenatal: increased nuchal thickness, detected on serum screening, chorionic villus sampling (CVS), or amniocentesis, abnormal fetal ultrasound (structural abnormalities common) Postnatal: dysmorphic apperance: flat facial profile, upslanting palpebral fissures, inner epicanthic folds, single palmar creases, sandal gap between hallux and second toe, and growth retardation Neurological features: hypotonia, developmental delay/learning disability (IQ usually in range 2550), seizures (uncommon), variety of cervical spine abnormalities causing vertebral instability (investigate any child with changes in bladder or bowel function, neck posturing, or loss of ambulatory skills particularly by imaging of cervical spine), dementia (virtually all patients over age of 30 develop neuropathological features of Alzheimer disease, about one-third of patients develop clinical signs of dementia), parkinsonism Ophthalmic abnormalities including: speckling of iris (Brushfield spots), fine lens opacities, refractive errors, nystagmus, strabismus, cataracts in adults, keratoconus Cardiac anomalies: usually structural (4050%), e.g., ventriculo-septal defect, patent ductus arteriosus, mitral/tricuspid valve prolapse, aortic regurgitation Other significant clinical problems: hearing loss (varying types), leukemia (acute lymphocytic) (2%), thyroid disorders, sleep-related upper airway obstruction Antenatal: increased nuchal thickness, detected on serum screening, CVS, or amniocentesis, abnormal fetal ultrasound (intrauterine growth retardation, polyhydramnios) Postnatal: growth retardation, dysmorphic features, congenital anomalies (90% have congenital heart disease), developmental delay (severe to profound), short life expectancy Antenatal: increased nuchal thickness, detected on serum screening, abnormal fetal ultrasound (high incidence of structural malformations), CVS, or amniocentesis, high rate of spontaneous fetal loss Postnatal: growth retardation, holoprosencephaly, microphthalmia, anophthalmia, cleft lip/palate, congenital heart disease, postaxial polydactyly, omphalocele, renal malformation, severe profound mental retardation
Genetic Abnormality and Recurrence Risks 95% caused by non-disjunction leading to trisomy 21; 2% caused by Robertsonian translocation, especially 14:21 or 21:21: 2% are mosaics; 1% rare chromosome rearrangements such as trisomy 21q22 Recurrence risks to siblings: cases caused by parental translocations have a high recurrence risk and parents should be referred for genetic counseling The recurrence risk for simple sporadic trisomy 21 in women up to age 39 is approximately 1% and in women 40 years and older is approximately twice the age-related risk. The risk increases to approximately 10% if two or more children are affected (presumed gonadal mosaicism). Prenatal diagnosis is usually offered for subsequent pregnancies
94% have trisomy 18, remainder have trisomy 18 mosaicism or partial 18q trisomy. Strong maternal age effect (as for trisomy 21) Recurrence risk to siblings 1/200
90% have trisomy 13, 510% caused by translocation usually unbalanced Robertsonian 13:14. Small proportion are mosaic Recurrence risks to siblings: low for sporadic cases, 1% in carriers of Robertsonian translocation
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normal, then examination of peripheral blood cells, or fibroblasts from a skin biopsy, is required to look for mosaicism. Echocardiogram and cardiac evaluation is required in all diagnosed cases and follow-up by a developmental pediatrician recommended. Recurrence risks are indicated in Table 17.1.
NUMERICAL ABNORMALITIES OF SEX CHROMOSOMES Klinefelter Syndrome (XXY) Males with Klinefelter syndrome usually present in adolescence with failure to develop secondary sexual characteristics, although some are detected during routine antenatal screening. As adults they tend to be tall and may have gynecomastia, and there is a small risk of breast cancer, although currently routine screening has not been recommended. Boys enter puberty normally, but by midpuberty the testes begin to involute, and they develop hypergonadotrophic hypogonadism with decreased testosterone production and elevated LH/FSH. Most patients are infertile, although some may produce a few sperm and intracytoplasmic sperm injection (ICSI) offers some patients the opportunity to father their own children. Early diagnosis (as soon as delayed puberty is detected) is therefore essential because of progressive hyalinization of the testes. In general IQ is normal, but there are some reports of specific difficulties in reading and writing and mild behavioral abnormalities. Scoliosis can occur during adolescence, and sometimes there is also mild to moderate ataxia. The recurrence risk to parents of a child with Klinefelter syndrome is small, and partly related to maternal age. If a man with Klinefelter syndrome does father a child then prenatal diagnosis should be offered because of an increased risk of aneuploidy.
XYY Syndrome This is usually detected during routine antenatal screening or when chromosome analysis is performed because of developmental delay. Most cases are probably never diagnosed. Boys with XYY tend to be taller and may have a lower IQ compared with siblings. There are some reports of relative weakness with poor fine motor coordination, a fine intention tremor and speech delay. Early reports suggesting that XYY males were over-represented in institutions for criminal behavior have not been confirmed by longitudinal studies. Patients with XYY are normally fertile and there is no increase in aneuploidy.
STRUCTURAL ABNORMALITIES Fragile X Syndrome (OMIM 300624) Fragile X syndrome is a significant cause of inherited learning disability in boys, although girls may also be affected. The name is derived from the
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Table 17.2 Clinical Phenotypes and CGG Repeat Sizes at the FRAXA Locus Normal individuals Intermediate allele Premutation carrier females and ‘‘normal transmitting’’ males Affected individuals and full-mutation carrier females
<45 repeats 4554 repeats 55200 repeats >200 repeats
observation that the mental retardation was found to segregate with a constriction at the end of the X chromosome seen under certain laboratory conditions. The cause of this constriction was found to be an expanded CGG repeat in the 50 region of a gene known as FRAXA located in Xq27.3. The genetic basis is complex and specialist advice is vital. In normal individuals the number of CGG repeats is <45 and these repeats are stable during meiosis (see Table 17.2). As the repeat length increases, so does the instability and tendency to increase in size (particularly during female meiosis), as well as the risk of a clinical phenotype. The consequences of large expansions are to methylate the gene so that no FMR1 protein is produced. In males the result is always mental retardation, but in females (who have two X chromosomes) the clinical phenotype depends, at least in part, on the degree of X inactivation of the mutant chromosome. Clinical Features Males with the Full Mutation (Fragile X Syndrome). Boys have developmental delay with mild hypotonia and motor delay. They may have marked speech disturbance with characteristic impairments of receptive and expressive vocabulary. Behavioral problems are common, particularly overactivity and inattention, and autistic features such as gaze-avoidance and difficulty with social interactions. The average IQ is 40. Other clinical features include: a long face, prominent ears, joint hypermobility, macro-orchidism, and mitral valve prolapse. About one-fifth of patients have epilepsy, which sometimes resembles benign focal epilepsy of childhood. Seizures are usually well controlled with anticonvulsants. Females with the Full Mutation. Up to 50% of females with the full mutation will have learning and behavioral difficulties that resemble those found in affected males. They may also occasionally have epilepsy. Premutation Carriers. Occasionally children with alleles in the premutation range are found to have learning difficulties. This may relate to fragile X, but other causes should also be sought. Genetic advice should be sought when a premutation is identified because of the offspring risk. If it is the index case of a family then cascade screening in the family may be offered. ADULT MALES. There is increasing evidence that males with premutations (‘‘normal transmitting males’’) are at risk of a progressive neurological
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syndrome called FXTAS (fragile X tremor ataxia syndrome; see Chapter 6). The features include cerebellar ataxia, tremor, parkinsonism, autonomic dysfunction (including impotence) and cognitive decline, usually developing after the age of 50. MRI findings include decreased T1 and increased T2 signal intensity in the cerebellar white matter and cerebellar cortical atrophy. It has been suggested that while full-mutation carriers have no FRAXA mRNA and no FMR1 protein, in premutation carriers there is increased mRNA which leads to reduced FMR1 protein (by negative feedback) leading to the neurological phenotype. The prevalence in premutation males is unknown although a recent report suggests that by age 80, 75% of premutation males will develop some of the clinical features of FXTAS. In adult neurology clinics patients with undiagnosed progressive neurological syndromes should have a detailed family history taken to look for mental retardation and should be considered for fragile X testing. Genetic counseling is required if such a mutation is identified to address the risks to other family members. ADULT FEMALES. Around 25% of females with a premutation will develop premature ovarian failure (defined as cessation of menses before age 40 years). This has significant reproductive implications for affected individuals and specialist referral is advised. There is increasing evidence that female premutation carriers may also develop a neurodegenerative syndrome. Differential Diagnosis The differential diagnosis includes both non-syndromic and syndromic causes of X-linked mental retardation, shown in Table 17.3. Genetic Advice In females with alleles in the premutation range there is a risk of having a child with the fragile X syndrome which increases with the size of the expanded allele (Table 17.4). Females with intermediate alleles may have children with alleles in the premutation range and the girls may then go on to have children with full expansions. Premutation males (‘‘normal transmitting males’’) usually pass on stable alleles but their daughters may in turn have affected children. Prenatal diagnosis is available but it is difficult to predict the phenotype of females with a full expansion. Cascade screening of adult family members is recommended when the fragile X syndrome is diagnosed. A premutation in a female may be inherited from her mother or father but a full mutation can only be inherited from the mother. Management Children with fragile X syndrome will need assessment by a developmental pediatrician. Some will manage mainstream school with support. Seizures are usually well controlled and may resolve as the child gets older. Females who are found to have premutation alleles need referral to clinical genetics services as well as referral to a fertility clinic.
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Table 17.3 Some Causes of X-Linked Mental Retardation (XLMR) Condition (OMIM) Non-Syndromic FRAXE MR
Non-specific XLMR
Syndromic ARX mutations (Aristaless-related homeobox) gene (300382)
Pelizaeus-Merzbacher disease (312080)
X-linked lissencephaly (300067)
Bilateral periventricular nodular heterotopia (300049) Rett syndrome (312750)
Clinical Features
Gene Locus
Gene
Speech and behavioral problems without dysmorphic features
Xq28
Expanded CCG repeat in FMR2 gene
Xq12
Oligophrenin-1 (OPH1)
X-linked lissencephaly with abnormal genitalia in males X-linked infantile spasms (West syndrome) X-linked mental retardation Partington syndrome (XLMR with dystonia) Rotatory movements of the head and eyes, spasticity, cerebellar ataxia, dementia, and parkinsonism, 3 types based on age of onset; carrier females may be affected; hypomyelination on MRI
Xp22.1
ARX
Xq22
Profound MR and seizures; males usually have anterior lissencephaly and females have subcortical band heterotopia Lethal in males, focal epilepsy in female carriers
Xq22.3
Proteolipid protein gene (PLP1) Some cases caused by a duplication within the gene which can be detected using FISH analysis Doublecortin (DCX)
Xq28
Filamin A (FLNA)
Classically normal early development in girls, with subsequent neurodevelopmental regression, stereotypic hand movements, acquired microcephaly, ultimately severe dementia, autism, jerky truncal ataxia; in males may be associated with neonatal encephalopathy
Xq28
MECP2
Genetically very heterogeneous; many genes still not identified Some patients have mutations in OPH1 and some with OPH1 mutations have ataxia with hypoplasia of cerebellar vermis
Continued
Neurological Aspects of Chromosomal Disorders
Table 17.3 Some Causes of X-Linked Mental Retardation (XLMR)—cont’d Condition (OMIM)
Clinical Features
Gene Locus
Gene
Renpenning syndrome (309500) Borjeson-ForssmanLehmann syndrome (301900) Simpson-Golabi-Behmel (312870)
Severe MR, microcephaly, short stature, small testes Short stature, microcephaly, obesity, hypogonadism, dysmorphic facial features Prenatal and postnatal overgrowth, coarse facial features, macrocephaly, consider surveillance for malignancy (Wilms tumor, neuroblastoma, and others described) Alpha-thalassemia without molecular abnormalities of globin gene, severe mental retardation, characteristic dysmorphic face, abnormal genitalia, HbH inclusions in erythrocytes stained with cresyl blue Severe MR, dysmorphic face, short stature, pectus deformity, kyphosis/scoliosis, mitral valve dysfunction, sensorineural hearing loss Agenesis of corpus callosum, macrocephaly, hypotonia, constipation Hypertelorism, laryngeal clefts causing swallowing problems, hypospadias
Xp11.2-11.4
PQBP1
Xq26.3
PHF6
Xq26
Glypican 3
Xq13
ATRX
Xp22.2-p22.1
Rsk-2 gene
Xq12-21.3 (in some families) Xp22 (autosomal dominant form on 22q)
Not known
X-linked alphathalassemia mental retardation syndrome (301040)
Coffin-Lowry (303600)
Opitz FG (305450)
OpitzG or G/BBB (300000)
MID1
Table 17.4 Risk of Maternal Premutation Expanding to Full Mutation Maternal CGG Premutation
Risk of Expansion to >200 Repeats (%)
5559 6069 7079 8089 9099 100139 >140
3.7 5.3 31.1 57.8 80.1 >94 100
(Adapted from Nolin SL, Brown HT, Glicksman A, et al. (2003). Expansion of fragile X CGG repeat in females with permutation or intermediate alleles. Am J Hum Genet, 72, 454464.)
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Table 17.5 Some Microdeletion Syndromes Associated with a Neurological Phenotype Condition (OMIM)
Clinical Features
Chromosomal Abnormality
Duchenne muscular dystrophy (310200)
May be part of contiguous gene deletion syndrome causing other disorders including congenital adrenal hypoplasia, chronic granulomatous disease, retinitis pigmentosa, and the McLeod phenotype (neuroacanthocytosis) Recurrent painless focal neuropathies, following minor trauma or compression to peripheral nerves. Symptoms improve within days, weeks or months. Persistent neurologic deficits are uncommon. Inherited as autosomal dominant with a high penetrance but variable expression ILS is characterized by lissencephaly and minimal or no other dysmorphic features. MDS is associated with lissencephaly, significant facial dysmorphism, and, occasionally, other congenital anomalies, such as renal, gastrointestinal, and cardiac defects. Patients with lissencephaly usually have mental retardation, intractable epilepsy, spasticity, and reduced longevity Moderate to profound mental retardation, delay/absence of expressive speech, hypotonia, normal to accelerated growth, and mild dysmorphic features Severe learning difficulties, ataxia, a seizure disorder with a characteristic EEG, subtle dysmorphic facial features, and a happy, sociable disposition
Deletion of varying parts of Xp21
Hereditary neuropathy with liability to pressure palsies (HNPP) (162500)
Miller-Dieker syndrome (MDS)/isolated lissencephaly sequence (ILS) (247200)
22q13 deletion syndrome (606232)
Angelman syndrome (105830)
Wolf-Hirschhorn syndrome (194190)
Developmental delay, microcephaly, seizures, craniofacial anomalies, mental retardation, cardiac defects, ophthalmic defects
1.5-megabase deletion on chromosome 17p11.2-12.
17p13.3
22q13 deletion
Variety of genetic abnormalities involving chromosome 15q11-13 which is subject to genomic imprinting. Include maternal deletion, paternal uniparental disomy, imprinting defects, and point mutations or small deletions within the UBE3A gene At least 4p16.3
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Other Chromosomal Abnormalities Some well-recognized neurological conditions are associated with small chromosomal deletions (microdeletions). These are documented in Table 17.5.
CONCLUSIONS Chromosomal abnormalities are a heterogenous and complex cause of neurological disorders in children and adults. Technologies to detect genetic abnormalities associated with these phenotypes are rapidly changing and evolving, and specialist genetic advice is recommended for all suspected cases, both for diagnosis and management, including reproductive risks.
BIBLIOGRAPHY www.fragilex.org.uk www.fragilex.org Nolin SL, Brown HT, Glicksman A, et al. (2003). Expansion of fragile X CGG repeat in females with permutation or intermediate alleles, Am J Hum Genet, 72, 454464.
Index
Page numbers for figures have suffix f, those for tables have suffix t, those for boxes have suffix b
A AAA proteins, 168 acid maltase deficiency, 240–241 ADNFL (autosomal dominant nocturnal frontal lobe epilepsy), 44 ADPEAF (autosomal dominant partial epilepsy with auditory features), 45 adrenoleukodystrophy (ALD), 97–99 neonatal, 290 X-linked, 291 adrenomyeloneuropathy (AMN), 97–99 age-related presentation (childhood disorders) infantile, 278 childhood, 279 neonatal, 277, 278t ALD, see adrenoleukodystrophy ALS (amyotrophic lateral sclerosis), 158–163 Alstrom syndrome, 68 Alzheimer’s disease, 26–30 clinical features, 26 genetics, 27 prognisis, 27 treatment, 28 amino acid catabolism disorders, 291–299 branched-chain, 295 isovaleric acidemia, 296 maple syrup urine disease, 295 methylmalonic aciduria, 296 non-ketotic hyperglycinemia, 296–297 phenylketonuria, 292–293 proprionic acidemia, 296 sulfite oxidase deficiency, 297 tetrahydrobiopterin deficiency, 293 tyrosinemia, 294–295 AMN (adrenomyeloneuropathy), 97–99 amyloidopathies, 24, 26–30 familial British dementias, 30 familial Danish dementias, 30
amyloidopathies (Continued) hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), 29–30 see also Alzheimer’s disease -amyloid precursor protein (APP) Alzheimer’s disease, 27–28 HCHWA-D, 30 amyotrophic lateral sclerosis (ALS), 158–163 ALS1, 161 clinical feature, 159 familial ALS (FALS), 159 genetic advice, 163 genetics, 160–162 monogenic forms, 160t primary lateral sclerosis, 174 sporadic ALS, 162 Andersen syndrome, 234–235 anticipation, 8 anticodons, 3 apolipoprotein E (ApoE) Alzheimer’s disease, 27 HCHWA-D, 29 APP, see -amyloid precursor protein ataxias, 75 ataxia telangiectasia, 85 ataxia with vitamin E deficiency, 84 autosomal dominant, 85–89 autosomal recessive, 79–85 congenital, 78–79t differential diagnosis, 78t early-onset, 83t episodic, 89, 89t investigation, 76–78 metabolic, 77t, 85 sporadic, 90 treatment, 90–91, 91t Unverricht-Lundborg disease, 84 see also autosomal dominant cerebellar ataxias; Friedreich’s ataxia; X-linked ataxias 321
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Austin disease, 95 autosomal dominant cerebellar ataxias (ADCAs), 85–88 classification, 86t clinical features, 86 genetics, 87t autosomal dominant demyelinating CMT (CMT1), 178–183 clinical featues, 180 investigations, 181t genetic counseling, 183 autosomal dominant nocturnal frontal lobe epilepsy (ADNFL), 44 autosomal dominant partial epilepsy with auditory features (ADPEAF), 45 autosomal recessive demyelinating CMT (CMT1 AR), 184 autosomes, 2 numerical abnormalities, 311–313 axonal neuropathies, 176 B Baltic myoclonus, 84 Bardet-Biedl syndrome (BBS), 67–68 basal ganglia, 102 Batten disease, 305–307 BBS (Bardet-Biedl syndrome), 67–68 Becker muscular dystrophy, 208–209, 209f Beevor’s sign, 216b benign familial neonatal convulsions (BFNC), 44 benign rolandic epilepsy, 46 Best disease, 66 BFNC (benign familial neonatal convulsions), 44 Bietti dystrophy, 65 biopsy muscle, 199, 251–252 nerve, 177 blepharospasm, 109 bradykinesia, 120 C CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), 138–141 CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), 142 cafe au lait patches, 265 CAG repeat disorders, 8 see also Huntington’s disease; Kennedy’s disease calpainopathy, 213 Canavan’s disease, 297–298 carbohydrate disorders, 300 carnitine palmitoyltransferase II deficiency, 243–244 carrier testing, 18–19 CDG Ia, 289–290
cell division, 4–5, 4f central core disease, 199–201 centronuclear myopathy, 202 cerebellar disorders, 75–91 ataxias, 76–78 cerebellar dysarthria, 75 cerebral hemorrhage 29–30 cerebral palsy, 176–174 cerebrovascular disease, 137–149 CADASIL, 138–141, 141f CARASIL, 142 clinical features, 138t familial cerebral cavernous malformations (CCM), 142–144 familial hemiplegic migraine, 144–146 familial intracranial berry aneurysm, 147 genetic risk factors, 148 hereditary hemorrhagic telangiectasia, 146 homocysteinuria, 144 Moyamoya disease, 147–148 single-gene disorders, 137–148 see also stroke channelopathies, 229–236 Andersen syndrome, 234–235 ataxias, 87t, 89t epilepsy, 44t genetic classification, 230t hyperkalemic periodic paralysis (hyperPP), 232–233 hypokalemic periodic paralysis (hypoPP), 230–232 malignant hyperthermia, 232, 237 myotonia and cramps, 237t myotonia congenita, 235–236 paramyotonia congenita, 233–234 Charcot-Marie-Tooth diseases (CMT), 177–190, 186f autosomal dominant demyelinating (CMT1), 178–183, 181t autosomal recessive demyelinating (CMT1 AR), 184 Charcot-Marie-Tooth type 2 (CMT2), 184–185 classification, 177 congenital hypomyelinating neuropathies, 184 Dejerine-Sottas disease, 184 familial amyloid polyneuropathies, 190 hereditary brachial plexus neuropathy, 188 hereditary neuropathy with liability to pressure palsies, 185–188 hereditary sensory and autonomic neuropathy, 188–189 X-linked (CMT1X), 183 cherry-red spots, 70 chiasmata, 4 childhood disorders, 276–309 carbohydrate disorders, 300 childhood presentation, 279 clinical manifestations, 276–280 congenital disorders of glycosylation, 289–290 glycoprotein metabolism disorders, 287–289, 288t
INDEX childhood disorders (Continued) infantile neuraxonal dystrophy, 307 infantile presentation, 278–279 investigations, 277–280, 278t lactic acidosis, 301 Lesch-Nyhan syndrome, 131 Menkes disease, 304–305 mucopolysaccharidoses, 284–287 neonatal presentation, 277–278 neuronal ceroid lipofuscinoses, 305–307 peroxisomal disorders, 290–291 sphingolipidoses, 280–284 subcellular organelle disorders, 280–291 Tay Sachs disease, 280–284 urea cycle disorders, 299–300, 300t vitamin metabolism disorders, 302t Wilson’s disease, 126–128 see also amino acid catabolism disorders; cholesterol metabolism defects; leukodystrophies; organic acid catabolism disorders cholesterol metabolism defects mevalonic aciduria, 304 Niemann-Pick type C, 130, 303–304 Smith-Lemli-Opitz syndrome, 301–303 Wolman disease, 304 chorea, 103 choreoacanthocytosis, 132–133 choroideremia, 65 chromosomes, 2 chromosomal disorders, 310–319 Down syndrome, 311–313, 312t Edward syndrome, 312t epilipsy, 43 genetic counseling, 311 Klinefelter syndrome, 313 microdeletion syndromes, 318t numerical disorders, 310, 311–313, 312t, Patau syndrome, 312t structural disorders, 310, 313–319 XYY syndrome, 313 see also fragile X syndrome CJD, see Creutzfeld-Jakob disease clinical hints acid maltase deficiency, 241b adrenoleukodystrophy/adrenomyeloneuropathy, 98b Andersen syndrome, 235b ataxias, diagnosis, 78b childhood-onset cerebellar ataxia, 83b congenital muscular dystrophies, 224b dystonia, 110b epilepsies with Mendelain inheritance, 44b facioscapulohumeral dystrophy (FSHD), 216b hereditary neuropathy with liability to pressure palsies (HNPP), 187b hereditary spastic paraplegia (HSP), 166b
323
clinical hints (Continued) limb girdle muscular dystrophy, 213b lipid myopathies, 243b mitochondrial disease, 246b myotonic dystrophy, 205b neuronal migration defects, 41b oculopharyngeal muscular dystrophy (OPMD), 219b porphyria, 195b retinal degeneration, 50b Sturge-Weber syndrome, 47b X-linked Charcot-Marie-Tooth disease, 183b cloning, clinical application, 9–10 CMT, see Charcot-Marie-Tooth diseases CMT1, see autosomal dominant demyelinating CMT (CMT1) CNS tumors, 261t cobblestone lissencephaly, 226t codons, 2 cone-rod dystrophies (CORD), 67 congenital absence of muscles, 226t congenital disorders of glycosylation (CDG), 289–290 congenital hypomyelinating neuropathies, 184 congenital muscular dystrophies (CMD), 223–225 merosin-deficient, 224–225 non-syndromic, 224t syndromic, 225, 226t congenital myasthenic syndromes (CMS), 226–227, 227t congenital myopathies, 199–204 copper metabolism disorders, 126, 304–305 CORD (cone-rod dystrophies), 67 creatine kinase assay, 198 Creutzfeld-Jakob disease (CJD), 33–37 familial CJD, 34 variant CJD (vCJD), 34 crossover, 4 cryptogenic epilepsy, 46 D deafness-dystonia-optic neuropathy syndrome, 117–118 Dejerine-Sottas disease, 184 dementia, 24–37 assessment, 24–26 classification, 25t clinical features, 26t genetic causes, 36t see also Alzheimer’s disease; amyloidopathies; prion diseases; tauopathies demyelinating neuropathies, 176 dentatorubro-pallidoluysian atrophy, 131 diagnosis, in genetic counseling, 12 diagnostic testing, 18 disease genes mapping, 5–7 clinical application, 9–10 DNA, 2, 4 mitochondrial, 245, 257
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dopa-responsive dystonia (DRD), 114–115 Down syndrome, 311–313, 312t DRD (dopa-responsive dystonia), 114–115 Duchenne muscular dystrophy, 208 dysferlinopathy, 214 dyskinesias, 102 see also paroxysmal dyskinesias dystonias, 109–111 classification, 110, 110t dopa-responsive dystonia, 114–115 dystonia-plus syndromes, 110 investigation, 111, 111t myoclonus dystonia syndrome, 115 primary, 110, 112t primary torsion dystonia, 111–114 rapid-onset dystonia parkinsonism, 115 secondary, 110 see also heredodegenerative disorders dystrophinopathies, 208–212, 208t genetic advice, 211–212 investigations, 210 E Edward syndrome, 312t electroretinogram, 51–52 Emery-Dreifuss muscular dystrophy (EDMD), 221–222 Emery-Dreifuss muscular dystrophy 2 (EDMD2), 222–223 epilepsy, 38–48 autosomal dominant nocturnal frontal lobe epilepsy, 44 autosomal dominant partial epilepsy with auditory features, 45 benign familial neonatal convulsions, 44 chromosomal disorders, 43 classification, 39 cryptogenic, 46 febrile seizures, 46–47 generalized epilepsy with febrile seizures plus, 45 genetic factors, 38 idiopathic, 43–46, 44t neuronal migration disorders, 40–41 progressive myoclonic epilepsies, 42–43, 43t single-gene disorders, 39–43, 39t Sturge-Weber syndrome, 47 symptomatic, 47 essential tremor, 118–119 ethnicity autosomal dominant cerebellar ataxias, 86–88 multiple sclerosis, 99 examination, in genetic counseling, 12–13 exclusion testing, 21 exons, 3 expressivity, 16–17
F Fabry’s disease, 192–193 facioscapulohumeral dystrophy (FSHD), 215–218, 216f clinical features, 215–216 genetic advice, 218 genetics, 217 investigations, 217, 217t familial amyloid polyneuropathies, 190 familial British dementias, 30 familial cerebral cavernous malformations (CCM), 142–144, 143f genetic advice, 144 familial CJD, 34 familial Danish dementias, 30 familial encephalopathy with neuroserpin inclusion bodies (FENIB), 37 familial hemiplegic migraine, 144–146 genetic advice, 146 investigations, 145–146 familial intracranial berry aneurysm, 147 family history, 12 fatal familial insomnia, 34 febrile seizures, 46–47 FENIB (familial encephalopathy with neuroserpin inclusion bodies), 37 follow-up, 20–21 fragile X-associated tremor/ataxia syndrome (FXTAS), 89–90 fragile X syndrome, 313–315 clinical features, 314–315 clinical phenotypes, 314t differential diagnosis, 315, 316t genetic advice, 315 Friedreich’s ataxia, 79–82 clinical features, 80, 80t genetic advice, 82 investigations, 81, 81f optic atrophy, 72 frontotemporal dementia (FTD), 30–33, 31f clinical features, 31 pathophysiology, 32 Pick’s disease, 30 FSHD, see facioscapulohumeral dystrophy FTD, see frontotemporal dementia FXTAS (fragile X-associated tremor/ataxia syndrome) 89–90 G gain of function mutations, 7 gait, Huntington’s disease, 104 gait ataxia, 75 -galactosidase A deficiency (Fabry’s disease) 192–193 GAN (giant axonal neuropathy), 195–196 Gaucher disease, 280, 282t generalized epilepsy with febrile seizures plus (GEFS+), 45
INDEX genes, 2 identifying disease genes, 5–7 linkage analysis, 5 mapping function, 5 positional cloning, 5–7 protein synthesis, 3–4 see also mutations genetic counseling diagnosis, 12 consultation, 13–23 examination, 12–13 family history, 12 follow-up, 20–21 investigations, 12–13 genetics nurse, 21 reproductive choices, 20 testing, 17–21 genetic disease manifestations expressivity, 16–17 heterogeneity, 17 modifiers, 17 penetrance, 16 genetic molecular analysis, 176 genetic testing, 17–21 carrier, 18–19 diagnostic, 18 exclusion, 21 predictive, 19–20, 22f genome, 2 Gerstmann-Straussler-Scheinker disease (GSS), 34, 35f giant axonal neuropathy (GAN), 195–196 Gille de la Tourette syndrome, 119–120 glutaric aciduria type 1, 298–299 glycogen storage myopathies, 238–241, 238t acid maltase deficiency, 240–241 ischemic lactate test, 240t myophosphorylase deficiency, 239–240 gyrate atrophy, 65 H Harding’s syndrome, 101 HARP syndrome, 130 hepatolenticular degeneration, 126–128 hereditary brachial plexus neuropathy, 188 hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), 29–30 hereditary hemorrhagic telangiectasia, 146 hereditary motor and sensory neuropathies (HMSN), see Charcot-Marie-Tooth diseases (CMT) hereditary motor neuropathies, 153t, 158 hereditary neuropathy with liability to pressure palsies (HNPP), 185–188, 186f hereditary sensory and autonomic neuropathy, 188–189, 189t
hereditary spastic paraplegia (HSP), 163–174 autosomal dominant complicated, 169t autosomal dominant pure, 168t autosomal recessive complicated, 171t autosomal recessive pure, 170t clinical features, 164–165 complicated forms, 164t differential diagnosis, 165t genetic advice, 171–173 genetic subtypes, 167 investigations, 166–167, 167t SPG1 HSP, 171 SPG2 HSP, 171 SPG31 HSP, 169 SPG3A HSP, 169 SPG4 HSP, 168 SPG7 HSP, 170 SPG11 HSP, 170 SPG16 HSP, 171 SPG17 HSP, 169 SPG20 HSP, 170 SPG21 HSP, 170 SPG22 HSP, 171 heredodegenerative disorders, 110 homocysteinuria, 144 HSP, see hereditary spastic paraplegia Hunter disease, 285 Huntington’s disease, 103–108 CAG repeat, 8–9, 106 clinical features, 103–104 cranial imaging, 104 differential diagnosis, 105t exclusion testing, 23f genetic advice, 107–108 genetics, 105–106 investigations, 104 juvenile, 104 predictive testing, 22f, 108 prenatal testing, 108 prevalence, 103 prognisis, 105 treatment, 106–107 Huntington disease-like 2 (HDL2), 109 Hurler disease, 285 4-hydroxybutyric aciduria, 298 L-2-hydroxyglutaric aciduria, 298 hyperCKemia, 208t hyperekplexia, 47–48 hyperkalemic periodic paralysis (hyperPP) 232–233 hyperkinesia, 102 hyperthermia, 237, 237t hyperphenylalanemia syndromes, 292–295 hypokalemic periodic paralysis (hypoPP), 230–232 hypokinesia, 102
325
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I idebenone, 82 idiopathic generalized epilepsies (IPEs), 45 infantile neuraxonal dystrophy, 307 infantile presentation (childhood disorders), 278–279 inheritance autosomal dominant (AD), 14, 14f autosomal recessive (AR), 14, 15f mitochondrial, 16 patterns of, 1, 13–16, 13f X-linked, 14–16 introns, 3 ion channels, 229 IPE (idiopathic generalized epilepsies), 45 ischemic lactate test, 240t isovaleric acidemia, 296 J Joubert syndrome, 68 juvenile Huntington’s disease, 104 K Kayser-Fleischer rings, 126 Kearns-Sayre syndrome, 247 Kennedy’s disease, 156–158 Klinefelter syndrome, 313 Krabbe disease, 96 Kugelberg-Welander disease, 153 L lactic acidosis, 301 lamin A/C gene mutations, 222b lamin A/C proteins, 222 laminin- 2-deficient congenital muscular dystrophy, 224–225 Leber congenital amaurosis (LCA), 56–57, 57t Leber’s hereditary optic neuropathy (LHON), 101, 255–256, 256t Leigh’s syndrome, 254–255, 254f Lesch-Nyhan syndrome, 131 leukodystrophies, 92–99, 93–94t adrenoleukodystrophy (ALD), 97–99 adrenomyeloneuropathy (AMN), 97–99 epidemiology, 92 Krabbe disease, 96 LGMD, see limb girdle muscular dystrophy syndromes LHON, see Leber’s hereditary optic neuropathy limb ataxia, 75 limb girdle muscular dystrophy syndromes (LGMD), 212–223 autosomal dominant, 212, 212t autosomal recessive, 212–215, 213t calpainopathy, 213 diagnosis, 214t dysferlinopathy, 214
limb girdle muscular dystrophy syndromes (LGMD) (Continued) genetic advice, 215 LMGD2I, 214 linkage analysis, 5 autosomal recessive disorders, 6 lipid myopathies, 241–242, 242t carnitine palmitoyltransferase II deficiency, 243–244 lissencephaly, 40t, 41, 41f, 42f cobblestone, 226t LOD scores, 5 loss of function mutation, 7 lysosomal diseases (childhood) mucopolysaccharidoses, 284–287 sphingolipidoses, 280–284 lysosomal storage disorders Niemann-Pick disease type C, 130 Pelizaeus-Merzbacher disease, 130 M macula, 49 macular dystrophies, 66–67 Maeda syndrome, 142 malignant hyperthermia, 237, 237t Manchester Clinical Diagnostic Criteria, 268t maple syrup urine disease, 295–296 mapping function, 5 maternally inherited diabetes and deafness, 250 maternally inherited Leigh syndrome, 257 McArdle’s disease, 239–240 McManis test, 231t MDS (myoclonus dystonia syndrome), 115 MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), 248 Mendelian inheritance, 1 idiopathic epliepsies, 43–45 Menkes disease, 304–305 merosin-deficient congenital muscular dystrophy, 224–225 MERRF (myoclonic epilepsy and ragged red fibers), 248–249 metabolic ataxias, 77t metabolic disorders, childhood, 280–308 metabolic myopathies, 238–244 acid maltase deficiency, 240–241 glycogen storage myopathies, 238–241, 238t lipid myopathies, 241–243, 242t lysosomal, 242t mitochondrial myopathies, 246, 247–253 myophosphorylase deficiency, 239–240 see also mitochondrial disease metachromatic leukodystrophy (MLD), 95–96 metal metabolism disorders neuroferritinopathy, 128–129 pantothenate kinase-associated neurodegeneration, 129–130 Wilson’s disease, 126–128
INDEX methylmalonic aciduria, 296 mevalonic aciduria, 304 microdeletion syndromes, 318t microsatellite markers, 6 mitochondria, 2, 245 mitochondrial disease, 245–258 clinical diagnosis, 245–246 genetic advice, 252–253 investigation, 250–252 Leber’s hereditary optic neuropathy, 101, 255–256 Leigh’s syndrome, 254–255 mitochondrial encephalomyopathies, 248–249 mitochondrial encephalopathies, 248 modes of inheritance, 252–253 mtDNA maintenance disorders, 257–258 muscle biopsy, 251t myopathic presentations, 249 neuropathy, ataxia, retinitis pigmentosa, 257 progressive external ophthalmoplegia, 247 ragged red fibers, 247–253 syndromes, 246t treatment, 258 mitochondrial disorders, 69–70 mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), 248 mitochondrial genome, 2, 16 mitochondrial inheritance, 16 mitochondrial neurogastrointestinal encephalopathy (MNGIE), 249–250 mixed movement disorders, 126–133 choreoacanthocytosis, 132–133 dentatorubro-pallidoluysian atrophy, 131 Lesch-Nyhan syndrome, 131 neurodegenerative disorders, 132 neuroferritinopathy, 128–129 Niemann-Pick disease type C, 130 pantothenate kinase-associated neurodegeneration (PKAN), 129–130 Pelizaeus-Merzbacher disease, 130 spinocerebellar ataxias, 132 Wilson’s disease, 126–128 MLD (metachromatic leukodystrophy), 95–96 MNGIE (mitochondrial neuro-, gastrointestinal encephalopathy), 249–250 Mohr-Tranebjaerg syndrome, 117–118 motor neuron diseases, 150–174 cerebral palsy, 173–174 clinical classification, 151t hereditary motor neuropathies, 158 lower motor neuron disorders, 150–158, 151t primary lateral sclerosis, 174 upper and lower motor neuron disorders, 158–163 upper motor neuron disorders, 163–174 X-linked spino-bulbar muscular atrophy, 156–158
327
motor neuron diseases (Continued) see also amyotrophic lateral sclerosis (ALS); hereditary spastic paraplegia (HSP); spinal muscular atrophy (SMA) movement disorders, 102–135 chorea, 103 deafness-dystonia-optic neuropathy syndrome, 117–118 dyskinetic, 102–120 dystonia, 109–111 essential tremor, 118–119 Gille de la Tourette syndrome, 119–120 Huntington disease-like 2, 109 hypokinetic, 120–125 myoclonus, 120 narcolepsy, 133–135 parkinsonism, 102, 120–125 restless legs syndrome, 135–136 sleep-related, 133–136 tics, 119–120 tremor, 118 see also dystonias; Huntington’s disease; mixed movement disorders; paroxysmal dyskinesias; Parkinson’s disease Moyamoya disease, 147–148 MPS, see mucopolysaccharidoses mtDNA depletion, 257–258 mucolipidoses, 287, 288t mucopolysaccharidoses (MPS), 284–287 classification, 286t multiple sclerosis, 99–101 differential diagnosis, 101t genetic advice, 100–101 risks to siblings, 100t muscle disease, see myopathies; channelopathies muscular dystrophies, 204–212 Becker, 208–209 congenital, 223–225 Duchenne, 208 dystrophinopathies, 208–212, 208t Emery-Dreifuss, 221–222 hyperCKemia, 208t myotonic dystrophy (DM1), 204–207 myotonic dystrophy type 2 (DM2), 208 oculopharyngeal muscular dystrophy, 219–221 see also congenital muscular dystrophies (CMD); limb girdle muscular dystrophy syndromes mutations, 7–9, 7t mosaic, 19 myelin disorders, 92–101 see also multiple sclerosis; leukodystrophies myoclonic epilepsy and ragged red fibers (MERRF), 248–249 myoclonus, 120 myoclonus dystonia syndrome (MDS), 115 myofibrillar myopathy, 203, 203t
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myopathies, 197–228 central core disease, 199–201 classification, 199 clinical features, 197–198 congenital, 199–204, 223–225 congenital absence of muscles, 226t congenital myasthenic syndromes, 226–227, 227t differential diagnosis, 201t distal, 223, 223t examination, 198 facioscapulohumeral dystrophy, 215–218, 216f investigations, 198–199 myofibrillar, 203, 203t myotubular, 202 rod, 203–204, 204t scapuloperoneal syndromes, 218–219 see also channelopathies; limb girdle muscular dystrophy syndromes (LGMD); metabolic myopathies; mitochondrial disease; muscular dystrophies myophosphorylase deficiency, 239–240 myotonia and cramps, 237t myotonia congenita, 235–236, 236t myotonic dystrophy (DM1), 204–207 genetics, 206–207, 206t multisystem features, 205t myotonic dystrophy type 2 (DM2), 208 myotubular myopathy, 202 N narcolepsy, 133–135 NARP (neuropathy, ataxia, retinitis pigmentosa), 257 neonatal presentation (childhood disorders), 277–278 neoplastic disease, 260 nerve biopsy, 177, 177–178f nerve conduction studies, 176 neuralgic amyotrophy, 188 neuroferritinopathy, 128–129 neurofibromatosis I (NF1), 265–268 diagnosis, 265 genetic testing, 267 management, 267 neurofibromatosis II (NF2), 268–271 clinical features, 268–269 diagnostic criteria, 268t genetics, 270 investigations, 269 neuronal ceroid lipofuscinoses, 305–307, 306t neuronal migration disorders, epilepsy, 40–41 neuropathies, 175–196 associated with CNS and other systems, 191t associated with metabolic defects, 191–196 axonal, 176 clinical features, 175, 176t demyelinating, 176 Fabry’s disease, 192–193
neuropathies (Continued) giant axonal, 195–196 investigations, 175–177 Leber’s hereditary optic neuropathy, 101, 255–256 Refsum’s disease, 193 Tangier disease, 191–192 see also Charcot-Marie-Tooth diseases (CMT); mitochondrial diseases; porphyrias neuropathy, ataxia, retinitis pigmentosa (NARP), 257 NF1, see neurofibromatosis I NF2, see neurofibromatosis II Niemann-Pick disease type C, 130, 303–304 non-ketotic hyperglycinemia, 296–297 genetics, 297 O oculopharyngeal muscular dystrophy (OPMD), 219–221 oligosaccharidoses, 288–289 ophthalmoplegia, progressive external, 247 OPMD (oculopharyngeal muscular dystrophy), 219–221 optic atrophy, 71–74, 71f Friedreich’s ataxia, 72 primary hereditary optic neuropathy, 71–72 rare causes, 73t septo-optic dysplasia, 74 Wolfram syndrome, 72–74 organic acid catabolism disorders, 297–299 Canavan’s disease, 297–298 glutaric aciduria type 1, 298–299 4-hydroxybutyric aciduria, 298 L-2-hydroxyglutaric aciduria, 298 P pachygyria, 41 pantothenate kinase-associated neurodegeneration (PKAN), 129–130 HARP syndrome, 130 paramyotonia congenita, 233–235, 236t parkinsonism, 102, 120–125 rapid-onset dystonia parkinsonism, 115 Parkinson’s disease, 121–125 clinical features, 121 genetic advice, 125 genetics, 122–125 idiopathic, 121 investigation, 121 PARK genes, 123–125, 123t Parkinson’s-plus syndromes, 122t secondary, 122t treatment, 125 paroxysmal dyskinesias, 116–117 Parsonage-Turner syndrome, 188 Patau syndrome, 312t pattern dystrophy, 59
INDEX patterns of inheritance, 1, 13–16 Pearson’s syndrome, 250 Pelizaeus-Merzbacher disease (PMD), 130 penetrance, 16 periodic paralysis, see channelopathies periventricular heteropia, 41 peroxisomal disorders, 290–291 pes cavus, 186f phenylketonuria, 292–293, 293f PKAN, see pantothenate kinase-associated neurodegeneration Pick’s disease, 30 PMD (Pelizaeus-Merzbacher disease), 130 PMEs (progressive myoclonic epilepsies), 42–43, 43t Pompe disease, 287, 288t porphyrias, 193–195 acute intermittent, 194 -aminolevulinic acid dehydratase deficiency, 194 coproporphyria, 194 genetics, 195 investigations, 194–195 variegate, 194 positional cloning, 5 potassium-aggravated myotonia, 233 predictive testing, 19–20 Huntington’s disease, 22f, 108 von Hippel-Lindau disease, 20 prenatal testing Huntington’s disease, 108 presenilins Alzheimer’s disease, 28 primary lateral sclerosis, 174 primary torsion dystonia, 111–114 genetics, 112–113, 112t recurrence risks, 113t prion diseases, 33–37, 33t Creutzfeld-Jakob disease, 33–34 fatal familial insomnia, 34 genetic advice and testing, 36–37 Gerstmann-Straussler-Scheinker disease, 34 prion protein, 33 progressive external ophthalmoplegia, 247, 247f progressive myoclonic epilepsies (PMEs), 42–43, 43t proprionic acidemia, 296 protein synthesis, 3–4 purine metabolism disorders Lesch-Nyhan syndrome, 131 R ragged red fibers, 246 mitochondrial diseases, 247–253 rapid-onset dystonia parkinsonism, 115 Refsum’s disease, 69, 69f, 193, 291 infantile, 290 reproductive choices, 20 restless legs syndrome, 135–136
retina, 49 retinal degeneration, 67–70 Alstrom syndrome, 68 Bardet-Biedl syndrome, 67–68 cherry-red spots, 70 Joubert syndrome, 68 management, 70–71 mitochondrial disorders, 69–70 Refsum’s disease, 69 spinocerebellar ataxia, 70 Usher syndrome, 68–69 vitreoretinal dystrophies, 70 retinitus pigmentosa, 53–66, 53f autosomal dominant, 54, 55t autosomal recessive, 55, 55t clinical features, 53–54 differential diagnosis, 65–66 digenic, 56 genetic counseling, 57–65 genetics, 54 Leber congenital amaurosis, 56–57, 57t simplex, 56 syndromic, 58–64t X-linked, 55–56, 56t Rett syndrome, 307–309, 308t rhizomelic chondrodysplasia punctata, 290 ribosomes, 3 RNA, 3 rod myopathies, 203–204, 204t Roussy-Levy syndrome, 180 RP, see retinitus pigmentosa S Salla disease, 287 sarcolemmal proteins, 200f sarcomeric proteins, 200f Sargardt fundus dystrophy, 66 scapuloperoneal syndromes, 218–219 schwannomatosis, 271 diagnostic criteria, 272t Seitelberger disease, 307 seizures, see epilepsy sensory ataxia, 75 septo-optic dysplasia, 74 sex chromosomes, 2 numerical disorders, 313 sialiuria, 287–288, 288t Silver syndrome, 169 sleep-related movement disorders narcolepsy, 133–135 restless legs syndrome, 135–136 SMA, see spinal muscular atrophy Smith-Lemli-Opitz syndrome, 301–303 spasmodic torticollis, 109 spasticity, 150 see also motor neuron diseases
329
330
INDEX
SPG loci, see hereditary spastic paraplegia (HSP) sphingolipidoses, 280–284, 281–283t Tay Sachs disease, 280–284 spinal muscular atrophy (SMA), 150–156 classification, 152t, 153t genetic advice, 155–156 genetics, 154–155 SMA I, 152 SMA II, 152 SMA III, 153 SMA IV, 153 spinocerebellar ataxia movement disorders, 132 retinal degeneration, 70 spinocerebellar disorders, see cerebellar disorders splicing, 3 stroke, 137 genetic risk factors, 148 see also cerebrovascular disease stroke susceptibility locus (STRK1), 148 Sturge-Weber syndrome, 47 sulfite oxidase deficiency, 297 symptomatic epliepsy, 47 synucleinopathies, 24 see also Parkinson’s disease T Tangier disease, 191–192 tauopathies, 24 frontotemporal dementia, 30–33 Tay Sachs disease, 280–284 genetics, 284 tetrahydrobiopterin deficiency, 293 tics, 119–120 tomaculous neuropathy, 187 tremor, 118 trinucleotide repeat disorders dentatorubro-pallidoluysian atrophy, 131 spinocerebellar ataxias, 132 trinucleotide repeats, 8–9 trisomy 21, 311–313, 312t tRNA, 3 tuberous sclerosis, 271–274 clinical features, 271 genetic advice, 274 investigation, 273 tumor predisposition syndromes, 260–275 schwannomatosis, 271 see also neurofibromatosis I (NF1); neurofibromatosis II (NF2); tuberous sclerosis; von Hippel-Lindau disease tumors, CNS, 261t tyrosinemia, 294–295
U Unverricht-Lundborg disease, 84 urea cycle disorders, 299–300, 300t Usher syndrome, 66, 68–69 V variant CJD (vCJD), 34 vision disorders, 49–74 cherry-red spots, 70 cone-rod dystrophies, 67 inherited retinal degeneration, 52–70 investigations, 51, 52 see also macular dystrophies; optic atrophy; retinal degeneration; retinitus pigmentosa visual evoked potential, 51–52 vitamin E deficiency, 84 vitamin metabolism disorders, 302t vitelliform dystrophy, 66 vitreoretinal dystrophies, 70 von Hippel-Lindau disease, 260–264 clinical features, 260–262 diagnostic criteria, 262t genetic advice, 264 genetic testing, 263 treatment, 264 von Recklinghausen’s disease, see neurofibromatosis I (NF1) W Werdnig-Hoffmann disease, 152 Wilson’s disease, 15f, 126–128 Wolfram syndrome, 72–74 Wolman disease, 304 Worster-Drought syndrome, 157 writer’s cramp, 109 X X-linked adrenoleukodystrophy, 291 X-linked ataxias, 89–90 Fragile X-associated tremor/ataxia syndrome, 89–90 X-linked Charcot-Marie-Tooth disease (CMT1X), 183 X-linked inheritance, 15–16 X-linked mental retardation, 316–317t X-linked spino-bulbar muscular atrophy (SBMA), 156–158, 156f XYY syndrome, 313 Z zebra bodies, 285 Zellweger syndrome, 290
