Genetics for Ophthalmologists
The Remedica Genetics for… Series Genetics for Cardiologists Genetics for Dermatologists Genetics for Hematologists Genetics for Oncologists Genetics for Ophthalmologists Genetics for Orthopedic Surgeons Genetics for Pulmonologists Genetics for Rheumatologists
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[email protected] www.remedica.com Publisher: Andrew Ward In-house editors: Tamsin White & Eilidh Jamieson Design: REGRAPHICA, London, UK © 2002 REMEDICA Publishing Limited All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher. ISBN 1 901346 20 X British Library Cataloguing-in Publication Data A catalogue record for this book is available from the British Library
Genetics for Ophthalmologists The molecular genetic basis of ophthalmic disorders Graeme CM Black Wellcome Senior Clinical Fellow, Academic Units of Ophthalmology and Clinical Genetics Manchester University, Manchester, UK Honorary Consultant in Genetics and Ophthalmology, Central Manchester and Manchester Children's University Hospitals NHS Trust, Manchester, UK
Series editor: Eli Hatchwell Investigator, Cold Spring Harbor Laboratory
Introduction to Genetics for… series Medicine is changing. The revolution in molecular genetics has fundamentally altered our notions of disease etiology and classification, and promises novel therapeutic interventions. Standard diagnostic approaches to disease focused entirely on clinical features and relatively crude clinical diagnostic tests. Little account was traditionally taken of possible familial influences in disease. The rapidity of the genetics revolution has left many physicians behind, particularly those whose medical education largely preceded its birth. Even for those who might have been aware of molecular genetics and its possible impact, the field was often viewed as highly specialist and not necessarily relevant to everyday clinical practice. Furthermore, while genetic disorders were viewed as representing a small minority of the total clinical load, it is now becoming clear that the opposite is true: few clinical conditions are totally without some genetic influence. The physician will soon need to be as familiar with genetic testing as he/she is with routine hematology and biochemistry analysis. While rapid and routine testing in molecular genetics is still an evolving field, in many situations such tests are already routine and represent essential adjuncts to clinical diagnosis (a good example is cystic fibrosis). This series of monographs is intended to bring specialists up to date in molecular genetics, both generally and also in very specific ways that are relevant to the given specialty. The aims are generally two-fold: (i)
to set the relevant specialty in the context of the new genetics in general and more specifically
(ii)
to allow the specialist, with little experience of genetics or its nomenclature, an entry into the world of genetic testing as it pertains to his/her specialty
Genetics for Ophthalmologists
These monographs are not intended as comprehensive accounts of each specialty — such reference texts are already available. Emphasis has been placed on those disorders with a strong genetic etiology and, in particular, those for which diagnostic testing is available. The glossary is designed as a general introduction to molecular genetics and its language. The revolution in genetics has been paralleled in recent years by the information revolution. The two complement each other, and the World Wide Web is a rich source of information about genetics. The following sites are highly recommended as sources of information: 1.
PubMed. Free on-line database of medical literature. http://www.ncbi.nlm.nih.gov/PubMed/
2.
NCBI. Main entry to genome databases and other information about the human genome project. http://www.ncbi.nlm.nih.gov/
3.
OMIM. On line inheritance in Man. The On-line version of McKusick’s catalogue of Mendelian Disorders. Excellent links to PubMed and other databases. http://www.ncbi.nlm.nih.gov/omim/
4.
Mutation database, Cardiff. http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html
5.
Retnet. A listing of cloned and/or mapped genes causing retinal diseases. http://www.sph.uth.tmc.edu/Retnet/disease.htm
Eli Hatchwell Cold Spring Harbor Laboratory
Introduction
Preface A decade ago, it was unimaginable that the entire genomic sequence would be completed within a few years. The identification and mapping of our genes has already led to a better understanding of their expression and function. Over this period a vast number of genes underlying monogenic ophthalmic disorders have been identified and our understanding of disorders affecting every part of the eye has been enhanced immeasurably. As genetic testing technologies become more readily available and accessible as an aid to both diagnosis and management, the impact on the practice of ophthalmology will be profound. As a result, an understanding of its power and capabilities has become essential. A working knowledge of the practice of genetics has become relevant and should no longer be regarded as a quaint academic pursuit. Furthermore, its importance should not be underestimated: in pediatric ophthalmology, around half (probably more) of the cases of childhood blindness have a genetic cause, while inherited factors contribute to the blinding effects of adult-onset diseases such as diabetes, glaucoma and age-related macular degeneration. As is clear from the clinical sections, awareness of extraocular manifestations is crucial to the diagnosis and correct management of many of the conditions in this book. Therefore, ophthalmologists must think broadly when approaching their genetic patients: without consideration of cardiac complications, the management of ectopia lentis in Marfan syndrome will not meet all of that patient’s needs. The same is true of the need for sun protection in albinism, or tumor surveillance in those with von Hippel Lindau disease. Fortunately, encyclopedic knowledge is not required. As with any branch of clinical medicine there are generalized principles in the approach to, and management of, inherited disorders whose understanding enables both the generalist and the subspecialist to deal in a standardized – and reliable – fashion with the often Genetics for Ophthalmologists
complex problems that are posed by genetic disease. The purpose of this book is to present current knowledge of a range of inherited ocular disorders in a concise, approachable format to enable the clinician to gather easily a working knowledge of the clinical manifestations and molecular features of each disorder. It is primarily aimed at the ophthalmologist but it will also be useful to trainees at all levels as well as clinical geneticists and molecular scientists who share an interest in genetic ophthalmology. Genetic testing An increasing number of genes are being cloned that are responsible for inherited ophthalmic conditions. While it is assumed – especially by patients and their families – that gene identification is followed closely and inevitably by routinely available genetic testing, this has been shown repeatedly not to be the case. The time lag leads to a significant gulf between the expectations of patients and the abilities of the clinician to fulfil them. There are a number of factors to consider: • Screening for mutations in most genes is a labor-intensive and time-consuming process that requires analysis of the whole gene. Exceptions to this are TIMP3 (Sorsby dystrophy) and BIGH3 (stromal corneal dystrophies) where the range of mutations is limited. Therefore, in the majority of cases screening may take a number of months. • In conditions where a broad range of genes may cause an identical phenotype (e.g. retinitis pigmentosa) there is no way to ascertain which gene is responsible; this makes screening impractical in a clinical setting, using current techniques. • Mutation detection procedures are not 100% sensitive. Many methods of identifying mutations within a gene are ~70% successful. Therefore, in many cases molecular analysis will not produce a ‘definitive’ result. Where mutation screening is appropriate, blood samples are usually only taken from an affected member of the family: mutation
Preface
screening of an unaffected family member is only of use once a mutation is found. Therefore, in a proportion of families that are seen, mutation screening is not available because a sample cannot be obtained from an affected member of the family. A negative result in an unaffected person may mean that a mutation is not present, or for technical reasons a mutation has not been detected, or that a mutation may be present in another gene. Genetic testing has come to mean mutation testing in the eyes of many. However, it should not be forgotten that chromosome analysis (karyotyping) is an important tool which, when used selectively in the correct circumstances, is critical to the management and diagnosis of many genetic conditions (see ‘karyotype’ in the glossary). Predictive testing Examining relatives in the clinic can be a valuable adjunct to diagnosis. This is true for both static, developmental disorders (congenital cataract, coloboma) and progressive disorders (retinal dystrophies). However, when faced with expectant, as yet unaffected, relatives or children what should the clinician do? Within genetic centers, protocols are in place for predictive testing (either through examination or genetic testing) in families with adult-onset genetic disorders. These are based on protocols for testing in families with Huntington disease. They include discussion of the risks associated with mutations, the implications to the wider family of a mutation result and a discussion of how patients may cope with a ‘bad’ news result that confirms a high risk of developing symptoms. Patients are advised to seek financial advice, as the situation with regard to access to results for insurance companies is currently uncertain. Within the ophthalmic setting there has been little consideration of the potential impact of presymptomatic genetic diagnosis – either through examination or genetic testing. It should be remembered that the aim of testing must be to improve diagnosis and management, and to facilitate counselling of patients and their families. Clearly, if such a test disadvantages patients then it fails to meet these aims.
Genetics for Ophthalmologists
Therefore, consideration needs to be given to the clinical need for genetic testing, and patients and their relatives need to understand the pros and cons of such a process. When approaching asymptomatic at-risk relatives it may be useful to ask these questions prior to examining or drawing blood: • Is there a clinical need in proceeding with presymptomatic diagnosis? • Does it need to be done now? (What is done can never be undone.) • Are there disadvantages to presymptomatic diagnosis (psychological, employment, financial)? • Does the patient really want to know? Genetic counselling The aim of genetic counselling is to inform patients and their families about how and why a condition affects them now and in the future, and to explain its reproductive implications. This is not simply a question of defining risks and explaining inheritance patterns. Fundamental to any counselling process is accurate clinical diagnosis and, within a genetic ophthalmic clinic, the clinician must be prepared to modify or even to change a previous diagnosis. Such a process takes time and an appropriate clinical setting is required such as a clinical genetic or joint genetic-ophthalmic clinic. Such a consultation will then allow accurate history/family history taking, examination (often of multiple family members), discussion, explanation and answering patients’ questions. Finally, when approaching genetic counselling, the expectations of the patient must be considered. It is important to understand what they are seeking and why they may be unsatisfied at the end of the process. Through the power of the internet, as well as the many excellent patient organizations, those with inherited ocular disorders are often well informed about their conditions – perhaps more
Preface
up-to-date than their physicians! While information is often what they require, either by way of confirmation or reassurance, two specific themes recur. Firstly, patients will often want genetic testing to define the risks to offspring. Sadly, current techniques often make this either impossible or unlikely to be successful. Secondly, and perhaps more importantly, patients are often keen to seek novel treatments that will either prevent or restore loss of sight. The latter is strongly fuelled by frenetic media coverage and leads to unrealistic expectations. In any counselling setting it is important to feel comfortable giving bad news. It is in no-one’s interest to be unrealistically optimistic about future prospects. Total pessimism is similarly unhelpful. Therefore, ‘cautious realism’ in explaining that hope for the future may not, in fact, be translated into practical help for the present is often important in helping families come to terms with the reality of a situation and in enabling them to begin to prepare for the future.
Genetics for Ophthalmologists
What the experts say Recent advances in molecular biology have impacted on all areas of clinical medicine including ophthalmology. Molecular genetic diagnosis is now possible for many inherited eye disorders and the identification of the genetic mutations causing eye disease has greatly improved our understanding of disease mechanisms. A new era of novel molecular targeted therapy beckons. All ophthalmologists will need to keep abreast of advances in this rapidly changing field. This excellent book, written by Dr Graeme Black, an international authority in the field of genetic eye disease, gives a wonderfully clear and concise summary of the many eye disorders that have a genetic basis. The text covers both isolated eye disease and multi-system disorders with an ocular component. The chapters follow a very clear structure detailing the clinical findings, age of onset, molecular genetics and diagnosis and this makes for great ease of use. The illustrations also serve to aid diagnosis. There is a very useful glossary at the end of the book that gives a clear explanation of genetic terminology with which the ophthalmologist may not be familiar. I can thoroughly recommend this excellent book; it will appeal not only to clinical ophthalmologists but to other specialists such as clinical geneticists and paediatricians. It is the ideal book to keep close at hand in the consulting room. AT Moore, Professor of Ophthalmology, Institute of Ophthalmology and Moorfields Eye Hospital, London, UK Advances in the molecular genetics of ophthalmology are revolutionizing the specialty. However, clinicians find it difficult to access or utilize this new genetic information. This book provides a solution. It does a spectacular job of presenting an authoritative, up to date summary of molecular ophthalmology. The clear style and excellent illustrations demystify the molecular genetics of ophthalmology. It will be an excellent reference book for any health care practitioner who wishes to incorporate molecular genetics into the management of his or her patients. It is easy to read and I wholeheartedly recommend it both as an educational and reference tool. Andrew Lotery, MD FRCOphth, Assistant Professor of Ophthalmology, University of Iowa Hospitals & Clinics, USA Genetics for Ophthalmologists
Genetics for Ophthalmologists is a comprehensive reference tool for the General Ophthalmologist to the Ophthalmic Geneticist. Hereditary eye diseases and syndromes are grouped ‘anatomically’ as a comprehensive catalog. Each disorder has a succinct synopsis of clinical features, illustrations, inheritance and information on the genes, mutations and presumed mechanism of action. Most importantly perspective on the utility and availability of genetic testing are given for each condition as well as a general opening section discussing issues relating to predictive testing and counselling. The extensive glossary gives a clear explanation of many terms used in genetics. Genetics for Ophthalmologists is an essential reference resource for every eye department. David Mackey, MD FRANZCO Centre for Eye Research, Australia Graeme Black has performed an extensive review of the ophthalmic genetic literature and provided a masterpiece that has been long awaited by those with an interest in the genetics of eye disease. Until now it has been extremely difficult for the clinician to find this information without spending hours at the computer searching for relevant publications. This book provides a comprehensive coverage of inherited eye diseases starting at the cornea and working back towards the optic nerve. The format is easy to follow with useful summaries of the clinical and diagnostic criteria for each condition. Information about inheritance patterns, penetrance, the effect of mutations and whether genetic screening is currently possible will be invaluable to all those involved in counselling families. There is also a very helpful Glossary for those less used to genetic terminology. Clinical Geneticists and Ophthalmologists alike will find this an indispensable tool in their clinics and every medical library should have a copy. Despite the fast pace of genetics I feel sure this book will remain a valuable text for many years to come. Amanda Churchill, PhD MBChB FRCOphth Consultant Senior Lecturer in Ophthalmology, University of Bristol, UK Genetics for Ophthalmologists
Acknowledgements I am extremely grateful to my colleagues – in particular Robyn Jamieson, Alan Ridgway and Jill Clayton-Smith – for taking the time to review the manuscript and for making corrections and helpful suggestions. I would also like to thank those listed below for supplying the following illustrations: Amanda Churchill (pp 78), Jill Clayton-Smith (pp 53–4, 252), Dian Donnai (pp 80, 153, 173–4, 178, 180), Susie Downes (pp 98, 127), Gareth Evans (pp 249, 255), John Grigg (pp188, 196), Chris Lloyd (pp 31, 46, 52, 58, 237, 220), David McLeod (pp 172,181), Francis Munier (pp 12, 31), Alan Ridgway (pp 10, 17, 23), Fiona Spencer (pp 61, 70), Andrew Webster (pp 90).
Contents Corneal disease Lens Glaucoma Inherited retinal disease Vitreoretinal disorders Optic nerve Defects of pigmentation Metabolic disorders Conditions associated with increased risk of malignancy Defects of ocular/adnexal development Glossary Abbreviations Index
Genetics for Ophthalmologists
1 27 57 81 169 187 201 213 241 267 279 333 341
Genetics for Ophthalmologists
1 1. Corneal disease
Abnormalities of corneal shape Cornea plana 5 Corneal dystrophies Epithelial Gelatinous drop-like corneal dystrophy 7 Meesmann corneal dystrophy 8 BIGH3-Related Bowman’s layer dystrophy type I 10 Bowman’s layer dystrophy type II 12 Granular corneal dystrophy 14 Lattice corneal dystrophy type I 18 Stromal Lattice corneal dystrophy type II 20 Macular corneal dystrophy 23 Endothelial Fuchs' endothelial corneal dystrophy 25
Introduction A wide range of inherited conditions, both ocular and multisystemic, are associated with abnormalities of corneal development, shape, clarity or integrity. Corneal size
Mean corneal diameter is around 10 mm at birth reaching a maximum of 12.5 mm at 2 years. Abnormalities of corneal size include microcornea (diameter <11 mm) and megalocornea (diameter >13 mm). Microcornea is often associated with other ocular abnormalities including microphthalmos (q.v.), coloboma or cataract. Isolated megalocornea, in the absence of other ocular abnormalities, is an uncommon, X-linked recessive condition of benign prognosis. It is often initially diagnosed as congenital glaucoma but may easily be distinguished by a high endothelial cell count.
Corneal shape
Cornea plana is associated with non-progressive reduced corneal curvatures. Increased corneal curvature is seen particularly in corneal ectasias, a subgroup of the corneal dystrophies. Of these, keratoconus is the most common. Isolated keratoconus affects 1:2–5000 of the population and has a well-recognized genetic predisposition, although the genetic etiology remains undefined. A small number of cases have been shown to carry mutations in the ocular transcription factor VSX1. The systemic associations include Down syndrome, Ehlers-Danlos syndrome and Leber congenital amaurosis.
Anterior segment dysgenesis
Corneal abnormalities are a feature of many forms of the developmental anterior segment disorders. In Peters anomaly, a severe developmental abnormality, corneal opacification (often central) is associated with a defect in Descemet's membrane often with adhesions between the cornea, the lens and/or iris. Hereditary forms are recognized including defects of PAX6, PITX2, CYP1B1 and MAF. Aniridia may be associated with abnormal peripheral corneal vascularization, which is often progressive and may be troublesome in later life.
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Genetics for Ophthalmologists
Corneal dystrophies
The corneal dystrophies have been defined as inherited, bilateral, slowly progressive disorders that alter corneal function in the absence of inflammation and systemic sequelae. In most cases this definition holds true, although exceptions can be found including unilateral cases, those of rapid progression and those with systemic associations. Traditionally, corneal dystrophies have been subdivided according to the anatomical site at which the presumed defect is located, i.e. anterior, stromal and posterior, or endothelial dystrophies, with a remaining group of ectatic dystrophies. Such morphological classification becomes increasingly cumbersome as the genetic bases for these disorders are defined. It is now evident that a remarkable number of supposedly distinct dystrophies share a common molecular etiology (see Table 1). While a morphological classification remains valid, this may prompt its re-evaluation.
Inborn errors of metabolism
A number of metabolic disorders are associated with corneal manifestations. These include Wilson disease or hepatolenticular degeneration (Kayser-Fleischer ring), Fabry disease (vortex keratopathy), mucopolysaccharidoses (corneal clouding) and cystinosis (crystal deposition). The following section includes a relatively small number of corneal dystrophies and isolated corneal developmental abnormalities for which the precise molecular defect has been defined. The chromosomal location is known for a number of other, similar conditions (see Table 2) and it is likely that this group will expand in the near future as the genes that underlie other corneal dystrophies are discovered.
Corneal disease
3
Table 1. Mutation of the common BIGH3-related dystrophies. Condition Reis-Bucklers Thiel-Behnke Granular Avellino Lattice type I
Exon 4 12 12 4 4
Mutation R124L R555Q R555W R124H R124C
Table 2. Inheritance pattern and chromosomal localization of the inherited corneal dystrophies. Condition Meesmann Lisch Cogan (Map-Dot Fingerprint) Gelatinous drop-like Reis-Bucklers Thiel-Behnke Thiel-Behnke Granular Avellino Macular Lattice type I Lattice type II Lattice type IIIa Schnyder crystalline Fuchs Posterior polymorphous Congenital hereditary endothelial Congenital hereditary endothelial
4
MIM 122100 121820 204870 121900 121900 602082 121900 121900 217800 122200 105120 122200 121800 136800 122000 121700 217700
Inheritance AD XL AD AR AD AD AD AD AD AR AD AD AD AD AD AD AD AR
Chromosome 12q, 17q Xq22.3 1p31 5q31 5q31 10q24 5q31 5q31 16q22 5q31 9q34 5q31 1p34.1–p36 20p11.2–q11.2 20cen 20p13
Gene K3, K12 M1S1 BIGH3 BIGH3 BIGH3 BIGH3 CHST6 BIGH3 Gelsolin BIGH3 VSX1 -
Genetics for Ophthalmologists
Cornea plana (also known as: CNA1; CNA2) MIM
217300; 603288 (KERA)
Clinical features
Both dominant and recessive forms are described, with the latter being the more severe. Anterior segment abnormalities include extreme hypermetropia (+10 D or more), a hazy corneal limbus with stromal opacities and marked arcus juvenilis. The cornea is thin with an indistinct sclerocorneal boundary. The two forms are distinguished by a round thickened central opacity, approximately 5 mm in width, which is seen in most recessive cases but not those of dominant inheritance. Iris malformations and iridocorneal adhesions are more prevalent in the recessive form. Mild microphthalmia may be present in the recessive form.
Age of onset
Congenital
Epidemiology
Rare in the UK. Although prevalence is uncertain, the condition has been described in autosomal dominant form in Cuba and autosomal recessive form in Finland (carrier frequency estimated at 1:126 in north-east Finland).
Inheritance
Autosomal dominant; autosomal recessive
Chromosomal location
12q21.3–q22 (autosomal recessive). Linkage analysis of a dominant form in a Cuban kindred confirmed linkage to the region of 12q implicated in recessive cornea plana. Finnish families with a dominant form of cornea plana do not link to 12q, suggesting two distinct dominant forms.
Gene
Keratocan (KERA) (recessive form)
Corneal disease
5
Mutational spectrum
Mutations have been found in the recessive form of cornea plana. One nonsense mutation and a missense mutation within the highly conserved leucine-rich repeat (LRR) have been described.
Effect of mutation
Keratan sulfate proteoglycans (KSPGs) are members of the small leucine-rich proteoglycan (SLRP) family. KSPGs, particularly keratocan, lumican and mimecan, are important to the transparency of the cornea. Keratocan is expressed early in neural crest development and later in corneal stromal cells. The missense mutation described results in an asparagine to serine substitution, affecting the most highly conserved amino acid in the LRR motif throughout the SLRP family.
Diagnosis
6
Clinical examination
Cornea plana
Gelatinous drop-like corneal dystrophy (also known as: GLDL; primary subepithelial corneal amyloidosis) MIM
204870; 137290 (M1S1)
Clinical features
Amyloid accumulation beneath the epithelium produces whitish deposits that are said to resemble a mulberry. These accumulations lead to photophobia, discomfort and reduced visual acuity. Histologically the amyloid deposits are seen above Bowman’s layer and within the epithelium as well as within the stroma.
Age of onset
Amyloid begins to accumulate in the cornea during the first two decades of life.
Epidemiology
1:300,000 (Japan). Rare but not unknown outside Japan.
Inheritance
Autosomal recessive
Chromosomal location
1p31
Gene
Membrane component, chromosome 1, surface marker 1 (M1S1)
Mutational spectrum
Four nonsense mutations described in a Japanese cohort of patients.
Effect of mutation
Protein truncating mutations result in the production of a shortened amyloidogenic protein that accumulates within the tissues of the anterior cornea. The function of the protein is unknown.
Diagnosis
GLDL is a clinical diagnosis. Genetic testing is not widely available and does not alter clinical management. Molecular analysis of patients with ‘gelatino-lattice’ dystrophy—in which there are overlapping features of type I lattice dystrophy and GLDL—has revealed a mutation in BIGH3 (R124C, see lattice dystrophy) but none in M1S1. It is likely that this does not represent GLDL.
Corneal disease
7
Meesmann corneal dystrophy (also known as: juvenile familial corneal dystrophy) MIM
122100; 148043 (KRT3); 601687 (KRT12)
Clinical features
Meesmann dystrophy is an epithelial corneal dystrophy. Slit-lamp examination reveals multiple intra-epithelial microcysts and symmetrical, sharply demarcated, intra-epithelial opacities of uniform size that resemble vesicles. Fragility of the corneal epithelium leads to recurrent erosions, often by the end of the first or during the second decade. Patients describe photophobia and lacrimation particularly during acute episodes but reduction in vision is generally relatively mild. However, frequent recurrent erosions and extreme sensitivity to minor trauma (such as intolerance of contact lenses) ultimately leads to superficial corneal scarring and reduced visual acuity. This may be severe enough to warrant keratoplasty.
Epithelial microcysts in Meesman dystrophy.
Age of onset
Signs of the disease are present early in life and may well be congenital. However, symptoms may be delayed into the second or third decades.
Inheritance
Autosomal dominant
8
Meesmann corneal dystrophy
Chromosomal location
17q12 (KRT3); 12q13 (KRT12)
Gene
Cornea-specific keratins: keratin 3 (KRT3) and keratin 12 (KRT12).
Mutational spectrum
Missense mutations within the helix-initiation or helix-termination motifs of KRT3 or KRT12. The majority have been described in KRT12, within the helix-initiation region.
Effect of mutation
Mutations act in a dominant negative manner leading to defective epithelial cytoskeletal function and epithelial fragility. Ultrastructural examination reveals cytoplasmic densities, which are likely to represent tonofilament clumping as seen in other dominant keratin disorders. Keratin proteins are structurally important intermediate filaments found in epithelia. The family of proteins is divided into type I (acidic, K9–K21) and type II (neutral or basic, K1–K8) and their expression is tissue-specific. Keratins 3 and 12 are coexpressed (paired) to form a heterodimer which is specific to the corneal epithelium. Several inherited epidermal diseases, such as epidermolysis bullosa simplex, are caused by keratin mutations. Each protein contains a helical domain flanked by a helix-initiation motif and a helixtermination motif. These are highly conserved and thought to play important roles in filament assembly and stability; they are recognized as a mutation hotspot.
Diagnosis
Corneal disease
Diagnosis is usually clear from history and slit-lamp examination. Mutation analysis is available on a research basis only, and does not alter clinical management.
9
Bowman’s layer dystrophy type I (also known as: type I – CDBI; Reis-Bucklers corneal dystrophy/geographic granular dystrophy) MIM
121900; 601692 (TGFBI)
Clinical features
Accurate differentiation of the subforms of Bowman’s layer corneal dystrophy has been a cause of controversy and it is for these groups that genetic characterization has been particularly helpful. Bilateral geographic subepithelial opacities begin in the first decade. These are initially irregular and asymmetric but eventually become widespread and uniform. Recurrent erosions begin during the first 5 years of life. Visual reduction is severe and leads to surgery during the second to third decades.
CDB type 1. Geographic opacification which is not homogenous is seen beneath the Bowman’s layer.
Age of onset
10
CDB1 presents with recurrent erosions in the first decade of life.
Bowman’s layer dystrophy type I
Chromosomal location
5q31
Gene
Beta-Ig-H3/transforming growth factor, beta-induced (BIGH3/TGFB1).
Mutational spectrum
There is a tight genotype-phenotype correlation amongst mutations in the BIGH3 gene (see granular dystrophy). CDBI is caused by an R124L mutation in exon 4. A single Sardinian family has been described with Reis-Bucklers dystrophy, a trinucleotide deletion of exon 12 (∆F540).
Effect of mutation
The R124L mutation is thought to cause abnormal folding of the BIGH3 protein (see granular dystrophy).
Diagnosis
Slit-lamp examination may be sufficient for diagnosis, aided by histopathological examination of the diseased cornea after surgery. In CDBI there is accumulation of Masson trichrome positive material above Bowman's layer, but may also be present in the anterior stroma. The material is characterized by rod-shaped bodies on electron microscopy and has led to the condition being called ‘superficial granular dystrophy’. Since the different mutations causing the Bowman’s layer dystrophies have clear phenotypic effects, confirmation of the diagnosis by molecular testing may aid prediction of prognosis and speed of progression.
Corneal disease
11
Bowman’s layer dystrophy type II (also known as: Type II – CDBII; Thiel-Behnke corneal dystrophy/honeycomb corneal dystrophy) MIM
602082 (type II)
Clinical features
CDBII usually presents with frequent recurrent erosions within the first years of life. Bilateral superficial opacification in a honeycomb pattern develops during early adult life but visual acuity is less severely affected than in CDBI.
CDB type II or honeycomb dystrophy. Irregular, honeycombed opacification is seen at the level of the Bowman’s layer.
Age of onset
CDBII presents with recurrent erosions in the first decade of life.
Chromosomal location
5q31 (BIGH3) 10q24 (see below)
Mutational spectrum
As mentioned previously, there is a tight genotype-phenotype correlation amongst mutations in the BIGH3 gene (see granular dystrophy).
12
Bowman’s layer dystrophy type II
CDBII is caused by an R555Q mutation in exon 12. Confusion is added by the description of a family with a superficial corneal dystrophy (also called Thiel-Behnke dystrophy or CDBII) which is linked to chromosome 10q24 and is not caused by mutations in the BIGH3 gene. This suggests further, poorly delineated, heterogeneity amongst the superficial Bowman’s layer dystrophies. Effect of mutation
Mutations are thought to cause abnormal folding of the BIGH3 protein (see granular dystrophy).
Diagnosis
Slit-lamp examination may be sufficient for diagnosis. Histopathological examination of the diseased cornea after surgery will facilitate diagnosis. In CDBII, the Bowman’s layer is replaced by a fibrous, paucicellular layer of variable thickness between the epithelium and stroma. On electron microscopy this material demonstrates the presence of short, twisted ‘curly fibers’. Since the different mutations causing Bowman’s layer dystrophies have clear phenotypic effects, confirmation of the diagnosis by molecular testing may aid prediction of prognosis and speed of progression.
Corneal disease
13
Granular corneal dystrophy (also known as: Groenouw type I corneal dystrophy; CDGG1; Avellino-type corneal dystrophy) MIM
121900; 601692 (TGFBI)
Clinical features
Granular corneal dystrophy is characterized by the progressive development of discrete, grayish-white opacities within the central anterior corneal stroma. The condition is bilateral and symmetrical and the intervening stroma remains clear. The number of opacities increases with time and their position within the stroma deepens but the limbal region of the cornea is spared. Two main forms of granular dystrophy exist. Classical granular dystrophy Visual acuity often deteriorates during the third decade. Such a decline continues to a point where penetrating keratoplasty is required, often during the fifth decade of life. Corneal erosions are described in the condition but do not represent a major symptom. While penetrating keratoplasty is effective in improving vision the condition recurs, presumably as a result of deposition of granular material into the graft from the recipient’s epithelium. Histopathological examination of the diseased cornea after surgery reveals anterior stromal opacities which stain red with the Masson trichrome stain.
Granular corneal dystrophy.
14
Granular corneal dystrophy
Granular corneal dystrophy host corneal button stained with Masson trichrome to demonstrate red granular deposits within stroma.
Atypical granular dystrophy The atypical form has ring-shaped or snowflake-like granular deposits that are fewer in number than in the classical form. Grafting is seldom required as visual acuity is affected to a considerably lesser degree. This form of granular dystrophy, also known as Avellino dystrophy, was first described in a family from a small town in Italy. This is the prevalent form of granular dystrophy in SE Asia and Japan and has now been described in many different parts of the world.
Atypical granular (Avellino) dystrophy.
Corneal disease
15
Age of onset
In classical granular dystrophy, symptoms of photophobia are seen within the first decade with visual acuity remaining good during childhood. In the atypical form, symptoms may not present until the third decade.
Mutational spectrum
Mutations in the BIGH3 gene show very strong genotype-phenotype correlation. The classical form of granular corneal dystrophy is caused by an arginine to tryptophan substitution of amino acid 555 (R555W). Atypical, or Avellino, dystrophy is caused by an arginine to histidine substitution of residue 124 (R124H). A third mutation (R124S) has also been described in a late-onset form of granular dystrophy. The arginine residues at positions 124 and 555 are important in the development of a number of corneal dystrophies.
Effect of mutation
Both mutations are thought to cause abnormal folding of the BIGH3 protein which results in abnormal aggregates or deposits of the protein within the cornea. The BIGH3 protein is an extracellular matrix molecule, which is induced by TGFb. The protein is widely expressed and, in the cornea, is produced by the epithelium and stromal keratocytes. It is thought to be important in the wound-healing response although its exact function in the cornea is not yet defined. The granular deposits are identical in both forms of granular dystrophy (R555W and R124H). However, deposition of amyloid material, as observed in lattice corneal dystrophy, is seen in some cases of atypical granular dystrophy.
16
Granular corneal dystrophy
Atypical granular dystrophy – a teenage girl with severe granular-like corneal dystrophy. She is homozygous for the R124H mutation. Recurrences within the grafts were frequent and severe.
Diagnosis
Slit-lamp examination may be sufficient for diagnosis. Since the different mutations have clear phenotypic effects, confirmation of the diagnosis by molecular testing may aid the prediction of prognosis. While granular dystrophy is autosomal dominant, the condition is strictly semi-dominant: homozygous patients within consanguineous families (i.e. those with two affected parents) show a severe and early-onset form of the disease which shows rapid progression and marked, early visual loss. In these cases the disorder recurs rapidly within grafted tissue (see above).
Corneal disease
17
Lattice corneal dystrophy type I (also known as: LCD; lattice corneal dystrophy, type III/IIIa [LCDIII]) MIM
122200; 601692 (TGFBI)
Clinical features
LCD is characterized by the development of anterior stromal opacities. In LCDI these are gray, linear and fine, situated mainly within the central cornea. The intervening cornea remains clear initially but becomes progressively hazy. As in granular dystrophy, the opacities do not extend to the limbus. Erosions may begin early, even in childhood, while visual acuity is usually normal until early adulthood. Grafting is usually required from the third decade. Recurrence within the graft can lead to further visual deterioration. The histologic findings are of congophilic deposits that have the characteristics of amyloid protein. In some forms of autosomal dominant LCD, termed lattice corneal dystrophy type IIIa, the onset of symptoms is delayed until the fifth/sixth decade when there is visual deterioration and development of recurrent erosions. Examination demonstrates the appearance of sparse, thick rope-like lattice lines which are often asymmetrical unlike those of LCDI. Histological examination is indistinguishable.
Isolated LCD type I. Fine linear opacities are seen within the stroma.
18
Lattice corneal dystrophy type I
LCD type IIIa. Stromal lattice lines are said to be thicker in late onset forms of isolated LCD.
Age of onset
First decade of life in LCDI; fourth/fifth decades in LCDIIIa.
Mutational spectrum
To date, all analyzed forms of early-onset LCD (LCDI) have been caused by a single mutation (R124C) within exon 4 of the BIGH3 gene. Amongst later-onset forms of isolated lattice dystrophy a broader range of missense mutations exist, usually in the later exons of the gene. This explains at least some of the clinical, interfamilial heterogeneity seen amongst patients with isolated lattice dystrophy. BIGH3 mutations underlying dominant, late-onset forms of LCD have not been found to have any geographic or racial bias.
Effect of mutation
As with the other BIGH3-related dystrophies it is hypothesized that there is abnormal folding of BIGH3 which has amyloidogenic potential and aggregates within the cornea. Amyloid deposits in corneas from patients with lattice dystrophy have been shown on immunohistochemical analysis to co-localize with BIGH3.
Diagnosis
Slit-lamp examination and histologic examination of corneal buttons. Mutation analysis can facilitate the determination of prognosis.
Corneal disease
19
Lattice corneal dystrophy type II (also known as: amyloidosis V; Finnish-type amyloidosis; Meretoja-type amyloidosis) MIM
105120; 137350 (Gelsolin)
Clinical features
This is one of the inherited systemic amyloidoses and is characterized by corneal lattice dystrophy and cranial neuropathy.
Lattice corneal dystrophy type II. Dermal amyloid accumulation gives skin a waxy appearance. The skin is lax with fullness of lips and brow. Note that nostrils are held open with a nasal prong.
Ocular Slit-lamp examination demonstrates bilateral lattice corneal opacification. Recurrent erosions are not a feature of the disorder and visual deterioration develops later in life. Progressive corneal anesthesia is common and may lead to neuropathic ulceration as well as compromising the success of penetrating keratoplasty. Glaucoma, presumably secondary to amyloid accumulation in the trabecular meshwork, is a recognized complication. 20
Lattice corneal dystrophy type II
Dermal Amyloid accumulation gives the face a waxy appearance with a full brow and lower lip, and laxity similar to cutis laxa. The fullness of the lower lip leads to drooling, slurred speech and even an inability to eat, while the nostrils may become occluded. Neurological Abnormalities are common. Cranial neuropathy (especially of the facial nerve), peripheral polyneuropathy (mainly affecting vibration and touch senses) and minor autonomic dysfunction are frequent. Facial paralysis is progressive although extraocular muscles are not affected and there is no ptosis. Amyloid deposition is widespread and can also cause cardiac and renal symptomatology. Age of onset
Slit-lamp examination may reveal subtle lattice lines from the fourth decade onwards. At this stage mild neurological abnormalities, such as corneal hypoesthesia and facial paresis, may be detected. There may then be evidence of dermal changes in the face, particularly in the brow and lower lip.
Inheritance
Autosomal dominant
Chromosomal location
9q34
Gene
Gelsolin
Mutational spectrum
Two missense mutations of residue 187 (Asp187Asn and Asp187Tyr).
Effect of mutation
Gelsolin is part of the extracellular actin-scavenger system which prevents the toxic effects of actin release into the extracellular space during necrosis. It is required by those cell types involved in mediating responses to stress and apoptosis. If transfected into mammalian cultured cells, the pathogenic substitutions result in the secretion of an aberrant polypeptide which contains an amyloidforming sequence.
Corneal disease
21
Diagnosis
22
Amyloidosis V is one of the differential diagnoses of late-onset lattice dystrophy. Although it is of higher frequency in Finland, the diagnosis should not be dismissed in other parts of the world. Patients should be screened for potential complications: from an ophthalmic viewpoint screening for glaucoma should be instituted.
Lattice corneal dystrophy type II
Macular corneal dystrophy (also known as: MCDC; Groenouw type II corneal dystrophy) MIM
217800; 605294 (CHST6)
Clinical features
Macular corneal dystrophy is characterized by a diffuse corneal stromal clouding and reduction of corneal thickness by about one-third. The opacity is initially superficial but deepens with time and results in progressive visual deterioration. Recurrent erosions do not occur. Unlike the granular and lattice dystrophies, corneal clouding does not spare the limbal region. On examination there are ill-defined grayish-white stromal opacities between which the intervening stroma is hazy. After penetrating keratoplasty, histological examination of corneal buttons shows staining of abnormal deposits with alcian blue demonstrating the presence of lakes of glycosaminoglycans within the stromal matrix.
Macular corneal dystrophy. Stromal deposits cause corneal clouding without discrete opacities. A. Opacification reaches the limbus.
B. Recurrence within the grafts is rare.
Age of onset
Corneal opacities may be present from the first decade of life. Visual deterioration is variable and penetrating keratoplasty is usually indicated from the third and fourth decades. Recurrence in the graft is exceptional and is not sight-threatening.
Inheritance
Autosomal recessive
Corneal disease
23
Chromosomal location
16q22
Gene
Carbohydrate sulfotransferase 6 (CHST6), also known as corneal N-acetylglucosamine-6-sulfotransferase.
Mutational spectrum
Type I MCDC is characterized by absent sulfated keratan sulfate in serum. Inactivating mutations of CHST6, including missense frameshift and deletion mutations, are described. Type II MCDC is characterized by the presence of sulfated keratan sulfate, in serum. Large rearrangements in the 5´ region upstream of CHST6 have been defined.
Effect of mutation
CHST6 is thought to be important in the production of sulfated keratan sulfate, which is essential for the maintenance of corneal clarity. It is hypothesized that mutations in type I MCDC result in the inactivation of CHST6. In type II MCDC, loss of tissue-specific regulatory elements are thought to abolish CHST6 expression in the cornea.
Diagnosis
MCDC is diagnosed clinically. Genetic testing is available on a research basis only but does not generally alter clinical management; delineation of type I or type II MCDC is not important clinically or for genetic counselling.
24
Macular corneal dystrophy
Fuchs’ endothelial corneal dystrophy (also known as: FECD)
Including: Posterior polymorphous dystrophy (PPCD) MIM
136800 (FECD); 122000 (PPCD)
Clinical features
FECD is one of the most common indications for corneal transplantation (up to 19%) in developed countries. Symptoms of painful visual loss result from corneal decompensation. The development in the central cornea of focal wart-like guttae arising from Descemet’s membrane, which is thickened by abnormal collagenous deposition. There is reduced endothelial function and cell density as well as cellular pleomorphism. PPCD is characterized by formation of blister-like lesions within the corneal endothelium or by regions of endothelial basement membrane thickening with associated corneal edema. There is replacement of the normal amitotic endothelial cells by epitheliallike cells that possess abundant intermediate filaments, desmosomes and microvilli. The endothelium becomes multilayered and the abnormally proliferating cells may extend outwards from the cornea over the trabecular meshwork to cause glaucoma. In this regard PPCD resembles iridocorneal endothelial (ICE) syndrome.
Age of onset
In FECD signs may be present from the 4th decade of life onwards. PPCD although variable in both penetrance and expressivity usually presents earlier and may be symptomatic from childhood.
Inheritance
FECD is usually sporadic although this may be a reflection of its late onset. Highly penetrant dominant forms are described. PPCD is inherited in an autosomal dominant manner.
Chromosomal location
FECD: 1p34.3–p32 (COL8A2) PPCD: 20p11.2–q11.2 (VSX1)
Corneal disease
25
Gene
Collagen type VIII, alpha 2 (COL8A2)
Mutational spectrum
Missense substitutions of the X position of the Gly-X-Y triplet of the collagenous triple helical domain of the α2 chain of type VIII collagen have been described in families with early-onset and classical Fuchs’ dystrophy as well as in PPCD. Mutations were found in <10% of patients with FECD.
Effect of mutation
Type VIII collagen is a member of the short chain collagen-like family of proteins that also includes type X collagen. It comprises two α-chains, α1(VIII) and α2(VIII). Type VIII collagen is a major component of the hexagonal lattice of Descemet’s membrane. It is thought that mutations disrupt the stability of supramolecular assembly. Type VIII collagen is abnormally deposited in the corneas in both FECD and PPCD.
Diagnosis
26
Clinical
Fuchs’ endothelial corneal dystrophy
2 2. Lens
Cataract 28 Aculeiform cataract 32 Anterior polar cataract 34 Cataract-dental syndrome 35 Congenital cerulean cataract 36 Congenital zonular cataract with sutural opacities 38 Coppock-like cataract 39 Polymorphic and lamellar cataract 41 Posterior polar cataract 42 Zonular pulverulent cataract 43 Syndromic cataract Hyperferritinemia-cataract syndrome 45 Lowe oculocerebrorenal syndrome 46 Myotonic dystrophy 49 Lens subluxation Marfan syndrome 52
Cataract Congenital, infantile cataract is estimated to have a prevalence of 1–3 cases per 10,000 live births. A large proportion of early-onset (i.e. non-senile) bilateral cataract, perhaps around 50%, is inherited. Although lens opacity is often an isolated finding, it may represent one feature of a great number of inherited conditions. Consequently the genetics of cataract is extremely complex. In developed countries around one-quarter to one-third of infantile cataract is autosomal dominant (autosomal dominant congenital cataract, ADCC). Because of this, examination of the parents and siblings of children with isolated congenital cataracts is mandatory. Variable expressivity and reduced penetrance are common. However, there is evidence, both in man and from studies of homologous forms of cataract in mice, that the morphology of lens opacity is often remarkably consistent within families. Examination and delineation of the clinical phenotype may help in diagnosis, in defining prognosis for other family members and directing molecular analysis of the different cataract subtypes. ADCC is highly heterogeneous and numerous genetic forms have been identified (see Table 2.1). Clinical delineation of the different forms of cataract depends upon the site of the opacities and their form. The form of opacities is usually a descriptive term such as pulverulent (dust-like), wedge-shaped, cerulean (blue-dot) or aculeiform (needle or crystal-like). The position of the opacity is also important (see Figure 2.1). Since the secondary lens fibers are deposited in a concentric manner, lamellae are formed within the lens. Opacification that is confined to a specific lamella is presumably produced during a discrete period of development. Other positional lens opacities include cortical opacities and sutural opacities, which occur at the anterior and posterior Y suture of the lens.
28
Cataract
Table 2.1. ADCC, reported loci and causative genes. Morphology of cataract Locus Gene
Chromosomal
Number of
Volkmann Zonular pulverulent Posterior polar Aculeiform Coppock-like Juvenile, progressive punctate Variable zonular pulverulent Juvenile/congenital Polymorphic/lamellar Zonular pulverulent Sutural “pouch-like” Marner/zonular Anterior polar Zonular with sutural opacity Cerulean Posterior polar Zonular nuclear Coppock-like Cerulean
location 1pter–p36.13 1q21–q25 11q22–q22.3 2q33–q35 2q33–q35 2q33–q35 2q33–q35 3q21–q25 12q14 13q11 15q21 16q22.1 17p13 17q11.1–q12 17q24 20p12–q12 21q22.3 22q11.2 22q11.2
families 1 2 1 2 1 1 1 2–3 2 3 1 1 1 2 1 1 1 1 1
CCV CZP1 CTPP2 CACA CCL CZP3 CAM CTAA2 CCZS CCA1 CPP3 CCA2
GJA8 CRYAB CRYGD CRYGC CRYGD CRYGC BFSP2 MIP GJA3 CRYBA1 CRYAA CRYBB2 CRYBB2
Cortex
Capsule
Anterior pole
Posterior pole
Embryonic nucleus Antero-posterior section
Fetal nucleus Cross section
Figure 2.1. The human lens.
Lens
29
Relatively few large kindreds and/or mutations have been described in detail. As a result, little information is available on the range of variability of genetic defects within, and between, different families and different genetic loci. In this chapter, the clinical details describe the range of morphologies and, where appropriate, the different forms of cataract ascribed to different loci. In addition, loci for which at present there is only linkage information (e.g. posterior polar cataract) are included in Table 2.1. However, it should be noted that as many different clinicians have described the clinical features of each disorder there is often inconsistency in their descriptions. Until now, identification of the genetic basis of ADCC has followed a candidate gene approach, targeting genes expressed in the lens. Defects have been identified in the crystallin genes, several highly expressed, membrane-bound, lens-specific genes (GJA3 and 8, MIP) and one of the major lens cytoskeletal elements (BFSP2). While these are important, the small number of families identified for each form suggest that much is still to be learned about human, inherited ADCC. In the Third World, childhood cataract (as with other causes of childhood blindness) is more common than in the developed world and this holds true for inherited forms of cataract, which is likely to be a reflection of increased levels of consanguinity in different populations. This suggests that autosomal recessive congenital cataracts (ARCC) are an important and as yet under-recognized entity. The molecular bases of ARCC are now being defined. One form results from a mutation in one of the a crystallin genes. Linkage has also been defined for a second form to 9q13–q22 (see Table 2.2). Table 2.2. ARCC, reported loci and causative genes. Morphology of cataract Locus Gene Recessive Pulverulent Recesssive progessive
CAAR CRYAA
CRYAA
Chromosomal location 3q 9q13-q22 21q22.2
Recessive presenile
LIM2
LIM2
11q22-q22.3
30
Number of families 6 1 1 1
Cataract
Pulverulent cataract.
Anterior polar cataract.
Congenital lamellar cataracts.
Aculeiform cataract.
Lens
Sutural cataract.
31
Aculeiform cataract (also known as: CACA) MIM
115700; 123690 (CRYGD)
Clinical features
Aculeiform cataract is characterized by needle-like crystals projecting in different directions, through or close to the axial region of the lens. The opacity does not respect sutures or the direction of lens fibers and appears to originate from the fetal and postnatal nuclei, suggesting a congenital origin with postnatal progression. Congenital crystal-forming cataracts have also been described in which multiple, fine, longitudinal crystals are found throughout the lens.
Age of onset
Cataract may be present at birth or noted during infancy.
Inheritance
Presumed autosomal dominant
Chromosomal location
2q33–q35
Gene
gD Crystallin (CRYGD)
Mutational spectrum
Two missense mutations in the gD crystallin, the most abundant of the g crystallins, have been shown to have differing phenotypes associated with crystal formation. The heterogeneous nature of ADCC is underlined by the observation that a congenital non-crystalline, punctate, progressive juvenile cataract is also caused by a missense mutation in CRYGD. Unlike many ADCC, these were not apparent at birth but were observed in the first year or two of life. The opacification was progressive and necessitated removal in childhood/early adolescence.
Effect of mutation
32
Presumed dominant negative mutations
Aculeiform cataract
Crystalline cataract Both mutations lead to crystal formation within the lens. Analysis demonstrated that they were crystals of CRYGD, in which the abnormal protein is normally folded but abnormally packed within the crystals. Punctate, progressive juvenile cataract A missense substitution, which does not affect protein folding, is thought to alter its surface properties.
Lens
33
Anterior polar cataract (also known as: CTAA2) MIM
601202
Clinical features
Anterior polar cataracts, small opacities on the anterior surface of the lens, do not usually interfere with vision as they are significantly removed from the nodal point of the eye. Anterior polar cataracts have also been described in association with forms of anterior segment dysgenesis as well as Fuchs’ endothelial corneal dystrophy.
Age of onset
Anterior polar cataract may be present at birth or noted during infancy.
Inheritance
While autosomal dominant forms are recognized, anterior polar cataracts have been described in consanguineous families, suggesting that the condition may also be autosomal recessive.
Chromosomal location
17q13 (type II, linkage only)
Gene
Unknown
Effect of mutation
Unknown
34
Anterior polar cataract
Cataract-dental syndrome (also known as: Nance-Horan syndrome [NHS]; X-linked cataract with Hutchinsonian teeth) MIM
302350
Clinical features
Affected males have dense nuclear cataracts and often have microcornea. Carrier females may show posterior Y-sutural cataracts and only slightly reduced vision. Dental anomalies include irregular diastema, cone-shaped incisors and supernumerary teeth (including a central, supernumerary upper incisor). Screwdriver incisors are found in heterozygotes. Affected males have prominent anteverted pinnae and short metacarpals. It is suggested that intellectual handicap or developmental delay is a feature in about one-third of patients. In most cases this is mild or moderate (80%) and not associated with motor delay. Severe handicap associated with autistic traits has been described. X-linked inheritance has been suggested in many kindreds with isolated cataract, but rarely proven. However, a single kindred with 'isolated cataract' has been mapped to the Nance-Horan region, suggesting that there may be a variety of X-linked cataract syndromes.
Age of onset
Congenital
Inheritance
X-linked recessive
Chromosomal location
Xp22.3–p21.1
Gene
Unknown
Effect of mutation
Unknown
Lens
35
Congenital cerulean cataract (also known as: CCA; congenital ‘blue-dot’ cataract) MIM
115660
Clinical features
Cerulean cataracts comprise predominantly peripheral blue/white opacities which are seen in concentric layers. The opacities are observed in the superficial layers of the fetal nucleus as well as the adult nucleus of the lens. Visual acuity is often only mildly reduced in childhood. Opacification is progressive and may lead to later lens extraction.
Age of onset
Cataract may be present during infancy. Symptoms may not begin until adult life.
Inheritance
Autosomal dominant
Chromosomal location
17q24 (Type I, CCA1, linkage only); 22q11.2 (Type II, CCA2)
Gene
CCA1 – unknown CCA2 – βB2 crystalin (CRYBB2)
Mutational spectrum
A single mutation resulting in the production of a polypeptide lacking the terminal 55 amino acid residues. This mutation has been shown to cause Coppock-like cataract in a second family.
Effect of mutation
Semi-dominant, resulting in protein truncation. It is not known whether this allows the formation of a functionally active mutant protein. A 12 bp, in-frame deletion in bB2 crystallin (CRYBB2) in the Philly mouse underlies an inherited mouse model of cataract. In this case, the mutation causes disruption of the tertiary structure of the protein.
36
Congenital cerulean cataract
Diagnosis
Lens
As with other forms of inherited human cataract, information is sparse regarding variability of mutations in the CRYBB2 gene. That the identical mutation causes cataract of different morphology and severity in different families suggests the heterogeneity exists amongst mutations at this locus. In one branch of the family with CCA2, an affected family member was the daughter of affected first cousins. She had bilateral microphthalmos and microcornea at birth. Severe cataracts required extraction by the age of 5 years and she lost all visual perception by adolescence. This suggests that the disorder is more severe in the homozygous state (i.e. partial or semi-dominant).
37
Congenital zonular cataract with sutural opacities (also known as: CCZS) MIM
600881; 123610 (CRYBA1)
Clinical features
Lamellar cataract with opacification of the Y-shaped sutures that represent the juxtaposed ends of the secondary lens fibers. There is considerable intrafamilial variability.
Age of onset
Congenital
Inheritance
Autosomal dominant
Chromosomal location
17q11–q12
Gene
βA1 crystallin (CRYBA1)
Mutational spectrum
A deletion of exons 3 and 4 as well as a splice-site mutation have been demonstrated in CRYBA1.
Effect of mutation
Not defined. The deletion would result in a significantly shortened protein consisting only of the C-terminal domain. In this case, it is not known whether the protein is formed, or whether the mutation results in haploinsufficiency. A mutation in the mouse homolog also causes cataract.
38
Congenital zonular cataract with sutural opacities
Coppock-like cataract (also known as: CCL; cataract embryonic nuclear) Including: variable zonular pulverulent cataract. MIM
604307; 604219 (variable zonular pulverulent cataract)
Clinical features
Dust-like lens opacities are mainly located within the fetal nucleus (central pulverulent) and do not affect the total nucleus. The absence of significant cortical lamellar opacities renders the cataract smaller than zonular pulverulent cataract (q.v.) and therefore causes a milder phenotype. A family described with variable dominant zonular pulverulent cataract demonstrates the intrafamilial variability within ADCC. Two-thirds had unilateral cataract of variable morphology including zonular and nuclear pulverulent cataract or dense nuclear cataracts that required early surgical removal.
Age of onset
Cataract is usually present at birth or develops during infancy.
Inheritance
Autosomal dominant. It has been suggested that there may be autosomal recessive forms (see below).
Chromosomal location
2q33–q35: γ3 crystallin (CRYGC)
and genes
22q11.2: βB2 crystallin (CRYBB2) (see page 36 for congenital cerulean cataract, Type II).
Mutational spectrum
The first family with Coppock-like cataract to be characterized at the molecular level resulted from a mutation in CRYGC. However, Coppock-like cataract is heterogeneous and a mutation in the βB2 crystallin gene has also been shown to cause Coppock-like cataract. Two mutations have been described in CRYGC that further show the variability within and between families for ADCC. In Coppock-like cataract a conserved missense substitution (thr5-to-pro) has been
Lens
39
described which would result in altered folding of the protein. In variable dominant zonular pulverulent cataract a 5 bp exon 2 duplication insertion was found within the gene. Effect of mutation
The gamma crystallins are a family of seven genes which encode major structural proteins of the lens. The g-crystallin proteins are folded into two domains containing a ‘Greek-key’ motif. Pathological effects of missense and nonsense mutations are therefore likely to be different and may explain the variability of phenotype.
Diagnosis
40
Clinical examination. Although most families follow a dominant pattern of inheritance, the description of Arab siblings with bilateral Coppock cataracts born to unaffected parents who were first cousins suggests that this phenotype may also be autosomal recessive.
Coppock-like cataract
Polymorphic and lamellar cataract MIM
154050; 604219 (MIP)
Clinical features
Autosomal dominant cataracts may show intrafamilial variability in severity and morphology. This is illustrated by two families with variable phenotypes shown to have a similar genetic basis. In the first family, affected individuals had congenital, progressive, punctate lens opacities limited to mid- and peripheral lamellae; some individuals had asymmetric anterior and posterior polar opacification. In the second family, affected members had congenital, fine, non-progressive lamellar and sutural opacities.
Age of onset
Cataract present at birth or noted during infancy
Inheritance
Autosomal dominant
Chromosomal location
12q13
Gene
Major intrinsic protein of the ocular lens fiber membrane (MIP); aquaporin O (AQPO).
Mutational spectrum
Missense mutations within conserved residues of transmembrane domain 4 of MIP.
Effect of mutation
Presumed dominant negative mutations. MIP is primarily expressed in the lens and has been shown to be defective in the mouse Fraser cataract. It is a member of the aquaporin family of membrane-bound water channels and it is predicted that the mutations alter water flux across the lens cell membranes.
Lens
41
Posterior polar cataract (also known as: CTPP) MIM
116600 (CTPP1); 123590 (CTPP2 – CRYAB); 605387 (CTPP3)
Clinical features
Posterior polar cataract may have a marked effect on visual acuity due to its location close to the optical center of the eye.
Age of onset
Among the families with isolated posterior polar cataract, the opacity is often present either at birth or soon afterwards. Often the site of the opacity remains very localized.
Inheritance
Autosomal dominant
Chromosomal location
1pter–p36.1 (CTPP1, single family) 11q22.3–q23.1 (CTPP2 [CRYAB] single family) 20p12–q12 (CTPP3)
Gene
CTPP2 – αB crystallin (CRYAB)
Mutational spectrum
A single frameshift mutation (450delA) that produces an aberrant protein from amino acid 149.
Effect of mutation
While the exact effect of this mutation is unknown it is suggested that protein aggregation as well as the chaperone activity of the protein is affected. The αB crystallin is a member of the small heat-shock protein family of molecular chaperones that protect other proteins under conditions of stress.
42
Posterior polar cataract
Zonular pulverulent cataract (also known as: CZP) CZP1 is said to be the first inherited disease to be linked to a human autosome. (Linkage to Duffy was described in 1963). The location of the Duffy locus on 1q was established in 1968. MIM
116200 (CZP1); 601885 (CZP3)
Clinical features
Zonular pulverulent lens opacities are located in what is thought to be the embryonic and fetal nucleus. There are innumerable scattered, powdery opacities in the nucleus with similar opacities in a lamellar distribution. There may also be more superficial cortical opacification.
Age of onset
Cataract is present at birth or develops during infancy. Surgery is usually required in early childhood.
Inheritance
Autosomal dominant
Chromosomal location and genes
MIM 121015 600897
Mutational spectrum
Two missense mutations have been described within the connexin (CX) 50 gene. Three missense mutations have been described within the CX46 gene.
Effect of mutation
Dominant negative
Locus CZP1 CZP3
Chromosome 1q21.1 13q11
Gene GJA8 GJA3
Other gene titles CX50 CX46
CX50 forms multimeric gap junction channels that are thought to maintain the homeostatic environment of, in particular, mature lens fibers. Mutant isoforms have been shown to abolish gap junction conductance. The mouse knockout develops a sharply demarcated particulate nuclear cataract and microphthalmia.
Lens
43
CX46 is also thought to be critical in maintaining the internal homeostasis of lens fibers and may even form heteromeric gap junction channels with CX50. In the mouse knockout, nuclear cataracts are associated with the proteolysis of crystallins. This has been shown to be dependent on the genetic background of the mouse, suggesting that genetic variability may exist amongst forms of cataract caused by CX46 abnormalities.
44
Zonular pulverulent cataract
Hyperferritinemia-cataract syndrome (also known as: hereditary hyperferritinemia with congenital cataracts) MIM
600886; 134790 (ferritin light chain)
Clinical features
Congenital nuclear cataract is associated with an elevated serum ferritin that is not related to iron overload. Hematological investigation reveals normal serum iron and transferrin saturation in the presence of a high serum ferritin. Red cell count is normal and venesection results in anemia. In suspected hemochromatosis cases, liver biopsy has shown faint iron staining and accumulation of light (L)-rich ferritins.
Age of onset
Affected members may have early-onset bilateral cataract in which there are dust-like spots (pulverulent cataract) throughout the lens with variable effects. Some patients remain asymptomatic into adulthood, while others require surgery in the first years of life.
Inheritance
Autosomal dominant
Chromosomal location
19q13.3–q13.4
Gene
Ferritin Light Chain (FTL)
Mutational spectrum
Mutations within the 5´, non-coding iron responsive element (IRE) have been described amongst 11 families.
Effect of mutation
Ferritin is the main iron-storing molecule, which comprises 24 subunits of two types: heavy (H) and light (L). Ferritin synthesis is regulated at the transcriptional level by the binding of a cytoplasmic protein, iron responsive protein (IRP), to the IRE of the FTL mRNA. When iron supply to the cell is reduced, the IRP binds to the IRE and represses ferritin synthesis. Mutations in the IRE lead to excess ferritin production which accumulates within tissues leading to hyperferritinemia and cataract.
Diagnosis
Diagnosis of this rare condition may be suspected among patients with hyperferritinemia with no evidence of hemochromatosis.
Lens
45
Lowe oculocerebrorenal syndrome (also known as: OCRL; Lowe syndrome) MIM
309000
Clinical features
Lowe oculocerebrorenal syndrome is an X-linked disorder involving the eyes, kidney and nervous system that is caused by loss of function in the OCRL1 gene.
Dense cataract in boy with OCRL.
Posterior capsular plaque in female OCRL carrier.
Ocular Congenital cataracts (100% of affected males), glaucoma (50% of affected males), corneal degeneration and strabismus. Although the risk of glaucoma lessens considerably after the first year, it may develop even after 10 years of age. Nystagmus and macular hypoplasia are common. Female carriers have significant numbers (>100 in each eye) of small, irregularly shaped, off-white, radially arrayed, peripheral cortical lens opacities. Often there are areas (‘clock hours’) with a relatively high density of opacities, whilst other areas are relatively spared. The opacities are more common in the anterior cortex. There may also be visually significant posterior polar lens opacities. Ocular examination may help to identify these phenomena.
46
Lowe oculocerebrorenal syndrome
Extraocular Hypotonia is present at or soon after birth, and motor development is delayed. Hypermobile joints are also common with about 50% of affected boys developing scoliosis. Short stature is common. Intellectual impairment varies widely; around 50% of individuals are severely delayed and 25% are in the mild to moderate range of mental retardation. Seizures occur in about 50% of patients. Day-to-day functioning is often impaired by characteristic behavior patterns. Boys have a characteristic facial appearance with frontal bossing, a hypotonic appearance and sunken eyes. Renal tubular dysfunction usually becomes apparent by 1 year of age and progresses to renal failure (a major cause of premature death) from about 10 years. As a result, vitamin D resistant rickets is common. Age of onset
Congenital
Inheritance
X-linked recessive
Chromosomal location
Xq26.1
Gene
OCRL1
Mutational spectrum
A large number of mutations have been described. Nonsense/ premature terminations form around 50% of mutations. Around 70% of missense mutations are found within conserved residues of exon 15.
Effect of mutation
It is likely that most mutations lead to loss of function. The OCRL1 gene encodes a polypeptide that is similar to human inositol polyphosphate 5-phosphatase, a ubiquitously expressed enzyme which is localized in the Golgi apparatus. The enzyme converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. Abnormalities of inositol metabolism/transport have been implicated in the pathogenesis of cataracts in galactosemia and diabetes mellitus.
Lens
47
Diagnosis
Although the condition may be suspected on clinical grounds and supported by abnormal urine amino acids, definitive diagnosis can now be confirmed by testing for the presence of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in fibroblasts. Detection of enzyme activity in amniocytes allows for prenatal diagnosis. Mutation testing may supplement biochemical analysis but is generally only available on a research basis. While most of the counselling issues regarding Lowe syndrome are likely to be dealt with by clinical geneticists, the ophthalmologist may be directly involved with carrier detection. In experienced hands this is highly sensitive, although the lens opacities are not in themselves pathognomonic of the condition.
48
Lowe oculocerebrorenal syndrome
Myotonic dystrophy (also known as: DM; dystrophia myotonica 1) MIM
160900
Clinical features
Ocular Cataract is the cardinal ocular feature of DM. Due to the variable nature of the condition as it passes from generation to generation (genetic anticipation, see below), cataract in older patients may be the presenting feature in a family. The characteristic feature is the ‘Christmas tree’ cataract in which there are multiple refractile colored opacities throughout the lens. These may be progressive and become associated with cortical or posterior subcapsular lens opacification. While retinal findings have been described in DM, including macular pigmentary disturbance and mild ERG changes, these are seldom visually significant. As the disease progresses muscle weakness can lead to ophthalmoplegia. Extraocular In the classical form, patients develop muscle weakness (particularly distal) and wasting. The typical impassive (myotonic) faces are due to facial muscle weakness, and are associated with frontal balding and ptosis. Myotonia (inability to relax muscles voluntarily, particularly in the cold) may interfere with daily activities such as using tools and household equipment. Smooth muscle involvement may produce dysphagia and gastrointestinal symptoms. DM seldom progresses to the point where the patient is confined to a wheelchair. Cardiac conduction abnormalities and cardiomyopathy are common and are a significant cause of early mortality. Affected females risk giving birth to children with congenital DM. Such infants may present before birth with polyhydramnios and reduced fetal movement. After birth the main features are severe generalized weakness, hypotonia and respiratory compromise.
Lens
49
In these children, mortality from respiratory failure is high but surviving infants experience gradual improvements in motor function. Mental retardation is present in 50–60% of such patients. Age of onset
The age of onset for classical myotonic dystrophy is typically in the second to third decades, although there may be subtle features evident in childhood.
Epidemiology
An approximate prevalence of 1:20,000 is estimated worldwide.
Inheritance
Autosomal dominant. The condition shows anticipation (increase in severity of disease symptoms and/or a decrease in age of onset of the relevant phenotype). When passed on by a female, the abnormal DM gene expansion may enlarge further since it is unstably transmitted through female meiosis. Since larger alleles have a more severe phenotypic effect, DM is likely to show increased severity as it passes through the generations. Data concerning the likelihood that an affected mother will have an offspring with a particular size CTG repeat or phenotype are useful in recurrence risk counselling.
Chromosomal location
19q13
Gene
Dystrophia myotonica protein kinase (DMPK)
Mutational spectrum
Within the non-coding portion of the gene there is a CTG trinucleotide repeat region (i.e. CTGCTGCTG……CTG). In normal individuals there are 5–37 CTG trinucleotides arranged in tandem. Expansions of 50–150 copies are seen in those with mild DM. Those with classical DM carry one allele with around 100–1000 copies, while those with congenital DM carry >1000.
Effect of mutation
DMPK is an intracellular protein found within heart and skeletal muscle in structures associated with intercellular conduction and impulse transmission. The effects of the CTG repeat are uncertain; it may be that the CTG repeat causes abnormal DMPK mRNA
50
Myotonic dystrophy
processing. In addition, the expansion may alter expression of genes close to DMPK. For example the SIX5 gene, which is nearby on chromosome 19, causes cataracts in the mouse when disrupted— it has been hypothesized that alteration of SIX5 expression may cause the cataracts in DM. Diagnosis
When cataract secondary to DM is suspected clinically, neurological investigation is indicated. Molecular analysis will enable detection of an abnormal repeat expansion. Since DM is, in its classical form, an adult-onset and progressive condition, the advent of genetic testing carries with it the potential hazards of presymptomatic diagnosis. In general this should not be undertaken by those unfamiliar with the recognized protocols for dealing with such circumstances. Surgery carries additional hazards in DM patients; some patients experience respiratory depression in response to benzodiazepines, opiates and barbiturates. Myotonia may be increased by depolarizing agents.
Lens
51
Marfan syndrome (including isolated ectopia lentis) (also known as: MFS1) MIM
154700; 129600 (isolated ectopia lentis); 134797 (fibrillin 1)
Clinical features
MFS1 is a multisystemic connective tissue disorder characterized in particular by skeletal, cardiac and ophthalmic manifestations. A positive diagnosis requires the presence of sufficient major features of the disorder in at least two categories (family history, cardiac, ocular, skeletal, pulmonary or spinal).
Lens subluxation in Marfan syndrome.
Ocular The major ophthalmic feature of MFS1 is displacement of the crystalline lens. Congenital upwards subluxation is common although this may be in any direction. Pupillary displacement may occur and occasionally zonules may be defective segmentally and seen only on pupil dilatation. Patients are often myopic resulting from alteration of lens shape, increased axial length and/or relative corneal flattening. Those with higher axial lengths and/or lens dislocation are at increased risk of retinal detachment. An autosomal dominant form of ectopia lentis has been described in which patients do not show the cardiac manifestations of MFS1, although there may be mild skeletal signs of the condition (e.g. arachnodactyly).
52
Marfan syndrome (including isolated ectopia lentis)
Extraocular MFS1 can affect a wide range of organ systems. Patients are generally tall, thin and often describe an inability to increase weight. A wide range of skeletal features are associated with MFS1. These include increased height with disproportionately long limbs (arm span = [>1.05] x height; the upper to lower segment ratio is reduced), arachnodactyly, pectus abnormality, pes planus, significant scoliosis, reduced elbow extension, and a narrow, highly arched palate. While these skeletal features are strong indicators of the disorder, many are also common among the normal population and sufficient features must be present to differentiate true MFS1 from those with a ‘Marfanoid habitus’.
Arachnodactyly.
Lens
53
Marfanoid habitus.
Lumbar striae.
The major complication of MFS1 is aortic root dilatation leading to aortic dissection or development of a thoracic aortic aneurysm. Mitral valve prolapse and regurgitation are also common. Patients with MFS1 may have a history of spontaneous pneumothorax. These result from apical pulmonary blebs. Patients with MFS1 often have striae (‘stretch marks’) which can be extremely prominent over the lumbar region and reflect both rapid growth and skin fragility. On MRI of the lumbosacral spine, dural ectasia is a common finding that represents a major criterion of high specificity and sensitivity. Family history
A family history of MFS1 or of a fibrillin gene defect are both important positive indicators that diagnostic criteria in first-degree relatives indicates true Marfan syndrome.
Epidemiology
Marfan syndrome has an incidence of 1:15,000–25,000 births
Age of onset
Lens luxation is of early-onset and patients may present with reduced vision during childhood. Infrequently, children with de novo fibrillin mutations may be born with ‘congenital Marfan syndrome’, in which they have loose skin, cardiac malformations and pulmonary emphysema. Skeletal features of MFS1 develop as the child grows.
54
Marfan syndrome (including isolated ectopia lentis)
Inheritance
Autosomal dominant with highly variable expression.
Chromosomal location
15q21.1
Gene
Fibrillin 1 (FBN1)
Mutational spectrum
A broad range of mutations throughout the FBN1 gene have been described. The majority are family-specific and are missense changes. There is little genotype-phenotype correlation. Mutations in exons 59–65 may be more likely to be associated with a mild phenotype than those in earlier exons, but this is not a sufficiently close relationship to be clinically useful. Mutations in neonatal MFS1 cluster around exons 24–32.
Effect of mutation
The FBN1 gene is large (~110 kb) and comprises 65 exons, which makes mutation testing highly labor-intensive. The gene encodes a 2871 amino acid protein that contains 47 tandem EGF domains, suggesting a role in protein-protein and cell-cell interactions. Fibrillin is a large ubiquitously distributed connective tissue glycoprotein, which is the major component of extracellular microfibrils. Elastic fibers are complex structures that comprise elastin, 10–12 nm microfibrils, lysyl oxidase and proteoglycans. The microfibrils consist of several proteins, one of which is fibrillin. Microfibrils associated with amorphous elastin are found in skin, lung, kidney, blood vessels, cartilage and tendons. In addition, they are found without elastin in the ciliary zonules. Microfibril function is poorly defined but it is suggested that they act as scaffolding for elastic fibers as well as potentially anchoring them to cells.
Diagnosis
Lens
MFS1 can lead to reduced life-expectancy from progressive aortic root dilatation, dissection or rupture, or valvular regurgitation which impairs cardiac function. Progression of the cardiac complications can be slowed in response to medical treatment (reducing blood pressure, slowing heart rate) and through avoidance of excessive physical activity. These should be monitored during high-risk periods such as pregnancy. 55
MFS1 shows a high degree of inter and intrafamilial variability in clinical expression. Furthermore, a number of conditions mimic MFS1 including MASS phenotype (Mitral valve prolapse, mild Aortic root dilatation, Skin involvement (striae) and Skeletal findings). As a result it is often difficult to make a positive diagnosis of MFS1 or to exclude the condition. There have been several attempts to classify the clinical findings of Marfan syndrome but none are entirely satisfactory (e.g. revised or ‘Ghent’ criteria: De Paepe, 1996). Molecular genetic analysis is not available on a routine basis, but may supplement clinical investigation. Mutation testing is unsuccessful in the majority of borderline cases and may only define a mutation in 70% of definite familial cases. A definitive diagnosis will commonly rely upon careful clinical examination (skeletal, ophthalmic and cardiovascular) and targeted investigation (e.g. ECG, CXR and MRI of the spine).
56
Marfan syndrome (including isolated ectopia lentis)
3 3. Glaucoma
Primary glaucomas Primary congenital glaucoma 58 Juvenile primary open angle glaucoma 61 Primary open angle glaucoma 63 Secondary glaucomas Aniridia 65 Anterior segment mesenchymal dysgenesis 68 Glaucoma-related pigment dispersion syndrome 70 Iridogoniodysgenesis 72 Nail-patella syndrome 74 Rieger syndrome 77 Rubinstein-Taybi syndrome 79
Primary congenital glaucoma (also known as: GLC3; primary congenital glaucoma; buphthalmos) Including: Peters' anomaly. MIM
601771 (CYP1B1)
Clinical features
Primary infantile glaucoma is not associated with extraocular manifestations or other ocular abnormalities. It is thought to be due to abnormal development of the drainage angle of the anterior chamber. Symptoms are of corneal enlargement or clouding, excessive tearing, photophobia or general malaise. The condition is usually bilateral although asymmetry is common.
Congenital glaucoma with corneal enlargement.
Congenital glaucoma with splits in Descemet membrane.
Age of onset
Onset is at birth or soon afterwards. Over 80% are symptomatic by 3 months of age.
Epidemiology
Incidence of 1:10,000
Inheritance
Autosomal recessive
58
Primary congenital glaucoma
Chromosomal location MIM Locus Gene Chromosome 231300 GLC3A CYP1B1 2p22–p21 600975 GLC3B 1p36.2–p36.1 GLC3C* Unknown * Around 60% of families with more than one affected individual demonstrate linkage to GLC3A. Around 50% of the non-GLC3A families are also not linked to GLC3B; linkage to a third specific region is undefined. Gene
Cytochrome P450B1 (CYP1B1)
Mutational spectrum
A large number of mutations has been described including protein truncating mutations, as well as missense mutations, of the conserved domains of the protein. Studies of an inbred population in Saudi Arabia, where primary infantile glaucoma is common, suggest that mutations in CYP1B1 show reduced penetrance and expressivity. A defect in CYP1B1 has been demonstrated in a single patient with bilateral congenital glaucoma and bilateral Peters’ anomaly. The individual carried two CYP1B1 mutations (compound heterozygote), one nonsense (protein truncating) and the other was likely to abolish translation. This finding underlies the phenotypic heterogeneity of individuals carrying mutations in this gene.
Effect of mutation
CYP1B1 is a member of the cytochrome P450 multigene superfamily, whose role is the physiological inactivation of both endogenous and exogenous substrates. CYP1B1 is the first of these enzymes identified to be involved in a developmental process and its role in ocular development remains unclear. Both protein truncation mutations and missense mutations in the heme-binding region have been described; it is thought that both may result in reduced heme binding, which is critical for the functioning of cytochrome P450 molecules.
Glaucoma
59
Diagnosis
60
Clinical. Mutation testing is available on a research basis only. Younger siblings of children with primary congenital glaucoma should be examined soon after birth for evidence of glaucoma.
Primary congenital glaucoma
Juvenile primary open angle glaucoma (also known as: open angle glaucoma type 1a [GLC1A]; juvenile-onset primary open angle glaucoma [JOAG]) MIM
137750; 601652 (myocilin)
Clinical features
Early onset POAG. Individuals do not develop buphthalmos and have normal anterior segment examination. Intraocular pressure may be high—often over 50 mmHg. Patients are often myopic and invariably require filtration surgery.
Grossly cupped disc in POAG.
Age of onset
JOAG typically affects children in their teenage years. Mean age at diagnosis in one study was 18 years, although onset from the age of 3 years is described.
Inheritance
Autosomal dominant with high penetrance (80–100% by age 20 years). One family with autosomal recessive JOAG has been described (see below).
Chromosomal location
Glaucoma
1q24.3–q25.2 Some families with juvenile POAG do not map to this region.
61
Gene
Myocilin (MYOC); alternative name: trabecular meshwork-induced glucocorticoid response protein gene (TIGR).
Mutational spectrum
JOAG – autosomal dominant MYOC is a widely expressed gene that encodes a 504-amino acid protein. The gene contains three exons. Exon 3 encodes a conserved C-terminal homologous to frog olfactomedin, an extracellular matrix glycoprotein of the olfactory epithelium. Mutations have been described in a number of families with JOAG–these are generally missense mutations within the conserved exon 3 domain. JOAG – autosomal recessive Recessive families with JOAG associated with homozygous proteinterminating MYOC mutations have been reported. These are associated with loss of function of MYOC. Adult-onset POAG The impact of MYOC mutation on more common forms of adultonset POAG has been extensively investigated. One study examined 1700 individuals from five populations and found MYOC mutations in 3–4% of adult POAG individuals. One mutation, Gln368Ter, is common and accounts for ~1.5% of all POAG.
Effect of mutation
Myocilin was originally shown to be upregulated by the administration of corticosteroids to the trabecular meshwork. Its function is not known. Mutations in juvenile forms of POAG may act in a dominant negative fashion. In one extensive Canadian kindred, several individuals who were homozygous for a highly penetrant dominant mutation did not develop glaucoma; it is presumed that the mutant protein is functional and, when homozygous, does not have a dominant negative effect.
Diagnosis
62
Clinical. Mutation testing in families with JOAG is available on a research basis. Testing for MYOC mutations in adult POAG is not currently undertaken due to the low frequency of mutations. Juvenile primary open angle glaucoma
Primary open angle glaucoma (also known as: POAG) MIM
See below
Clinical features
POAG is a common, highly variable condition of complex etiology that causes a characteristic optic neuropathy, progressive disc cupping and arcuate field loss. It is likely to be caused by a number of interacting factors, both genetic and environmental. Raised intraocular pressure is a major risk factor but not an absolute requirement for diagnosis. Family history is another major risk factor which justifies the screening of first-degree relatives. 1 in 10 first degree relatives of affected individuals are themselves affected. Like many complex disorders (e.g. heart disease, schizophrenia or obesity), our understanding of the pathogenesis of POAG is surprisingly rudimentary. POAG has a number of uncommon Mendelian subforms which are amenable to analysis using current techniques. Our understanding of the more common forms of POAG may be improved by characterizing the genes underlying these single gene disorders. In the table below, chromosomal locations are listed for different forms of open angle glaucoma. Genes have been found to underlie juvenile POAG and nail-patella syndrome at the GLC1A, GLC1E and NPS loci, respectively. The others have been defined by linkage analyses in single families or, in one case (GLC1B), by pooling small families. These are statistical methodologies for localizing putative chromosomal positions. Within single families it is generally assumed that a single gene defect affects all members of a family; this assumption renders these techniques prone to error as it is not possible to differentiate clinically identical, genetically distinct ‘phenocopies’ affecting different individuals of a family. Final proof of their true relevance will follow confirmation of linkage in other families or discovery of a causative gene at a given location.
Glaucoma
63
Age of onset
Adulthood
Epidemiology
POAG is the second most common adult-onset cause of blindness in the developed world. It affects around 2% of the adult population.
Inheritance
The mode of inheritance of the common forms of POAG is complex. The Mendelian forms are autosomal dominant.
Chromosomal location MIM Locus Gene 137750 GLC1A MYOC 137760 GLC1B 601682 GLC1C 602429 GLC1D 602432 GLC1E* 603383 GLC1F 161200 NPS (q.v.) LMX1B * Family had normal tension glaucoma.
Chromosome 1q24.3–q25.2 2cen–q13 3q21–q24 8q23 10p14–p15 7q35–q36 9q34.1
Method of localization Gene Pooled families Single family Single family Single family Single family Gene
Genes
Myocilin (MYOC; see juvenile POAG) and LIM homeo box transcription factor 1, beta (LMX1B; see nail-patella syndrome).
Mutational spectrum
Unknown
Effect of mutation
Unknown
Diagnosis
Genetic testing is not yet available for POAG.
64
Primary open angle glaucoma
Aniridia MIM
106210
Total aniridia. Note ‘frill’ of iris remnant and cataract.
Partial aniridia; in some patients this may resemble an ‘atypical’ coloboma.
Clinical features
There is usually total absence of iris tissue. Partial or segmental aniridia may manifest as ‘atypical colobomata’. There may be segmental iris hypoplasia. There is often intrafamilial variability in severity and complications. The condition affects numerous ocular structures. Peripheral corneal vascularization associated with stem cell failure leads to a progressive keratitis and ocular surface abnormalities that may be problematic in later life. Abnormal development of the anterior segment/trabeculum/angle structures poses a significant life-time risk of developmental glaucoma in 20–50% of cases. Cataract, in particular anterior polar cataracts, may occur.
Glaucoma
65
In the posterior segment, foveal hypoplasia is a major contributor to reduced vision. There may be associated optic nerve hypoplasia. Posterior segment abnormalities commonly lead to the development of nystagmus. Age of onset
Congenital
Inheritance
Aniridia is usually autosomal dominant. Sporadic cases are well documented and in these cases a deletion may encompass adjacent loci including the WT1 gene, which underlies Wilms’ tumor.
Chromosomal location
11p13
Gene
Paired box gene 6 (PAX6)
Mutational spectrum
Around 140 mutations have now been described throughout the gene (Human PAX6 Allelic variant database; http://www.hgu.mrc.ac.uk/Softdata/PAX6/). Missense mutations are under-represented. A wide variety of ocular phenotypes are associated with PAX6 mutations; apart from ‘simple’ aniridia these include Peters’ anomaly, autosomal dominant keratitis, autosomal dominant cataract and isolated foveal hypoplasia. One compound heterozygote has been reported. The infant had severe craniofacial and central nervous system defects and no eyes. The head was small with large ears; the brain was small with abnormal cerebral hemispheres and a partially absent corpus callosum. The infant died after 8 days.
Effect of mutation
66
The majority of mutations lead to premature termination of the PAX6 protein and are thought to act by means of haploinsufficiency.
Aniridia
Diagnosis
In the absence of a family history, aniridia may be due to a deletion of 11p13, which could include neighboring genes. Of these, WT1, when absent, may predispose to Wilms’ tumors. One such contiguous gene syndrome is the WAGR syndrome (Wilms’ tumor, Aniridia, Genitourinary abnormalities and mental Retardation). Among individuals with a presumed de novo mutation, chromosomal analysis and FISH should be used to exclude a WT1 deletion. In classical cases, in particular those with a family history, the diagnosis is often simple. However, variant cases with partial aniridia or atypical colobomata (in particular those not affecting the inferior iris) or with other forms of anterior segment dysgenesis may be suspected in the presence of nystagmus and/or foveal hypoplasia, which is almost invariant among individuals with PAX6 mutations. Mutation testing is available through diagnostic laboratories. However, in most cases this is not of major clinical significance. Prenatal diagnosis has been undertaken.
Glaucoma
67
Anterior segment mesenchymal dysgenesis (also known as: ASMD; anterior segment ocular dysgenesis [ASOD]) MIM
107250; 602669 (PITX3); 601094 (FOXE3)
Clinical features
As discussed under iridogoniodysgenesis (q.v.), isolated anterior segment dysgenesis forms a heterogeneous group. ASMD is a generic term describing the broad range of anterior dysgenesis phenotypes. The term suggests a potential pathogenic mechanism common to different forms of anterior segment dysgenesis. Axenfeld, Rieger and Peters’ anomalies may occur in the same family—this suggests that these clinical distinctions do not necessarily reflect underlying differences in etiology.
Age of onset
A developmental disorder which is present at birth. Secondary developmental glaucoma commonly develops during childhood.
Inheritance
Isolated anterior segment dysgenesis is often autosomal dominant. However, affected sib-pairs and affected children within consanguineous marriages suggest that autosomal recessive forms exist.
Chromosomal location
10q25 (paired-like homeodomain transcription factor 3 [PITX3]) 1p32 (forkhead box E3 [FOXE3])
Gene
PITX3; FOXE3. Other families with dominant forms of the disease do not have defects in these genes. This suggests that other genes cause a similar phenotype.
Mutational spectrum
PITX3: a single premature protein truncation mutation was observed in one family with ASMD. There was a variable phenotype including Peters’ and Axenfeld anomalies as well as cataract. The protein truncation mutation removes a highly conserved C-terminal domain, thought to be involved in protein-protein interaction. Similar, presumed haploinsufficiency mutations in PITX2 (q.v. Rieger
68
Anterior segment mesenchymal dysgenesis
syndrome) have been described. PITX2 and PITX3 are highly homologous homeodomain-containing proteins that are critical to ocular development. One missense mutation was observed in a family with bilateral congenital cataract. FOXE3: A mutation has been defined in a single family with anterior segment ocular dysgenesis and cataracts. A frameshift mutation resulted in an abnormal terminal amino acid sequence with the addition of 111 amino acids. Effect of mutation
PITX3 is a developmental transcription factor expressed in the developing lens placode and through all stages of lenticular development. In addition, the gene is expressed in the midbrain, tongue and mesenchymal structures around the sternum, vertebrae and head muscles. A spontaneous mouse mutant aphakia, in which mice have small eyes with no lens, has a deletion mutation of the murine homolog, Pitx3. FOXE3 is a transcription factor that is critical during lens development. It is regulated by other modulators of ocular development such as PAX6. During development, FOXE3 is expressed in developing lens tissues from the start of lens placode induction and becomes turned off after lens fiber cell differentiation.
Diagnosis
Glaucoma
Clinical examination. Children who are at risk need regular follow-up to monitor the potential development of glaucoma.
69
Glaucoma-related pigment dispersion syndrome (also known as: GPDS1; pigment dispersion syndrome; pigmentary glaucoma) MIM
1
600510
2
3
Clinical features
70
Pigment dispersion syndrome is an early-onset form of open angle glaucoma. There is pigment loss from the iris epithelium leading to slit-shaped defects visible on transillumination (1). Pigment is deposited throughout the anterior segment, onto the lens, lens zonules, iris, trabecular meshwork (2) and corneal endothelium, where it forms Krukenberg spindles (3). Pigment loss is thought to occur from physical abrasion between the iris and the lens zonules. Initially, increased pressure may result directly from pigment accumulation (for example, there may be an increase in pressure after exercise). Ultimately, this pigment is phagocytosed, leading to trabecular meshwork damage.
Glaucoma-related pigment dispersion syndrome
The disorder is said to be more common in myopes and males, although autosomal dominant inheritance has been demonstrated. Pigment dispersion is a strong risk factor for glaucoma but does not always lead to glaucomatous damage. Age of onset
Usually affects individuals under the age of 40 years.
Inheritance
Autosomal dominant. The occurrence of many sporadic individuals suggests that there may be reduced penetrance.
Chromosomal location
7q35–q36
Gene
The gene underlying GPDS has not been defined.
Effect of mutation
Unknown
Diagnosis
Clinical, including examination of first-degree relatives. Gene identification may aid screening of family members.
Glaucoma
71
Iridogoniodysgenesis type I (also known as: IRID1; iridogoniodysgenesis anomaly [IGDA]; familial iridogoniodysplasia) MIM
601631; 601090 (FOXC1)
Clinical features
Autosomal dominant IGDA is characterized by iris hypoplasia and goniodysgenesis. The major risk is of childhood-onset developmental glaucoma. The phenotype is highly variable and may include Axenfeld anomaly, Rieger syndrome and iris hypoplasia. In general, there are no extraocular manifestations.
Age of onset
This is a developmental disorder which is present at birth. Developmental glaucoma is common during childhood.
Inheritance
Isolated anterior segment dysgenesis/iridogoniodysgenesis is often autosomal dominant. However, affected sib-pairs and affected children within consanguineous marriages suggest that autosomal recessive forms exist.
Chromosomal location
6p25
Gene
Forkhead box C1 (FOXC1) (alternative names: FREAC3/FKHL7). There are other known dominant families that are not caused by defects in this locus; this suggests that other genes cause a similar phenotype.
Mutational spectrum
Nonsense mutations that result in premature protein truncation and missense mutations within the forkhead transcription domain have been described. The range of phenotypes shows intrafamilial variability. One family with Rieger syndrome with extraocular manifestations has been shown to carry a FOXC1 mutation. Affected patients with a duplication of 6p25 have been described. This is not visible microscopically but results in the presence of three functional copies of FOXC1. This suggests that increased, as well as decreased, dosage of FOXC1 can cause anterior segment abnormalities.
72
Iridogoniodysgenesis type I
Effect of mutation
FOXC1 is a transcription factor that regulates the expression of genes critical to ocular anterior segment development. The mutations currently described result in haploinsufficiency. Those within the forkhead transcription domain abolish the ability of the protein to bind to specific DNA sequences.
Diagnosis
Clinical examination. At-risk children need to be maintained under regular follow-up as the risk of developmental glaucoma is high (>50% in many proven dominant families). Genetic testing, while possible, has few clinical benefits, although exclusion of a mutation among the children of proven gene-carriers gives confidence that an individual carries no risk of developmental glaucoma.
Glaucoma
73
Nail-patella syndrome (also known as: NPS; onychoosteodysplasia) MIM
161200; 602575 (LMX1B)
Clinical features
Ocular Primary open angle glaucoma is common. Ophthalmic follow-up is therefore suggested for all patients. Extraocular Hypoplasia or aplasia of the patellae is a cardinal feature, leading to instability of the knee and recurrent patellar dislocation. Generalized joint laxity is also described. On x-ray examination there may be iliac horns on the pelvis. Patients may have reduced extension and/or supination/pronation of the elbow due to radial head dysplasia/dislocation. The nails of the hand are dystrophic and small. They split easily and have triangular lunules at the base. Around a quarter of patients develop renal disease, which may manifest at any age. About 5% may develop renal failure. Renal symptoms include proteinuria, nephrotic syndrome and glomerulonephritis. Thickening of the glomerular basement membrane may be observed on renal biopsy.
Age of onset
Congenital
Epidemiology
2:100,000
Inheritance
Autosomal dominant
Chromosomal location
9q34.1
Gene
LIM homeobox transcription factor 1beta (LMX1B)
74
Nail-patella syndrome
Lester sign. Patients with NPS have a characteristic ‘clover-leaf’ iris.
Patellar aplasia.
Nail dystrophy.
Mutational spectrum
A broad range of mutations have been described. Premature protein termination mutations are common. Missense mutations, when present, are often within important, conserved residues of both the LIM and homeodomains.
Effect of mutation
Haploinsufficiency. There is no genotype-phenotype correlation. Functional studies have shown that missense mutations disrupt sequence-specific DNA binding. LMX1B is a conserved transcription factor. LIM-homeodomain proteins are characterized by the presence of two tandem cysteine/histidine-rich, zinc-binding LIM domains. LMX1B has been shown to be important in dorsoventral limb patterning. Expression patterns also show it to be important in renal and ocular development.
Glaucoma
75
Diagnosis
76
Clinical. While DNA diagnosis is now possible this is largely of academic interest. Prenatal diagnosis is rarely an issue as this can only detect the presence of a mutation rather than predict its severity. NPS is highly variable and ocular complications are rarely present early in life: families should be aware of the risks and ongoing screening made available to them.
Nail-patella syndrome
Rieger syndrome (also known as: iridogoniodysgenesis with somatic anomalies; iridogoniodysgenesis type II; autosomal dominant iris hypoplasia) MIM
180500 (type I); 601499 (type II)
Clinical features
Ocular Rieger syndrome is characterized by anterior segment dysgenesis associated with goniodysgenesis, posterior embryotoxon and anterior synechiae. Variable iris hypoplasia is often associated with corectopia and/or polycoria. In Rieger syndrome, the ocular manifestations are variable and may include iris hypoplasia, Axenfeld anomaly or Peters’ anomaly, and anterior polar cataract. Foveal hypoplasia is not seen and, in the absence of media opacity, vision may be normal. However, the risk of developmental glaucoma is extremely high (perhaps 75%).
(R) Rieger anomaly and (L) Peters’ anomaly from a patient with a mutation in PITX2.
Extraocular The most common extraocular manifestation is abnormal dental development, which can vary from peg-shaped incisors, widely spaced teeth or missing teeth to total anodontia. Redundant umbilical skin is also commonly seen. Other extraocular manifestations include cleft palate, anterior-placed anus and anal atresia.
Glaucoma
77
Dental hypoplasia/aplasia.
Redundant umbilical skin.
Age of onset
Congenital
Inheritance
Autosomal dominant
Chromosomal location
4p25 (type I); 13p13 (type II)
Gene
Paired-like homeodomain transcription factor 2 (PITX2). Bicoid-related homeobox-containing gene (type I). The gene for type II is unknown.
Mutational spectrum
Splice-site mutations, missense mutations (in particular within the homeodomain) and nonsense mutations are all described. Many patients (~50%) have no proven genetic abnormality.
Effect of mutation
It is likely that most mutations result in functional haploinsufficiency. All families with PITX2 mutations have evidence of some systemic abnormalities (in particular dental/umbilical abnormalities).
Diagnosis
Systemic features suggest the presence of a PITX2 mutation that may be tested on a research basis. Visual impairment will be seen in those with significant media opacities (e.g. Peters’ anomaly) or resulting from the complications of developmental glaucoma. The high risk of glaucoma requires life-long screening.
78
Rieger syndrome
Rubinstein-Taybi syndrome (also known as: RSTS) MIM
180849; 600140 (CREBBP)
Clinical features
Rubinstein-Taybi syndrome is a rare cause of mental handicap associated with characteristic facial dysmorphism, broad thumbs and toes. Ocular The ocular manifestations of RSTS are under-recognized but wideranging. There may be congenital or early-onset glaucoma due to goniodysgenesis with high iris insertions. Congenital cataract of variable severity is also described. Retinal dystrophy is a frequent and important finding (>70%), which becomes more common with age. Retinal examination and ERG investigation demonstrate cone and cone-rod dystrophy. Extraocular Developmental delay is often severe with a mean IQ of around 50. Children are generally shorter than average, with relative microcephaly. Facial features are characteristic with down-slanting palpebral fissures, long beaked nose and unusual thickened ears. Thumbs and big toes are broad with spatulate distal phalanges.
Age of onset
Congenital
Inheritance
Most cases are sporadic
Chromosomal location
16p13.3
Gene
CREB-binding protein (CREBBP)
Glaucoma
79
(L) Characteristic facial features include a long beaked nose with prominent columella. (R) Spadulate distal phalanx of the thumb in Rubinstein-Taybi syndrome.
Mutational spectrum
A microdeletion of 16p13.3 is estimated to cause around 10–15% of RSTS. Mutations of CREBBP have been described; the majority result in protein truncation.
Effect of mutation
It is likely that loss of function of one copy of CREBBP leads to RSTS. CREBBP is a transcriptional co-activator that binds to the transcription factor CREB. The exact functions of CREB (and hence of CREBBP) are not fully understood.
Diagnosis
Children with RSTS have significant handicaps. Screening for ocular abnormalities and recognizing multisensory handicap are important in their long-term care. When suspected clinically, FISH analysis may detect a 16p13.3 microdeletion. Mutation analysis is available on a research basis only.
80
Rubinstein-Taybi syndrome
4 4. Inherited retinal disease
Cone dystrophies
Progressive rod-cone dystrophies
Achromatopsia 82
Retinitis pigmentosa 122
Blue cone monochromatic color blindness 84
Autosomal dominant retinitis pigmentosa 125
Progressive cone dystrophy 86
Peripherin/RDS 127
Macular dystrophies 88 Doyne familial honeycombed choroiditis 90 Pseudoxanthoma elasticum 92
Rhodopsin 130 Autosomal recessive retinitis pigmentosa 132 Retinitis pigmentosa, PPRPE type 135
Sorsby pseudoinflammatory fundus dystrophy 96
Digenic retinitis pigmentosa 137
Stargardt disease 98
X-linked retinitis pigmentosa 138
Vitelliform macular dystrophy 104 Miscellaneous retinal dystrophies Choroideremia 107 Cone-rod dystrophy 110
Stationary night blindness Congenital stationary night blindness 141 Fundus albipunctatus 144 Oguchi disease 145
Enhanced S-cone syndrome 112
Syndromic retinal dystrophies
Leber congenital amaurosis 114
Alström syndrome 147
Retinitis punctata albescens 120
Bardet-Biedl syndrome 149 Cockayne syndrome 153 Cohen syndrome 156 Joubert syndrome 158 Mitochondrial disease and retinopathy 159 Usher syndrome 163
Achromatopsia (also known as: ACHM2; ACHM3; rod monochromatism) MIM
216900 (ACHM2); 262300 (ACHM3)
Clinical features
Achromatopsia or rod monochromatism is a stationary cone disorder characterized by an absence of normally functioning cones. Patients present with congenital nystagmus at birth or early in life. They are photophobic and describe vision that is better in dim light. Achromats have normal retinal examination. There is complete color blindness and visual acuity of around 6/60. ERG shows an absence of cone responses, in the presence of normal rod responses. Some patients with partial achromatopsia retain better visual acuity with residual cone function.
Epidemiology
Achromatopsia is estimated to affect around 1:30,000 in the USA.
Age of onset
Congenital
Inheritance
Autosomal recessive
Chromosomal location
2q11 (ACHM2); 8q21–q22 (ACHM3)
Gene
ACHM2: cyclic nucleotide-gated cation channel, alpha subunit (CNGA3) ACHM3: cyclic nucleotide-gated cation channel, beta subunit (CNGB3)
Mutational spectrum
82
CNGA3: missense mutations (including frameshift and protein truncating mutations) have been described in highly conserved amino acids. It is likely that the missense mutations result in improper folding or inability to integrate the protein into the plasma membrane. CNGA3 mutations have also been described in a small number of patients with evidence of severe progressive cone dystrophy.
Achromatopsia
CNGB3: missense, frameshift and protein truncation mutations have all been described. Homozygous null mutations cause an identical phenotype to missense mutations. Effect of mutation
It is likely that all mutations result in loss of function. Cyclic nucleotide-gated channels are important in vertebrate sensory systems. CNGA3 and CNGB3 encode the a- and b-subunits of a single cyclic nucleotide-gated channel that is located in the photoreceptor plasma membrane. The cone cGMP-gated cation channel is an a/b-2 heteromeric tetramer required for development of the light-evoked responses of cones. The proteins contain six transmembrane domains and a hydrophilic pore structure. Loss of function would result in an inability to respond to cGMP, and elimination of the dark current resulting in a situation akin to permanent light exposure.
Diagnosis
Inherited retinal disease
Mutation screening is available on a research basis only.
83
Blue cone monochromatic color blindness (also known as: CBBM; blue cone monochromatism) MIM
303700
Clinical features
Blue cone monochromats have only functional rods and short wavelength (blue) cones. Patients have severely reduced central vision and photophobia, abnormal color discrimination and nystagmus. Retinal examination is normal. ERG examination reveals normal scotopic and photopic responses demonstrating absence of cone responses to white and red light. There is preservation of blue cone function, which allows discrimination of yellow objects on a blue field.
Age of onset
Congenital
Epidemiology
Rare, less than 1:100,000
Inheritance
X-linked recessive
Chromosomal location
Xq28
Gene
Red cone pigment, including protanopia (MIM 303900). Green cone pigment, including deuteranopia (MIM 303800).
Mutational spectrum
The red and green pigment genes are carried on the X chromosome at Xq28. They lie in a head-to-tail tandem array, which predisposes to homologous recombination and rearrangement of the region. This mechanism gives rise to over 90% of the red and green cone color vision variations. In the normal state, each X chromosome carries one red pigment gene and one or more green pigment genes. Blue cone monochromatism results from a number of conformations of the red/green pigment arrays including:
84
Blue cone monochromatic color blindness
• deletion of locus control region. Deletion of a region that lies upstream of the red pigment transcription start site. This region is essential for normal transcription of both red and green pigment genes. This mechanism accounts for 40% of families. • point mutations inactivating X chromosome pigment genes. In the majority of individuals in this group, homologous recombination reduces the pigment gene array to a single gene. A second mutational event then inactivates this gene. Both missense and nonsense changes are described, but the mutation of cysteine to arginine at codon 203 is the most common. Effect of mutation
Absence of functional red and green cones. In general, this is a static condition although some patients have a late-onset, slowly progressive, central retinal dystrophy. This suggests that normal genes are required for long-term maintenance of cones.
Diagnosis
CBBM, when suspected clinically, may be confirmed by ERG testing. There is often a clear history consistent with X-linked inheritance. In some cases, female carriers are said to have abnormal cone responses on ERG testing.
Inherited retinal disease
85
Progressive cone dystrophy (also known as: retinal cone dystrophy; cone dystrophy 3; COD3) MIM
602093
Clinical features
The cone dystrophies are heterogeneous disorders, which may be progressive or non-progressive (achromatopsia). The progressive cone dystrophies are characterized by reduced central visual function (reduced VA, altered color vision, photophobia) and abnormal conemediated ERGs. Fundoscopy reveals pigment disturbance at the macula in the early stages of the disease or a typical bull’s eye appearance. There is progression over time with the development of atrophic macular scarring, although this is variable in degree.
48-year old male with progressive cone dystrophy.
Age of onset
Variable. Some individuals with cone dystrophies have early-onset disease (in the first decade of life), while others develop symptoms in early adulthood. Patients in one family with COD3 showed symptoms in adulthood.
Inheritance
Autosomal dominant; X-linked recessive. Many cases are sporadic.
Chromosomal location
6p21–6cen (RDS peripherin) – see section on RDS peripherin/ADRP. 6p21.1 (COD3); Xp11.4 (linkage); Xq27 (linkage).
86
Progressive cone dystrophy
Gene
RDS/peripherin (RDS) Guanylate cyclase activator 1A (GUCA1A); MIM 600364 Cyclic nucleotide-gated cation channel, alpha subunit (CNGA3)
Mutational spectrum
A small number of families with missense changes in RDS (e.g. serine-27-phenylalanine) have been described with progressive cone dystrophy (see section on RDS). A single missense mutation (Y99C) has been described in GUCA1A.
Effect of mutation
GUCA1A is a calcium-binding protein expressed exclusively in photoreceptors, particularly cones. In photoreceptors, cGMP is synthesized by RetGC, which is activated by GUCA1A at low levels of intracellular Ca2+ (i.e. light-adapted photoreceptors) and inhibited at high Ca2+ levels. At all physiological Ca2+ concentrations, the mutant GUCA1A results in RetGC activation, which leads to constitutive cGMP synthesis. Elevated cGMP alters Ca2+/Na+ flux and this is thought to result in progressive retinal damage.
Diagnosis
Inherited retinal disease
Many patients with a childhood-onset cone dystrophy pattern develop rod dysfunction (i.e. cone-rod dystrophy). The genetic basis of the most progressive cone dystrophies remains undefined and genetic testing is not yet available.
87
Macular dystrophies Age-related macular degeneration (ARMD) is the most common cause of blindness in the developed world and genetic factors are extremely important in its pathogenesis. One avenue towards identifying such factors is through the analysis of the early-onset, monogenic macular dystrophies, and a large number of their genetic localizations have now been identified (see Table 5.1). More recently this has included the identification of loci (e.g. ARMD1 on chromosome 1q25–q31: MIM 603075) that underlie phenocopies of ARMD. Several genes underlying the Mendelian macular dystrophies have now been characterized including Stargardt and Best disease (ABCA4, VMD2), Doyne honeycomb dystrophy and Sorsby fundus dystrophy (EFEMP1, TIMP3). These are discussed in the following sections. In addition, mutations in the RDS gene, which was identified as the causative gene in some forms of adRP, are associated with a range of macular phenotypes including adult vitelliform and butterfly-shaped dystrophies as well as one form of central areolar choroidal dystrophy (see section on RDS). Finally, certain maternally inherited mitochondrial mutations have now been shown to cause abnormal macular function (see mitochondrial section). Common forms of ARMD There has been considerable work investigating the role of the genes underlying the Mendelian macular dystrophies as etiological factors in common forms of ARMD. Currently, there is no convincing evidence that implicates EFEMP1, TIMP3 or VMD2. ABCA4 The situation with regard to ABCA4 is more confusing. The ABCA4 gene and the protein it encodes vary significantly from person to person (i.e. there is a high level of polymorphism). It is therefore difficult to define whether or not changes that are relatively common within a population significantly alter the predisposition to ARMD, a condition that is also common. While many studies have found little
88
Macular dystrophies
evidence to support the hypothesis, some have found that certain missense mutations may be associated with ARMD. It is also suggested that some people who are heterozygous for mutations in the gene (the parents and siblings of Stargardt disease patients) may have a higher predisposition to ARMD. The significance of this is uncertain. Current evidence suggests that the ABCA4 gene is not a major contributing factor to a large proportion of ARMD cases. Table 5.1 Disorder
Gene
Chromosome
Inheritance
MIM
Age-related macular degeneration
-
1q25–q31
AD
603075
Stargardt disease
ABCA4
1p21–p22
AR
248200
Doyne honeycomb dystrophy
EFEMP1
2p16–p21
AD
126600
STGD4
-
4p
AD
603786
Adult vitelliform dystrophy
RDS
6p21.2-cen
AD
179605
Butterfly-shaped dystrophy
RDS
6p21.2-cen
AD
179605
Central areolar choroidal dystrophy
RDS
6p21.2-cen
AD
179605
Best disease
VMD2
11q13
AD
153700
Pseudoxanthoma elasticum
ABCC6
16p13.1
AD/AR
177850
Stargardt disease (3)
ELOVL4
6q14
AD
600110
North Carolina macular dystrophy
-
6q14–q16.3
AD
136550
Central areolar choroidal dystrophy
-
17p13–p12
AD
215500
Sorsby fundus dystrophy
TIMP3
22q12.1–q13.2
AD
136900
Inherited retinal disease
89
Doyne familial honeycombed choroiditis (also known as: Doyne honeycomb retinal dystrophy; DHRD; Doyne honeycomb degeneration of retina; Malattia Leventinese [MLVT]; autosomal dominant radial drusen) MIM
126600
Clinical features
Characteristically, drusen involving the posterior pole, macula and optic disc (including nasal to the disc) appear in early adult life. The drusen are frequently distributed in a radial pattern and may progress to form a ‘honeycomb’. In younger individuals there may be hard drusen at the macula. The syndromes described by Doyne in England and by Vogt in Switzerland (malattia leventinese) represent the same condition.
A 55-year-old patient with a dominant family history of early central visual loss and acuities of 6/24 in each eye. Notice the juxta-papillary lesions characteristic of this disorder.
Age of onset
90
While there are occasional reports of patients with early-onset visual loss, the majority of patients will not develop symptoms until adult life. Advanced disease is associated with severe visual loss and posterior pole atrophy. Increasing age is not invariably associated with severe visual loss.
Doyne familial honeycombed choroiditis
Inheritance
True autosomal dominant. One individual who is homozygous for the characteristic mutation has been shown to have a retinal phenotype identical to heterozygotes of similar age.
Chromosomal location
2p16–21
Gene
EGF-containing fibrillin-like extracellular matrix protein 1 (EFEMP1)
Mutational spectrum
A single missense mutation (arginine to tryptophan substitution of residue 345) has been found in all families.
Effect of mutation
The exact role of this extracellular molecule in retinal function is unclear. As a result it is not yet known why defects lead to DHRD.
Inherited retinal disease
91
Pseudoxanthoma elasticum (also known as: PXE; Grönblad-Strandberg syndrome) MIM
264800 (autosomal recessive); 177850 (autosomal dominant); 603234 (ABCC6)
Clinical features
PXE is characterized by yellowish papular plaques in the skin of the flexures (pseudoxanthomata) associated with angioid streaks of the retina.
Angioid streaks.
Ocular About 50% of those with angioid streaks are said to have PXE, although this may be an underestimate. They are irregular broad gray lines, often present around the papilla, and represent breaks in the elastic lamina of Bruch’s membrane. They are not present at birth and age of onset varies; they can be identified in some PXE patients before the age of 10 years. The most common early retinal feature is a ‘peau d’orange’ appearance, a mottled fundus that classically precedes the appearance of streaks and is often seen in the mid-periphery. Other retinal changes include ‘salmon patches’ and yellow/white dot-like foci, both of which represent resolving hemorrhage. Optic nerve head drusen have been associated with PXE. The major complication of angioid streaks is the development of subretinal neovascular membranes. As a result, sequential and dramatic loss of central vision is common in middle age. 92
Pseudoxanthoma elasticum
Pseudoxanthoma elasticum. Angioid streaks in 40-year-old female with no family history who described recent alteration of vision (bottom). Fluorescein angiography revealed a small sub-retinal neovascular membrane (top).
Pseudoxanthomata in the antecubital fossa in a teenage girl with PXE.
Inherited retinal disease
93
Dermatological Pseudoxanthomata are yellowish papules or plaques that are seen on the flexural aspects including the neck, axillae, antecubital fossa and groin. Although asymptomatic, they may have poor cosmetic consequences. The skin in these areas may become lax with time, and surgery, attempted for cosmetic reasons, may heal poorly. Gastrointestinal Gastric hemorrhage is a recognized complication. Although the exact prevalence is uncertain, a 10% lifetime risk of hemorrhage is quoted. An increased frequency of GI bleeds during pregnancy has also been reported. Cardiovascular Mitral valve prolapse, hypertension, ischemic heart disease and peripheral vascular disease have all been associated with PXE. Their exact prevalence is uncertain. Age of onset
While ocular manifestations (e.g. peau d’orange) may be present in childhood, angioid streaks develop later. Subretinal neovascular membranes (SRNVMs) generally develop during adulthood.
Epidemiology
Incidence has been estimated at 1:25,000–50,000.
Inheritance
Among those cases with a family history, the majority are consistent with autosomal recessive inheritance. However, autosomal dominant kindreds may be seen. A large number of cases are sporadic.
Chromosomal location
16p13.1
Gene
ATP-binding cassette, subfamily C, member 6 (ABCC6); alternative name: multidrug resistance protein 6 (MRP6).
94
Pseudoxanthoma elasticum
Mutational spectrum
Among autosomal recessive pedigrees, homozygous mutations including deletions, frameshifts, splice-site and missense mutations have all been described. These include a recurrent R1141X mutation which generates a stop codon and is shown to result in loss of ABCC6 expression. Both frameshift and missense mutations have been described in presumed dominant families. These also include the R1141X mutation, which has therefore been shown to be associated with PXE phenotypes in both the heterozygous and homozygous state. The majority of sporadic individuals have been found to have heterozygous mutations although some are recessive. There is, as yet, no clear-cut genotype/phenotype correlation.
Effect of mutation
ABCC6 is a member of the ATP-binding cassette transmembrane transporter family (like ABCA4, see Stargardt disease), and is involved in drug-resistance, especially relating to cancer chemotherapy. ABCC6 is expressed highly in the kidney and liver where its function is unknown. It is suggested that altered ABCC6 function may result in the defective transport of compounds that are essential for extracellular matrix turnover or deposition.
Diagnosis
PXE is diagnosed on clinical grounds. Mutation analysis is not yet widely available. In addition to PXE, angioid streaks are seen in sickle cell anemia, thalassemia, Paget disease of bone and beta alipoproteinemia. All patients with angioid streaks should be examined for evidence of PXE. Patients with apparently isolated angioid streaks should be monitored to exclude the possibility of PXE, which may become more apparent with time. Patients should be aware of the risks of SRNVM and are advised to seek specialist help if there is any change or distortion of vision, or altered performance on an Amsler grid test. While GI and cardiovascular complications are recognized, they are not common.
Inherited retinal disease
95
Sorsby pseudoinflammatory fundus dystrophy (also known as: SFD) MIM
136900; 188826 (TIMP3)
Clinical features
SFD is characterized by loss of central vision due to subretinal neovascular membrane (SRNVM) formation in middle life. The eyes are affected sequentially leading to severe and sudden loss of vision in virtually all affected individuals. Examination prior to the development of SRNVM demonstrates pigmentary disturbance, fine drusen-like deposits and atrophic lesions at the macula. The peripheral retina is affected and patients may also describe nyctalopia, which may precede the maculopathy. This may be accompanied by peripheral visual field loss, decrease in dark adaptation, and subnormal scotopic and photopic ERGs. There is progressive peripheral chorioretinal atrophy and a generalized retinal dystrophy may develop with bone spicule pigmentation, vascular attenuation and choroidal atrophy.
A 45-year-old female with family history of Sorsby fundus dystrophy, proven on TIMP3 mutation analysis. Vision is normal. Note the distribution of drusen around the arcades.
Age of onset
Major symptoms result from development/hemorrhage of SRNVM. This occurs in the fourth and fifth decades.
Inheritance
Autosomal dominant. Reports of recessive inheritance have been shown to be incorrect.
96
Sorsby pseudoinflammatory fundus dystrophy
Chromosomal location
22q12.1–q13.2
Gene
Tissue inhibitor of metalloproteinase 3 (TIMP3)
Mutational spectrum
Only six mutations in this gene have been described to date, five of which are missense mutations introducing a novel cysteine residue into the C-terminal domain. Of these mutations, one (a serine to cysteine substitution of residue 181) has been found in the majority of UK families tested to date. This suggests a stronger founder effect in British families.
Effect of mutation
Gain of function/dominant negative effect. All mutations give rise to a protein that has characteristics of the normally functioning protein but which forms stable dimers. These are thought to accumulate in the retina, giving rise to an increase in TIMP3 activity within the retina, which ultimately causes the disease process. Increased TIMP3 expression has been observed in other retinal dystrophies and it is suggested that TIMP3 overexpression may be a secondary step in the progression of other degenerative retinopathies.
Diagnosis
In suspected SFD patients, genetic analysis is quick and highly reliable. However, while proving an aid to diagnosis, DNA testing does not alter the management of the condition. SFD is a highly penetrant autosomal dominant condition associated with sudden and severe loss of vision. Counselling of at-risk individuals is highly complex. Both clinical examination and genetic testing can identify those who are carriers of causative mutations. For many, the knowledge of future visual disability is an enormous burden. As some may live to regret presymptomatic diagnosis, genetic testing and examination of unaffected relatives should be undertaken with caution and with the support of those familiar with presymptomatic testing protocols for other late-onset inherited conditions.
Inherited retinal disease
97
Stargardt disease: autosomal recessive (also known as: STGD; fundus flavimaculatus) Including: age-related macular degeneration; RP19; CORD3 MIM
248200; 601691 (ABCA4)
Macular atrophy in autosomal recessive Stargardt disease.
Clinical features
STGD is one of the most common early-onset forms of macular degeneration. The course of the disease is rapidly progressive and the final visual outcome is poor. The condition causes progressive loss of central vision, but, in general, patients have good preservation of peripheral/night vision even in the final stages of the disorder. Visual loss continues over a period of several years, progressing to, and stabilizing at, around 6/36–3/60. Many patients with STGD are registered blind. Throughout the posterior pole there are round, linear or pisiform lesions—the characteristic retinal flecks—which may extend to the equator. Fundus flavimaculatus (in which such retinal flecks are more widespread) and STGD form part of a spectrum of flecked-
98
Stargardt disease: autosomal recessive
retina disorders. The retinal flecks represent lipofuscin-containing deposits which accumulate in the RPE layer. The deposition of lipofuscin gives rise to the ‘dark choroid’ sign on fluorescein angiography due to masking of the underlying choroidal vasculature. Electrophysiology is relatively uninformative. ERGs are normal early in the disease but show reduction in the later stages. EOGs may be normal or slightly depressed. With time, the retinal flecks may reduce or disappear. There is progressive and generalized atrophy of the RPE and choroidal vascular atrophy leading to widespread macular/RPE atrophy and the development of a ‘beaten-bronze’ appearance at the macula. Age of onset
Patients are usually diagnosed before the age of 20 years. Loss of central vision may begin from around 6 years of age. However, sometimes symptoms do not appear until adulthood.
Epidemiology
STGD is one of the most common causes of macular degeneration in children, with a frequency of around 1:10,000.
Inheritance
Autosomal recessive
Chromosomal location
1p21–p22.1
Gene
ATP-binding cassette, subfamily A, number 4 (ABCA4); alternative name: ATP-binding cassette transporter, retina-specific (ABCR).
Mutational spectrum
Mutations of this gene show a broad range of phenotypic heterogeneity. STGD and fundus flavimaculatus A wide variety of disease-causing mutations have been described in STGD. Using current techniques, mutations are found in around 60% of cases. While both protein truncating and missense mutations may cause STGD, the majority are missense mutations affecting amino acids that are conserved between species and are thought to be necessary for protein function.
Inherited retinal disease
99
RP19 Mutations in ABCA4 have also been discovered in families with arRP. The age of onset of nyctalopia is around 8 years, followed by a decrease in visual acuity, starting at 14 years of age. It is hypothesized that more severe mutations (abolition of function) give rise to RP rather than STDG. CORD3 ABCA4 mutations have been shown to be an important cause of autosomal recessive CRD. ARMD The role of ABCA4 in the etiology of classical ARMD remains controversial. Effect of mutation
While the major expression of ABCA4 is confined to rods, immunofluorescence microscopy and Western blot analysis suggest that the protein is present in cones as well. It is uncertain whether the pathogenic effects relate to direct cone-mediated damage or a more widespread effect. In the rod, ABCA4 is found on the disc membrane of the retinal outer segments. ABCA4 knockout mice show delayed dark adaptation, increased levels of all-trans-retinaldehyde following light exposure and lipofuscin deposition. Biochemical data suggest that ABCA4 facilitates transmembrane transport. Abnormal ABCA4 is hypothesized to lead to accumulation of an opsin/all-transretinaldehyde complex in discs.
Diagnosis
100
Ophthalmic examination and electrophysiological assessment are often sufficient for diagnosis. STGD1 is often diagnosed in a child after parents have decided to have more offspring and carries a 25% a priori risk to siblings. A small number of dominant phenocopies are described, although these are rare.
Stargardt disease: autosomal recessive
ABCA4 is a 6819 bp gene encoding a 2273-amino acid protein. It contains 51 exons ranging in size from 33–266 bp. Analysis of such a gene is an enormous task, and one that is not yet available outside the research sphere.
Inherited retinal disease
101
Stargardt disease: autosomal dominant (also known as: STGD; fundus flavimaculatus) MIM
600110 (STGD3); 603786 (STGD4)
Clinical features
STGD is one of the most common early-onset forms of macular degeneration. As discussed in the previous section, the condition is generally autosomal recessive. However, a number of phenocopies are recognized that are inherited in a dominant manner. Amongst the dominant forms at least two have been shown to link to regions distinct from chromosome 1, ABCA4 locus that causes the typical recessive form of STGD. The form linked to chromosome 6 (STGD3) shows reduced central vision (onset is in the first and second decades) progressing to a final visual acuity in the range of 3/60 or less. Patients have a well circumscribed atrophic lesion of the choriocapillaris and RPE at the macula with surrounding flecks. As with ‘typical’ STGD, the ERG is well preserved early on although there may be mild reduction in later life. Fluorescein angiography demonstrates absence of the ‘dark choroid’ sign that is seen in typical, recessive STGD.
Stargardt disease.
102
Stargardt disease: autosomal dominant
Age of onset
First or second decades
Epidemiology
The dominant forms of STGD are rare
Inheritance
Autosomal dominant
Chromosomal location
6cen–q14 (STGD3) 4p (STGD4)
Gene
Elongation of very long-chain fatty acids-like gene 4 (ELOVL4; MIM 605512).
Mutational spectrum
To date, a single 5 bp deletion has been described in five families; four families had AD STGD while the fifth family had ‘autosomal dominant macular atrophy’.
Effect of mutation
The mutation described results in a frameshift and premature protein termination. ELOVL4 is a member of a family of genes important in fatty acid elongation. The gene is highly expressed in the photoreceptors and shows low expression in the brain.
Diagnosis
STGD is generally a recessive condition and the majority of individuals have been found to carry mutations in the ABCA4 gene on chromosome 1. Ophthalmic examination and electrophysiological assessment are usually sufficient for diagnosis. Among the few proven dominant families the ‘dark choroid’ sign seen on fluorescein angiography was not found. However, the single family with a dominant form of STGD linked to chromosome 4 does show the ‘dark choroid’ sign. As a result this cannot be used as a reliable indicator of inheritance pattern. Currently, genetic testing of the Stargardt genes is on a research basis only.
Inherited retinal disease
103
Vitelliform macular dystrophy (also known as: VMD2; Best macular dystrophy; Best disease) MIM
153700
(L) ‘Egg yolk’ lesion early in disease progression. At this stage central visual acuity remains good. (R) Scarring of macular region. This 40-year-old has a visual acuity of 6/18.
Clinical features
In the initial stages, a bright yellow cyst forms under the RPE beneath the macula. This classical lesion is the round or oval, yellow ‘egg yolk’ (vitelliform) lesion at the macula. Characteristically, fundoscopic changes precede visual impairment and, despite the presence of the cyst, visual acuity may remain normal or near normal (between 6/9 and 6/18) for many years. Peripheral vision is generally unaffected. In many individuals, the cyst eventually ruptures (vitelliruptive stage) leading to visual loss from macular/RPE atrophy. At this stage there may be deterioration of central vision. Amongst the inherited macular dystrophies, clinical outcome in VMD2 is relatively optimistic. Many patients retain a binocular visual acuity of 6/18 or better, at a late stage of the disease course. Significant asymmetry is often noted. While older patients tend to have worse visual acuities, many retain useful central vision in one eye with a visual acuity of about 6/12 in the better eye. There is marked intrafamilial variability in macular pathology (even amongst families with different mutations within the VMD2 gene).
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Vitelliform macular dystrophy
Diagnosis is confirmed by electrophysiology. There is a grossly reduced EOG (reduced light-induced rise <125%) which, in the presence of a normal ERG, is strongly suggestive of VMD2. The abnormal EOG is suggestive of a primary pathology of the RPE; this is supported by evidence from histopathologic analysis of postmortem eyes showing widespread RPE accumulation of lipofuscin. Age of onset
Although the age of onset of VMD2 can vary, it is usually diagnosed during childhood or adolescence. The age of onset of manifest visual disability varies significantly from early childhood to middle-age.
Inheritance
Autosomal dominant. This is a truly dominant condition since descriptions of homozygotes suggest that they are phenotypically indistinguishable from heterozygotes.
Chromosomal location
11q13
Gene
VMD2
Mutational spectrum
A large number of mutations, predominantly missense, have now been described in the VMD2 gene for bestrophin; the majority are situated in the first half of the gene. In addition, some patients with adult vitelliform macular dystrophy carry mutations in the VMD2 gene. A single case of ‘bull’s-eye’ maculopathy has been reported with a VMD2 mutation. However, results of analysis in two large series of patients suggest that VMD2 does not play a major role in the etiology of ARMD.
Effect of mutation
The VMD2 gene encodes a 585-amino acid protein that is predicted to contain four transmembrane domains. Apart from expression in the Sertoli cells of the testes, the gene is exclusively expressed in the RPE.
Diagnosis
Fundoscopic examination and electrodiagnostic evaluation (i.e. grossly reduced EOG), particularly in association with a positive
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105
family history, are usually sufficient for diagnosis. Therefore, genetic analysis of VMD2 is usually unnecessary. Since a significant number of individuals have normal—or near normal—vision, an abnormal EOG may be useful for identification of gene carriers. EOGs are reduced to the same degree in virtually all gene-carrier patients regardless of severity of symptoms. The diagnosis of an early-onset macular dystrophy has enormous implications for education, career and family planning. As with other inherited macular dystrophies, patients often require the clinician to devote time to discuss the implications of diagnosis.
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Vitelliform macular dystrophy
Choroideremia (also known as: CHM; choroidal sclerosis) MIM
303100
Adult male with choroideremia.
Clinical features
Symptoms of visual field constriction and night blindness are similar to those of RP. Effects on central visual function follow much later. The fundoscopic appearances are characteristic. In the first decade, there is RPE loss and granularity with subsequent development of scalloped lesions through which large choroidal vessels can be seen. During the second and third decades the characteristic peripheral, geographic loss of choriocapillaris and RPE spreads centrally with the characteristic scalloped areas of loss finally encroaching upon the posterior pole. The ERG is markedly reduced with delays in b-wave implicit time and absence of rod responses. Virtually all heterozygous females describe no symptoms and have no visual defects. However, they often show striking fundoscopic changes with irregular pigmentary disturbance. Their ERGs are usually normal. A small number of affected females have been reported, of whom several had X chromosomal rearrangements.
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Age of onset
In the majority of boys, fundoscopic abnormalities are visible from around 10 years onwards. Diffuse chorioretinal degeneration is first seen between 10–20 years. Central macular function is preserved until very late in the course but affected males retain little, if any, useful vision beyond 60 years.
Choroideremia: fundus periphery of female carrier showing abnormal pigment distribution. Patient had no symptoms and normal ERGs.
Inheritance
X-linked recessive
Chromosomal location
Xp21.2
Gene
Rab escort protein 1 (REP-1)
Effect of mutation
Virtually all mutations result in absence of the REP-1 protein product or in abolition of its function. Rab proteins are GTPases that are crucial for vesicular membrane trafficking. Post-translational modification of these proteins by addition of 20-carbon isoprenoid (geranylgeranyl) groups to cysteine motifs in the C-terminal is important for their membrane association and function. This is catalyzed by Rab geranylgeranyl transferase (Rab-GGTase), a multi-subunit enzyme consisting of a catalytic heterodimer and an accessory component, REP-1.
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Choroideremia
REP-1 is a widely expressed protein but it is hypothesized that certain retinal or ocular-specific Rab proteins depend upon REP-1 function. If so, this might explain the ocular-specific phenotype. Diagnosis
Inherited retinal disease
In familial cases, intragenic polymorphic markers may be used for accurate presymptomatic and carrier diagnosis. If required, mutation testing for sporadic cases—or those in which the diagnosis is uncertain—may be achieved either by conventional DNA-based mutation testing or by protein truncation testing (q.v.).
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Cone-rod dystrophy (also known as: CRD) Clinical features
CRD is often characterized by early impairment of vision. In the outset there is reduced visual acuity and loss of color vision, reflecting initial degeneration of cones. This is followed by night blindness and loss of peripheral vision, due to rod degeneration. The condition is progressive and symptoms are accompanied by widespread retinal degeneration affecting both central and peripheral retina. Initially, ERG changes usually show loss of cone-mediated responses, although later there will be widespread reduction of both cone and rod-mediated responses.
Age of onset
First decade. Some families are described (e.g. CORD7) with adult-onset.
Inheritance
Autosomal dominant; autosomal recessive; X-linked
Chromosomal location and genes Gene Locus Chromosomal location MIM CORD1 18q21.1–q21.3 600624 CRX CORD2 19q13.3 120970 ABCA4 CORD3 1p13–p21 604116 CORD5 17p12–p13 600977 GUCY2D CORD6 10p13 600179 CORD7 6cen–q14 603649 CORD8 1q12–q24 CORD9 8p12–q11 HRG4 Cone-rod dystrophy 17q11.2 RPGR COD1 Xp11.4 304020 AD: autosomal dominant; AR: autosomal recessive. (CORD2, CORD3 and CORD6 are described under their respective genes)
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Inheritance Deletion AD AR AD AD AD AR AR AD X-linked
Cone-rod dystrophy
Diagnosis
Inherited retinal disease
CRD is often a distressing diagnosis as it is frequently severe and of early-onset. The condition is highly heterogeneous both genetically and phenotypically and as a result molecular analysis is not yet available.
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Enhanced S-cone syndrome (also known as: ESCS) Including: Goldmann-Favre syndrome MIM
268100; 604485 (NR2E3)
Clinical features
ESCS is a rare retinal degenerative disease. Fundoscopy reveals degenerative changes around the vascular arcades including yellow flecks, RPE atrophy or pigment deposition. Macular changes are common and include CMO in around 50% of cases. Dark adaptation shows little or no rod contribution. ERG testing is characteristic. In the dark-adapted state there is no response to dim stimuli. There is a large, often supernormal, slow response to a single white flash in both the light-adapted and darkadapted states. The photopic ERG is more sensitive to blue/green wavelengths than red/orange. While there is decreased sensitivity of rods and middle- and long-wavelength cones there is enhanced sensitivity of short wavelength (blue) cones, or S-cones.
Age of onset
Patients have early-onset night blindness, but few problems with peripheral or color vision.
Inheritance
Autosomal recessive
Chromosomal location
15q23
Gene
Nuclear receptor subfamily 2, group E, member 3 (NR2E3)
Mutational spectrum
In one study, mutations were found in over 90% of patients with ESCS. The majority were loss of function mutations including one splice-site alteration, a single in-frame 9 bp deletion and several missense mutations. Mutations have been found in a form of arRP seen in Portuguese crypto-Jews. This suggests either that ESCS is
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Enhanced S-cone syndrome
similar to RP in later stages or that the phenotype may differ on different genetic backgrounds. Effect of mutation
Members of the nuclear receptor family are transcription factors, characterized by discrete DNA and ligand-binding domains. They have various functions including the regulation of pathways involved in development. NR2E3 is a photoreceptor cell-specific nuclear receptor that is thought to have a role in controlling the normal development and topography of cone subtypes.
Diagnosis
ESCS is diagnosed by characteristic ERG responses. Enhanced S-cone function is seen in Goldmann-Favre syndrome, a recessive retinal degeneration that is also characterized by vitreous degeneration and foveal and peripheral schisis. It has been suggested that ESCS and Goldmann-Favre syndrome are allelic.
Inherited retinal disease
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Leber congenital amaurosis (also known as: LCA) Clinical features
The LCAs are a group of autosomal recessive early-onset retinal dystrophies that are a common cause of congenital visual impairment. Infants may have photophobia and eye-poking (Franceschetti’s sign). Patients have roving eye movements and are unable to fix and follow at birth. Nystagmus develops later. Pupil reactions are sluggish, occasionally with a paradoxical response. Refractive error is common and many patients are highly hypermetropic. Keratoconus is a recognized association. Initially, fundoscopy is normal but this changes with time. Ultimately, there is evidence of a widespread retinopathy with peripheral pigmentation, vessel attenuation and optic disc pallor. Macular changes are common—in many there is early pigment disturbance with later atrophic changes. Macular colobomatous changes have also been described and reflect the range of heterogeneity. Patients have a non-detectable ERG by 3 months of age. Classically, LCA is an isolated retinal dystrophy. The mutations in the underlying genes have been found amongst individuals without extraocular manifestations. Heterogeneity amongst early-onset dystrophies includes the association of mental retardation in some patients. Herein, LCA is defined solely as an ocular condition.
Age at onset
Birth, or in the first few weeks of life.
Inheritance
Autosomal recessive As there is evidence for some correlation of genotype and phenotype among the different types of LCA, the phenotypic range of mutations in GUCY2D, CRX, etc. are described here.
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Leber congenital amaurosis
Chromosomal location Disorder LCA1 LCA2 LCA3 LCA4 LCA5 LCA6 LCA LCA
Gene GUCY2D RPE65 AIPL1 RPGRIP1 CRX CRB1
Chromosome 17p13.1 1p31 14q24 17p13.1 6q11–q16 14q11 19q13.3 1q31–q32.1
MIM 204000 204100 604232 604393 604537 605446 604393 604210
Variability of phenotypes Disorder
Gene
Phenotypes
MIM
LCA1
GUCY2D
LCA1 adCORD6
600179
LCA2
RPE65
LCA Juvenile retinal dystrophy RP20 (arRP)
180069
LCA4
AIPL1
LCA
604392
LCA
CRX
LCA adRP adCORD2
602225
LCA
CRB1
LCA 604210 RP12 (arRP) RP with Coats-like exudative vasculopathy
GUCY2D Clinical features
Leber congenital amaurosis (LCA1) Mutations in GUCY2D are said to result in a severe, early-onset cone-rod degeneration. Characteristically, there is high hypermetropia and severe photophobia. Retinal changes develop with time while the ERG is unrecordable. The degree of blindness does not alter with time.
Inherited retinal disease
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Autosomal dominant cone-rod dystrophy (CORD6) Affected individuals display cone dysfunction (reduced VA, photophobia, altered color vision) in the first decade. At this stage there is severe loss of photopic ERG with relative preservation of the scotopic ERG. Visual acuity decreases dramatically during the second and third decades, to be followed by night blindness in the fourth and fifth decades, at which stage the ERG becomes unrecordable. Gene
Guanylate cyclase 2D (GUCY2D); alternative name: RetGC1.
Mutational spectrum
LCA1 A broad range of mutations have been found to cause LCA1. The frequency of mutations in cases of LCA1 is uncertain—reports vary from 6–20%. These include frameshift, nonsense, splice-site and missense mutations. CORD6 Missense mutations in residues 837 and 838 alter a region critical to dimerization of GUCY2D. These result in autosomal dominant cone-rod dystrophy.
Effect of mutation
Phototransduction results in hydrolysis of cGMP, closure of cGMPgated cation channels, and plasma membrane hyperpolarization. In the dark (recovery) phase, cGMP levels are restored through the conversion of GTP to cGMP by guanylate cyclase, which reopens the channels and leads to an influx of Ca2+ and Na+. In LCA1, it is presumed that there is loss of function of RetGC1. cGMP-gated channels are permanently closed as cGMP levels are not restored to dark levels. In effect there is constant light exposure, explaining the early impairment of rod and cone function. In CORD6, GUCY2D mutations in the dimerization domain result in gain of function (i.e. dominant negative) effects. The mutations result in altered sensitivity to Ca2+ and increased sensitivity to activation by GUCA1A (see CORD3). The resultant alteration of
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Leber congenital amaurosis
Ca2+ concentration and cGMP channel activity may result in retinal degeneration. A mutation in GUCA1A in cone dystrophy also results in alteration of the GUCA1A/Ca2+ sensitivity, suggesting that the two diseases share a similar etiology.
RPE65 Clinical features
Patients with RPE65 mutations have a severe early-onset retinal degeneration characterized by moderate or absent hypermetropia (even low myopia). Symptoms are noted from birth onwards, as in other forms of LCA, with an inability to follow light or objects, and roving eye movements. This is followed by the development of pendular nystagmus. Parents notice a transient improvement in vision, particularly in well-lit conditions, while night blindness is a major symptom. Central visual acuity is in the range of 6/36–6/60. Visual fields are recordable and show concentric field loss while the ERG is unrecordable. In some families there is an early-onset severe retinal dystrophy, which is said to be less aggressive than LCA, although whether this is truly a different entity to LCA is debatable. Patients are noted to have a rod-cone dystrophy causing severe visual impairment before the age of 5 years (i.e. not at birth). Such patients retain useful visual function up to (and in some cases beyond) the age of 10 years.
Gene
Retinal pigment epithelium-specific protein, 65 kDa (RPE65)
Mutational spectrum and effect of mutation
RPE65 is a 65 kDa protein expressed in the RPE. The protein is important in retinal vitamin A metabolism and is thought to be essential for isomerization of 11-cis retinol, a key step in the RPE visual cycle. Mutations in the LRAT gene, encoding lecithin retinol acyltransferase (an early enzyme in the pathway involved in 11-cis retinal synthesis) causes a similar, early-onset and severe, recessive retinal dystrophy. Premature termination, nonsense, splicing and missense mutations cause 6–16% of cases of LCA and are thought to abolish RPE65 function.
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Screening of a panel of patients with arRP demonstrated mutations in around 2% of cases. Some families had one allele with a missense mutation that did not alter amino acid charge. It is thought that these mutations retain some residual function (hypomorphic allele) which may explain the milder phenotype.
AIPL1 Clinical features
Although the retinal features associated with mutations in AIPL1 are not distinctive, many patients with LCA4 also have keratoconus.
Gene
Arylhydrocarbon-interacting receptor protein-like 1 (AIPL1)
Mutational spectrum and effect of mutation
Missense, nonsense and frameshift mutations are all described, suggesting that mutations result in severe diminution or loss of function. One study suggests that AIPL1 mutations cause around 7% of LCA. The function of AIPL1 in the retina is not known although it is thought to be important in protein folding or trafficking.
RPGRIP1 Clinical features
The clinical features of LCA type VI are typical of classical forms of the condition.
Gene
RPGRIP1 (RPGR-interacting protein)
Mutational spectrum and effect of mutation
RPGR is the gene mutated in one form of X-linked RP (RP3). RPGRIP1 is expressed strongly in the retina and interacts with RPGR and co-localizes with it in the photoreceptors. It is suggested that RPGRIP1 is important in the connecting cilia of rods and cones. The protein is predicted to have two coiled-coil domains which are seen in proteins involved in vesicular trafficking.
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Leber congenital amaurosis
Patients from LCA families have been found to carry mutations (both frameshift and missense) in RPGRIP1, suggesting that this may be the cause for around 6% of LCA.
Cone-rod homeobox (CRX) Clinical features
A wide variety of clinical phenotypes have been described associated with CRX mutations, including classical forms of LCA, cone-rod dystrophy and late-onset rod-cone dystrophy. CRX mutations are found in 2–3% of cases of LCA.
Gene
CRX is a photoreceptor-expressed transcription factor that binds to DNA sequences upstream of several photoreceptor-specific genes including opsins, arrestin and b-phosphodiesterase.
Mutational spectrum
Mutations in CRX have demonstrable effects in the heterozygous state. Frameshift and missense mutations have been described. The majority of missense changes are within the homeodomain.
Effect of mutation
Cases of LCA have been shown to be due to de novo mutations that were not present in the parents. One exception was a family with LCA in which both parents were heterozygous for a missense mutation that caused a mild cone-rod dystrophy. The homozygous state was associated with LCA.
Diagnosis
LCA was originally defined as a recessive condition of severe and early onset. Genetic testing is not widely available. However, demonstration that de novo mutations in CRX are associated with LCA suggests that in some families the condition is a new dominant. Therefore, in these families, recurrence risks are significantly lower than 25%, and affected individuals have a 50% chance of passing the condition on to their offspring.
Inherited retinal disease
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Retinitis punctata albescens (also known as: RPA) MIM
180090 (RLBP1)
Clinical features
RPA is characterized by the presence of numerous, punctate yellow/white dots throughout the fundus. They spare the macular region and often fan out in apparently radial patterns, being most numerous in the equatorial region. The punctate lesions may show little change with time, although as retinal degeneration continues there may be more classical features of RP with pigment deposition, arteriolar attenuation and optic disc pallor. Symptoms of night blindness, peripheral visual loss and reduced visual acuity are similar to other rod-cone dystrophies and are variable in their age of onset. Among six unrelated families with RLBP1 mutations, all had RPA. One family from Sweden had a form of RPA, known as Bothnia dystrophy, which is common in northern Sweden.
Age at onset
In patients with RLBP1 mutations, night blindness is noted in the first decade progressing to legal blindness in their 20s. Often, even late in the disease, there is no retinal pigment dispersion.
Inheritance
Autosomal recessive Autosomal dominant. Mutations in rhodopsin and RDS/peripherin have been shown to cause progressive retinal degeneration associated with retinal flecks.
Chromosomal location
15q26 (recessive RPA)
Gene
Retinaldehyde-binding protein 1 (RLBP1); alternative name: cellular retinaldehyde-binding protein (CRALBP).
Mutational spectrum
Missense mutation of conserved residues, splice-site mutation and frameshift mutations have all been described.
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Retinitis punctata albescens
Effect of mutation
The majority of isolated retinal degenerations described to date result from defects in proteins expressed in the photoreceptors. A number are now recognized, such as RLBP1, that are expressed in the RPE. RLBP1 is involved in the visual cycle, the process whereby 11-cis retinaldehyde (which is converted to its all-trans isomer by light) is regenerated via a complex biochemical pathway that involves both photoreceptors and RPE. RLBP1 binds 11-cis retinol and promotes its oxidation to 11-cis retinaldehyde within the RPE before the latter is transferred back to the photoreceptor. Mutated versions of RLBP1 have been shown to lack the ability to bind 11-cis retinaldehyde. This may lead to an inability to regenerate rhodopsin or, through the depletion of 11-cis retinaldehyde, may lead to a disturbance of rod outer-segment physiology.
Diagnosis
Inherited retinal disease
RPA is characterized by the presence of yellowish dots throughout the fundus. It should not be confused with fundus albipunctatus, which is a stationary disorder (see section on congenital stationary night blindness).
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Retinitis pigmentosa RP is the most well known of the inherited disorders of the eye. It is not a single entity and is often used as a collective term for the large group of inherited disorders in which abnormalities of the photoreceptors or RPE lead to progressive visual loss.
Bone spicule retinal pigmentation of retinitis pigmentosa.
Clinical features
Patients first experience night blindness, constriction of the peripheral visual field and eventually lose central vision. They describe difficulties in dark or poorly-lit surroundings and have trouble changing from wellto poorly-lit conditions, reflecting abnormal dark adaptation. Some patients may also have photophobia. Diagnosis is based on a progressive, bilateral, photoreceptor dysfunction associated with undetectable or reduced amplitude ERGs in which rod-mediated responses are more severely affected than cone-mediated (i.e. rod-cone dystrophy). However, within these boundaries there are wide variations at the clinical level, as defined by inheritance pattern, age at onset, speed of progression and fundoscopic appearance. Fundoscopy classically shows redistribution of pigment with RPE disturbance and intraretinal accumulation in a bone-spicule distribution. Pigment may also be seen within the vitreous cavity. The pigment may be distributed in a perivascular fashion and is
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Retinitis pigmentosa
often prominent in the mid-periphery. There is progressive loss of RPE and retina with resultant optic atrophy and vascular attenuation. Visual acuity is variably affected and may be reduced late in the course of the disorder reflecting cone dysfunction. Visual fields show a progressive, generalized restriction. ERG examination in RP is variable, but shows attenuation or even total loss at the time of presentation. Early in the course of the disease there is impairment of rod responses, while in advanced RP both rod and cone-mediated ERGs are unrecordable. Epidemiology
The prevalence of RP is around 1:3500–4000 in the USA and Europe.
Molecular analysis of retinitis pigmentosa
RP is extremely heterogeneous and, prior to the molecular era, efforts to classify it clinically were unsuccessful in the majority of patients. Molecular analysis has served to underline the degree of heterogeneity. As genes have been identified underlying autosomal dominant, autosomal recessive and X-linked forms of RP, recurring themes have been observed. Firstly, defects in a large number of the genes cause identical and indistinguishable phenotypic manifestations. By contrast defects of one gene may cause a wide range of different clinical entities. Identification of the genes underlying these disorders has followed one of two main paths, the candidate gene approach and the positional cloning approach. In the former, genes that encode retinal proteins are targeted as genes likely to cause retinal dystrophy. This approach has been extremely successful, as shown by the number of genes acting within the phototransduction cascade that have been found to underlie different dystrophies. A number of mammalian models of retinal dystrophies are also recognized and have been characterized at the molecular level—these also serve as ideal candidate genes for human disorders. The relative ease of this approach will tend to skew the apparent importance of well-characterized pathways, which have already been identified as being important in RP.
Inherited retinal disease
123
Positional cloning describes the process whereby a disease-causing gene is localized firstly by genetic mapping (linkage analysis) then by the definition of its sequence and structure from a small chromosomal region. This highly labor-intensive approach is extremely powerful and takes no account of function, sequence or phenotype. It allows identification of previously unknown genes or genes having an unexpected role in a given condition. The number of known genes underlying RP continues to grow, especially for the recessive forms. In general, there is a wide range of mutations within each of these genes that may have a deleterious effect. This suggests that in the future, genetic testing of an individual will have to be extremely sophisticated in order to identify a single mutation from this group of genes. Such technology is not yet available and as a consequence the impact of gene identification upon the wider RP population has been modest, except in a small number of cases.
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Retinitis pigmentosa
Autosomal dominant retinitis pigmentosa (also known as: adRP) Clinical features
The clinical characteristics of adRP may be highly variable. As with other inheritance patterns, there are now a large number of different genes that are recognized to cause adRP, which represents around 20–25% of cases of RP.
Autosomal domant retinitis pigmentosa.
Genes
The majority of the genes known to cause adRP are photoreceptorspecific. Of the remainder, NRL (neural retinal-specific leucine zipper transcription factor gene) has been shown to display its highest level of expression in the photoreceptor. Rhodopsin (RHO), RDS/peripherin and ROM1 are all found in the rod outer segments. RHO was the first gene shown to cause RP and is a significant cause of adRP; it is estimated that 30–40% of adRP is caused by RHO mutations. Mutations in RDS/peripherin have been shown to cause a wide range of retinal phenotypes including one form of RP, termed ‘digenic’, in which mutations of two genes (RDS/peripherin and ROM1) together result in a phenotypic effect. Of the remaining genes, both CRX and NRL are retinal-specific transcription factors that are important in regulating developmental gene expression. RP1, a form of adRP linked to chromosome 8q11,
Inherited retinal disease
125
has been shown to be caused by defects of a gene identified in a mouse model of oxygen-induced retinal neovascularization. The function of the protein is, like many others involved in RP, yet to be defined. Three forms of RP (RP11, RP13 and RP18) are caused by defects in genes (HPRP3, PRPC8 and PRP31, respectively), which are ubiquitously expressed and are highly conserved between yeast and humans. The genes are involved in regulating mRNA processing and splicing; it is unclear why defects in these genes should cause a tissue-specific disorder such as RP. Loci and genes
Gene
Locus
Chromosomal
MIM
PRP31 RHO RDS/peripherin IMPDH1 RP1 ROM1/RDS NRL PRPC8 CRX HPRP3
RP18 RP4 RP7 RP9 RP10 RP1 Digenic RP RP27 RP13 RP17 RP11
location 1q13–q23 3q21–q24 6p21.2–cen 7p13–p15 7q31.3 8q11–q13 11q13 14q11.2 17p13.3 17q22 19q13.3 19q13.4
601414 180380 179605 180104 180105 180100 180721 162080 600059 600852 602225 600138
implicated in adRP
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Autosomal dominant retinitis pigmentosa
Peripherin/RDS (also known as: peripherin/retinal degeneration slow [RDS]-related retinitis pigmentosa) Including: autosomal dominant macular dystrophy; pattern/butterflyshaped dystrophy; adult vitelliform dystrophy; central areolar choroidal dystrophy (CACD); retinitis punctata albescens; progressive cone dystrophy. MIM
179605
Clinical features
The range of phenotypes caused by mutations in the peripherin/RDS gene is remarkable, including widespread dystrophies such as RP, macular dystrophies and isolated cone dystrophies. There is significant inter and intrafamilial variation. Many of the early-onset macular dystrophies have been named on morphological grounds. Adult vitelliform dystrophy is characterized by small, circumscribed subfoveal lesions that present from the third decade of life onwards. Morphologically similar to Best disease, the condition lacks the characteristic EOG changes. Adult vitelliform dystrophy may be relatively mild, but in some cases can progress and result in significant bilateral macular damage. ERG/EOG examination is normal.
Adult vitelliform distrophy.
Inherited retinal disease
127
Pattern and butterfly-shaped dystrophy are two descriptions of the same group of disorders characterized by peculiar-shaped yellow/white pigmented macular lesions. The lesions can resemble the wings of a butterfly. Patients may have mild to moderate loss of central vision. ERG is normal, although EOGs may show slight reduction of the light-induced rise. CACD is a progressive macular degeneration. Bilateral, circumscribed lesions result from atrophy of neural retina, RPE and choroid in the macular region. The area of atrophy may reach close to the optic disc. Visual impairment begins in adult life and generally progresses to legal blindness. Electrodiagnosis is normal. CACD is genetically heterogeneous with one locus on 17p in addition to mutations in RDS.
Buttterfly-shaped dystrophy.
A number of families with progressive, isolated cone dystrophy (i.e. macular dysfunction associated with abnormal cone-mediated ERGs) have been found to have missense mutations in RDS/peripherin. Chromosomal location
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6p21.1–cen
Peripherin/RDS
Gene
Retinal degeneration slow (RDS). The RDS gene was the second gene shown to cause RP. In the mouse a naturally occurring mutant causes the RDS phenotype.
Mutational spectrum
A broad range of mutations have been described throughout the gene including missense, nonsense and frameshifts. The protein contains four transmembrane domains and is situated in the rod outer segment discs. There are two cytoplasmic loops situated in the lumen of the discs. Many mutations are situated in the larger of the intradiscal loops.
Effect of mutation
RDS is an integral structural protein of rod outer segment discs associated with ROM1 (q.v.). These proteins are situated at the lip of the discs and are thought to be important in stabilization of the curved disc edges. It is presumed that the mutations have specific dominant negative effects that result in photoreceptor degeneration.
Inherited retinal disease
129
Rhodopsin (also known as: RHO) Including: rhodopsin-related retinitis pigmentosa; autosomal recessive retinitis pigmentosa; retinitis punctata albescens; congenital stationary night blindness, rhodopsin-related; autosomal dominant retinitis pigmentosa type 4; RP4. MIM
180380
Clinical features
A wide variety of pedigrees with rhodopsin mutations have now been analyzed. These demonstrate a high degree of inter and intrafamilial variability. Some individuals have severe RP4 in the first and second decades, in others it is delayed (fourth-fifth decades or later). ERG examination reflects this variability, with some patients having extinguished or severely reduced ERGs early in life. Others may have entirely normal examination until adulthood. In general, ERGs show early deterioration of rod-mediated responses; cone-mediated responses decline later in life. Fundoscopy may also vary widely. The majority of patients have classical RP. Sector RP has been described, in which the inferior retina is more severely affected than the superior retina, with superior field loss. Retinitis punctata albescens is a dominantly inherited retinal dystrophy in which the characteristic feature is the presence of white/yellow dots scattered throughout the fundus. CNSB has also been associated with certain rhodopsin mutations.
Chromosomal location
3q21–q24
Gene
RHO
Mutational spectrum
A wide range of mutations have been described throughout the gene. The majority are missense mutations with no strong evidence of genotype-phenotype correlation. There is a general tendency
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Rhodopsin
towards a gradient of severity with the more severe mutations being located at the 3´ end of the gene and the milder ones at the 5´ end. Certain mutations have been associated with the specific phenotypes described above, although the findings are by no means clear-cut. An arginine to tryptophan substitution at position 135 has been described in association with retinitis punctata albescens and classical RP in the same family. Sector RP has been described with missense mutations at the 5´ end of the gene while CSNB has also been described in association with a small number of missense changes (see CSNB). A small number of families have been found with arRP as a result of null rhodopsin mutations. These cause absent rhodopsin expression. Effect of mutation
Inherited retinal disease
In recessive mutations it is likely that retinal dystrophy is caused by the absence of rhodopsin. As heterozygous carriers of such mutations do not manifest symptoms, haploinsufficiency is not disease-causing and in the majority of cases missense mutations are likely to act in a dominant-negative manner. The exact cause of photoreceptor decay is not certain; accumulation of the abnormal protein has been demonstrated in the endoplasmic reticulum, cytoplasm and cell membrane and is thought to contribute to photoreceptor apoptosis.
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Autosomal recessive retinitis pigmentosa (also known as: arRP) A large number of different genes are recognized to cause autosomal recessive retinal dystrophies. In addition to those causing Leber congenital amaurosis and syndromic forms of arRP (e.g. Usher syndrome and Bardet-Biedl syndrome), around 20 loci are already known to cause isolated arRP. arRP represents 15–30% of cases of RP. Clinical features
The clinical characteristics amongst patients with arRP—age at onset, speed of progression, visual acuity—vary widely and cannot be generalized. With the burgeoning information regarding the genes involved, many groups have developed large screening panels of DNA from patients with arRP. Such groups of patients are analyzed for each novel gene and mutations are defined. Detailed clinical descriptions are often not allied to such a process. However, there are some recessive retinal dystrophies with characteristic clinical features such as PPRPE or retinitis punctata albescens (multiple punctate white/yellow dots). These are dealt with in separate sections below.
Genes
A large number of genes are known to cause arRP, suggesting that a range of mutations can result in a similar ‘final common pathway’ of photoreceptor and RPE dysfunction, apoptosis and retinal atrophy. The majority of these arRP genes are expressed in the photoreceptor and a number of photoreceptor-specific processes have been implicated—the most important of which is the phototransduction cascade. Several proteins involved in phototransduction (such as RHO, PDE6A, PDE6B and CNGA1) and its recovery phase (such as arrestin or SAG) are now recognized to cause isolated arRP. A number of RPE-specific proteins have also been identified, such as RPE65 (see Leber congenital amaurosis), LRAT and RLBP1 (see retinitis punctata albescens).
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Autosomal recessive retinitis pigmentosa
The function of many of the genes that have been identified is currently unknown. An example is TULP1 which causes rare forms of arRP. A member of a family of highly conserved proteins, TULP1 is expressed in photoreceptors and is thought to play a role in their development and maintenance. However, as with many other genes that cause isolated retinal dystrophies, TULP1 is not exclusively expressed in the retina and is found in extraocular tissues. As would be expected, the majority of mutations in the genes underlying arRP result in loss of function. In almost all cases one normal allele (i.e. the heterozygous state) is compatible with normal function. Diagnosis
Diagnosis of arRP remains a complex issue, in particular amongst cases of simplex or isolated RP, and requires careful clinical examination and evaluation. Amongst the childhood-onset forms, symptoms often become apparent at a stage when parents may already have had further children. The clinician is then faced with asymptomatic younger siblings who have a 25% risk of developing symptoms. Deciding when to examine family members and then preparing parents for bad news is a difficult issue that may require considerable clinic time. The high proportion of single individuals with no family history of the disease (simplex RP) remains one of the greatest diagnostic challenges among patients with non-syndromic RP. While the majority represent recessive forms, it is nevertheless possible that some will be due to new or reduced penetrance dominant mutations, or even X-linked forms of RP. The advent of molecular testing will undoubtedly have a significant role to play in the future for facilitating the diagnosis of such forms of RP and will help to define inheritance patterns and prognosis for those in whom family history offers no clue. However, the sheer complexity of RP is only now beginning to unfold and technology is as yet unable to offer adequate genetic screening tests to answer these questions.
Inherited retinal disease
133
Genes and chromosomal locations of isolated, recessive forms of retinitis pigmentosa Gene RPE65 ABCA4 CRB1 USH2A MERTK SAG RHO PROML1 PDE6B CNGA1 LRAT PDE6A TULP1 RGR RBP4 RLBP1 -
134
Locus RP20 RP19 RP12 USH2A RP28 MERTK RP26 SAG RP4 PROML1 PDE6B CNGA1 LRAT RP29 PDE6A RP14 RP25 RGR RBP4 RLBP1 RP22
Chromosomal location 1p31 1p21–p22 1q31–q32.1 1q41 2p11–p15 2q14.1 2q31–q33 2q37.1 3q21–q24 4p12–p16.2 4p16.3 4p12–cen 4q31.2 4q32–q34 5q31.2–q34 6p21.3 6cen–q15 10q23 10q24 15q26 16p12.1–p12.3
MIM 180069 601718 268030 279901 604705 181031 180380 604365 180072 123825 604863 180071 600139 602772 600342 180250 180090 602594
Autosomal recessive retinitis pigmentosa
Retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium (also known as: retinitis pigmentosa, PPRPE type; retinitis pigmentosa type 12 [RP12]) Including: Leber congenital amaurosis, RP with Coats’-like exudative vasculopathy. MIM
268030; 600105 (RP12); 604210 (CRB1)
Clinical features
This is an uncommon and aggressive form of early-onset arRP with a characteristic retinal phenotype. Within areas of generalized retinal atrophy there is relative preservation of the para-arteriolar retinal pigment epithelium. Visual acuity is lost early in the disease process. Patients are often hypermetropic and may have disc drusen.
Age of onset
First decade of life
Inheritance
Autosomal recessive
Chromosomal location
1q31–q32.1
Gene
Crumbs, Drosophila homolog of, 1 (CRB1)
Mutational spectrum
PPRPE: amongst patients with PPRPE, both homozygous missense and protein truncating mutations have been described. LCA: a significant proportion of patients with Leber congenital amaurosis carry mutations in the CRB1 gene. While there is variability of phenotype associated with mutations in this gene, there is no obvious correlation with site or type of mutation. However, patients with null alleles and nonsense, frameshift and splice-site mutations (i.e. those that would not be predicted to form a protein) most frequently develop LCA rather than PPRPE.
Inherited retinal disease
135
RP with Coats’-like exudative vasculopathy: a small number of patients with RP develop an exudative vasculopathy reminiscent of Coats’ disease, often unilaterally. A number of patients with CRB1 mutations have been found to have a Coats’-like reaction, although this was not always present in affected family members. Effect of mutation
In Drosophila melanogaster, the crumbs protein is important in maintaining epithelial polarity. The homology to CRB suggests a role for CRB1 in cell-cell interaction and in maintenance of cell polarity in the retina. The distinctive RPE changes suggest that CRB1 mutations act via a novel pathogenic mechanism.
136
Retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium
Digenic retinitis pigmentosa MIM
180721 (ROM1)
Clinical features
Classical retinitis pigmentosa
Inheritance
Digenic
Chromosomal location
11q13
Gene
Rod outer segment protein 1 (ROM1)
Mutational spectrum
Mutations in ROM1 alone have not been proven to be pathogenic. However, when present in association with a specific RDS/peripherin missense mutation (leucine to proline substitution of residue 185), ROM1 mutations result in RP. Since this requires specific genetic changes at two loci this is termed ‘digenic inheritance’. Digenic inheritance is difficult to identify, but may explain how mutations at different loci interact to cause disease or to modify the phenotypic effects of a mutation. Such interactions may underlie the variability seen in some genetic conditions.
Effect of mutation
Inherited retinal disease
ROM1 is found in the rod outer segment discs, where it is important for stabilizing the disc edges. The protein interacts closely with RDS/peripherin, which explains the pathogenicity of the combination of the two genetic changes.
137
X-linked retinitis pigmentosa (also known as: XLRP) Clinical features
XLRP is a severe form of RP that affects males in their first decade of life and progresses to blindness by the third or fourth decades. Males are generally myopic and present with a rod-cone dystrophy, although families with variable presentation have also been described and individuals within proven RP3 kindreds have been shown to have cone-rod dystrophy. XLRP is an important cause of RP accounting for 10–23% of all cases. In addition to these forms of XLRP, X-linked forms of CSNB, cone-rod and cone dystrophies have been described. Linkage has been defined for several of the X-linked loci, but for many the underlying genes have not been identified. It remains possible, therefore, that mutations at novel loci might be responsible for more than one of these phenotypes. Clinical manifestations in carrier females As with other X-linked conditions, female carriers may manifest symptoms of XLRP, albeit to a milder degree than their male relatives. The age of onset among female carriers is highly variable. This mild phenotype has been ascribed to the variability of X-inactivation. However, in certain pedigrees symptomatic females are common. This suggests that for some forms of XLRP, inheritance may be X-linked dominant. Determination of carrier status is often possible by fundoscopy and ERG examination, although this is less reliable in younger females. Clinically, the two most common forms of XLRP (RP3 and RP2) may be differentiated by the presence in carrier females of a ‘tapetal-like’ reflex on direct ophthalmoscopy. This glistening metallic white/gold reflex is most noticeable in the paramacular region and is suggestive of an RPGR mutation. It is not present in all carriers or within all pedigrees linked to the RPGR gene.
138
X-linked retinitis pigmentosa
Tapetal-like reflex in female carrier of XLRP (RP3).
Age of onset
XLRP begins in the first decade.
Inheritance
X-linked recessive. Some families are recognized in which phenotypic manifestations are common in carrier females, suggesting X-linked dominant inheritance.
Chromosomal location and genes
As with other inherited forms of RP, XLRP shows both clinical and genetic heterogeneity.
Gene RPGR RP2 -
Locus RP23 RP6 RP3 RP2 RP24
Chromosomal location Xp22 Xp21.3–p21.2 Xp21.1 Xp11.3 Xq26–q27
MIM 312612 312610 312600 300155
Frequency Single family Single family 75% 10% Single family
Mutational spectrum
RP3
and effects of mutation
RP3 is caused by mutations in the RPGR gene. The RPGR protein is localized in the Golgi apparatus and contains a conserved domain thought to interact with PDEd, which is attached to the discs of rod outer segments. RPGR is thought to modulate intracellular vesicular transport, which is critical to endocytic pathways.
Inherited retinal disease
139
The majority of mutations are found within an alternatively spliced exon (ORF 15), which shows preferential expression within the retina. This region is repetitive and represents a mutational hot-spot that accounts for around 80% of RPGR mutations. Of the mutations outside this region (i.e. the remaining 20%), the majority lie in the conserved N-terminal region of the protein. RP2 RP2 is a ubiquitously expressed protein of unknown function. The protein is localized to the cell membrane in fibroblasts and the cytoplasm of COS-7 cells. The localization in retinal cells is undetermined. The N-terminus is homologous to cofactor C, a chaperone protein which acts as a protein involved in the folding of a- and b-tubulins. Mutations fall into two classes: missense mutations clustered in the cofactor C homologous domain – these mutations do not alter subcellular localization of the protein and are hypothesized to reduce function of the important N-terminal domain; premature protein truncation – these constitute the majority of the remaining mutations. Diagnosis
140
Identification of X-linked inheritance is important when defining recurrence risks in families with RP. Clinical definition of carrier status in females of child-bearing age within families affected by XLRP can be unsatisfactory. Recent developments in identification of the RP2 and RPGR genes allow accurate definition of carrier status and early diagnosis in young males in the majority of XLRP families.
X-linked retinitis pigmentosa
Congenital stationary night blindness (also known as: CSNB) A number of conditions are associated with stationary night blindness including CSNB, fundus albipunctatus and Oguchi disease. Distinct genetic forms of stationary night blindness Disorder CSNB1 CSNB2 CSNB3 CSNB3 CSNB3
Gene NYX CACNA1F GNAT1 RHO PDE6B
Clinical features
Chromosomal location Xp11.4 Xp11.23 3p21 3q21–q24 4p16.3
Inheritance XL XL AD AD AD
MIM 310500 300071 163500 180380 180072
CSNB is characterized by night blindness in the presence of normal retinal examination. Nystagmus is common and patients are often diagnosed as having ‘congenital nystagmus’. Patients have variable reduction in visual acuity. In autosomal dominant forms, this may be in the normal range (6/6–6/12) while in recessive and X-linked forms there may be a more significant reduction (6/24 or greater). Patients with the complete form of X-linked CSNB (CSNB1) are often moderately or highly myopic. Visual field testing in photopic conditions is normal, as is color vision. Electrophysiology is required to diagnose CSNB. A number of different ERG patterns have been described and while these do not respect an inheritance pattern exactly, a number of generalizations can be made: • normal A wave, absent/small amplitude B wave on scotopic ERG. This ‘negative wave ERG’ pattern is seen in the X-linked and autosomal recessive forms of CSNB. When dark adaptation is tested, some patients have no rod contribution (complete CSNB, CSNB1); others have reduced rod contribution (incomplete CSNB, CSNB2).
Inherited retinal disease
141
• reduced A wave, reduced B wave (B>A wave) on scotopic ERG. This ‘positive wave ERG’ pattern is often seen amongst dominant forms of CSNB.
Male patient with X-linked CSNB and moderate myopia. There are few retinal findings apart from the peripapillary atrophic changes of myopia.
Age of onset
Birth
Genes
Gene
Gene name
MIM
CACNA1F
Calcium channel alpha-1 subunit
300110
NYX
Nyctalopin
300278
GNAT1
Alpha subunit of rod transducin
139330
RHO
Rhodopsin
180380
PDE6B
Beta subunit, rod cGMP phosphodiesterase
180072
Mutational spectrum The genetic mutations that lead to stationary forms of night and effects of mutations blindness have a variety of pathogenic mechanisms. X-linked CSNB A variety of mutations in CACNA1F are described including missense, frameshift and nonsense mutations. They are predicted to result in loss 142
Congenital stationary night blindness
of function. CACNA1F encodes a voltage-gated calcium channel that is retina-specific. It is thought that the mutations result in an alteration of Ca2+-mediated neurotransmitter release from photoreceptors in response to light. There are at least two forms of X-linked CSNB, and mutations in CACNA1F are associated with the incomplete form. NYX, which encodes a leucine rich extracellular matrix proteoglycan, nyctalopin, has been shown to be mutated in the complete form of X-linked CSNB. Frameshift, missense and whole exon deletions have all been defined. The 481 amino acid protein is expressed within the kidney and retina. Within the retina it is expressed in the inner segment, inner and outer nuclear layers and in the ganglion cells. Leucine-rich repeats are generally involved in protein-protein interactions and, while the function of the protein is not known, other members of this family of molecules are implicated in cell growth, adhesion and migration. Autosomal dominant CSNB Dominant negative RHO mutations associated with CSNB are found in residues that lie within a similar region of the folded rhodopsin molecule. They result in constitutive, light-independent activation of transducin, and hence of the phototransduction cascade (see page 130, rhodopsin adRP). A specific missense mutation (His258Arg) in the b subunit of phosphodiesterase (PDE) also causes CSNB (the majority of mutations in this gene cause autosomal recessive RP). This mutation is found near to the N-terminal portion of the protein and is thought to alter the inactivation of PDE in dark-adapted conditions. Reduced inactivation of PDE results in constitutive activation of phototransduction. The single missense mutation of GNAT1 alters a conserved residue. Transducin is the second component of the phototransduction cascade, which in turn binds to the third protein, PDE. The mutant transducin does not bind to the inhibitory g subunit of PDE suggesting that this does not cause CSNB via activation of the phototransduction cascade, but acts via a different pathogenic mechanism.
Inherited retinal disease
143
Diagnosis
When suspected clinically, diagnosis of CSNB is generally supported by electrodiagnosis. At the current time, the degree of heterogeneity precludes molecular analysis, which is not widely available.
Fundus albipunctatus MIM
136880; 601617 (RDH5)
Clinical features
In fundus albipunctatus, congenital night blindness is present with well-preserved, or normal, visual acuity. Fundus examination reveals white dots scattered throughout the retina. There is no RPE degeneration and no progression with time. ERG testing is characteristic of CSNB with reduction on the B wave of the scotopic ERG. However, this returns to normal with prolonged dark adaptation (up to 3 h).
Fundus albipunctatus. 20-year-old Asian female with non-progressive night blindness.
Age of onset
Birth
Inheritance pattern
Autosomal recessive
Chromosomal location
12q13–q14
144
Fundus albipunctatus
Gene
Retinol dehydrogenase 5 (RDH5)
Mutational spectrum
Both missense and frameshift mutations have been described in RDH5.
Effects of mutations
Several molecules that are important in the visual cycle regenerating retinol dehydrogenase 5 have been implicated in retinal degeneration. RDH5 is expressed in the RPE and catalyzes the conversion of 11-cis retinol to 11-cis retinal. RDH5 mutations have been shown severely to reduce its activity. It is thought that reduced enzyme levels lead to reduced production of 11-cis retinal, which in turn leads to abnormally slow regeneration of cone and rod photopigments. Ultimately, photopigments do regenerate, which may explain the normalization of the ERG after prolonged dark adaptation, and may result from residual enzyme activity.
Diagnosis
When suspected clinically, diagnosis of fundus albipunctatus, as opposed to retinitis punctata albescens, is supported by electrodiagnosis. Mutation testing is only available on a research basis at the current time.
Oguchi disease MIM
258100; 181031 (SAG); 180381 (RHOK)
Clinical features
Oguchi disease is a form of congenital stationary night blindness (CSNB) rarely seen outside Japan. In the light-adapted state, the retina has a greenish hue that returns to normal after dark adaptation. ERG testing reveals a CSNB negative waveform pattern. Unlike fundus albipunctatus, this does not improve with dark adaptation.
Age of onset
Birth
Inheritance pattern
Autosomal recessive
Inherited retinal disease
145
Chromosomal location
2q37.1 (SAG) 13q34 (RHOK)
Gene
S-antigen (SAG); alternative name: arrestin. Rhodopsin kinase (RHOK)
Mutational spectrum and effect of mutations
Rhodopsin kinase and arrestin act together to deactivate rhodopsin after stimulation by light. RHOK phosphorylates rhodopsin at specific residues. This modified form of rhodopsin is then complexed by arrestin. Null mutations in both result in the same clinical phenotype. Loss of function mutations (deletion, missense and frameshift) are described in RHOK, and protein truncation mutations in arrestin. Mutations would, therefore, result in reduced deactivation of rhodopsin.
Diagnosis
Oguchi disease is rare ouside Japan.
146
Oguchi disease
Alström syndrome (also known as: ALMS1) MIM
203800
Clinical features
ALMS1 is an under-diagnosed multisystemic condition associated with obesity, diabetes, retinal degeneration and acanthosis nigricans. Unlike Bardet-Biedl syndrome, polydactyly is not present and intelligence is often normal. Ocular Children with ALMS1 develop an early-onset severe cone-rod dystrophy. Nystagmus is often present and children are photophobic. The ERG is usually extinguished when tested but, if present, shows better preservation of rod responses. Patients may progress to having no light perception by the end of the second decade. Fundoscopy reveals vessel attenuation early in the course of the disease with disc pallor. Bull’s eye maculopathy or bone corpuscular pigmentation is rare. Extraocular The majority of children are found to have dilated cardiomyopathy, which is a common cause of death in infancy. Children are overweight and often develop hearing loss before 10 years of age. Children may have acanthosis nigricans. Diabetes and progressive renal dysfunction may develop in adult life.
Age of onset
Birth
Inheritance
Autosomal recessive
Chromosomal location
2p13
Gene
ALMS1
Inherited retinal disease
147
Mutational spectrum
Frameshift and nonsense mutations have been described.
Effect of mutation
The ALSM1 protein is an uncharacterized protein encoded by a ubiquitously expressed gene of 23 exons. The protein is large (4169 amino acids) and contains a tandem repeat encoding 47 amino acids.
Diagnosis
Diagnosis is on clinical grounds and may be supported by ophthalmic investigation. An autosomal recessive condition, recurrence risks are 25% for further children. Currently, DNA diagnosis is not available.
148
Alström syndrome
Bardet-Biedl syndrome (also known as: BBS) MIM
604896 (MKKS)
Clinical features
BBS is an autosomal recessive condition associated with postaxial polydactyly, obesity, mental retardation and retinal degeneration. The condition is highly variable, which occasionally leads to delays in diagnosis.
Severe retinal dystrophy in Bardet-Biedl syndrome with vessel attenuation and disc pallor. There were also classical bone-spicule changes in the periphery.
Large atrophic lesion of the macula in a 47-year-old male with BBS.
Inherited retinal disease
149
Ocular Retinal dystrophy in BBS is an extremely common, perhaps invariant, finding. Visual deterioration is of early onset—often within the first 5 years of life. Presenting features include nyctalopia, nystagmus and photophobia. Reduced visual acuity is often an early feature and a large number of patients are myopic. On examination there is usually evidence of widespread retinal changes. Macular changes, which range from mild pigmentary disturbance and bull’s eye maculopathy to gross atrophic lesions, are seen in the majority of patients. ERG measurements are often unrecordable.
Brachydactyly in BBS.
Nubbin of postaxial polydactyly.
Polydactyly in BBS – this adult patient had early surgery to remove extra digit from this foot.
150
Bardet-Biedl syndrome
Extraocular Postaxial polydactyly is variable; in one study around two-thirds to three-quarters of patients had obvious polydactyly. However, others will have a skin tag, while brachydactyly is also seen. Obesity is common but is only apparent from around the age of 2–3 years. Developmental delay (particularly in fine and gross motor skills) is noted in around a third of patients. Learning difficulties are not invariable and about a quarter of patients will stay in mainstream schooling with supplementary help. Genitourinary malformations are common. Most males will have small external genitalia, while female structural genital abnormalities (including uterus duplex, septate vagina, vaginal atresia and congenital hydrometrocolpos) are described. Severely reduced renal function leading to early chronic renal failure is a common cause of premature death. Age at onset
In one study the average age at diagnosis was about 9 years. However, polydactyly is present at birth, obesity within the first 2–3 years, and visual problems noticed at around 5 years of age.
Inheritance
Autosomal recessive
Chromosomal location and genes
Disorder BBS1 BBS2 BBS3 BBS4 BBS5 BBS6
Mutation spectrum and
BBS2
effect of mutations
A widely expressed, 17 exon gene of unknown function. The gene has no known homology to genes of known function, and has no known functional relationship to other genes that cause BBS. Both
Gene BBS2 BBS4 MKKS
Chromosome 11q13 16q21 3p13–p12 15q22.3–q23 2q31 20p12
MIM 209901 209900 600151 600374 603650 604896
nonsense and missense mutations have been identified. It has been estimated that this is the second most common form of BBS accounting for around 9% of cases. Inherited retinal disease
151
BBS4 A widely expressed, 16 exon gene of unknown function. The gene is homologous to O-linked N-acetylglucosamine (O-GlcNAc) transeferase (OGT) which is thought to be involved with insulin resistance in humans and may play a role in diabetes mellitus. Both nonsense and splice-site mutations have been identified in consanguineous BBS families. BBS4 mutations are thought to account for around 1% of BBS. MKKS (McKusick-Kaufman Syndrome gene) Recessive mutations have been found in the MKKS gene in BBS as well as McKusick-Kaufman syndrome (MKKS). The gene has been estimated to cause around 4% of BBS. MKKS is a rare autosomal recessive condition characterized by hydrometrocolpos, postaxial polydactyly and congenital heart disease. It has been suspected, prior to gene identification, that this condition may overlap with BBS because a number of girls with postaxial polydactyly and structural genital abnormalities (including uterus duplex, septate vagina, vaginal atresia and congenital hydrometrocolpos) had later developed mental deficiency, obesity and retinal dystrophy. In BBS, the majority of mutations defined have been frameshifts, suggesting that the phenotype results from loss of function mutations in both alleles. Missense mutations are present in families with MKKS suggesting that the phenotype is seen amongst patients in whom there is retention of some protein function. The MKKS gene encodes a putative chaperonin protein that is responsible for the folding of a wide range of proteins. The exact role of the protein is not defined. Diagnosis
152
BBS is a clinical diagnosis that is often delayed. However, DNA testing is not yet available to facilitate the diagnosis.
Bardet-Biedl syndrome
Cockayne syndrome (also known as: CKN)
Clinical features
Cockayne syndrome is a rare recessive disorder resulting from defective DNA repair. Ocular Poor vision, often associated with nystagmus is of diverse etiology. Corneal damage is secondary to reduced tear production, as well as lagophthalmos. Early-onset or congenital cataracts are common. In addition, there is a progressive retinal dystrophy associated with peripheral retinal pigmentation, optic atrophy and arteriolar attenuation. Extraocular Children with CKN have a characteristic facial appearance with a beaked nose and sunken eyes. Progressive leukodystrophy is associated with increasing microcephaly and calcification of basal
Inherited retinal disease
153
ganglia. There is extreme failure to thrive associated with poor weight gain and loss of adipose tissue. Children have skeletal deformities including kyphosis and contractures (e.g. of the hip and fingers). Neurosensory hearing loss is common and may be the presenting feature. Extreme skin photosensitivity, reflecting defective DNA repair, may be noticeable even through glass. There is progressive deterioration and in severe cases children may die during the first decade of life. They seldom survive beyond the end of the second decade. Age at onset
Cataracts may be noted at birth. Some patients will feed poorly from early in life, but weight gain is often reasonable for the first few months before progressive emaciation and developmental delay become evident during the first year. The majority of patients present at around the age of 3 years with neurosensory deafness, failure to thrive and developmental delay.
Chromosomal location and genes
Gene ERCC8 ERCC6
Mutational spectrum
While there is variability in the severity of CKN, the phenotypes associated with mutations in the two genes are indistinguishable; 80% have mutations in ERCC6, the majority being frameshift and nonsense mutations. Recessive mutations in ERCC8 include nonsense and deletion mutations.
Effect of mutations
ERCC8 encodes a 396 amino acid protein containing WD40 repeats. ERCC6 encodes a 1493 amino acid protein with helicase motifs. Mutations in either gene affect transcription-coupled repair (TCR), the mechanism by which damaged DNA in RNA polymerase II transcribed genes is preferentially repaired. CKN cells fail to breakdown RNA polymerase II after UV exposure and to remove the transcription complex which is stalled at sites of DNA damage.
154
Chromosome Locus 5q11.2 CKN1 10q11 CKN2
MIM 216400 133540
Cockayne syndrome
Diagnosis
Inherited retinal disease
CKN can usually be diagnosed after clinical investigation. Currently, supplemental molecular and genetic tests are available on a research basis only. Cultured fibroblasts show increased sensitivity to UV light; there is decreased survival and reduced levels of DNA/RNA synthesis several hours after irradiation. UV sensitivity tests have been used for both postnatal and prenatal diagnosis. Mutation testing is available on a research basis only.
155
Cohen syndrome (also known as: COH1) MIM
216550
Clinical features
Cohen syndrome is an uncommon multisystemic condition associated with developmental delay, a characteristic dysmorphic appearance and retinal degeneration. The condition is under-recognized leading to delays in diagnosis. Ocular Children with Cohen syndrome often develop early-onset myopia that may be severe. The classical manifestation is an early-onset retinal dystrophy. There is reduced acuity, night blindness and restriction of visual fields suggesting widespread degeneration. Bull’s eye maculopathy is common. Patients are often registered as partially sighted/blind in their teenage years. Less common associations include keratoconus, lens dislocation and retinal coloboma. Extraocular Children have a characteristic facial appearance with a short philtrum (revealing apparently large upper incisors), a beaked nose and a snarling smile. There is mild microcephaly associated with moderate to severe developmental delay. Children have childhoodonset truncal obesity and elongated hands and feet with tapering digits. Patients have a neutropenia that is generally benign although frequent gum infections have been described.
Age of onset
Birth. Myopia is noted in the first 2–3 years and visual symptoms are common in the first decade.
Inheritance
Autosomal recessive
156
Cohen syndrome
Long, tapering fingers.
Chromosomal location
8q22–q23
Gene
Unknown
Diagnosis
Diagnosis is on clinical grounds and may be supported by ophthalmic and hematological investigation. Being an autosomal recessive condition, recurrence risks are 25% for further children. Currently, DNA diagnosis is not available and, although linkage has been defined, genetic testing is likely to await gene identification.
Characteristic facial appearance with short philtrum and prominent incisors. Despite truncal obesity, the extremities remain slender.
Inherited retinal disease
157
Joubert syndrome (also known as: JBTS1; cerebelloparenchymal disorder IV (CPD IV); cerebellar vermis agenesis; Joubert-Boltshauser syndrome) MIM
213300
Clinical features
JBTS1 is a rare autosomal recessive syndrome with a variable phenotype. There is complete or partial cerebellar vermian agenesis. During the neonatal period, characteristic breathing difficulties include episodic tachypnea and apnea. Children are hypotonic and development is significantly delayed. Associated abnormalities include renal cystic disease (<10% of patients) and polydactyly (12% of patients). It has been postulated that patients with JBTS1 can be divided into two groups: those with retinal dystrophy and those without. When present, the retinal dystrophy is said to run true in families. Patients with retinal dystrophy are more likely to have renal cysts. Patients have a severe and early-onset cone-rod dystrophy associated with highly attenuated ERGs. Some families are described in which individuals have chorioretinal coloboma.
Age of onset
Birth
Inheritance
Autosomal recessive
Chromosomal location
9q34.3
Gene
Unknown
Diagnosis
Diagnosis is on clinical grounds and may be supported by ophthalmic and renal investigation. An autosomal recessive condition, recurrence risks are 25% for further children. DNA diagnosis is not available.
158
Joubert syndrome
Mitochondrial disease and retinopathy Maternally inherited disorders associated with defects in the mitochondrial genome (mtDNA) may have a wide range of phenotypic manifestations. Among these a number are associated with retinal dystrophy.
Retinal dystrophy in male with mitochondrial cytopathy, diabetes and deafness. There is widespread RPE disturbance and evidence of hyperpigmentation. Note peripapillary changes.
Inherited retinal disease
159
Kearns-Sayre syndrome (also known as: KSS) MIM
530000
Clinical features
KSS is a variable phenotype associated with a combination of features including progressive ptosis and ophthalmoplegia (CPEO), and pigmentary retinal degeneration. Cardiomyopathy and cardiac conduction defects may also be present. Other less frequent features include peripheral and pharyngeal weakness and deafness. Muscle biopsy demonstrates ragged red fibers in skeletal muscle, corresponding to the presence of clusters of abnormal mitochondria.
Mitochondrial etiology
In the majority of familial cases transmission is exclusively maternal, although dominant forms (which predispose to mtDNA abnormalities) are now recognized. KSS is caused by the presence of mtDNA rearrangements including duplications and deletions. The level of deletion often varies between tissues of the same individual; often the deletion will not be present in blood and will only be found on muscle biopsy. This is a manifestation of heteroplasmy, the presence of different forms of mtDNA in the same individual. This gives rise to variations in the age of onset, symptomatology and severity, even within families carrying identical mtDNA rearrangements. Some patients who carry mitochondrial deletions display no symptoms.
160
Kearns-Sayre syndrome
Macular pattern dystrophy, deafness and diabetes Clinical features
A number of patients have now been described with pattern dystrophy (see peripherin/retinal degeneration slow) and neurosensory deafness and diabetes. It is interesting to note that some patients with flecked retina syndrome have also been described who have the 11778 LHON mutation.
Mitochondrial etiology
Patients with this condition have been found to carry a mutation at mtDNA position 3243 (A3243G). This mutation has also been found to cause MELAS (mitochondrial encephalopathy, lactic acidosis and stroke) syndrome, demonstrating the wide variability of clinical manifestations of mutations in mtDNA.
Diagnosis of mitochondrial disorders
The range of ocular manifestations of mitochondrial disease is now recognized to be wide including optic neuropathy, ophthalmoplegia, retinal degeneration and macular dystrophy. As a result, mitochondrial DNA mutations may be considered among the differential diagnoses of patients with retinal/early-onset macular dystrophy with deafness, diabetes, muscle weakness or neurological dysfunction. For some, diagnosis is routinely available by a blood test. However, for many patients (e.g. Kearns-Sayre syndrome), definitive diagnosis may require analysis of mtDNA from muscle biopsy. While inheritance of mtDNA abnormalities is usually maternal, the presence of heteroplasmy makes the prediction of outcome, and hence counselling, extremely complex.
Inherited retinal disease
161
Neuropathy, ataxia and retinitis pigmentosa (also known as: NARP) MIM
551500
Clinical features
NARP is a combination of developmental delay, RP, proximal neurogenic muscle weakness and a progressive neurodegeneration (including seizures, ataxia, sensory neuropathy and dementia). The condition has only recently been recognized. In the past, retinal dystrophy associated with mitochondrial disorders has been described as a ‘salt and pepper’ dystrophy. More recent evaluation has shown that, with time, this may proceed to a classical bone-spicule distribution of pigment. Rod-cone, cone-rod and even predominantly cone dystrophies have been described.
Mitochondrial etiology
162
A point mutation at position 8993 (T8993G) within the gene encoding subunit six of MTATP6. As in other mitochondrial conditions, heteroplasmy often contributes to a wide variation in clinical phenotype. As a result the index of suspicion for mitochondrial disease should be high amongst patients with RP and neuromuscular symptomatology.
Neuropathy, ataxia and retinitis pigmentosa
Usher syndrome Clinical features and age of onset
Usher syndrome is a recessive condition in which retinal dystrophy is associated with neurosensory deafness. Heterogeneity has long been recognized and three major forms have been defined on clinical grounds. Type I Profound congenital deafness, early onset RP (by the age of 10 years) and congenitally absent vestibular function. Children have delayed motor milestones and clumsiness due to the vestibular defect. Type II Moderate to severe congenital deafness (high frequency hearing loss) and onset of RP in late teens. Individuals with Usher syndrome type II have normal vestibular function. Children usually continue in mainstream schooling and have few problems until their teenage years. Type III RP first noted at puberty with non-congenital, progressive hearing loss. Both hearing and vision are normal at birth and progressively deteriorate over several decades. More recently, the advent of molecular testing has revealed the true degree of heterogeneity among the different forms of Usher syndrome. To date, 10 different forms of autosomal recessive Usher syndrome have been identified suggesting that a number of molecules are important in the maintenance of normal retinal, auditory and vestibular function.
Inherited retinal disease
163
Epidemiology
The frequency of Usher syndrome varies widely between different populations. As in other recessive conditions, certain population isolates (e.g. a French-Acadian group in Louisiana) show high frequencies. Estimates of prevalence vary, although studies in the USA and Norway suggest 3.5–4.5:100,000. Estimates of the relative frequencies vary although types I and II appear to be most common.
Inheritance
Autosomal recessive
Chromosomal location
Disorder
Clinical
Gene
Chromosomal location
USH1A USH1B USH1C USH1D USH1E USH1F USH2A USH2B USH2C USH3 Genes
164
Type I Type I Type I Type I Type I Type I Type II Type II Type II Type III
MYO7A USH1C/harmonin USH1D/CDH23 PCDH15 USH2A/usherin USH3
14q32 11q13.5 11p14.3 10q21–q22 21q21 10q11.2-q21 1q41 3p24.2–p23 5q 3q24–q25
Disorder
MIM
Gene
USH1B
276903
MYO7A Usher (Myosin VIIa) AR non-syndromic deafness AD non-syndromic deafness
Phenotypes
USH1C
605242
USH1C Harmonin
Usher
USH1D
601067
USH1D CDH23
Usher AR non-syndromic deafness
USH1F
602083
PCDH15
Usher
USH2A
276901
USH2A Usherin
Usher arRP
Usher syndrome
Mutational spectrum Usher syndrome type IB (myosin VIIa) and effects of mutations It is estimated that 75% of Usher type I is caused by mutations in MYO7A. Myosin VIIa is expressed by the photoreceptors, RPE as well as in embryonic cochlear and vestibular neuroepithelia of the ear. Myosin VIIa is unconventional, in that it is an intracellular motor molecule that moves along actin filaments. Its tail tethers to different macromolecules which then move relative to the actin filaments. In photoreceptors, this molecule may play a role in intracellular transport, in particular between the inner and outer segments of the photoreceptors. In the mouse model of Usher syndrome IB there is defective distribution of melanosomes in the RPE, suggesting that myosin VIIa may be necessary for melanosome localization in melanocytes. A single in-frame 9 bp deletion of a coiled-coil region has been described in autosomal dominant non-syndromic deafness. This is thought to interfere with dimerization, which would explain its dominant negative effect. A range of mutations have been described that are associated with recessive hearing loss. The precise reasons why some cause isolated hearing loss and others cause Usher syndrome are not known. Usher syndrome type IC (harmonin) Usher syndrome type IC has been described in particular amongst the Louisiana Acadian population. The USH1C gene encodes a PDZ domain-containing protein, harmonin. This acts as a scaffold protein coordinating organization of intracellular signaling and cytoskeletal proteins. Protein truncation and splicing mutations within the gene are likely to lead to loss of function. In addition, a non-coding mutation within intron 5 has been described. In this case a short region of 45 bp, which is repeated many times in all individuals, is found to be greatly expanded within patients with Usher syndrome (VNTR expansion). Such an expansion is likely to inhibit transcription. A form of non-syndromic deafness also maps to this region (11p14.3) and may be allelic.
Inherited retinal disease
165
Usher syndrome type ID (Cadherin-like gene CDH23) Cadherins are a large family of intercellular adhesion proteins that promote cell-to-cell adhesion. A large number of proteins that share similar domains have been described and include the cadherin-like gene, CDH23. The gene has a restricted expression pattern and has been shown to be expressed by the cochlea and the neuroretina. Mutation screening of CDH23 has demonstrated missense mutations in families with autosomal recessive deafness. In families with Usher syndrome, both nonsense and frameshift mutations have been described. In one family, patients homozygous for a splice-site mutation (which results in loss of function) had more severe RP than those patients who were compound heterozygotes for this mutation and a second missense change. This suggests that loss of function alleles cause a more severe phenotype (i.e. Usher syndrome) than those that retain some residual function (which cause isolated autosomal recessive deafness). Usher syndrome type IF (PCDH15) PCDH15 encodes a protocadherin which is expressed in a wide range of tissues including the retina and inner ear. Protocadherins are part of a family of calcium-dependent cell to cell adhesion molecules that have been shown to be required for neural development and synapse formation. Although the function of the PCDH15 protein in the retina is unknown, it is hypothesized that it regulates the developmental orientation of the inner ear neuroepithelium. Disease causing mutations in USH1F include frameshift, protein truncating mutations and a single splice-site mutation. In the mouse, a mutation in this gene causes the waltzer phenotype, which is characterized by deafness and vestibular dysfunction. Usher syndrome type II (USH2A) USH2A encodes a protein that is predicted to be a component of the extracellular matrix. Its function has not been identified.
166
Usher syndrome
Disease-causing mutations are scattered throughout the gene and include nonsense, missense, deletion and insertion mutations. One common mutation, a single bp deletion (2299delG), is found in around 16% of all USH2A mutations. The majority of protein truncating and missense mutations give rise to a similar phenotype suggesting that they result in loss of function. In addition, a missense mutation (cysteine to phenylalanine at position 759) has been found in around 10 out of 224 patients with autosomal recessive RP. USH3 encodes a 120 amino acid protein. Unlike other Usher syndrome-causing genes, which are expressed in the retina and inner ear, USH3 is widely expressed. The protein contains two predicted transmembrane domains but is of unknown function. Disease-causing mutations include missense, deletion and protein truncating changes. Diagnosis
Inherited retinal disease
Usher syndrome is regarded to be the most common cause of deaf-blindness in humans and accounts for 3–6% of deaf children. While there are no specific ophthalmic implications of the condition, affected individuals need a high degree of specialized input. Deaf-blindness, or more correctly ‘combined sensory loss’, has profound effects and should be regarded as a separate entity requiring specific registration rather than dual registration.
167
168
5 5. Vitreoretinal disorders
Familial exudative vitreoretinopathy 170 Incontinentia pigmenti 172 Knobloch syndrome 175 Norrie disease 177 Stickler syndrome 180 X-linked retinoschisis 185
Familial exudative vitreoretinopathy (also known as: exudative vitreoretinopathy 1; EVR1; FEVR; Criswick-Schepens syndrome) MIM
133780
Clinical features
The abnormalities of exudative vitreoretinopathy result from abnormal peripheral vascularization and may progress with time. In many of the families described penetrance is high but there is significant variability of phenotype. The abnormalities may be present from birth and may mimic ROP.
Organized fibrovascular membrane in exudative vitreoretinopathy causing abnormal traction on retina and retinal vessels.
Abnormal peripheral retinal vascularization in familial exudative vitreoretinopathy. The findings are similar to the elevated ridge and fibrovascular proliferation seen in retinopathy of prematurity.
170
Familial exudative vitreoretinopathy
Organized membranes cause vitreoretinal traction and may lead to dragging of the disc and vessels or to macular displacement. There are often scattered vitreous opacities. Traction may lead to localized retinal detachment associated with sub- and intraretinal exudation as well as peripheral retinal neovascularization. In some patients there may be congenital retinal folds, which may represent one manifestation of the disorder. Diagnosis in those mildly affected may be difficult and may require fluorescein angiography for identification of peripheral vascular abnormalities. The ocular phenotype of the X-linked form, EVR2, is identical to that of autosomal dominant exudative vitreoretinopathy, EVR1 (see Norrie disease). There are no extraocular manifestations. Age of onset
Congenital/childhood
Inheritance
Autosomal dominant (EVR1); X-linked (EVR2). Recessive inheritance has been suggested in some families.
Chromosomal location
11p13–q23 (EVR1). A second autosomal dominant locus maps to chromosome 11p12–p13.
Gene
Not known
Effect of mutation
Not known
Diagnosis
As gene expression can be very variable, diagnosis in those mildly affected may be difficult; fluorescein angiography may be required for identification of peripheral vascular abnormalities.
Vitreoretinal disorders
171
Incontinentia pigmenti type II (also known as: IP2; Bloch-Sulzberger syndrome) MIM
308310; 300248 (NEMO)
Clinical features
IP2 is a multisystemic X-linked dominant disorder characterized by a vesicular erythematous skin rash. The condition affects females and is lethal to males. About one-third of patients have ocular abnormalities. Ocular IP2 is associated with defects of peripheral retinal vascularization that resemble ROP. In some cases this leads to tractional retinal detachment and development of a vascularized retrolental mass. IP2 is, therefore, one of the differential diagnoses of leukokoria. In addition, defective foveal vascularization may lead to macular ischemia and occasionally to neovascularization. Extraocular Affected females have an erythematous, blistering rash that appears at, or soon after, birth. The rash evolves with time, becomes pigmented and then fades to leave patches of hypopigmentation. The areas of pigmentation and depigmentation are linear and follow Blaschko’s lines, the paths of embryonic dermal cell migration. The skin eruptions may lead to patchy hair loss. Hypodontia may occur. Intellect generally is normal although a portion may have seizures/delay.
Age of onset
The blistering skin rash generally develops soon after birth. The greatest risk of retinal detachment occurs in the first months of life, resulting from defective retinal vascularization.
Inheritance
X-linked dominant
172
Incontinentia pigmenti type II
Blistering skin rash.
Late pigmented skin rash. Pigment is linear, following developmental lines of cell migration (Blaschko's lines).
Abnormal dentition.
Vitreoretinal disorders
173
Dystrophic nails.
Chromosomal location
Xq28
Gene
NFκB essential modulator (NEMO)
Mutational spectrum
About 80% of new mutations are the result of an intragenic recombination, which leads to deletion of exons 4–10 of NEMO. In addition, missense mutations, frameshift mutations and nonsense mutations have been described. There is no genotype-phenotype correlation.
Effect of mutation
NEMO is essential for the activation of NFkB, a transcription factor that is activated by cytokines. NFkB activation has been implicated in inflammatory processes such as autoimmunity, asthma, glomerulonephritis, inhibition of apoptosis and inappropriate immune cell development. Thus NEMO is essential in the modulation of immune, inflammatory and apoptotic responses. Defective NFkB activation has been demonstrated in IP2 patients. In the dermis it is hypothesized to cause defective cell growth and apoptosis, which is thought to be the primary cause of the skin rash.
Diagnosis
174
Clinical. IP2 is usually diagnosed by the characteristic rash; girls should have regular ophthalmic assessment in early life. Genetic testing is available on a research basis only.
Incontinentia pigmenti type II
Knobloch syndrome (also known as: KNO; retinal detachment and occipital encephalocoele) MIM
267750; 120328 (COL18A1)
Clinical features
KNO is a rare recessive disorder characterized by retinal detachment, high myopia and occipital encephalocoele. Ocular These are poorly defined. There is very high myopia, vitreoretinal degeneration and macular abnormalities. In one report, myopia was –15 D at 7 months and greater than –20 D by the age of 3 years. Fundus examination shows high myopic changes and severe hypoplasia of the macular region. In some patients there is straightening of temporal vessels, suggestive of retrolental fibroplasia or exudative vitreoretinopathy. Vitreous abnormalities and early onset retinal detachment may lead to phthisis or neovascular glaucoma. Extraocular Occipital encephalocoele is seen in the majority of patients. This can range from minor abnormalities, such as mid-line scalp defects, to the presence of a mid-line skull defect associated with meningocystocoele. Subtle dysmorphic features are described in some reports but are not diagnostic.
Age of onset
Congenital
Inheritance
Autosomal recessive
Chromosomal location
21q22.3
Gene
Collagen XVIII, a1 (COL18A1)
Vitreoretinal disorders
175
Mutational spectrum
COL18A1 is a large 43-exon gene. Splice-site and frameshift mutations that result in premature protein truncation have been demonstrated.
Effect of mutation
It is not known why defects in collagen XVIII give rise to ocular and brain abnormalities. Collagen XVIII is a widely expressed heparan sulfate proteoglycan of the extracellular matrix. One short form is found in brain and retina and is localized to vascular and epithelial basement membranes suggesting a role in vascular development.
176
Knobloch syndrome
Norrie disease (also known as: NDP) Including: X-linked familial exudative vitreoretinopathy (EVR2). MIM
310600; 305390 (EVR2)
Clinical features
Norrie disease is a cause of X-linked congenital blindness that very rarely has manifestations in carrier females. Ocular Boys are generally born with severe congenital visual disability. The most common finding is a retrolental yellowish, vascularized mass. This represents an abnormally vascularized, congenitally detached retina, which is drawn up and attached to the posterior lenticular surface. This congenital detachment, which may be present as leukokoria, leads to secondary cataract and ultimately phthisis bulbi. In some patients with EVR2, visual disability is less marked and some residual vision is retained. EVR2 is characterized by abnormalities of peripheral retinal vascularization (see exudative vitreoretinopathy section). Individuals with this milder ocular phenotype do not have associated hearing problems or intellectual disability. Extraocular In around one-third of patients there is associated hearing loss. This may not be present early on and may be progressive. In addition, one-third have some degree of developmental delay. In a small group of patients, often those with severe visual disability and deafness, the delay is severe and is associated with behavioral problems, progressive microcephaly and minor facial dysmorphism. Some of these severely affected patients have a small X chromosome deletion that is presumed to encompass other genes.
Vitreoretinal disorders
177
Young boys with Xp11.4 microdeletion encompassing NDP locus and neighboring monoamine oxidase genes. Both are blind, microcephalic and severely delayed.
Age of onset
Congenital
Inheritance
X-linked recessive
Chromosomal location
Xp11.4
Gene
NDP
Mutational spectrum
A large number and wide variety of mutations have been described. The gene is small and is composed of 3 exons encoding a protein of 133 amino acids. The coding sequence is found within the final two exons. The majority of mutations are found in exon 3. Whole gene deletions, in particular those that encompass the neighboring monoamine oxidase genes, are associated with the most severe phenotype. Among missense mutations there is little obvious correlation between site of mutation and the severity of ocular, auditory or CNS complications.
178
Norrie disease
EVR2 is also caused by missense mutations within NDP. It is not known why some mutations are less severe. Effect of mutation
The exact function of the encoded protein remains uncertain. There is some evidence to suggest that the protein, which shares structural similarities with TGF-b, is important in developmental retinal vasculogenesis, although its function in the ear and brain remains uncertain. The similarity of ocular phenotype in patients with whole gene deletions and missense mutations suggests that many act through loss of function.
Diagnosis
Vitreoretinal disorders
Norrie disease is associated with severe, usually congenital, visual disability which may be compounded by further sensory deficit. The X-linked nature of the condition and the availability of genetic testing make genetic counselling necessary in potential cases. Mutation analysis is now widely available to complement clinical evaluation and, as a result, carrier detection and prenatal diagnosis are both possible.
179
Stickler syndrome (also known as: STL; hereditary progressive arthro-ophthalmopathy) MIM
108300 (STL1); 604841 (STL2); 184840 (STL3)
Young child with Stickler syndrome. There is severe mid-facial flattening. The patient is highly myopic and has significant sensorineural deafness.
Clinical features
Ocular Most patients develop high-degree, early-onset myopia (congenital myopia). Cortical, segmental, comma-shaped lens opacities are common, congenital and non-progressive. The vitreous gel is degenerate and becomes condensed leaving a large volume of the cavity optically empty. The vitreous changes have been classified into type I (vestigial vitreous occupying the immediate retrolental space surrounded by a folded membrane) and type II (a sparse vitreous consisting of bundles of beaded filaments). Broadly speaking, patients with type I vitreous anomaly have type I Stickler syndrome caused by mutations in COL2A1, while the type II anomaly has been found in patients with COL11A1 mutations. Abnormalities of vitreoretinal adhesion result in paravascular pigmented lattice degeneration. Stickler syndrome is the most
180
Stickler syndrome
common inherited cause of rhegmatogenous retinal detachment (RRD) in childhood. Giant retinal tears (GRT), which are commonly bilateral, are a frequent cause of blindness. Prediction of those at greatest risk of RRD/GRT is difficult, other than by identification of extreme myopia. Long-term vitreoretinal follow-up is advisable.
360 degree retinal detachment, secondary to a giant retinal tear in Stickler syndrome.
Perivascular lattice.
Vitreoretinal disorders
181
Orofacial Stickler syndrome is associated with a distinctive pattern of orofacial features and growth. At birth, around one-quarter of individuals have evidence of clefting, ranging from a Pierre-Robin sequence to a bifid uvula. Micrognathia may be severe at birth but becomes significantly less marked during the first months after birth. There is marked mid-face hypoplasia; at birth there is often almost no nasal bridge (a problem with high myopia), anteverted nares and prominent eyes. Mid-face flattening becomes less marked in the majority and may become almost unnoticeable. Hearing loss Hearing difficulties in Stickler syndrome are caused by cleft/palatal abnormalities causing serious otitis media, and conductive and sensorineural hearing loss, which is seen in around 40% of patients. Many have no symptoms but hearing loss can be severe and have early-onset. Arthropathy In early life, patients may describe significant joint laxity. Later this becomes less marked and with time degenerative arthropathy develops, typically in the third to fourth decade, often leading to hip and/or knee replacements in mid-life. Age of onset
Myopia may be present from birth, although this is usually progressive. Clefting and mid-face hypoplasia are usually congenital. Hearing loss may be progressive and may develop at any stage.
Inheritance
Autosomal dominant
Chromosomal location
MIM 120140 120280 120290
182
Locus STL1 STL2 STL3
Gene COL2A1 COL11A1 COL11A2
Chromosome 12q13.11–q13.2 1p21 6p21.3
Stickler syndrome
Mutational spectrum
COL2A1 (type II collagen, a-1) COL2A1 mutations cause a range of skeletal dysplasias and account for over 50% of Stickler syndrome cases. STL1 generally results from premature polypeptide termination. Kneist dysplasia, in which affected individuals have a more severe skeletal phenotype but a similar ocular phenotype, is usually caused by small in-frame COL2A1 deletions. A small number of individuals with ocular-only Stickler syndrome carry a mutation within the alternatively spliced exon 2 which is only expressed in ocular tissues. COL11A1 (type XI collagen, a-1) The majority of mutations result in alteration of RNA splicing of 54-bp exons. These patients have the characteristic Marshall phenotype with severe mid-face hypoplasia that does not diminish with age, early-onset severe hearing loss and few retinal detachments. Other mutations (e.g. missense) are more typical of Stickler syndrome. COL11A2 (type XI collagen, a-2) A small number of families with Stickler syndrome have COL11A2 defects. Ocular features are lacking. This is due to absence of the a-2 chain of type XI collagen in the vitreous gel matrix.
Effect of mutation
Vitreoretinal disorders
The vitreous gel is comprised of water with a proteinaceous matrix, which is mainly collagenous. Defects in COL2A1 and COL11A1 result in premature collapse of the vitreous gel, abnormal vitreoretinal adhesion leading to lattice degeneration and RRD. Collagen molecules form a rod-like trimeric helix. COL2A1 mutations resulting in premature termination lead to defective trimer formation and abnormal construction of the collagenous matrix. Type XI collagen aggregates with type II in thin fibrils of hyaline cartilage and vitreous gel; as a result, defects in these molecules give rise to a similar phenotype.
183
Diagnosis
184
Stickler syndrome is highly variable (the diagnosis may first be made in a child with Pierre-Robin sequence/cleft palate). Such variability, even within families, makes predictions of the presence or absence of any one feature difficult, complicating the counselling of prospective parents. Early ophthalmic assessment of affected individuals is important to assess refraction and the necessity for prophylaxis against retinal detachment. DNA diagnosis is possible in a number of centers on a research basis only. However, since prenatal diagnosis is not commonly requested, such analysis is generally supplemental to clinical diagnosis.
Stickler syndrome
X-linked retinoschisis (also known as: RS1) MIM
312700
Clinical features
RS1 occurs exclusively in males. The condition usually becomes apparent during the first decade. It is variable within and between families and prognosis is therefore difficult to predict. Visual deterioration generally occurs during early childhood and vision attained by teenage years often remains constant during early and middle adult life. Central visual loss due to presenile macular degeneration is common.
Foveal schisis in XLRS.
Retinoschisis is defined as ‘splitting of the retina’ and on examination the most common abnormality is a bicycle-wheel spoke-like appearance of the macula. Foveal schisis is caused by cystic changes and leads to visual reduction in the range 6/9 to 6/60. Peripheral schisis is common and is caused by a split within the inner retinal layers (as opposed to the inner plexiform layer in degenerative retinoschisis) with blood vessels visible within the inner leaf of the schisis.
Vitreoretinal disorders
185
Hemorrhage, either into the retina or into the vitreous occurs in around 25% of cases. Retinal detachment is less common but may occur when a full thickness hole develops within the inner retinal layers of a peripheral schisis. ERG examination is a valuable diagnostic tool. Virtually all affected males show selective loss of the dark-adapted B-wave. Age of onset
While schisis may be present from birth, visual reduction is generally noticed in the early school years.
Epidemiology
1:5000–25,000
Inheritance
X-linked recessive. There are no manifestations in females.
Chromosomal location
Xp22.2–p22.1
Gene
RS1
Mutational spectrum
A wide range of mutations has been demonstrated, including protein truncating mutations (small deletions/insertions/splice-site mutations) and missense mutations. Missense mutations are clustered within the so-called discoidin domain.
Effect of mutation
The lack of any genotype-phenotype correlation suggests that mutations act via loss of protein function. Retinoschisin is an extracellular matrix protein secreted by the photoreceptor. It contains a discoidin domain but is of unknown function. The protein is found in its highest concentration in the inner retinal layers. Loss of the B wave on ERG suggests that the protein may interact with Müller cells.
Diagnosis
Clinical examination. ERG is useful to confirm the diagnosis. Mutations may be found by direct gene sequencing in over 90% of cases. This is useful for carrier detection, which is not otherwise possible.
186
X-linked retinoschisis
6 6. Optic nerve
Dominant optic atrophy, type 1 188 Leber hereditary optic neuropathy 190 Renal-coloboma syndrome 194 Septo-optic dysplasia 196 Wolfram syndrome 199
Dominant optic atrophy, type 1 (also known as: DOA; OPA1; juvenile optic atrophy; Kjer-type optic atrophy) MIM
165500
Clinical features
DOA is of gradual onset with deterioration through childhood. Only a small minority remains subclinical. Visual acuity (VA) varies from perception of light to 6/6 (mean is 6/36). Around one-sixth retain adequate VA for driving. Field testing reveals central, centrocecal or, in some, severe scotomata. The disc pallor is generally temporal with characteristic excavation but there may be generalized atrophy.
Temporal pallor of disc in dominant optic atrophy.
Epidemiology
Estimated prevalence of 1:12,000–50,000
Age of onset
In general, symptoms are noted from the age of 4–6 years. Some patients may be diagnosed as early as 1 year of age.
Inheritance
Autosomal dominant
Chromosomal location
3q28–q29. Some families with isolated optic atrophy have been shown to map to 18q12.2–12.3.
188
Dominant optic atrophy, type 1
Gene
Optic atrophy 1 (OPA1)
Mutational spectrum
OPA1 is a 29-exon gene that is ubiquitously expressed. A range of mutations has been described including frameshifts, nonsense and missense mutations.
Effect of mutation
OPA1 encodes a dynamin-related protein that is thought to be essential in the maintenance of mtDNA. OPA1 is localized to the mitochondrion. It is hypothesized that mutations result in altered function and alteration in the cellular distribution of mitochondria throughout the cell. To date, there is little evidence of genotypephenotype correlation, and no obvious phenotypic differences between missense and deletion mutations.
Diagnosis
Clinical evaluation; penetrance is said to be 98%. However, molecular analysis suggests that this may be considerably lower in some families.
Optic nerve
189
Leber hereditary optic neuropathy (also known as: LHON; Leber optic atrophy) MIM
535000; 516003 (NADH dehydrogenase, subunit 4); 516000 (NADH dehydrogenase, subunit 1); 516006 (NADH dehydrogenase, subunit 6)
Clinical features
Ocular Patients with LHON present with acute or subacute painless central visual loss in mid-life. In the acute phase fundoscopic examination reveals peripapillary telangiectasia, disc swelling (which does not leak on fluorescein angiography) and vascular tortuosity. Optic nerve damage leads to optic atrophy, particularly temporal, and development of a centrocecal scotoma. Amongst family members peripapillary telangiectasia and vascular tortuosity may be seen in asymptomatic maternal relatives. However, the predictive value of such findings in mutation carriers is unclear. Progression and outcome of LHON is variable with a final visual acuity ranging from 20/40 to no light perception. There are no clinical predictors of outcome or recovery. Extraocular Visual loss is the primary, and generally only, clinical manifestation in most Leber pedigrees, however, cardiac conduction defects have been noted in some families. Amongst Finnish and Japanese patients, pre-excitation syndromes such as Wolff-Parkinson-White and Lown-Ganong-Levine are common. The nucleotide position (np) 11778 mutation has been associated with multiple sclerosis in some families and occasional individuals have been described with a more generalized neurodegenerative picture. It is not clear to what extent other mtDNA (mitochondrial DNA) changes might contribute to this picture.
190
Leber hereditary optic neuropathy
Age of onset
The mean age of onset is around 30 years in men but is later in women; the range is 1–70 years. The eyes can be affected simultaneously or sequentially with an average interval of about two months. Visual deterioration can range from acute, complete loss to a progressive decline over 2 years; mean progression time is around 3.7 months.
Inheritance and population genetics
LHON is caused by mutations in mtDNA and is only inherited from the ovum. If all the mitochondria contain the same mutant form of mtDNA then the chances of a female passing this form on to her children is 100%. However, some individuals carry both mutant and normal forms of mtDNA—this is termed heteroplasmy. In heteroplasmic individuals the proportion of mutant to normal DNA passed to each egg, and hence each child, is unpredictable. During development the proportion of mutant to normal DNA passed to each cell or tissue is also unpredictable. Such variabilities in the level of mutant mitochondria lead to phenotypic variability. Many individuals represent isolated cases. The proportion of patients with family histories varies from <50% for np 11778, to 78% for np 3460. Families homoplasmic for these common mutations generally exhibit reduced penetrance, with the percentage of affected relatives in np 11778 families ranging from 33–60%, for np 3460 from 14–40% and for np 14484 from 27–80%.
Chromosomal location
Mitochondrial DNA: a 16569 bp closed circular loop of DNA found within the mitochondria. It encodes a number of proteins that are important in the electron transport chain.
Genes and mutational spectrum
Defects in a number of the mitochondrial subunits have been associated with LHON. Of these, there are three mtDNA mutations that definitely cause the disease as they are found in patients but never in healthy subjects.
Optic nerve
191
These are designated by the np of the mutation within mtDNA: • 11778 mutation (np 11778): NADH dehydrogenase, subunit 4 (complex 1, subunit 4; ND4) • 3460 mutation (np 3460): NADH dehydrogenase, subunit 1 (complex 1, subunit 1; ND1) • 14484 mutation (np 14484): NADH dehydrogenase, subunit 6 (complex 1, subunit 6, ND6) ND4, ND1 and ND6 are three of the seven mtDNA encoded subunits of respiratory complex I (NADH:ubiquinone oxidoreductase), which accepts electrons from NADH and transfers them to ubiquinone. The energy released is used to pump protons across the mitochondrial inner membrane. There is a great deal of literature about the effects of other mtDNA variants on the likelihood of developing symptoms. As there is high variation in mtDNA it is difficult to define the exact significance of many mtDNA variations and whether a given DNA alteration causes the disorder or predisposes to the development of symptoms. Effect of mutation
Mutations in complex 1 are likely to cause a defect in the electron transport chain. It is not clear why this should affect males more than females, cause an isolated optic neuropathy or develop acutely in adult life. There is evidence for phenotypic correlation amongst these mitochondrial mutations. The most severely impaired np 11778 patients may lose light perception. By comparison the most severely impaired np 3460 patients retain light perception and np 14484 patients retain the ability to count fingers. While males are affected more than females (in the UK 80–90% of sufferers are males, compared with 60–90% in Japan), the proportion of males differs for the different mutations: 80% of np 11778, 33–66% of np 3460, and 68% of np 14484 mutations are in males.
192
Leber hereditary optic neuropathy
The probability of visual recovery varies between mutations: 4% of np 11778 patients show some recovery an average of 36 months after onset. By contrast, 22% of np 3460 patients and 37% of np 14484 patients show significant recovery within 4–18 months. Diagnosis and counselling issues
Clinical history and examination. The majority of other investigations (e.g. B12) will be normal. If the diagnosis is suspected, mtDNA testing is now possible as a clinical service. Worldwide, around 90% of patients carry one of the three primary mutations. LHON is a devastating disorder and the etiology is poorly understood. Homoplasmic females (i.e. those with only mutant mtDNA) are certain to pass on an abnormal gene. This is unusual for an inherited disorder and is a fact that many patients find hard to cope with. However, the chance of a child developing visual symptoms is much lower. While genetic testing is available and is useful as a diagnostic and prognostic tool, its utility in counselling the extended family is uncertain. It should not be used indiscriminately. For those found to carry mutant mtDNA, there is no way to alter the likelihood of developing symptoms. Furthermore, testing may carry deleterious psychological consequences, while the implications for future insurability are uncertain. The probability of developing symptoms for mutation carriers is not 100%, one Australian study proposed that the risk of visual loss for males with the np 11778 mutation is 20% and for females is 4%. The risks may vary for different mutations, as well as the likelihood of recovery and final visual outcome. Risk factors are also poorly understood. There have been anecdotal reports that smoking, recreational drug use/abuse, stress and excessive alcohol abuse may contribute to the development of symptoms, but there is no substantial evidence to back up these claims.
Optic nerve
193
Renal-coloboma syndrome (also known as: optic nerve coloboma with renal disease; ONCR) MIM
120330; 167409 (PAX2)
Clinical features
Ocular Optic nerve colobomas are the most common ocular manifestation, with a high degree of heterogeneity both within, and between, families and variable functional effect. Optic discs may be normal in some, while in more severe cases optic nerve abnormalities include optic nerve hypoplasia/aplasia and morning glory syndrome. Only one patient has been described with a retinal coloboma, suggesting that non-optic nerve coloboma are uncommon in ONCR. Extraocular Renal abnormalities are the most common non-ocular features. These are variable and include vesicoureteric reflux, renal hypoplasia (or even unilateral aplasia), renal tubular atrophy, glomerulosclerosis and proteinuria. Mutation carriers who are relatives of severely affected patients may have no detectable abnormalities. Of 21 patients with proven PAX2 mutations, 10 had end-stage renal failure. Some patients have neurosensory hearing loss, while developmental delay is occasionally described in association with microcephaly.
Age of onset
Ocular abnormalities are congenital. Renal abnormalities, while they may have a congenital aspect (e.g. renal aplasia/hypoplasia) are progressive. Renal dysfunction often presents in the first decade.
Inheritance
Autosomal dominant
Chromosomal location
10q24.1–q25.1
Gene
Paired box gene 2 (PAX2)
194
Renal-coloboma syndrome
Mutational spectrum
The majority of mutations result in premature protein termination. Missense mutations within the conserved-paired domain are also described. A sequence of six G-residues in exon 2 is an apparent ‘hot spot’ for mutation.
Effect of mutation
Haploinsufficiency. As in many conditions associated with haploinsufficiency, there is a high degree of variability of phenotype.
Diagnosis
Clinical. PAX2 mutations are extremely rare in patients with isolated optic nerve colobomata.
Optic nerve
195
Septo-optic dysplasia (also known as: de Morsier syndrome; SOD) Including: optic nerve hypoplasia (ONH) MIM
182230; 165550 (ONH); 601802 (HESX1)
Optic nerve hypoplasia.
MRI showing midline defects in septo-optic dysplasia.
196
Septo-optic dysplasia
Clinical features
Both SOD and ONH are developmental abnormalities that are generally sporadic. In a very small number of cases they have been shown to be familial. Patients with bilateral severe ONH present with early onset of poor vision associated with roving eye movements (nystagmus). The disc is small and may have a pale halo and a characteristic double ring. However, there is a range of severity and ONH may present with lesser visual problems or, in asymmetrical cases, with unilateral visual reduction. SOD is characterized by ONH in association with absence of the septum pellucidum. Midline neurodevelopmental abnormalities may also include agenesis of the corpus callosum. Endocrinologic investigations may demonstrate growth hormone, ACTH and ADH deficiencies, and even panhypopituitarism. Patients with apparently isolated ONH, including those with normal cerebral imaging studies, may have endocrinologic evidence of pituitary dysfunction and, therefore, require appropriate investigation.
Age of onset
Congenital
Inheritance
Sporadic. A small number of autosomal recessive cases have been described. There is one report of dominant ONH.
Chromosomal location
3p21.2–21.1 (autosomal recessive form)
Gene
Homeobox gene expressed in ES cells (HESX1); alternative name: Rathke pouch homeobox (RPX).
Mutational spectrum
A homozygous missense mutation within the homeodomain of HESX1 has been described in consanguineous siblings with SOD. In addition a small number of individuals with SOD, have been found to have heterozygous mutations. Such heterozygous mutations demonstrate incomplete penetrance and variable expressivity.
Effect of mutation
Optic nerve
HESX1 is a developmental transcription factor. Expression is high in the developing forebrain, in particular in Rathke’s pouch, the
197
primordium of the anterior pituitary, and in the developing anterior pituitary. Mouse mutants lacking HESX1 have variable defects that resemble SOD. The mutant form of the protein fails to bind to the target DNA sequences that are bound by the normal protein. This suggests that the mutation causes loss of function. Diagnosis
198
Clinical. Cases of ONH, both unilateral and bilateral, should be investigated for evidence of structural brain abnormalities and endocrinologic disturbance. Growth should be carefully monitored during the first years of life. Familial cases are extremely rare and the condition is not generally regarded as inherited; recurrence risks are, therefore, low.
Septo-optic dysplasia
Wolfram syndrome (also known as: WFS; diabetes insipidus, diabetes mellitus, optic atrophy and deafness [DIDMOAD]) MIM
222300
Clinical features
Ocular Progressive optic atrophy presents during childhood. The majority of patients have a visual acuity of 6/60 or less. Nystagmus may be present in those with cerebellar degeneration. Extraocular Juvenile diabetes mellitus and optic atrophy often develop during childhood. Diabetes insipidus is a more variable feature (present in 70–75% of patients). Neurosensory deafness develops in around two-thirds of patients, while other neurological features (e.g. urinary tract atony, ataxia, peripheral neuropathy and mental retardation) are common. WFS is characterized by a progressive neurodegeneration. Many patients have episodes of psychiatric disturbance including severe depression and psychosis.
Age of onset
Diabetes is often the first feature, developing in the first decade. Optic atrophy is noted towards the end of the first decade or the beginning of teenage years.
Epidemiology
The estimated prevalence in the UK is <1:700,000.
Inheritance
Autosomal recessive
Chromosomal location
4p16.1 (WFS1); 4q22–q24 (WFS2, linkage only)
Gene
Wolframin (WFS1)
Optic nerve
199
Mutational spectrum
WFS1 mutations include premature protein truncating mutations and missense mutations. There are no clear-cut genotype-phenotype correlations. Mutations are distributed throughout the gene.
Effect of mutation
WFS1 is a transmembrane protein, its function is unclear although it is hypothesized to be important in islet cell and neuronal survival.
Diagnosis
Diabetes insipidus is difficult to diagnose due to problems with fluid restriction in patients with diabetes mellitus. A high index of suspicion is required for patients with optic atrophy and diabetes mellitus. Mutation testing of WFS1 is only available on a research basis at present.
200
Wolfram syndrome
7 7. Defects of pigmentation
Oculocutaneous albinism 202 Chediak-Higashi syndrome 207 Hermansky-Pudlak syndrome 209 Ocular albinism, type 1 211
Oculocutaneous albinism (also known as: OCA) MIM
203100 (OCA1); 203200 (OCA2)
Fundus appearance of albinism.
Non-identical twins with oculocutaneous albinism.
Clinical features
202
OCA is a group of autosomal recessive disorders affecting melanin synthesis characterized by hypopigmentation of skin, hair and eyes.
Oculocutaneous albinism
Ocular Children with OCA often have delayed visual maturation for the first weeks or months of life. This is followed by coarse ocular nystagmus which gradually lessens with age. Improvement in visual attention occurs during the first year. Defective melanin production has a number of consequences for the development of the anterior visual pathway. Significant refractive errors and strabismus are common, both of which require regular ophthalmic review. There is gross iris transillumination, easily elicited on the slit lamp in early infancy. Fundoscopy reveals an albinotic retina with prominent choroidal vasculature. The fovea is hypoplastic with anomalous retinal vessel distribution. Visual evoked potentials may reveal crossed asymmetry of responses reflecting a reduction in uncrossed fibers in the optic tract. This may help to differentiate albinism from other forms of nystagmus. Visual acuity (VA) is worse when viewing objects at a distance when nystagmus is not damped by convergence. VA varies, reflecting the degree of ocular pigmentation. There is considerable overlap between the different genetic forms of OCA, individuals with OCA1A having a VA in the range 6/36–6/60 while those with OCA1B may have a better prognosis with some individuals attaining a VA of 6/12 or greater. Extraocular Normal melanogenesis is required for the development of melanin pigment in the skin and hair. As with ocular pigmentation the degree of skin hypopigmentation can vary. Individuals with the classical form of OCA, OCA1A, have minimal pigment with profoundly white hair. The skin is white and does not tan and the irides are fully translucent. In so-called ‘yellow albinism’ or OCA1B there is some pigment accumulation within both irides and hair that darkens a little with time.
Defects of pigmentation
203
Individuals with OCA2 are also significantly hypopigmented at birth and often have somewhat pigmented hair that darkens with age. With time there is development of freckles and nevi but no generalized skin pigmentation. There may be minimal tanning ability in later life. Iris pigmentation may also develop. Age of onset
Congenital
Epidemiology
OCA1 Prevalence of around 1:40,000 in most populations with a carrier rate of around 1:100. OCA2 The most prevalent type of albinism with an estimated frequency in the USA of approximately 1:36,000. More common in sub-Saharan indigenous African populations and African-Americans. Rufous OCA This has been described amongst southern African blacks only; in this population there is a frequency of approximately 1:8500. Brown OCA Brown OCA is a distinct phenotype in southern Africa characterized by cream/light tan skin, beige/brown hair and blue-green to brown irides. The ocular phenotype is of OCA.
Inheritance
Autosomal recessive
Chromosomal location
Disease OCA1 OCA2/OCA4 OCA3 OCA4
204
Locus 11q14–q21 15q11.2–q12 9p23 5p
Gene TYR P gene TRP1 MATP
Oculocutaneous albinism
Gene
Tyrosinase (TYR), OCA1: a transmembrane copper-containing enzyme that catalyzes the first two steps in melanin synthesis. Pink-eye (P) gene, OCA2 and OCA4: a transmembrane protein found within the melanosomes. The function of the P gene is not yet defined. Tyrosine-related protein 1 (TRP1), OCA3: this regulates the formation of insoluble melanin and acts late in the melanin production pathway. Membrane-associated transporter protein (MATP), OCA4; this gene, whose orthologue underlies the murine underwhite phenotype, encodes a membrane transporter protein of unknown function.
Mutational spectrum
OCA1 In OCA1A, the majority of TYR mutations are missense mutations that abolish catalytic activity (TYR null mutations). However, deletion, nonsense and splicing mutations have also been described. Those associated with OCA1B retain some enzyme activity. Sequencing of the coding sequence defines around 50% of mutations. OCA2 In OCA2 the majority of mutations are missense mutations, although both frameshift and splicing mutations have been described. Patients with brown OCA have also been found to carry mutations in the P gene. The majority is heterozygous for a small deletion of 2.7 kb within the P gene and it is assumed that they carry a milder mutation on the other allele. OCA3 Only two mutations have been described within OCA3: S166X (serine to stop) and a frameshift mutation in patients with rufous OCA. OCA4 A single splicing mutation has been identified in the MATP gene that is presumed to result in an in-frame deletion.
Defects of pigmentation
205
Diagnosis
Clinical evaluation. Often children with OCA have visual inattention for some weeks after birth, which can lead some parents and relatives to believe that the baby is blind. It is important to give reassurance that vision will improve over the first year of life. The majority of children with OCA will be able to cope with mainstream schooling, albeit with additional help. Ocular and oculocutaneous albinism are frequently missed and a high index of suspicion should be aroused by the coincidence of developmental nystagmus and delayed visual maturation in the absence of other obvious causes. In general, individuals with OCA have no tanning ability. It is essential to ensure effective protection from the sun by use of high-factor sun blocks. Previously, the formal diagnosis of OCA1 or OCA2 was based on detection of levels of tyrosinase activity. Diagnosis is more easily made using molecular genetic analysis, generally available on a research basis only. This does not alter disease management but can be used for prenatal diagnosis although this is not commonly requested.
206
Oculocutaneous albinism
Chediak-Higashi syndrome (also known as: CHS1) MIM
214500
Clinical features
CHS1 is a form of syndromic OCA. Ocular The ocular features are similar to those seen in patients with other forms of OCA. Children with CHS1 usually present with OCA. Extraocular There is partial hypopigmentation of the skin and hair—hair color varies from blond to dark brown. Abnormal susceptibility to infection occurs as a result of the absence of natural killer and cytolytic T cell function. There are large perinuclear eosinophilic, peroxidase-positive inclusion bodies in myeloblasts and promyelocytes of bone marrow. A predisposition to a lymphoproliferative disorder is observed – the so-called ‘accelerated phase’. Viral infection (e.g. Epstein Barr virus) may initiate a lymphoma-like condition incorporating fever, generalized lymphadenopathy, hepatosplenomegaly, pancytopenia and sepsis. Patients often die before the age of 10 years.
Age of onset
Congenital
Inheritance
Autosomal recessive
Chromosomal location
1q42.1–q42.2
Gene
Lysosomal trafficking regulator (LYST)
Mutational spectrum
To date, all mutations in LYST have resulted in premature termination of the protein.
Defects of pigmentation
207
Effect of mutation
LYST is involved in membrane targeting of the proteins present in secretory lysosomes. Mutations are associated with loss of function.
Diagnosis
Clinical evaluation and hematological investigation. DNA diagnosis is now possible on a research basis and mutation testing can be performed both by conventional methods and by the use of protein truncation testing.
208
Chediak-Higashi syndrome
Hermansky-Pudlak syndrome (also known as: HPS) MIM
203300; 604982 (HPS gene); 603401 (AP3B1)
Clinical features
HPS is multisystem disorder characterized by OCA, a bleeding diathesis and, in some patients, pulmonary fibrosis. Ocular The ocular features are similar to those of OCA. Extraocular There is hypopigmentation of the skin and hair. In addition, HPS is characterized by a bleeding disorder that results in easy bruising, frequent epistaxis and variable bleeding associated with surgery. Ceroid deposition in a number of tissues results in pulmonary fibrosis, the major cause of death after 1 year of age, and granulomatous colitis.
Epidemiology
HPS is rare in most regions of the world with an estimated prevalence of 1:500,000–1,000,000. However, in Puerto Rico the frequency is about 1:1800; the origin of this increase has been traced to southern Spain.
Age of onset
Congenital
Inheritance
Autosomal recessive
Chromosomal location and genes
10q23.1–q23.3 (HPS gene); 5q13 (adaptin beta-3a, AP3B1)
Mutational spectrum
To date, mutations in the HPS gene have resulted in premature protein truncation. Both protein truncation and missense mutations have been described in AP3B1.
Defects of pigmentation
209
Effect of mutation
The HPS gene encodes two transcripts. The gene product is thought to be a transmembrane protein that is a component of cytoplasmic organelles and is important for their normal development and function. Expression has been demonstrated in normal human melanocytes. AP3B1 mutations result in drastically reduced levels of AP-3, which is involved in the formation of intracellular vesicles (e.g. lysosomes and melanosomes). The AP-3 deficiency results in altered trafficking of integral lysosomal membrane proteins, which show increased expression on the cell surface.
Diagnosis
210
Clinical evaluation and hematological investigation showing absent dense bodies on electron microscopy of platelets. Molecular genetic testing of HPS is available for patients of Puerto Rican heritage on a clinical basis, while genetic testing of the AP3B1 gene is available on a research basis only.
Hermansky-Pudlak syndrome
Ocular albinism type 1 (also known as: OA1; Nettleship-Falls type ocular albinism) MIM
300500
Clinical features
OA1 is an X-linked recessive disorder affecting melanin synthesis, characterized by hypopigmentation of the eyes with virtually no signs in the skin and hair. Males with OA1 have ocular features indistinguishable from that of OCA. Vision ranges from 6/6 to 6/60, although over 70% can read better than 6/36. Boys with OA1 are often blond but pigmentation is within the normal range and tanning in response to UV light is normal. Females are invariably asymptomatic; ocular examination in OA1 kindreds is helpful in definition of carrier status in 80–90% of cases. There is significant iris transillumination and fundoscopy reveals a peripheral ‘mud-splattered’ appearance. Skin biopsy reveals macromelanosomes in the majority of patients, although this is rarely indicated.
Age of onset
Congenital
Epidemiology
Unknown, although it is estimated to be around 1:60,000 in Denmark.
Inheritance
X-linked recessive
Chromosomal location
Xp22.3
Gene
OA1
Mutational spectrum
Over 20 OA1 mutations have been described. Of these, more than 50% are missense mutations clustered in the central coding region; deletions, insertions and frameshift mutations have also been described.
Defects of pigmentation
211
Effect of mutation
The function of OA1 is unclear. Recent evidence suggests that the protein acts as a G protein-coupled receptor (GPCR), GPCRs are involved in the common signal transduction systems located at the plasma membrane. The OA1 gene appears to be a pigment cellspecific member of the GPCR superfamily found on melanosomes. There is no evidence as yet for genotype-phenotype correlation—the number of reported missense mutations is small and it is, therefore, difficult to determine whether their position in the gene is important in defining phenotypic outcome.
Diagnosis and counselling issues
Clinical evaluation. Definition of carrier status can be difficult although careful ophthalmic evaluation is usually sufficient. Carrier status may have been defined before the birth of the first child. It is important therefore, to prepare parents-to-be without creating unnecessary concern. As in OCA, children often have visual inattention for some weeks after birth and reassurance should be given that vision will improve. The majority of boys with OA1 cope with mainstream schooling. DNA testing is now available and, according to one study, will detect an abnormality in over 75% of cases. This may be helpful in confirming diagnosis and defining carrier status. Parents do not request prenatal diagnosis very often.
212
Ocular albinism type 1
8 8. Metabolic disorders
Fabry disease 215 Galactokinase deficiency 217 Galactosemia 219 GM2 gangliosidoses 222 Gyrate atrophy of the choroid and retina 226 Homocystinuria 228 Juvenile neuronal ceroid lipofuscinosis type 3 (Batten disease) 231 Mucopolysaccharidoses 234 Nephropathic cystinosis 237 Refsum disease 239
Introduction A number of inborn errors of metabolism have ocular complications including early-onset corneal opacification (e.g. mucopolysaccharidoses), congenital cataract (e.g. galactosemia, Lowe and Zellweger syndromes) and early-onset retinal dystrophy (e.g. Batten disease and gyrate atrophy). None or these conditions are common, but it is important to recognize them due to their early onset and progressive nature. In some (e.g. Batten disease) the presenting feature is ocular and the ophthalmologist is ideally placed to make the diagnosis. There are existing treatment options that may alter the course of the disease, as in Refsum disease, gyrate atrophy and homocystinuria. As a result it is important to exclude these by means of biochemical testing. More recently, molecular analysis has been used to augment the options for investigation and management.
214
Genetics for Ophthalmologists
Fabry disease (also known as: Anderson-Fabry disease) MIM
301500
Clinical features
Fabry disease is an X-linked inborn error of glycolipid metabolism caused by deficiency of the lysosomal enzyme a-galactosidase A (GLA). Diagnosis is often delayed, but the ocular features are characteristic. Patients have an increased risk of renal and cardiac disease and reduced life expectancy. Ocular Although characteristic, ocular manifestations are not usually visually significant. Cornea verticillata, similar to that seen with various drugs such as amiodarone, is seen in both affected males and the majority of female carriers. Wedge-shaped anterior lens opacities, as well as branching spoke-like opacities, are seen in around one-third of patients. Tortuosity of the retinal and conjunctival vessels is common. Neurological Debilitating episodes of pain (Fabry crises or acroparesthesiae) begin in childhood, lasting hours or sometimes days. These often affect the peripheries and may be excruciating. Abdominal or flank pain is also common. Skin Small blue-purple telangiectatic lesions (angiokeratomas) are seen in childhood, in particular over the buttocks and umbilical region. They increase in number with age. Vascular Cardiac abnormalities are common and may cause premature death; left ventricular hypertrophy, mitral valve disease and conduction defects have been described. Cerebral vascular disease is common
Metabolic disorders
215
and may lead to infarction. Avascular necrosis of the femur or talus head may lead to pain or a limp. Renal Proteinuria is common, and end-stage renal failure is a frequent cause of premature death in the second to fourth decades. Age of onset
Although symptoms may begin in childhood, diagnosis is often delayed until the third or fourth decades.
Inheritance
X-linked
Gene
Galactosidase alpha (GLA)
Chromosomal location
Xq22
Mutational spectrum
Around 160 mutations have been described. Over 50% are missense changes found throughout the gene. However, nonsense, splice-site and small deletions or insertions have also been described.
Effect of mutation
Mutations result in abolition of enzyme activity. A number of patients with some residual activity have an atypical cardiac form of Fabry disease. Mutations cause progressive deposition of the glycosphingolipids in the endothelium of blood vessels (the major pathological feature) and in the kidneys.
Diagnosis
Due to the non-specific nature of early symptoms, diagnosis is often delayed. Fabry disease is associated with premature death (mean age <45 years) as a result of renal, cardiac and cerebrovascular complications. The ocular features are characteristic and may be diagnostic. Diagnosis may be confirmed by GLA estimation in WBC or fibroblasts, which is used as the basis of prenatal diagnosis on CVS or amniocytes. While the majority of carriers may be detected clinically (e.g. by ophthalmic examination), DNA diagnosis is now available through certain centers and may also be used as a means of prenatal diagnosis.
216
Fabry disease
Galactokinase deficiency (also known as: galactokinase deficiency galactosemia; GALK deficiency) MIM
230200; 604313 (GALK1)
Clinical features
Lamellar cataract develops in the fetus or in early infancy. This disorder should be excluded in all children with isolated cataracts. It has been suggested that gene carriers and individuals with mild homozygous GALK1 variant alleles are predisposed to pre-senile cataracts. Dietary manipulation may prevent or delay cataract formation.
Age of onset
First year of life
Epidemiology
The prevalence is not as well documented as in galactose-1phosphate uridyltransferase (GALT) galactosemia and galactokinase deficiency is considered to be rare in comparison. In Italy, carrier frequency is estimated to be around 1:300. Newborn screening data suggest that in general the gene frequency is very low world-wide but higher frequencies are observed among Romani families in Europe, where carrier rates may be as high as 5%.
Inheritance
Autosomal recessive
Chromosomal location
17q24
Gene
Galactokinase 1 (GALK1)
Mutational spectrum
Substitution, termination and nonsense mutations have all been described.
Effect of mutation
Galactokinase is the first enzyme involved in the metabolism of galactose, and is highly conserved between E. coli bacteria and man. The enzyme is ubiquitously expressed and expression studies of mutant alleles in Xenopus oocytes demonstrate very low
Metabolic disorders
217
galactokinase activity levels. Accumulation of osmotically active compounds within the lens is thought to lead to cataract formation. Diagnosis
218
If suspected, diagnosis can be made on urinalysis demonstrating the presence of a non-glucose reducing substance. There is absent galactokinase activity in red blood cells.
Galactokinase deficiency
Galactosemia (also known as: galactose-1-phosphate uridyltransferase (GALT) deficiency) MIM
230400
Clinical features
The most common features are failure to thrive, associated with jaundice, hypotonia and lethargy. Vomiting and diarrhea begins within days of initiating milk ingestion, and jaundice occurs within the first few weeks after birth due to unconjugated hyperbilirubinemia. Hepatomegaly and abnormal liver function develops after prolonged exposure to unlimited quantities of milk and if left untreated will progress to cirrhosis. There is an increased rate of neonatal death as a result of E. coli sepsis, perhaps because of reduced leukocyte bactericidal activity (galactosemia is one of the differential diagnoses in neonates with E. coli sepsis). Lens changes may be observed on slit-lamp examination within a few days of birth. There is an ‘oil-droplet sign’ in the red reflex due to the increased refractive index of the lens nucleus. It is thought that this is due to accumulation of osmotically active sugar alcohols (e.g. galactitol) in the lens leading to water influx. This phenomenon is reversible by strict dietary control, without which permanent lens opacity develops. Regular ophthalmic follow-up is required even in the presence of good dietary control. Dietary therapy does not preclude long-term consequences. A reduction in IQ is observed in the majority of patients, even with apparently good dietary control. Severe delay is uncommon but delayed speech and verbal dyspraxia are common as are visuospatial, mathematical and attention span difficulties. Almost all females have primary ovarian failure due to hypergonadotrophic hypogonadism. However, prospective dietary therapy prevents other complications such as cataract, liver disease and E. coli sepsis.
Metabolic disorders
219
Galactosemia cataract: this lens opacity had cleared substantially in the few days of dietary therapy between diagnosis and examination—the ‘oil droplet’ is visible inferiorly.
Age of onset
Within days of birth and the onset of milk feeding. Lens changes may be present within 1–2 weeks.
Epidemiology
Estimates show significant variation from country to country—the prevalence at birth is estimated to be 1:70,000 in the UK and 1:30,000 in Ireland. In the USA, frequencies vary from 1:35,000 in the state of New York to 1:190,000 in Massachusetts. Carrier frequencies vary from 0.9–1.25:100.
Inheritance
Autosomal recessive
Chromosomal location
9p13
Gene
Galactose-1-phosphate uridylyl transferase (GALT)
Mutational spectrum
A broad mutational spectrum (>130 mutations) has been recognized in a wide number of populations; the majority are missense mutations. Within Caucasian populations, two mutations (Q188R and K285N) account for >70% of galactosemia-producing alleles, while in black populations the S135L allele accounts for >60%.
220
Galactosemia
Several common normal variants are recognized, such as the Duarte variant that is associated with 50% enzyme activity, this has a population prevalence of around 5–6%. There may be a phenotypic spectrum associated with the different alleles between which biochemical differences can be observed (e.g. the common S135L allele is associated with normal GALT activity in white blood cells). It is likely that the genotypic heterogeneity underlies biochemical, as well as phenotypic, variation. Effect of mutation
GALT catalyzes the conversion of galactose-1-phosphate and UDP-glucose to glucose-1-phosphate and UDP-galactose. This is critical to the metabolism of galactose in most organisms. Functional assays of a variety of mutations have shown that most result in virtual abolition of enzyme activity. The cause of long-term, diet-independent complications remains unclear and may be tissue-specific.
Diagnosis
A presumptive diagnosis can be made on urinalysis demonstrating the presence of a reducing substance—although lactose, fructose and pentose may all give a similar result. Definitive identification of galactose may be achieved using paper or gas-liquid chromatography. Diagnosis is confirmed by means of a biochemical assay of GALT function in heparinized blood.
Metabolic disorders
221
GM2 gangliosidoses Including: GM2 gangliosidosis type I, or Tay-Sachs disease (hexosaminidase A deficiency); GM2 gangliosidosis type II, or Sandhoff disease (hexosaminidase B deficiency). MIM
272800 (Tay-Sachs); 268800 (Sandhoff)
Clinical features
The gangliosidoses are a group of inborn errors of sphingolipid metabolism that result in neuronal accumulation of a glycolipid, GM1 or GM2 ganglioside. GM1 gangliosidosis is a rare AR condition occurring as a result of b-galactosidase deficiency. Children with this deficiency have severe cerebral degeneration and die by the age of 2 years. The GM2 gangliosidoses, which are also AR conditions, cause lipid (GM2 ganglioside) accumulation in the lysosomes of neurons of the brain, which results in enlargement of the head due to cerebral gliosis, progressive neurodegeneration and blindness. Affected children usually die by the age of 2–4 years.
Tay-Sachs disease: cherry-red spot at the macula.
222
GM2 gangliosidoses
Ocular Dilated fundus examination reveals a characteristic cherry-red spot at the macula. The gray-white area around the prominent red fovea is due to opacification of lipid-laden ganglion cells. With time, the ganglion cells die, leading to progressive optic atrophy and loss of the cherry-red spot. The ERG is normal in the gangliosidosis (see Batten disease), although the VER is extinguished. Extraocular Affected infants generally appear completely normal at birth but show progressive weakness and loss of motor skills from 3–6 months of age. There is decreased attentiveness and pronounced extension in response to sound (startle reaction). Progressive neurodegeneration is associated with seizures and spasticity and leads to death before the age of 4 years. In Sandhoff disease (type II), unlike Tay-Sachs (type I), there are coarse features, hepatosplenomegaly and skeletal abnormalities. Age of onset
Loss of motor skills occurs in the first year of life. A cherry-red spot is present in the early stages. There is a range of phenotypes in both type I and II GM2 gangliosidoses with juvenile (in which symptoms begin from 2–10 years of age) and adult-onset forms.
Epidemiology
Tay-Sachs disease is present in all populations but is most common among Ashkenazi Jews (about 1:3600 in Ashkenazi Jewish births in the USA, with a carrier rate of about 1:30). Among Sephardic Jews and all non-Jews, the gene frequency is about 100-times less common. The carrier rate for Sandhoff disease has been estimated to be 1:500 in Jews and 1:300 in non-Jews.
Inheritance
Autosomal recessive
Chromosomal location
15q23–q24 (HEXA); 5q13 (HEXB)
Metabolic disorders
223
Gene
Hexosaminidase A (HEXA) – Tay-Sachs; hexosaminidase B (HEXB) – Sandhoff.
Mutational spectrum
Over 70 mutations have been described in HEXA. In the infantile form, null alleles resulting from frameshifts or premature terminations are common. Amongst the Ashkenazi Jewish population, three common mutations account for 90–95% of the alleles and testing is routinely available. This facilitates diagnostic and carrier screening. Two pseudodeficiency alleles resulting from missense alterations have also been identified. These alleles, when present in the heterozygous state, result in HEXA enzymatic activity similar to that of a heterozygote for Tay-Sachs. However, as the allele is not disease-causing when present with a true null allele this can give a false indication of carrier status on biochemical testing. Over 20 mutations have now been described in HEXB, including missense, nonsense, splicing and deletion mutations. Both juvenile onset and more attenuated adult forms of Sandhoff disease are caused by mutations in HEXB.
Effect of mutation
The phenotypic consequences of the majority of mutations occur as a result of alterations in protein folding and intracellular transport rather than abolition of enzyme activity. Hexosaminidase A is a heterodimeric protein comprising an a chain and a b chain (encoded by HEXA and HEXB genes, respectively). It cleaves a terminal b-linked N-acetylgalactosamine from GM2 ganglioside. Hexosaminidase B is a homodimeric protein. HEXA mutations (Tay-Sachs disease) result in reduced levels of HEXA enzyme activity. HEXB mutations result in reduced levels of HEXA and HEXB enzyme activity (Sandhoff disease).
Diagnosis
224
Tay-Sachs disease is one of a number of conditions associated with a cherry-red spot at the macular. Others include Niemann-Pick disease type A, a disorder of the metabolism of sphingomyelin—a
GM2 gangliosidoses
cell membrane component. In type A Niemann-Pick disease symptoms begin in the first months of life with poor feeding, hepatosplenomegaly and loss of motor skills. There is progressive neurodegeneration and death occurs by the age of 2–3 years. Clinical diagnosis of GM2 gangliosidosis may be confirmed using the relevant white cell enzyme assays. In Tay-Sachs disease this relies upon demonstration of reduced serum and/or WBC b-HEXA activity in the presence of normal or elevated b-HEXB activity. In Sandhoff disease there is absence of both b-HEXA and b-HEXB activity. HEXA gene mutation analysis testing is widely available. It supplements genetic counselling and allows the identification of pseudodeficiency alleles. Prenatal diagnosis is available for parents who are proven to be carriers, either by mutation analysis or by enzyme activity estimation on fetal cells.
Metabolic disorders
225
Gyrate atrophy of the choroid and retina (also known as: ornithine aminotransferase (OAT) deficiency) MIM
258870
Gyrate atrophy: fundus periphery of 7-year-old child presenting with night blindness.
Clinical features
Patients present with night blindness in the first decade of life. There is a loss of peripheral vision and ultimately central visual function; 90% of patients are highly myopic. Examination reveals sharply demarcated scalloped areas of chorioretinal atrophy that are first seen in the periphery and then spread posteriorly towards the macula. These become confluent during the second and third decades. Patients develop posterior subcapsular lens opacities.
Age of onset
Night blindness develops during the first 5 years. By the time symptoms occur, retinal changes will be apparent.
Inheritance
Autosomal recessive
Chromosomal location
10q26
226
Gyrate atrophy of the choroid and retina
Gene
Ornithine aminotransferase (OAT)
Mutational spectrum
A broad spectrum of mutations within the OAT gene have been described. These include whole exon deletions that lead to absence of mRNA, protein truncating mutations and missense mutations.
Effect of mutation
Mutations lead to loss of enzyme function. The mechanism of progressive retinal degeneration is unknown. Ornithine is a non-essential amino acid that is metabolized within the urea cycle and is an important intermediate in the production of glutamate and proline. It may be produced by metabolism of dietary arginine. OAT is a mitochondrial matrix enzyme that converts a-ketoglutarate and ornithine to glutamate and glutamate-g-semi-aldehyde.
Diagnosis
Diagnosis of the proband relies upon the presence of suggestive symptomatology and clinical findings. Younger siblings may be diagnosed on biochemical grounds. High ornithine levels can be detected in the blood or urine of all patients—OAT activity is absent or severely reduced. Gyrate atrophy is one of the few retinal dystrophies for which there is a potential treatment. In some patients, administration of the co-enzyme (vitamin B6, pyridoxine) reduces ornithine levels. Longterm clinical evaluation in humans has been difficult to achieve. Recently a mouse model of OAT deficiency has been developed that is characterized by a retinal dystrophy analogous to gyrate atrophy. In the mouse, a low-arginine diet can help to reduce ornithine levels and prevent the development of retinal dystrophy. This is strong evidence to suggest that dietary manipulation, although difficult to follow, maybe worthwhile for affected children.
Metabolic disorders
227
Homocystinuria (also known as: cystathionine b-synthase deficiency) MIM
236200
Lens subluxation in homocystinuria.
Clinical features
Homocystinuria is an inborn error of metabolism resulting from a deficiency of cystathionine b-synthase. Clinical manifestations involve the eye, the CNS, and the skeletal and vascular systems. Ocular The major ocular complication of homocystinuria is ectopia lentis. Classically this is inferior subluxation but it may occur in any direction. Ectopia lentis is not present at birth but is progressive. It may be the presenting feature at the age of 3–5 years. It is present in the majority of patients who are either untreated or do not respond to medical therapy. Medical therapy reduces its frequency. Extraocular Patients with homocystinuria tend to be blond and hypopigmented presumably because homocystine inhibits the activity of tyrosinase.
228
Homocystinuria
Skeletal Patients with homocystinuria have a variable Marfanoid habitus with dolichostenomelia (tall stature and thin body), arachnodactyly, pectus abnormalities, pes cavus, high-arched palate and kyphoscoliosis. Patients tend to have stiffness of joints, in contrast to Marfan syndrome in which patients may have joint laxity. CNS Mental retardation is common among untreated patients (>50%); mean IQ is 50–60 among patients who are unresponsive to vitamin B6. Seizures and psychoses are common. Intellectual development is significantly improved by early diagnosis and medical treatment. Vascular Around one-sixth to one-quarter of patients will suffer thromboembolic events. These may be arterial or venous and may affect large or small vessels. Patients treated early have significantly fewer episodes. Treatment involves administration of vitamin B6 (pyridoxine) or a cofactor of cystathionine b-synthase or, for those who do not respond, a low methionine diet +/- betaine supplementation. Age of onset
Birth. In those countries where neonatal screening occurs (e.g. Ireland and certain parts of the UK) diagnosis may be early. Ectopia lentis is usually diagnosed around the age of 3 years.
Epidemiology
Worldwide; incidence is variable and estimated to be 1:300–500,000. It is higher in Ireland.
Inheritance
Autosomal recessive
Chromosomal location
21q22.3
Metabolic disorders
229
Gene
Cystathionine beta synthase (CBS)
Mutational spectrum
The majority of mutations in CBS are missense mutations.
Effect of mutation
CBS catalyzes the conversion of homocystine and serine to cystathionine. A deficiency of CBS leads to accumulation of homocystine and methionine in the blood and tissues. Mutations in the gene have been shown to abolish CBS enzyme activity. Homocystine metabolism has been implicated in the etiology of neural tube defects and vascular disease.
Diagnosis
Patients have a positive cyanide-nitroprusside test in fresh urine. Both urine and plasma levels of homocystine are raised. Molecular genetic testing is supplemental.
230
Homocystinuria
Juvenile neuronal ceroid lipofuscinosis type 3 (also known as: CLN3; Batten disease (UK); Vogt-Spielmeyer disease (European continent); juvenile neuronal ceroid lipofuscinosis) MIM
204200
Clinical features
The neuronal ceroid lipofuscinoses are a group of recessive disorders that result in the accumulation of lipopigments throughout the body. The group includes a number of genetically distinct conditions that, although related, have quite different clinical courses. Of these conditions, the juvenile form of Batten disease is most likely to be seen by the ophthalmologist. Ocular Batten disease may first present with symptoms and signs of a rod-cone dystrophy. Symptoms of night blindness and visual field constriction may be noted, while on examination there may be ‘salt and pepper’ changes in the peripheral retina with mild alteration of macular pigmentation. Children often demonstrate ‘over-looking’ with eccentric fixation above the object of gaze. Occasionally there may be a bull's-eye maculopathy. With time, classical signs of a widespread retinal degeneration (disc pallor, vascular attenuation and peripheral pigmentation), become apparent. Full-field ERGs demonstrate absent rod responses and severely reduced cone responses. The retinal degeneration is both severe and widespread, and shows a rapid progression early in the disease course. Extraocular Batten disease is a fatal neurodegenerative disorder that begins in childhood. Early symptoms usually appear between the ages of 5 and 10 years. Some patients present with early signs of subtle personality and behavior change, developmental delay or clumsiness. Over time,
Metabolic disorders
231
affected children suffer mental impairment, psychoses, worsening seizures and progressive loss of sight and motor skills. Eventually children become blind, bedridden and demented. Batten disease is progressive and fatal. Death is usually in the late teens or early 20s, although some patients may live into their 30s. Age of onset
Onset is at the age of 5–10 years. Batten disease represents an important differential diagnosis in previously healthy, normally sighted children who develop progressive visual failure and retinal dystrophy at around this age.
Epidemiology
Batten disease and other forms of neuronal ceroid lipofuscinoses are relatively rare, occurring in an estimated 2–4 of every 100,000 births in the USA. They appear to be more common in Finland, Sweden, Newfoundland and Canada.
Inheritance
Autosomal recessive
Chromosomal location
16p12.1
Gene
Ceroid lipofuscinosis, neuronal type 3 (CLN3)
Mutational spectrum
Around 70–85% of chromosomes from patients with Batten disease carry an allele with a 1.02 kb deletion within the gene. This is predicted to result in the production of a significantly truncated protein. Other deletion mutations are also described that have a similar prognosis. Among patients with other mutations, a small number of missense changes have been described that affect residues that are conserved across species and are thought to be crucial to protein function. These may result in delayed onset or slower progression. In some individuals, visual deterioration was noted in the first decade of life but CNS deterioration was delayed for some decades.
232
Juvenile neuronal ceroid lipofuscinosis type 3
Effect of mutation
CLN3 has no known homology to other proteins and its function has not yet been defined. The protein is highly conserved and has a homolog in Saccharomyces cerevisiae. Mutations are thought to severely reduce or abolish enzyme activity. Missense mutations associated with a milder phenotype may result in some residual enzyme activity.
Diagnosis
A number of supplementary investigations can support the diagnosis if there is clinical suspicion of Batten disease. Examination of leukocytes may demonstrate inclusions, although these are not totally conclusive. The disorders are characterized by accumulation of autofluorescent lipopigments in neurons, as well as in other cells of the body to a lesser extent. These appear as fingerprint inclusions on electron microscopy. Historically the diagnosis was confirmed by brain, sural nerve or rectal biopsy. However, it is now possible to detect the characteristic changes in skin, or even conjunctival tissue biopsy. Batten disease is a devastating diagnosis in which visual and intellectual deterioration develop in a formerly healthy individual. Inevitably, this has enormous consequences throughout the family. The diagnosis is often made after the birth of younger siblings who have a 25% risk of being affected.
Metabolic disorders
233
Mucopolysaccharidoses (also known as: MPS) Clinical features
The mucopolysaccharidoses are a group of progressive disorders characterized by the intralysosomal accumulation of mucopolysaccharides (glycosaminoglycans). They are classified into types I–VII. The MPS have a wide range of severity from profound growth, developmental retardation and childhood death, to mild manifestations with normal intelligence and survival to adulthood. However, some clinical features are common to the whole group: characteristic coarse facial features with frontal bossing, prognathism and a depressed nasal bridge, hepatosplenomegaly and skeletal abnormalities ranging from generalized growth deficiency with kyphosis to mild joint contractures. In some MPS (e.g. Hurler syndrome), developmental delay is associated with progressive neurological deterioration.
Mucopolysaccharides associated with corneal clouding. MPS
Skeletal
Intellect
Life expectancy
Other
Hurler (I-H) Coarse
Short stature; kyphosis; contractures
Profound retardation
Death by 10 years of age
Respiratory + infections; myocardial/ cardiac valve dysfunction
Scheie (I-S) Mildly coarse
Contractures (e.g. of hand)
Normal
Normal
Aortic valve disease
Morquio (IV)
Mildly coarse
Short stature; kyphosis; contractures
Normal
Third to fourth Cardiac valve Mild decade of life disease
MaroteauxLamy (VI)
Coarse
Short stature; kyphosis; contractures
Normal
Second to third decade of life
234
Face
Corneal clouding
+
Aortic/mitral + valve disease
Mucopolysaccharidoses
Although type I has been divided into Hurler and Scheie syndromes, these are caused by defects in the same gene and represent different ends of the spectrum of the same condition. The ocular features vary amongst the MPS. They may be helpful in diagnosis and are important in their management. Corneal clouding Mucopolysaccharide accumulation within the cornea leads to intraand extracellular accumulation in all cornea layers. Types I, IV and VI are associated with corneal clouding, it is usually most severe in MPS I and MPS VI (Maroteux-Lamy) and milder in MPS IV (Morquio). In patients for whom corneal grafting is judged appropriate, recurrence will occur within the graft. Retinal degeneration Retinal dystrophy has been described in all forms of MPS with ERG changes suggestive of a rod-cone degeneration. Optic nerve head swelling or optic atrophy are common. These may contribute to visual deterioration and may limit the success of corneal grafting. Glaucoma Early-onset glaucoma, presumed to be secondary to intracellular mucopolysaccharide accumulation in the anterior chamber drainage angle, is a rare complication of the MPS. Age of onset
Diagnosed in the first few years of life, from around 6 months for severe MPS I, to 5 years in mild cases.
Epidemiology
It is estimated that 1:25,000 births will be affected by one of the MPS disorders.
Inheritance
Autosomal recessive (MPS I, III, IV, V, VI and VII). X-linked (MPS II/Hunter syndrome).
Metabolic disorders
235
Chromosomal location and genes MPS
MIM
Gene
Chromosome
Enzyme
I (Hurler/Scheie)
252800
IDUA
4p16.3
a-L-iduronidase
II (Hunter)
309900
IDS
Xq28
Iduronate sulfate sulfatase
IVA (Morquio A)
253000
GALNS
16q24.3
Galactosamine-6-sulfate sulfatase
IVB (Morquio B)
253010
GLB1
3
b-galactosidase
VI (MaroteauxLamy)
253200
ARSB
5q13.3
N-acetylgalactosamine-4-sulfatase
The MPS disorders are caused by mutations in a diverse group of enzymes, which lead to the accumulation of different mucopolysaccharides. All result from mutations that substantially reduce or abolish enzyme activity. In the case of Hurler/Scheie syndrome, caused by mutations in a-L-iduronidase, milder phenotypes result from mutations that retain residual enzyme activity. Diagnosis
236
When suspected clinically, MPS can be detected biochemically by the presence of elevated urine glycosaminoglycans. Enzyme activity can be measured in lymphocytes and/or fibroblasts as well as in cultures of chorionic villi or amniocytes. DNA testing and mutation analysis offer an alternative method of diagnosis as well as prenatal diagnosis, although this is not as widely available as biochemical testing.
Mucopolysaccharidoses
Nephropathic cystinosis (also known as: CTNS; infantile nephropathic cystinosis) MIM
219800
Clinical features
Cystinosis is a rare AR lysosomal storage disorder characterized by elevated levels of intracellular cystine. Tissue damage results from accumulation of cystine crystals.
Corneal crystals in cystinosis.
Ocular Cystine crystals develop in the peripheral cornea throughout its width during the first 18 months of life and accumulate in such numbers that by the teenage years the cornea is packed with crystals and has a generalized haze, maximal peripherally. Crystals are visible in the conjunctiva. Photophobia, blepharospasm and recurrent erosions are common. Cysteamine eye drops deplete corneal/conjunctival cystine and reduce crystal accumulation. A mild ‘salt and pepper’ retinopathy may also develop, which can contribute to reduction of vision. Extraocular Children are healthy at birth and during the first months of life. However, renal tubular reabsorption deteriorates and polyuria and Metabolic disorders
237
polydipsia develop later. By 1 year of age there is growth retardation, rickets and, on biochemical investigation, metabolic acidosis and increased renal excretion of glucose, phosphate and potassium. Children fail to thrive and without therapeutic intervention remain short and underweight. Tubular dysfunction (renal Fanconi syndrome) develops in the first year progressing to end-stage renal failure by the age of 9 years on average. Age of onset
The classic form presents in the first year of life. In late-onset nephropathic cystinosis (MIM 219900) there are similar signs and symptoms but of a later onset with the age of presentation ranging from 2–26 years.
Epidemiology
The incidence is estimated to be 1:50,000.
Inheritance
Autosomal recessive
Chromosomal location
17p13
Gene
Cystinosin (CTNS)
Mutational spectrum
A broad range of mutations have been described, including protein truncating mutations and missense mutations. A common 57 kb deletion is found in 75% of European patients.
Effect of mutation
CTNS encodes a lysosomal membrane protein involved in cystine transport across the lysosomal membrane. Protein truncation mutations and missense mutations within transmembrane domains are thought to result in loss of function and cause severe disease. Mutations having milder effects occur within regions that are functionally unimportant.
Diagnosis
When suspected clinically, cystinosis can be diagnosed by WBC cystine determination. This can also be achieved using fibroblast cultures. Prenatal diagnosis is carried out using amniocentesis or CVS.
238
Nephropathic cystinosis
Refsum disease MIM
266500; 602026 (PHYH)
Clinical features
Refsum disease is a peroxisomal disorder that results in accumulation of phytanic acid. The characteristic clinical features are peripheral neuropathy, RP and cerebellar ataxia. Peripheral neuropathy affects 90% of patients, resulting in both motor and sensory loss; cerebellar ataxia is present in 75% of patients. In addition, the majority of patients show electrocardiographic changes while some have nerve deafness and an ichthyotic skin rash. The retinal dystrophy in Refsum disease may be the presenting feature with weakness and loss of balance developing later or being subtle features at the time of presentation. Phytanic acid is derived entirely from the diet in dairy products, egg yolk, some fish, lamb and beef, white bread and boiled potatoes. Avoidance of these foods will lower its plasma concentration and may lead to improvement of the peripheral neuropathy and ichthyosis, although retinal changes are not arrested. Plasmaphoresis may supplement dietary manipulation if this is ineffective on its own. An infantile form of Refsum disease has been identified (MIM 266510) in which there is an early-onset severe retinal dystrophy associated with dysmorphism, mental retardation, hepatomegaly and neurosensory hearing loss. Strictly this is a peroxisomal disorder, although infants with the condition also have raised levels of phytanic acid.
Age of onset
In classic Refsum disease, night blindness may begin in the second decade of life or later in adulthood.
Inheritance
Autosomal recessive
Chromosomal location
10pter–p11.2
Metabolic disorders
239
Gene
Phytanoyl-CoA hydroxylase (PHYH)
Mutational spectrum
Missense splicing and frameshift mutations have been described.
Effect of mutation
PHYH is a peroxisomal protein that catalyzes the first step in the alpha-oxidation of phytanic acid. In vitro assays have shown that mutations in PHYH result in loss of enzyme activity.
Diagnosis
If Refsum disease is suspected, diagnosis can be confirmed by demonstrating elevated plasma phytanic acid levels.
240
Refsum disease
9 9. Conditions associated with increased risk of malignancy
Adenomatous polyposis of the colon 244 Basal cell nevus syndrome 247 Neurofibromatosis type I 251 Neurofibromatosis type II 254 Retinoblastoma 257 Tuberous sclerosis complex 261 von Hippel-Lindau syndrome 264
Tumor predisposition and the eye Many Mendelian disorders predispose to tumor development and the genes underlying familial forms of breast, ovarian, prostate and gastric cancers have now been identified. Several tumor-causing conditions with important ophthalmic manifestations are described in this section. In some, the major ocular features are directly related to tumor formation (e.g. retinoblastoma, NF1 and von Hippel-Lindau disease), while in others the ocular features are valuable for defining clinical diagnosis (e.g. NF2). Gene identification is not simply of academic interest. The advent of molecular genetic testing has greatly improved the clinician’s ability to diagnose many tumor-causing conditions and, when linked with prospective surveillance, enables early tumor detection and improved disease management. Delineation of an exact genotype allows accurate estimation of risk to family members and better prediction of probable phenotypic manifestations. Genetic testing for tumor-causing conditions may reduce unnecessary screening of individuals who are not at risk and may allow effective targeting of tumor surveillance strategies. However, this should not be carried out in a clinic that is unfamiliar with the required protocols. A positive result has serious consequences, including reduced likelihood of gaining employment or insurance and a significant psychological burden that will influence the remainder of that individual’s life. He or she should be well informed, adequately supported and able to cope with the outcome. Tumor suppressor genes: The disorders in this section are caused by defects in tumor Knudson’s two-hit suppressor genes, such gene defects are dominantly inherited. hypothesis However, loss of one allele is not sufficient for tumor development and a second mutational event—a second hit—must occur. Knudson proposed that the frequency and distribution of retinoblastomas in familial and sporadic cases could be explained by a 'two-hit' mutational mechanism.
242
Tumor predisposition and the eye
Familial cases An individual affected with familial retinoblastoma passes on their family gene to half of his or her children, who will then carry a single defective copy in all the cells of their body. At each round of mitosis after formation of the zygote there is a small but finite chance of mutation at any locus. Newly produced cells carrying a mutation on the second retinoblastoma allele, a second hit, will carry no functional copies of the retinoblastoma gene. If such cells are within the retina they will be released from normal cell cycle control and will continue to divide unchecked and develop into a retinoblastoma tumor. An individual carrying a mutation on one allele in all of his or her cells is almost certain to develop a second hit in at least one site in both eyes. That individual will develop bilateral retinoblastomas which may be multiple. Sporadic cases An individual having no prior family history of retinoblastoma receives two normal copies of the retinoblastoma gene from each parent. However, during early development a single somatic mutation—the first hit—may arise in a progenitor cell, which is then passed on to all of its daughter cells. Should a second hit occur by chance in one of these daughter cells it will develop into a retinoblastoma. Since the likelihood of an individual having two consecutive hits during development is very small, this mechanism will usually result in a unilateral retinoblastoma.
Conditions associated with increased risk of malignancy
243
Adenomatous polyposis of the colon (also known as: APC; familial adenomatous polyposis (FAP); Gardner syndrome) MIM
175100
Clinical features
Ocular Multiple bilateral congenital hypertrophic lesions of the retinal pigment epithelium (CHRPE) are a strong marker of APC. In APC, CHRPEs are often shaped like fish tails and have a pale halo around them. Single CHRPEs are common in the general population.
CHRPEs in familial adenomatous polyposis – these are bilateral, multiple and have a surrounding area of hypopigmentation.
Extraocular Adenomatous colorectal polyps develop in the second decade and increase in number. Malignant transformation is very high, of the order of 90% by 50 years of age. Tumor surveillance should begin from around the age of 12 years and may ultimately lead to elective colectomy. GI polyps are also seen in the stomach and small bowel. Duodenal polyps are associated with a significant risk of malignant transformation. Around 10% of patients will develop desmoid tumors, which are benign but locally invasive of fibrous tissue. These are most common within the abdomen or retroperitoneally. Dental anomalies such as osteomas, missing or supernumerary teeth are common. 244
Adenomatous polyposis of the colon
A
B
C A. Bowel of patient with FAP showing multiple polyps as well as large carcinomatous lesion. B. FAP patient with jaw swelling from mandibular osteoma. C. Dental panoramic tomograph of patient with FAP. Note osteoma (o) and unerupted secondary dentition (arrowed).
Conditions associated with increased risk of malignancy
245
Age of onset
CHRPEs present from birth. Polyps usually develop in the second decade of life.
Epidemiology
Prevalence 2–3:100,000. Incidence 1:10,000.
Inheritance
Autosomal dominant
Chromosomal location
5q21–q22
Gene
Adenomatous polyposis of the colon (APC)
Mutational spectrum
Mutations are found in around two-thirds of families. Virtually all mutations result in premature protein truncation. The large size of the gene (the open reading frame is 8538 bp) makes conventional mutation analysis laborious. However the presence of a genotypephenotype correlation may direct mutation analysis. CHRPEs suggest the presence of a mutation between codons 463–1387. Mutations of exons 4, 5, 9 and distal 15 produce an attenuated phenotype, those between codons 1250 and 1464 produce a severe phenotype.
Effect of mutation
Mutations lead to loss of protein function. Different domains of the large APC protein have been shown to have a wide range of cellular functions, including cell adhesion, migration and proliferation as well as maintenance of normal apoptotic responses.
Diagnosis
In general those without a family history will be diagnosed at colonoscopy. Family members will undergo genetic testing via PTTbased or conventional mutation testing and linkage analysis if the causative defect is known. For families in whom CHRPEs are a marker of the disease, their observation may be a useful adjunct to detection of carrier status.
246
Adenomatous polyposis of the colon
Basal cell nevus syndrome (also known as: BCNS; nevoid basal cell carcinoma syndrome (NBCCS); fifth phakomatosis; Gorlin syndrome; Gorlin-Goltz syndrome) MIM
109400
Clinical features
The ocular features of BCNS have led to it being known as the ‘fifth phakomatosis’. The major morbidity is related to skin tumor formation (multiple basal cell carcinomas). Ocular BCCs on the eyelid are a major consequence of BCNS. The condition should remain part of the differential diagnosis in those patients under the age of 25 years with multiple BCCs.
A
B Fundus abnormalities in Gorlin syndrome. A. Hamartomatous disc lesion. B. Abnormal retinal myelination.
Conditions associated with increased risk of malignancy
247
The exact frequency of ocular abnormalities is uncertain. Strabismus and amblyopia are common. Developmental abnormalities are common and mostly unilateral. They include microphthalmia, coloboma, congenital cataract and PHPV. Retinal abnormalities include widespread myelination and preretinal membrane formation. Extraocular The major complications relate to BCCs. These are numerous and are found in all areas, regardless of sun-exposure. Odontogenic keratocysts are seen in around 75% of cases and develop from the first decade onwards. These occur in the mandible and cause swelling, abnormal dentition, pain and bony destruction. Around 5% of patients develop medulloblastoma. Radiation-based therapy can predispose to massive numbers of BCCs in the field of treatment.
Gorlin syndrome: falx calcification.
248
Basal cell nevus syndrome
A
B A. Segmentation defects including abnormalities of rib development. B. Multiple BCCs in Gorlin syndrome.
Age of onset
Many features are present at birth (e.g. bifid ribs, cleft lip), although the diagnosis may not be apparent until later. By the age of 25 years, 50% of Caucasians with BCNS have BCCs; by the age of 40 years this has increased to over 95%. Odontogenic keratocysts generally present in the second/third decade of life. Medulloblastoma is relatively uncommon but may present in early childhood.
Epidemiology
Prevalence reported as between 1:56,000 and 1:164,000. This is likely to be much higher amongst individuals under 20 years of age who have BCCs.
Inheritance
Autosomal dominant. Around 15% represent new mutations.
Chromosomal location
9q22.3
Conditions associated with increased risk of malignancy
249
Gene
The human homolog of the Drosophila patched gene (PTCH).
Mutational spectrum
Around 80% of mutations result in premature protein truncation. Mutations occur throughout the gene.
Effect of mutation
PTCH is the cell surface transmembrane receptor for the Shh protein, a developmental signaling molecule. Shh is mutated in some forms of holoprosencephaly. Signal transduction, through the Shh/PTCH pathway results in developmental transcriptional regulation. It is thought that a reduction in PTCH levels gives rise to the developmental features of BCNS. In addition, PTCH is a tumor suppressor gene and a ‘two-hit’ mechanism is required for the development of BCCs.
Diagnosis
When suspected clinically, BCNS is usually confirmed through clinical investigation. Genetic testing, using standard techniques, may be useful to aid diagnosis in family members: this is available through clinical genetic diagnostic laboratories.
250
Basal cell nevus syndrome
Neurofibromatosis type I (also known as: NF1; von Recklinghausen disease) MIM
162200
Clinical features
NF1 is a completely penetrant highly variable autosomal dominant disorder. The majority of patients escape the most severe complications. Ocular Lisch nodules, melanocytic hamartomas of the iris, are the most common ocular lesions, and are present in almost all patients. Unilateral glaucoma is also described and may be congenital, often with buphthalmos. Approximately 10% of NF1 patients develop CNS tumors, half of which are optic nerve gliomas that generally develop by the age of 5 years. Therefore, ophthalmic follow-up and screening is advised through clinical examination of visual acuity, orthoptic assessment, fundoscopy and/or field examination during the first years of life. Prospective brain imaging is not generally recommended as many patients (around two-thirds of children) have asymptomatic gliomas or other unidentified bright objects (UBOs), the identification of which is incidental and often unhelpful. Extraocular Multiple café-au-lait spots occur in the skin of nearly all patients. The spots increase in number over the first few years of life and fade later. Axillary or inguinal freckling is present in around 90% of patients. Often, adults have many benign cutaneous or subcutaneous neurofibromas. Plexiform neurofibromas are less common and usually present before mid-teenage years. These often grow and can undergo sarcomatous transformation. One site of predeliction is the upper lid and this can become disfiguring.
Conditions associated with increased risk of malignancy
251
B
A
C
A. Multiple café-au-lait patches in NF1. B. Axillary freckling. C. Lisch nodules.
About 30% of patients have mild but specific learning difficulties, although intelligence is generally normal. Skeletal manifestations include scoliosis, especially during periods of growth, and pseudarthrosis. Hypertension is common in adults and although renal artery stenosis and pheochromocytoma have been reported, it is generally found to be essential hypertension. Malignant transformation of tumors to fibrosarcoma, neurofibrosarcoma or malignant schwannoma is not uncommon and is seen in around 10% of patients. Age of onset
252
The characteristic features of NF1 develop at different ages, hence pseudoarthroses may be present at birth. Café-au-lait patches may be noted in the first year of life but these increase in frequency during the first decade. Optic nerve gliomas usually develop under
Neurofibromatosis type I
the age of 5 years. Most patients develop sufficient features for a positive diagnosis by the age of 5 years. Epidemiology
1:3000–4000
Inheritance
Autosomal dominant. 50% of individuals have new mutations.
Chromosomal location
17q11.2
Gene
Neurofibromin (NF1)
Mutational spectrum
A wide range of mutations has been described. Routine mutation testing protocols define a mutation in one-half to one-third of patients.
Effect of mutation
The majority of mutations result in premature protein truncation. NF1 is a common condition that is highly variable. Little evidence of a genotype-phenotype correlation exists suggesting the existence of modifying environmental and genetic effects. Neurofibromin appears to down regulate p21 (ras), a major regulator of cell growth. It has been postulated that NF1 mutations result in abnormal ras signaling and thereby contribute to tumor development.
Diagnosis
Diagnosis is clinical and is based on the presence of particular criteria, such as Lisch nodules. Regular childhood assessment for the multisystemic effects of NF1 is necessary. In addition, annual ophthalmic review is recommended throughout childhood. DNA testing is available through molecular diagnostic laboratories although this is laborious and seldom undertaken.
Conditions associated with increased risk of malignancy
253
Neurofibromatosis type II (also known as: NF2) MIM
101000
Clinical features
Ocular Pre-senile posterior subcapsular, cortical or wedge-shaped opacities are found in the majority of patients (~80%). Prospective screening for the opacities is of no value as they are seldom visually significant. They may occasionally progress with time. Lisch nodules are not found in NF2. Macular and paramacular epiretinal membranes and hamartomatous lesions of the retina and RPE are seen in around 50% of patients. Neuro-ophthalmic complications are a major result of vestibular schwannomas (acoustic neuromas) or, more commonly, the surgery required to remove them. Facial nerve palsy results in lagophthalmos and decreased lacrimal secretion, while trigeminal damage causes corneal anesthesia. Extraocular The tumors most frequently associated with NF2 are bilateral vestibular schwannomas. These cause hearing loss, tinnitus and balance dysfunction. Around two-thirds of patients develop spinal tumors, most commonly schwannomas, although astrocytomas and ependymomas have also been observed. Spinal tumors are a significant cause of morbidity. Approximately 50% of patients with NF2 develop meningiomas, both intracranial and spinal. Patients rarely have more than five café-au-lait patches. Flat, dysplastic skin tumors and subcutaneous spherical nodular tumors on the trunk and limbs are common and represent cutaneous schwannomas.
254
Neurofibromatosis type II
B
C
A
NF2: A. Bilateral acoustic neuromata. B. Placoid skin tumors. C. Peripheral schwannomata.
Age of onset
Symptoms usually begin during the second and third decades. Lens opacities may be asymptomatic but present from an earlier age.
Epidemiology
The prevalence is estimated to be approximately 1:37,000.
Inheritance
Autosomal dominant
Chromosomal location
22q12.2
Gene
Merlin; alternative name: schwannomin (SCH)
Mutational spectrum
Mutations are found in around two-thirds of patients. A broad range has been described including deletion, splice-site, nonsense and missense mutations. Interfamilial variability is greater than intrafamilial variability, suggesting that mutation type alters gene
Conditions associated with increased risk of malignancy
255
expression and/or protein function and thereby influences phenotypic outcome. Therefore, there is evidence for genotypephenotype correlation. Effect of mutation
Most of the mutations result in protein truncation, and are presumed to result in severe diminution, or loss, of function. The NF2 protein, merlin (moezin-ezrin-radixin like protein), is homologous to a family of cytoskeleton-associated proteins. Abnormal protein products have been shown to display altered cell adhesion, which may be an initial step in tumorigenesis.
Diagnosis
Ocular abnormalities are common but generally do not result in bilateral visual loss. When suspected clinically, as in patients with isolated unilateral or bilateral vestibular schwannoma, ophthalmologists may be asked to investigate for the presence of lens opacities or retinal hamartomas. DNA testing is available through recognized molecular diagnostic laboratories.
256
Neurofibromatosis type II
Retinoblastoma (also known as: RB1) MIM
180200
Clinical features
Ocular Retinoblastoma is a childhood malignancy derived from retinal cells. The tumor develops between the ages of 1–4 years, very rarely presenting later. Improvements in treatment have increased 5 year survival to 94% in the UK. The most common presentations are leukocoria and strabismus. However, retinoblastoma may mimic developmental glaucoma, orbital cellulitis, uveitis, hyphema or vitreous hemorrhage. Tumors may spread towards the vitreous cavity (endophytic spread) or towards the outer layers of the eye and subretinal space (exophytic tumor). Histologically, they are characterized by necrosis and calcification with primitive small cells, which may resemble primitive photoreceptors and form Flexner-Wintersteiner rosettes. Extraocular Those with a germline mutation carry a predisposing mutation in all cells and have an increased risk of non-ocular malignancy such as osteosarcomas, soft tissue sarcomas and melanomas. Their cumulative incidence, 50 years after diagnosis of retinoblastoma, is 20–30% in non-irradiated patients and >50% in those receiving external beam radiation. In addition there is a low risk of pinealomas which have a poor prognosis. A small number of patients carry large chromosomal deletions encompassing the RB1 gene and the genes surrounding it on 13q (see figure). The deletions may cause clinical manifestations due to loss of these genes—a contiguous gene syndrome—including developmental delay and facial dysmorphism.
Conditions associated with increased risk of malignancy
257
A
B
Retinoblastoma in first trimester fetus with multiple abnormalities. A visible deletion of chromosome 13q was seen on karyotype analysis. A. The fetus has a small jaw, low set ears, short, broad neck and short thumbs. B. Swelling of the right eye was noted. Macroscopic and histopathological analysis revealed a large retinoblastoma.
Age of onset
Mean age of onset for bilateral cases is 15 months and for unilateral cases 24 months.
Epidemiology
Incidence of 4:1,000,000, or about 1:23,000 live births.
Inheritance
Autosomal dominant. Penetrance is >99% for most mutations that abolish RB1 function. However, in some families penetrance is reduced to around 40%. Around 10% of individuals have a positive family history, most of these developing bilateral multifocal tumors. Approximately 30% of patients have no family history but develop bilateral tumors; they are assumed to have new germline mutations. The remaining 60% develop unilateral tumors wherein the majority result from somatic mutations arising after the production of the zygote.
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Retinoblastoma
Chromosomal location
13q14.1–q14.2
Gene
Retinoblastoma (RB1)
Mutational spectrum
RB1 is a large gene containing 27 exons covering over 180 kb of genomic DNA. While major deletions are reported, the majority of mutations are single base changes. All forms of mutation have been described including protein truncating mutations, splice-site mutations and missense changes. The majority of mutations (80–85%) result in premature termination.
Effect of mutation
RB1 is a tumor suppressor gene that expresses a nuclear protein involved in cell cycle regulation and transition from G1–S phase. RB1 acts to inhibit cellular transcription factors and tRNA/rRNA gene transcription. Mutations in RB1 that cause low penetrance forms of retinoblastoma have been shown to retain some function.
Diagnosis and counselling issues
Clinical. Using sensitive screening techniques around 80–90% of mutations can be found in patients with germline mutations. Genetic testing is now widely available. Ongoing screening of both affected children and unaffected siblings is a major cause of anxiety. However, mutation testing may be useful in reducing the need for examination under anesthetic and repeated fundoscopy in unaffected siblings who are not mutation carriers. A major area of concern is the possibility that the proband or one of his or her parents has a germline mutation that may be passed on to other family members. Family history and mutation analyses can be used to help determine these risks. In unilateral cases, negative screening of blood does not exclude the possibility of mosaicism as both affected and unaffected germ cells may exist and can be passed on to offspring. Molecular genetic testing of tumor DNA may aid the search for mutations. If two disease causing mutations are identified in a tumor, peripheral blood from relatives can then be screened for these mutations.
Conditions associated with increased risk of malignancy
259
Family history
Tumor type
Probability of germline mutation
Risk to offspring
Risk to siblings
Positive
Bilateral retinoblastoma
100%
50%
-
Negative
Bilateral retinoblastoma
95%
Assumed to be 50%
Around 3–5% (due to germline mosaicism)
Negative
Multifocal, unilateral retinoblastoma
Uncertain
Difficult to determine
Difficult to determine
Negative
Unifocal, unilateral retinoblastoma
5–10%
2–5%
1%
260
Retinoblastoma
Tuberous sclerosis complex (also known as: TSC; tuberous sclerosis) MIM
191100 (TSC1); 191092 (TSC2)
Clinical features
TSC is a highly variable autosomal dominant disorder in which affected individuals have a high risk of seizures and renal disease, both of which are significant causes of premature mortality. Ocular These are usually asymptomatic. The classical lesions are retinal astrocytic hamartomas, ‘mulberry tumors’, or small intraretinal translucent patches. In addition, achromic patches analogous to the hypopigmented skin lesions are present. One or more of these lesions may be present in up to 75% of patients. CNS Tumors include subependymal glial nodules and giant cell astrocytomas as well as cortical and subcortical tubers. Over 80% of patients diagnosed with TSC have seizures, and at least 50% have developmental delay. Renal Benign angiomyolipomas occur in at least 70% of patients and can cause hemorrhage or replacement of renal tissue. Some patients have a combined phenotype with features of TSC and PKD and in these patients cystic disease may lead to renal failure. Skin Facial angiofibromas (adenoma sebaceum), periungual fibromas, hypomelanotic macules and shagreen patches are all observed.
Conditions associated with increased risk of malignancy
261
A
B
C A & B. Astrocytic hamartomata of disc. C. Hypopigmented patches in tuberous sclerosis.
262
Tuberous sclerosis complex
Cardiac Cardiac rhabdomyoma Other Minor manifestations include multiple dental pits, hamartomatous rectal polyps, bone cysts and gingival fibromas. Age of onset
Signs of the disorder may be present from birth, although it is generally diagnosed during childhood.
Epidemiology
The prevalence of TSC is suggested to be as high as 1:5800 births.
Inheritance
Autosomal dominant. About 70% of all cases are new mutations.
Chromosomal location
9q34 (TSC1); 16p13 (TSC2)
Gene
Tuberous sclerosis complex 1 and 2 (TSC1, TSC2)
Mutational spectrum
More than 300 mutations have been described in TSC1. None are missense mutations. Of over 250 mutations described in TSC2, around 75% are gene rearrangements, splice mutations and nonsense mutations, 25% are missense mutations.
Effect of mutation
Both TSC1 and TSC2 are thought to act as tumor suppressor genes. The two genes have been shown to form heterodimers and are believed to regulate cell cycle and cell proliferation.
Diagnosis
Clinical. The role of the ophthalmologist is to aid diagnosis by recognition of retinal lesions. While mutation testing for both TSC1 and TSC2 is now available, this will only identify mutations in 60–80% of cases.
Conditions associated with increased risk of malignancy
263
von Hippel-Lindau syndrome (also known as: VHL) MIM
193300
Clinical features
Ocular About 70% of patients have retinal hemangioblastomas, which are often the presenting feature of the disorder. Hemangioblastomas are vascular tumors associated with feeder and draining vessels and are mainly located in the temporal periphery of the retina, although they may also be found at the posterior pole and optic disc. The angiomas are usually asymptomatic when small. As they enlarge they may cause exudation, hemorrhage and retinal detachment. Laser photoablation or cryotherapy of early retinal angiomas results in regression. Optic disc tumors are not amenable to treatment. The average number of retinal angiomas per patient is two (there may be up to 15); this number does not increase with age. Extraocular CNS hemangioblastomas are the classic lesion of VHL. Around 80% develop in the cerebellar hemispheres, the remaining 20% in the spinal cord. Multiple renal cysts are common. In addition, clear-cell renal carcinoma occurs in >40% of patients. Pheochromocytoma, either symptomatic or asymptomatic, may be seen within the adrenal glands or elsewhere. Multiple pancreatic cysts are frequent, and occasionally pancreatic tumors develop. Tumors of the endolymphatic sac of the membranous labyrinth are rare but may cause early deafness. Epididymal cystadenomas are relatively common in males with VHL syndrome but rarely cause problems.
Age of onset
264
Symptoms are rare before the age of 5 years. Annual screening should begin from around the age of 5 years because photoablation can successfully treat retinal lesions and preserve vision.
von Hippel-Lindau syndrome
Epidemiology
Prevalence in the UK has been estimated to be approximately 1:50,000.
Inheritance
Autosomal dominant
Chromosomal location
3p25–p26
Gene
von Hippel-Lindau (VHL)
Mutational spectrum
Mutations are found in almost all patients. Around one-third are caused by partial or whole gene deletion, the remainder result from point mutations. A wide range of mutations including truncating, splice-site and missense mutations have been described. There is significant genotype-phenotype correlation for mutations in the VHL gene: truncating and null mutations generally cause VHL without pheochromocytoma, while patients with pheochromocytoma generally have a missense mutation.
Effect of mutation
The VHL protein (pVHL) is involved in the regulation of hypoxicallyinduced vascular endothelial growth factor (VEGF) and glucose transporter-1 (GLUT-1). It is also involved in the degradation of hypoxia-inducible factor-1 (HIF-1). HIF-1 usually controls factors promoting the formation of blood vessels. If pVHL is abnormal, the degradation of HIF-1 does not take place resulting in abnormal proliferation of blood vessels. This could account for the vascular tumors seen in VHL. Further work is ongoing to fully understand the interactions of pVHL with other proteins and to understand the genotype/phenotype correlation. The VHL gene is a tumor suppressor gene requiring biallelic loss for tumorigenesis, however, the presence of a genotype-phenotype correlation suggests that some missense mutations retain aspects of protein activity.
Diagnosis
Patients with retinal angiomas should be investigated for the presence of other characteristic lesions. DNA testing is available through molecular diagnostic laboratories.
Conditions associated with increased risk of malignancy
265
266
10 10. Defects of ocular/adnexal development
Alacrima 268 Blepharophimosis, ptosis and epicanthus inversus 270 Congenital fibrosis of extraocular muscles 272 Isolated microphthalmos 274
Alacrima (also known as: achalasia-addisonianism-alacrima syndrome (AAAS); triple-A syndrome; Allgrove syndrome) MIM
231550; 605378 (Aladin)
Clinical features
AAAS is a variable condition in which patients may have some, but not all, of the features. Ocular features Congenital alacrima is present in most patients and leads to significant ocular discomfort. Autonomic disturbance may lead to anisocoria. The pupil is hypersensitive to topical parasympathomimetics. Optic atrophy is described in a small number of patients. Extraocular manifestations Adrenal insufficiency is usually diagnosed in the first years of life. Symptoms relating to recurrent hypoglycemia generally begin between the ages of 1–8 years. This is often associated with hyperpigmentation of the skin. Adrenal insufficiency responds to steroid replacement. A number of patients also have evidence of mineralocorticoid deficiency. Achalasia of the esophageal cardia is present in the majority of patients and is diagnosed between the ages of 2–20 years, often before cortisol deficiency is noted. When diagnosed, the majority of patients require surgical intervention. Neurological manifestations are highly variable but include evidence of upper and lower motor neuron dysfunction, ataxia, sensory impairment, as well as autonomic dysfunction. There may be lateonset progressive neurological symptoms including cerebellar ataxia and mild dementia.
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Alacrima
Age of onset
While a diagnosis of AAAS is often delayed, features of the condition are usually present in the first years of life.
Inheritance
Autosomal recessive
Chromosomal location
12q13
Gene
Achalasia-addisonianism-alacrima syndrome gene (AAAS)
Mutational spectrum
The majority of mutations described are frameshift and truncating mutations that result in premature protein truncation. However, a number of missense mutations have also been described.
Effect of mutation
The AAAS gene encodes a 546 amino acid protein (Aladin), which contains so-called WD-repeats. While it is expressed in all tissues, there is high expression in the adrenal gland, gastrointestinal structures, pituitary and cerebellum. WD-proteins form a b-propeller structure which facilitates protein-protein interactions. The exact function of the protein, or the identity of the proteins with which it interacts, is unknown. However, the presence of a peroxisomal targeting signal suggests a peroxisomal function.
Diagnosis
Diagnosis of AAAS may be delayed, and the ophthalmic features are often valuable in facilitating this process. Mutation testing is available on a research basis only.
Defects of ocular/adnexal development
269
Blepharophimosis, ptosis and epicanthus inversus (also known as: BPES) MIM
110100; 605597 (FOXL2)
Clinical features
Ocular BPES is associated with abnormal development of the eyelid structures.
BPES: Note upward insertion of inner canthus of lower lid.
Blepharophimosis leads to horizontal shortening of the palpebral fissure; in BPES this is 2–2.2 cm as compared with a normal adult horizontal length of 2.5–3 cm. Ptosis results from reduced horizontal fissure length as well as from abnormal levator function. This leads to a chin-up head-tilt and arching of the eyebrows. Epicanthus inversus is characterized by a small fold of skin, running upwards from the medial aspect of the lower lid, which appears to override the medial insertion of the upper lid. There is often telecanthus (lateral displacement of the inner canthi). Occasionally, individuals with BPES have been described with ocular malformations such as anophthalmos and microphthalmos. Extraocular Female infertility is common in some families with BPES, and has been termed ‘type I BPES’. There are differing degrees of ovarian failure, from streak gonads to ovaries of essentially normal appearance but with irregular or infrequent menstruation associated with abnormal hormonal function. Type II describes isolated BPES.
270
Blepharophimosis, ptosis and epicanthus inversus
Age of onset
Congenital
Inheritance
Autosomal dominant. There is a high number of sporadic cases. Infertility is sex-limited (i.e. only in females) but may be passed on by males.
Chromosomal location
3q23
Gene
Forkhead transcription factor (FOXL2)
Mutational spectrum
In patients with type I BPES, there are premature protein termination mutations. These are likely to result in loss of function of the FOXL2 transcription factor. In patients with type II BPES, intragenic duplications result in expansion of a 14-residue polyalanine amino acid domain. This may result in reduction, rather than abolition of protein function. Several patients with translocations through 3q23 have been described. The translocations lie within several hundred kb of FOXL2.
Effect of mutation
FOXL2 is a transcription factor whose expression is highly tissuespecific. During development, expression is confined to the periocular mesenchyme—the developing eyelid structures. In the adult, expression is confined to the ovary.
Diagnosis
Distinction between types I and II is important in order to counsel females regarding the possible risks of infertility, in particular amongst those with de novo mutations and no family history. The gene has only recently been described, therefore mutation testing is only on a research basis.
Defects of ocular/adnexal development
271
Congenital fibrosis of extraocular muscles (also known as: CFEOM; FEOM1; FEOM2) MIM
135700 (FEOM1); 602078 (FEOM2)
Clinical features
Affected individuals are born with non-progressive restriction of ocular movement. The disorder is characterized by anchoring of the eyes in downgaze with ptosis and a chin-up head-tilt. There is restrictive ophthalmoplegia with the globes frozen, often in extreme abduction, with little or no ability to adduct, elevate or depress them. In addition to fibrosis of the extraocular muscles and Tenon’s capsule, adhesions between muscles, Tenon’s and the globe are seen. It is thought that CFEOM is caused by abnormal development of oculomotor subnuclei resulting in anomalous innervation of the extraocular musculature.
CFEOM: In these individuals, from the same family, the eyes are held in a depressed position, in abduction. There is absent levator function. Vision is normal in both cases.
Age of onset
Congenital
Inheritance
Autosomal dominant (FEOM1); autosomal recessive (FEOM2).
272
Congenital fibrosis of extraocular muscles
Chromosomal location
12p11.2–q11.2 (FEOM1); 11q13.2 (FEOM2).
Gene
Drosophila aristaless homeobox gene homolog (ARIX); MIM 602753 (FEOM2).
Mutational spectrum
In autosomal recessive FEOM, both splice-site mutations and a missense mutation of a conserved amino acid have been described.
Effect of mutation
Unknown
Diagnosis
It is likely that the splice mutations would result in the production of an unstable transcript or truncated, non-functional proteins. ARIX encodes a homeodomain-containing transcription factor that is required for generation and preservation of adrenergic neurons and brainstem motor neurons. It is thought to be important for the development of the cranial nerve nuclei.
Defects of ocular/adnexal development
273
Isolated microphthalmos (nanophthalmos and anophthalmos) Microphthalmia is not a single clinical entity. It may be associated with a large number of single gene disorders as well as developmental abnormalities of broad etiology, including chromosomal abnormalities, maternal infection, maternal toxin ingestion (e.g. anti-epileptic drugs or alcohol) and fetal disruptions. Environmental influences have also been suggested. MIM
142993 (CHX10)
A
B
C
A. Colobomatous microphthalmia. B & C. Right sided microcornea in a patient with branchio-oculo-facial syndrome has bilateral chorioretinal colobomata. Note the hemangioma.
274
Isolated microphthalmos (nanophthalmos and anophthalmos)
Clinical features
Microphthalmia is defined as an axial length of <19.5 mm at the age of 1 year, or 21.5 mm at the age of 10 years. The condition may be unilateral or bilateral. There is some confusion in the terminology as nanophthalmos (in which patients have a short axial length, high hypermetropia and a high risk of angleclosure glaucoma, but normal visual function) is probably an identical entity. It is likely that anophthalmia is part of this spectrum, and does not represent a separate condition. Microphthalmia may be associated with reduced anterior and/or posterior segment growth and may be seen with other ocular abnormalities, including microcornea, anterior segment dysgenesis, cataract, persistent hyperplastic vitreous and coloboma. (The description of microphthalmic individuals within kindreds with autosomal dominant congenital cataract reflects the importance of the lens in inducing ocular, particularly anterior, segment development.) There is no satisfactory clinical, molecular or etiological subclassification of microphthalmia.
Age of onset
Congenital
Epidemiology
The incidence of microphthalmia is approximately 2:10,000. This varies in different populations.
Inheritance
Autosomal dominant; autosomal recessive; X-linked. While true X-linked isolated microphthalmia has not been described, X-linked anophthalmia is recognized in males with developmental delay (IQ <50), anophthalmia and a secondary underdevelopment of the bony orbit.
Defects of ocular/adnexal development
275
Chromosomal location Disorder Anophthalmos
Inheritance XL
Locus Xq27–q28
Gene -
Nanophthalmos
AD
11p
-
Colobomatous microphthalmia
AD
15q12–q15
-
Microphthalmos
AR
14q32
-
Microphthalmos
AR
14q24
CHX10
Cataract and Microphthalmia
AR
22q11.2
CRYBB2
Microcornea/Cataract
AD
16q23.2
MAF
Microphthalmia/Cornea plana
AR
12q21.3–q22
KERA
Microphthalmia/Persistant hyperplastic primary vitreous
AR
10q21
-
Cataract and Microphthalmia AD 21q22.3 CRYAA * patients with microphthalmos have a translocation between 16p13.3 and 2p22.3. Gene
CEH10 homeodomain-containing homologue (CHX10)
Mutational spectrum
In two families, both consanguineous, homozygous missense alterations of a highly conserved arginine residue (in the DNA-recognition helix of the homeodomain of CHX10) were described in individuals with microphthalmia. The parents were normal.
Effect of mutation
CHX10 is expressed in the developing neuroretina and in the inner nuclear layer of the mature retina (bipolar cells) and is therefore crucial for normal retinal development and maintenance. Mutation of the homeodomain of CHX10 disrupts normal function of the protein by altering its DNA-binding specificity. In the mouse, CHX10 defects also cause microphthalmia, progressive destruction of the retina, and absence of the optic nerve.
276
Isolated microphthalmos (nanophthalmos and anophthalmos)
Diagnosis
Microphthalmos is often sporadic and may be unilateral. Accurate definition of recurrence risks is extremely difficult and often only empiric risks can be given. Assessing whether microphthalmia is genuinely isolated and examining parents for signs of mild optic nerve abnormality, retinal coloboma formation and anterior segment dysgenesis are useful for helping to exclude genetic forms.
Defects of ocular/adnexal development
277
278
11 11. Glossary
A Adenine (A)
One of the bases making up DNA and RNA (pairs with thymine in DNA and uracil in RNA).
Agarose gel electrophoresis
See electrophoresis
Allele
One of two or more alternative forms of a gene at a given location (locus). A single allele for each locus is inherited separately from each parent. In normal human beings there are two alleles for each locus (diploidy). If the two alleles are identical, the individual is said to be homozygous for that allele; if different, the individual is heterozygous. For example, the normal DNA sequence at codon 6 in the beta-globin gene is GAG (coding for glutamic acid), whereas in sickle cell disease the sequence is GTG (coding for valine). An individual is said to be heterozygous for the glutamic acid → valine mutation if he/she possesses one normal (GAG) and one mutated (GTG) allele. Such individuals are carriers of the sickle cell gene and do not manifest classical sickle cell disease (which is autosomal recessive).
Allelic heterogeneity
Similar/identical phenotypes caused by different mutations within a gene. For example, many different mutations in the same gene are now known to be associated with Marfan’s syndrome (FBN1 gene at 15q21.1).
Amniocentesis
Withdrawal of amniotic fluid, usually carried out during the second trimester, for the purpose of prenatal diagnosis.
Amplification
The production of increased numbers of a DNA sequence. 1. In vitro In the early days of recombinant DNA techniques, the only way to amplify a sequence of interest (so that large amounts were available
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for detailed study) was to clone the fragment in a vector (plasmid or phage) and transform bacteria with the recombinant vector. The transformation technique generally results in the ‘acceptance’ of a single vector molecule by each bacterial cell. The vector is able to exist autonomously within the bacterial cell, sometimes at very high copy numbers (e.g. 500 vector copies per cell). Growth of the bacteria containing the vector, coupled with a method to recover the vector sequence from the bacterial culture, allows for almost unlimited production of a sequence of interest. Cloning and bacterial propagation are still used for applications requiring either large quantities of material or else exceptionally pure material. However, the advent of the polymerase chain reaction (PCR) has meant that amplification of desired DNA sequences can now be performed more rapidly than was the case with cloning (a few hours cf. days), and it is now routine to amplify DNA sequences 10 million fold. 2. In vivo Amplification may also refer to an increase in the number of DNA sequences within the genome. For example, the genomes of many tumors are now known to contain regions that have been amplified many fold compared to their non-tumor counterparts (i.e. a sequence or region of DNA that normally occurs once at a particular chromosomal location may be present in hundreds of copies in some tumors). It is believed that many such regions harbor oncogenes, which, when present in high copy number, predispose to development of the malignant phenotype. Aneuploid
Possessing an incorrect number (abnormal complement) of chromosomes. The normal human complement is 46 chromosomes, any cell that deviates from this number is said to be aneuploid.
Aneuploidy
The chromosomal condition of a cell or organism with an incorrect number of chromosomes. Individuals with Down syndrome are described as having aneuploidy, because they possess an extra copy of chromosome 21 (trisomy 21), making a total of 47 chromosomes.
Glossary
281
Anticipation
A general phenomenon that refers to the observation of an increase in severity, and/or decrease in age of onset, of a condition in successive generations of a family (see Figure 1). Anticipation is now known, in many cases, to result directly from the presence of a dynamic mutation in a family. In the absence of a dynamic mutation, anticipation may be explained by ‘ascertainment bias’. Thus, before the first dynamic mutations were described (in Fragile X and myotonic dystrophy), it was believed that ascertainment bias was the complete explanation for anticipation. There are two main reasons for ascertainment bias: 1. Identical mutations in different individuals often result in variable expressions of the associated phenotype. Thus, individuals within a family, all of whom harbor an identical mutation, may have variation in the severity of their condition. 2. Individuals with a severe phenotype are more likely to present to the medical profession. Moreover, such individuals are more likely to fail to reproduce (i.e. they are genetic lethals), often for social, rather than direct physical reasons. For both reasons, it is much more likely that a mildly affected parent will be ascertained with a severely affected child, than the reverse. Therefore, the severity of a condition appears to increase through generations.
Figure 1. Autosomal dominant inheritance with anticipation. In many disorders that exhibit anticipation, the age of onset decreases in subsequent generations. It may happen that the transmitting parent (grandparent in this case) is unaffected at the time of presentation of the proband (see arrow). A good example is Huntington’s disease, caused by the expansion of a CAG repeat in the coding region of the huntingtin gene. Note that this pedigree would also be consistent with either gonadal mosaicism or reduced penetrance (in the carrier grandparent).
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Anticodon
The 3-base sequence on a transfer RNA (tRNA) molecule that is complementary to the 3-base codon of a messenger RNA (mRNA) molecule.
Ascertainment bias
See anticipation
Autosomal disorder
A disorder associated with a mutation in an autosomal gene.
Autosomal dominant (AD) inheritance
An autosomal disorder in which the phenotype is expressed in the heterozygous state. These disorders are not sex-specific. Fifty percent of offspring (when only one parent is affected) will usually manifest the disorder (Figure 2). Marfan syndrome is a good example of an AD disorder; affected individuals possess one wild-type (normal) and one mutated allele at the FBN1 gene.
Figure 2. Autosomal dominant (AD) inheritance.
Autosomal recessive (AR) inheritance
An autosomal disorder in which the phenotype is manifest in the homozygous state. This pattern of inheritance is not sex-specific and is difficult to trace through generations because both parents must contribute the abnormal gene, but may not necessarily display the disorder. The children of two heterozygous AR parents have a 25% chance of manifesting the disorder (see Figure 3). Cystic fibrosis (CF) is a good example of an AR disorder; affected individuals possess two mutations, one at each allele.
Figure 3. Autosomal recessive (AR) inheritance.
Glossary
283
Autosome
Any chromosome, other than the sex chromosomes (X or Y), that occurs in pairs in diploid cells.
B Barr body
An inactive X chromosome, visible in the somatic cells of individuals with more than one X chromosome (i.e. all normal females and all males with Klinefelter’s syndrome). For individuals with n X chromosomes, n-1 Barr bodies are seen. The presence of a Barr body in cells obtained by amniocentesis or chorionic villus sampling used to be used as an indication of the sex of a baby before birth.
Base pair (bp)
Two nucleotides held together by hydrogen bonds. In DNA, guanine always pairs with cytosine, and thymine with adenine. A base pair is also the basic unit for measuring DNA length.
C Carrier
An individual who is heterozygous for a mutant allele (i.e. carries one wild-type (normal copy) and one mutated copy of the gene under consideration).
CentiMorgan (cM)
Unit of genetic distance. If the chance of recombination between two loci is 1%, the loci are said to be 1 cM apart. On average, 1 cM implies a physical distance of 1 Mb (1,000,000 base pairs) but significant deviations from this rule of thumb occur because recombination frequencies vary throughout the genome. Thus if recombination in a certain region is less likely than average, 1 cM may be equivalent to 5 Mb (5,000,000 base pairs) in that region.
Centromere
Central constriction of the chromosome where daughter chromatids are joined together, separating the short (p) from the long (q) arms (Figure 4).
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Chromosome p arm Centromere q arm DNA Double helix
Nucleus Chromatid Telomere
AT A T T
A G A
C
Figure 4.
T
Chorionic villus sampling (CVS)
Prenatal diagnostic procedure for obtaining fetal tissue at an earlier stage of gestation than amniocentesis. Generally performed after 10 weeks, ultrasound is used to guide aspiration of tissue from the villus area of the chorion.
Chromatid
One of the two parallel identical strands of a chromosome, connected at the centromere during mitosis and meiosis (see Figure 4). Before replication, each chromosome consists of only one chromatid. After replication, two identical sister chromatids are present. At the end of mitosis or meiosis, the two sisters separate and move to opposite poles before the cell splits.
Chromatin
A readily stained substance in the nucleus of a cell consisting of DNA and proteins. During cell division it coils and folds to form the metaphase chromosomes.
Chromosome
One of the threadlike ‘packages’ of genes and other DNA in the nucleus of a cell (see Figure 4). Humans have 23 pairs of chromosomes, 46 in total: 44 autosomes and two sex chromosomes. Each parent contributes one chromosome to each pair.
Glossary
285
Chromosomal disorder
A disorder that results from gross changes in chromosome dose. May result from addition or loss of entire chromosomes or just portions of chromosomes.
Clone
A group of genetically identical cells with a common ancestor.
Codon
A three-base coding unit of DNA that specifies the function of a corresponding unit (anticodon) of transfer RNA (tRNA).
Complementary DNA (cDNA)
DNA synthesized from messenger RNA (mRNA) using reverse transcriptase. Differs from genomic DNA because it lacks introns.
Complementation
The wild-type allele of a gene compensates for a mutant allele of the same gene so that the heterozygote’s phenotype is wild-type.
Complementation analysis
A genetic test (usually performed in vitro) that determines whether or not two mutations that produce the same phenotype are allelic. It enables the geneticist to determine how many distinct genes are involved when confronted with a number of mutations that have similar phenotypes. Occasionally it can be observed clinically. Two parents who both suffer from recessive deafness (i.e. both are homozygous for a mutation resulting in deafness) may have offspring that have normal hearing. If A and B refer to the wild-type (normal) forms of the genes, and a and b the mutated forms, one parent could be aa, BB and the other AA, bb. If alleles A and B are distinct, each child will have the genotype aA, bB and will have normal hearing. If A and B are allelic, the child will be homozygous at this locus and will also suffer from deafness.
Compound heterozygote
An individual with two different mutant alleles at the same locus.
Concordant
A pair of twins who manifest the same phenotype as each other.
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Consanguinity
Sharing a common ancestor, and thus genetically related. Recessive disorders are seen with increased frequency in consanguineous families.
Consultand
An individual seeking genetic advice.
Contiguous gene syndrome
A syndrome resulting from the simultaneous functional imbalance of a group of genes (see Figure 5). The nomenclature for this group of disorders is somewhat confused, largely as a result of the history of their elucidation. The terms submicroscopic rearrangement/deletion/ duplication and micro-rearrangement/deletion/duplication are often used interchangeably. Micro or submicroscopic refer to the fact that such lesions are not detectable with standard cytogenetic approaches (where the limit of resolution is usually 10 Mb, and 5 Mb in only the most fortuitous of circumstances). A newer, and perhaps more comprehensive, term that is currently applied to this group of disorders is segmental aneusomy syndromes (SASs). This term embraces the possibility not only of loss or gain of a 22
21
15.3 15.2 15.1 14
p
13 12
7
11.2 11.1 11.1 11.21 11.22
11.23
Williams syndrome region: 1.5—2.5 Mb in size.
21.1 21.2 21.3
22.1
q
31.1 31.2
31.3
32 33 34 35
36
Figure 5 Schematic demonstrating the common deletion found in Williams syndrome, at 7q11.23. The common deletion is not detectable using standard cytogenetic analysis (even high resolution), despite the fact that the deletion is at least 1.5 Mb in size. In practice, only genomic rearrangements that affect at least 5—10 Mb are detectable, either by standard cytogenetic analysis or, in fact, any technique whose endpoint involves analysis at the chromosomal level. Such deletions are termed microdeletions or submicroscopic deletions. Approximately 20 genes are known to be involved in the 7q11.23 microdeletion, and work is underway to determine which genes contribute to which aspects of the Williams syndrome phenotype.
Glossary
287
chromosomal region that harbors many genes (leading to imbalance of all those genes), but also of functional imbalance in a group of genes, as a result of an abnormality of the machinery involved in their silencing/transcription (i.e. methylation-based mechanisms that depend on a master control gene). In practice, most contiguous gene syndromes result from the heterozygous deletion of a segment of DNA that is large in molecular terms but not detectable cytogenetically. The size of such deletions is usually 1.5–3 Mb. It is common for one to two dozen genes to be involved in such deletions, and the resultant phenotypes are often complex, involving multiple organ systems and, almost invariably, learning difficulties. A good example of a contiguous gene syndrome is Williams syndrome, a sporadic disorder that is due to a heterozygous deletion at chromosome 7q11.23. Affected individuals have characteristic phenotypes, including recognizable facial appearance and typical behavioral traits (including moderate learning difficulties). Velocardiofacial syndrome is currently the most common microdeletion known, and is caused by deletions of 3 Mb at chromosome 22q11. Crossing over
Reciprocal exchange of genetic material between homologous chromosomes at meiosis (see Figure 6).
Cytogenetics
The study of the structure of chromosomes.
Cytosine (C)
One of the bases making up DNA and RNA (pairs with guanine).
Cytotrophoblast
Cells obtained from fetal chorionic villi by chorionic villus sampling (CVS). Used for DNA and chromosome analysis.
D Deletion
288
A particular kind of mutation that involves the loss of a segment of DNA from a chromosome with subsequent re-joining of the two extant ends. It can refer to the removal of one or more bases within a gene or to a much larger aberration involving millions of bases. The Genetics for Ophthalmologists
A
A’
A
A’
B C
B’ C’
B’ C’
B C
Figure 6. Schematic demonstrating the principle of recombination (crossing over). On average, 50 recombinations occur per meiotic division (1–2 per chromosome). Loci that are far apart on the chromosome are more likely to be separated during recombination than those that are physically close to each other (they are said to be linked, see linkage), i.e. A and B are less likely to co-segregate than B and C. Note that the two homologues of a sequence have been differentially labeled according to their chromosome of origin.
term deletion is not totally specific, and differentiation must be made between heterozygous and homozygous deletions. Large heterozygous deletions are a common cause of complex phenotypes (see contiguous gene syndrome); large germ-line homozygous deletions are extremely rare but have been described. Homozygous deletions are frequently described in somatic cells, in association with the manifestation of the malignant phenotype. The two deletions in a homozygous deletion need not be identical but must result in the complete absence of DNA sequences that occupy the ‘overlap’ region. Denature
Broadly used to describe two general phenomena: 1. The ‘melting’ or separation of double-stranded DNA (dsDNA) into its constituent single strands, which may be achieved using heat or chemical approaches.
Glossary
289
2. The denaturation of proteins. The specificity of proteins is a result of their 3-dimensional conformation, which is a function of their (linear) amino acid sequence. Heat and/or chemical approaches may result in denaturation of a protein—the protein loses its 3-dimensional conformation (usually irreversibly) and, with it, its specific activity. Diploid
The number of chromosomes in most human somatic cells (46). This is double the number found in gametes (23, the haploid number).
Discordant
A pair of twins who differ in their manifestation of a phenotype.
Dizygotic
The fertilization of 2 separate eggs by 2 separate sperm resulting in a pair of genetically non-identical twins.
DNA (deoxyribonucleic acid)
The molecule of heredity. DNA normally exists as a double-stranded (ds) molecule; one strand is the complement (in sequence) of the other. The two strands are joined together by hydrogen bonding, a non-covalent mechanism that is easily reversible using heat or chemical means. DNA consists of 4 distinct bases: guanine (G), cytosine (C), thymine (T) and adenine (A). The convention is that DNA sequences are written in a 5’ to 3’ direction, where 5’ and 3’ refer to the numbering of carbons on the deoxyribose ring. A guanine on one strand will always pair with a cytosine on the other strand, while thymine pairs with adenine. Thus, given the sequence of bases on one strand, the sequence on the other is immediately determined: 5’ – AGTGTGACTGATCTTGGTG – 3’ 3’ – TCACACTGACTAGAACCAC – 5’ The complexity (informational content) of a DNA molecule resides almost completely in the particular sequence of its bases. For a sequence of length ‘n’ base pairs, there are 4n possible sequences. Even for relatively small n, this number is astronomical (4n = 1.6 x 1060 for n = 100).
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The complementarity of the two strands of a dsDNA molecule is a very important feature and one that is exploited in almost all molecular genetic techniques. If dsDNA is denatured, either by heat or by chemical means, the two strands become separated from each other. If the conditions are subsequently altered (e.g. by reducing heat), the two strands eventually ‘find’ each other in solution and re-anneal to form dsDNA once again. The specificity of this reaction is quite high, under the right circumstances—strands that are not highly complementary are much less likely to re-anneal compared to perfect or near perfect matches. The process by which the two strands ‘find’ each other depends on random molecular collisions, and a ‘zippering’ mechanism, which is initiated from a short stretch of complementarity. This property of DNA is vital for polymerase chain reaction (PCR), Southern blotting and any method that relies on the use of a DNA/RNA probe to detect its counterpart in a complex mix of molecules. DNA chip
A ‘chip’ or microarray of multiple DNA sequences immobilized on a solid surface (see Figure 7). The term chip refers more often to semiconductor-based DNA arrays, in which short DNA sequences (oligos) are synthesized in situ, using a photolithographic process akin to that used in the manufacture of semiconductor devices for the electronics industry. The term microarray is much more general and includes any collection of DNA sequences immobilized onto a solid surface, whether by a photolithographic process, or by simple ‘spotting’ of DNA sequences onto glass slides. The power of DNA microarrays is based on the parallel analysis that they allow for. In conventional hybridization analysis (i.e. Southern blotting), a single DNA sequence is usually used to interrogate a small number of different individuals. In DNA microarray analysis, this approach is reversed—an individual’s DNA is hybridized to an array that may contain 30,000 distinct spots. This allows for direct information to be obtained about all DNA sequences on the array in one experiment. DNA microarrays have been used successfully to directly uncover point mutations in single genes, as well as detect
Glossary
291
Figure 7. DNA chip. DNA arrays (or ‘chips’) are composed of thousands of ‘spots’ of DNA, attached to a solid surface (normally glass). Each spot contains a different DNA sequence. The arrays allow for massively parallel experiments to be performed on samples. In practice, two samples are applied to the array. One sample is a control (from a ‘normal’ sample) and one is the test sample. Each sample is labeled with fluorescent tags, control with green and test with red. The two labeled samples are co-hybridized to the array and the results read by a laser scanner. Spots on the array whose DNA content is equally represented in the test and control samples yield equal intensities in the red and green channels, resulting in a yellow signal. Spots appearing as red represent DNA sequences that are present at higher concentration in the test sample compared to the control sample and vice versa.
alterations in gene expression associated with certain disease states/cellular differentiation. It is likely that certain types of array will be useful in the determination of subtle copy number alterations, as occurs in microdeletion/microduplication syndromes. DNA methylation
Addition of a methyl group (-CH3) to DNA nucleotides (often cytosine). Methylation is often associated with reduced levels of expression of a given gene and is important in imprinting.
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DNA replication
Use of existing DNA as a template for the synthesis of new DNA strands. In humans and other eukaryotes, replication takes place in the cell nucleus. DNA replication is semi-conservative—each new double-stranded molecule is composed of a newly synthesized strand and a pre-existing strand.
Dominant (traits/diseases)
Manifesting a phenotype in the heterozygous state. Individuals with Huntington’s disease, a dominant condition, are affected even though they possess one normal copy of the gene.
Dynamic/ non-stable mutation
The vast majority of mutations known to be associated with human genetic disease are inter-generationally stable (no alteration in the mutation is observed when transmitted from parent to child). However, a recently described and growing class of disorders result from the presence of mutations that are unstable inter-generationally. These disorders result from the presence of tandem repeats of short DNA sequences (e.g. the sequence CAG may be repeated many times in tandem), see Table 1. For reasons that are not completely clear, the copy number of such repeats may vary from parent to child (usually resulting in a copy number increase) and within the somatic cells of a given individual. Abnormal phenotypes result when the number of repeats reaches a given threshold. Furthermore, when this threshold has been reached, the risk of even greater expansion of copy number in subsequent generations increases.
E Electrophoresis
The separation of molecules according to size and ionic charge by an electrical current. Agarose gel electrophoresis Separation, based on size, of DNA/RNA molecules through agarose. Conventional agarose gel electrophoresis generally refers to electrophoresis carried out under standard conditions, allowing the resolution of molecules that vary in size from a few hundred to a few thousand base pairs.
Glossary
293
Table 1. ‘Classical’ repeat expansion disorders. Disorder
Protein/location
Repeat
Repeat location
Normal range
Pre-mutation
Full mutation
Type
MIM
Progressive myoclonus epilepsy of UnverrichtLundborg type (EPM1)
cystatin B 21q22.3
C4GC4G CG
Promoter
2-3
12-17
30-75
AR
254800
Fragile X type A (FRAXA)
FMR1 Xq27.3
CGG
5’UTR
6-52
~60-200
~200->2,000
XLR
309550
Fragile X type E (FRAXE)
FMR2 Xq28
CGG 5
C’UTR
6-25
-
>200
XLR
309548
Friedreich’s ataxia (FRDA)
frataxin 9q13
GAA
intron
1 7-22
-
200- >900
AR
229300
Huntington’s disease (HD)
huntingtin 4p16.3
CAG
ORF
6-34
-
36-180
AD
143100
Dentatorubal-pallidoluysian atrophy (DRPLA)
atrophin 12p12
CAG
ORF
7-25
-
49-88
AD
125370
Spinal and bulbar muscular atrophy (SBMA – Kennedy syndrome)
androgen receptor CAG Xq11-12
ORF
11-24
-
40-62
XLR
313200
Spinocerebellar ataxia type 1 (SCA1)
ataxin-1 6p23
CAG
ORF
6-39
-
39-83
AD
164400
Spinocerebellar ataxia type 2 (SCA2)
ataxin-2 12q24
CAG
ORF
15-29
-
34-59
AD
183090
Spinocerebellar ataxia type 3 (SCA3)
ataxin-3 14q24.3-q31
CAG
ORF
13-36
-
55-84
AD
109150
Spinocerebellar ataxia type 6 (SCA6)
PQ calcium channel 19p13
CAG
ORF
4-16
-
21-30
AD
183086
Spinocerebellar ataxia type 7 (SCA7)
ataxin-7 3p21.1-p12
CAG
ORF
4-35
28-35
34- >300
AD
164500
Spinocerebellar ataxia type 8 (SCA8)
SCA8 13q21
CTG
3’UTR
6-37
-
~107-2501
AD
603680
Spinocerebellar ataxia type 10 (SCA10)
SCA10 22q13-qter
ATTCT
intron 9
10-22
-
500-4,500
AD
603516
Spinocerebellar ataxia type 12 (SCA12)
PP2R2B 5q31-33
CAG
5’UTR
7-28
-
66-78
AD
604326
Myotonic dystrophy (DM)
DMPK 19q13.3
CTG
3’UTR
5-37
~50-180
~200- >2,000
AD
160900
1Longer alleles exist but are not associated with disease. AD: autosomal dominant; AR: autosomal recessive; ORF: open reading frame (coding region); 3’ UTR: 3’ untranslated region (downstream of gene); 5’ UTR: 5’ untranslated region (upstream of gene); XLR: X-linked recessive.
Polyacrylamide gel electrophoresis Allows resolution of proteins or DNA molecules differing in size by only 1 base pair. Pulsed field gel electrophoresis (Also performed using agarose) refers to a specialist technique that allows resolution of much larger DNA molecules, in some cases up to a few Mb in size.
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Empirical recurrence risk – recurrence risk
Based on observation, rather than detailed knowledge of, e.g., modes of inheritance or environmental factors.
Endonuclease
An enzyme that cleaves DNA at an internal site (see also restriction enzyme).
Euchromatin
Chromatin that stains lightly with trypsin G banding and contains active/potentially active genes.
Euploidy
Having a normal chromosome complement.
Exon
Coding part of a gene. Historically, it was believed that all of a DNA sequence is mirrored exactly on the messenger RNA (mRNA) molecule (except for the presence of uracil in mRNA compared to thymine in DNA). It was a surprise to discover that this is generally not the case. The genomic sequence of a gene has two components: exons and introns. The exons are found in both the genomic sequence and the mRNA, whereas the introns are found only in the genomic sequence. The mRNA for dystrophin, an X-linked gene associated with Duchenne muscular dystrophy (DMD), is 14,000 base pairs long but the genomic sequence is spread over a distance of 1.5 million base pairs, because of the presence of very long intronic sequences. After the genomic sequence is initially transcribed to RNA, a complex system ensures specific removal of introns. This system is known as splicing.
Expressivity
Glossary
Degree of expression of a disease. In some disorders, individuals carrying the same mutation may manifest wide variability in severity of the disorder. Autosomal dominant disorders are often associated with variable expressivity, a good example being Marfan’s syndrome. Variable expressivity is to be differentiated from incomplete penetrance, an all or none phenomenon that refers to the complete absence of a phenotype in some obligate carriers.
295
C
A
T
G
T
T
T
T
C
C
C
C
C
A
C
C
C
A
PITX2 sequence
Mutant (protein)
ATG Met
TTT Phe
TCC Ser
CCC Pro
ACC Thr
CAA Gln
Normal (protein)
ATG Met
TTT Phe
TCC Ser
CCA Pro
CCC Pro
AAC Asn
Figure 8. Frameshift mutation. This example shows a sequence of PITX2 in a patient with Rieger’s syndrome, an autosomal dominant condition. The sequence graph shows only the abnormal sequence. The arrow indicates the insertion of a single cytosine (C) residue. When translated the triplet code is now out of frame by one base pair. This totally alters the translated protein’s amino acid sequence. This leads to a premature stop codon later in the protein and results in Rieger’s syndrome.
F Familial
Any trait that has a higher frequency in relatives of an affected individual than the general population.
FISH
Fluorescence in situ hybridization (see In situ hybridization).
Founder effect
The high frequency of a mutant allele in a population as a result of its presence in a founder (ancestor). Founder effects are particularly noticeable in relative genetic isolates, such as the Finnish or Amish.
Frameshift mutation
Deletion/insertion of a DNA sequence that is not an exact multiple of 3 base pairs. The result is an alteration of the reading frame of the gene such that all sequence that lies beyond the mutation is effectively nonsense (see Figure 8). A premature stop codon is usually encountered shortly after the frameshift.
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G Gamete (germ cell)
The mature male or female reproductive cells, which contain a haploid set of chromosomes.
Gene
An ordered, specific sequence of nucleotides that controls the transmission and expression of one or more traits by specifying the sequence and structure of a particular protein or RNA molecule. Mendel defined a gene as the basic physical and functional unit of all heredity.
Gene expression
The process of converting a gene’s coded information into the existing, operating structures in the cell.
Gene mapping
Determines the relative positions of genes on a DNA molecule and plots the genetic distance in linkage units (centiMorgans) or physical distance (base pairs) between them.
Genetic code
Relationship between the sequence of bases in a nucleic acid and the order of amino acids in the polypeptide synthesized from it (see Table 2). A sequence of three nucleic acid bases (a triplet) acts as a codeword (codon) for one amino acid or instruction (start/stop).
Genetic counselling
Information/advice given to families with, or at risk of, genetic disease. Genetic counselling is a complex discipline that requires accurate diagnostic approaches, up-to-date knowledge of the genetics of the condition, an insight into the beliefs/anxieties/wishes of the individual seeking advice, intelligent risk estimation and, above all, skill in communicating relevant information to individuals from a wide variety of educational backgrounds. Genetic counselling is most often carried out by trained medical geneticists or, in some countries, specialist genetic counsellors or nurses.
Genetic heterogeneity
Association of a specific phenotype with mutations at different loci. The broader the phenotypic criteria, the greater the heterogeneity
Glossary
297
1st
1st
1st
1st
T
C
A
G
2nd
2nd
2nd
T
C
A
2nd G
TTT Phe [F]
TCT Ser [S]
TAT Tyr [Y]
TGT Cys [C]
T
TTC Phe [F]
TCC Ser [S]
TAC Tyr [Y]
TGC Cys [C]
C
TTA Leu [L]
TCA Ser [S]
TAA Ter [end]
TGA Ter [end]
A
TTG Leu [L]
TCG Ser [S]
TAG Ter [end]
TGG Trp [W]
G
CTT Leu [L]
CCT Pro [P]
CAT His [H]
CGT Arg [R]
T
CTC Leu [L]
CCC Pro [P]
CAC His [H]
CGC Arg [R]
C
CTA Leu [L]
CCA Pro [P]
CAA Gln [Q]
CGA Arg [R]
A
CTG Leu [L]
CCG Pro [P]
CAG Gln [Q]
CGG Arg [R]
G
ATT Ile [I]
ACT Thr [T]
AAT Asn [N]
AGT Ser [S]
T
ATC Ile [I]
ACC Thr [T]
AAC Asn [N]
AGC Ser [S]
C A
ATA Ile [I]
ACA Thr [T]
AAA Lys [K]
AGA Arg [R]
ATG Met [M]
ACG Thr [T]
AAG Lys [K]
AGG Arg [R]
G
GTT Val [V]
GCT Ala [A]
GAT Asp [D]
GGT Gly [G]
T
GTC Val [V]
GCC Ala [A]
GAC Asp [D]
GGC Gly [G]
C
GTA Val [V]
GCA Ala [A]
GAA Glu [E]
GGA Gly [G]
A
GTG Val [V]
GCG Ala [A]
GAG Glu [E]
GGG Gly [G]
G
3rd
3rd
3rd
3rd
Table 2. The genetic code. To locate a particular codon (e.g. TAG, marked in bold) locate the first base (T) in the left hand column, then the second base (A) by looking at the top row, and finally the third (G) in the right hand column (TAG is a stop codon). Note the redundancy of the genetic code—for example, three different codons specify a stop signal, and threonine (Thr) is specified by any of ACT, ACC, ACA and ACG.
(e.g. mental retardation). However, even very specific phenotypes may be genetically heterogeneous. Tuberous sclerosis is a good example: this autosomal dominant condition is now known to be associated (in different individuals) with mutations either in the TSC1 gene at 9q34 or the TSC2 gene at 16p13.3. There is no obvious distinction between the clinical phenotypes associated with these two genes. Genetic heterogeneity should not be confused with allelic heterogeneity, which refers to the presence of different mutations at the same locus. Genetic locus
A specific location on a chromosome.
Genetic map
A map of genetic landmarks deduced from linkage (recombination) analysis. Aims to determine the linear order of a set of genetic markers along a chromosome. Genetic maps differ significantly from physical maps, in that recombination frequencies are not identical across different genomic regions, resulting occasionally in large discrepancies.
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Genetic marker
A gene that has an easily identifiable phenotype so that one can distinguish between those cells or individuals that do or do not have the gene. Such a gene can also be used as a probe to mark cell nuclei or chromosomes, so that they can be isolated easily or identified from other nuclei or chromosomes later.
Genetic screening
Population analysis designed to ascertain individuals at risk of either suffering or transmitting a genetic disease.
Genetically lethal
Prevents reproduction of the individual, either because the condition causes death prior to reproductive age, or because social factors make it highly unlikely (although not impossible) that the individual concerned will reproduce.
Genome
The complete DNA sequence of an individual, including the sex chromosomes and mitochondrial DNA. The genome of humans is estimated to have a complexity of 3.3 x 109 base pairs (per haploid genome).
Genomic
Pertaining to the genome. Genomic DNA differs from complementary DNA in that it contains non-coding as well as coding DNA.
Genotype
Genetic constitution of an individual, distinct from expressed features (phenotype).
Germ line
Germ cells (those cells that produce haploid gametes) and the cells from which they arise. The germ line is formed very early in embryonic development. Germ line mutations are those present constitutionally in an individual (i.e. in all cells of the body) as opposed to somatic mutations, which affect only a proportion of cells.
Giemsa banding
Light/dark bar code obtained by staining chromosomes with Giemsa stain. Results in a unique bar code for each chromosome.
Guanine (G)
One of the bases making up DNA and RNA (pairs with cytosine).
Glossary
299
H Haploid
The chromosome number of a normal gamete, containing one each of every individual chromosome (23 in humans).
Haploinsufficiency
The presence of one active copy of a gene/region is insufficient to compensate for the absence of the other copy. Most genes are not ‘haploinsufficient’—50% reduction of gene activity does not lead to an abnormal phenotype. However, for some genes, most often those involved in early development, reduction to 50% often correlates with an abnormal phenotype. Haploinsufficiency is an important component of most contiguous gene disorders (e.g. in Williams syndrome, heterozygous deletion of a number of genes results in the mutant phenotype, despite the presence of normal copies of all affected genes).
Hemizygous
Having only one copy of a gene or DNA sequence in diploid cells. Males are hemizygous for most genes on the sex chromosomes, as they possess only one X chromosome and one Y chromosome (the exceptions being those genes with counterparts on both sex chromosomes). Deletions on autosomes produce hemizygosity in both males and females.
Heterochromatin
Contains few active genes, but is rich in highly repeated simple sequence DNA, sometimes known as satellite DNA. Heterochromatin refers to inactive regions of the genome, as opposed to euchromatin, which refers to active, gene expressing regions. Heterochromatin stains darkly with Giemsa.
Heterozygous
Presence of two different alleles at a given locus.
Histones
Simple proteins bound to DNA in chromosomes. They help to maintain chromatin structure and play an important role in regulating gene expression.
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Holandric
Pattern of inheritance displayed by mutations in genes located only on the Y chromosome. Such mutations are transmitted only from father to son.
Homologue or homologous gene
Two or more genes whose sequences manifest significant similarity because of a close evolutionary relationship. May be between species (orthologues) or within a species (paralogues).
Homologous chromosomes
Chromosomes that pair during meiosis. These chromosomes contain the same linear gene sequences as one another and derive from one parent.
Homology
Similarity in DNA or protein sequences between individuals of the same species or among different species.
Homozygous
Presence of identical alleles at a given locus.
Human gene therapy
The study of approaches to treatment of human genetic disease, using the methods of modern molecular genetics. Many trials are underway studying a variety of disorders including cystic fibrosis. Some disorders are likely to be more treatable than others—it is probably going to be easier to replace defective or absent gene sequences rather than deal with genes whose aberrant expression results in an actively toxic effect.
Human genome project
Worldwide collaboration aimed at obtaining a complete sequence of the human genome. Most sequencing has been carried out in the USA, although the Sanger Centre in Cambridge, UK has sequenced one third of the genome, and centers in Japan and Europe have also contributed significantly. The first draft of the human genome was released in the summer of 2000 to much acclaim. The finished sequence may not be available until 2003. Celera, a privately funded venture, headed by Dr Craig Ventner, also published its first draft at the same time.
Glossary
301
Hybridization
Pairing of complementary strands of nucleic acid. Also known as re-annealing. May refer to re-annealing of DNA in solution, on a membrane (Southern blotting) or on a DNA microarray. May also be used to refer to fusion of two somatic cells, resulting in a hybrid that contains genetic information from both donors.
I Imprinting
A general term used to describe the phenomenon whereby a DNA sequence (coding or otherwise) carries a signal or imprint that indicates its parent of origin. For most DNA sequences, no distinction can be made between those arising paternally and those arising maternally (apart from subtle sequence variations); for imprinted sequences this is not the case. The mechanistic basis of imprinting is almost always methylation—for certain genes, the copy that has been inherited from the father is methylated, while the maternal copy is not. The situation may be reversed for other imprinted genes. Note that imprinting of a gene refers to the general phenomenon, not which parental copy is methylated (and, therefore, usually inactive). Thus, formally speaking, it is incorrect to say that a gene undergoes paternal imprinting. It is correct to say that the gene undergoes imprinting and that the inactive (methylated) copy is always the paternal one. However, in common genetics parlance, paternal imprinting is usually understood to mean the same thing.
In situ hybridization
Annealing of DNA sequences to immobilized chromosomes/cells/ tissues. Historically done using radioactively labeled probes, this is currently most often performed with fluorescently tagged molecules (fluorescent in situ hybridization – FISH, see Figure 9). ISH/FISH allows for the rapid detection of a DNA sequence within the genome.
Incomplete penetrance
Complete absence of expression of the abnormal phenotype in a proportion of individuals known to be obligate carriers. To be distinguished from variable expressivity, in which the phenotype always manifests in obligate carriers but with widely varying degrees of severity.
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Figure 9. Fluorescence in situ hybridization. FISH analysis of a patient with a complex syndrome, using a clone containing DNA from the region 8q24.3. In addition to that clone, a control from 8pter was used. The 8pter clone has yielded a signal on both homologues of chromosome 8, while the ‘test’ clone from 8q24.3 has yielded a signal on only one homologue, demonstrating a (heterozygous) deletion in that region.
Index case – proband
The individual through which a family medically comes to light. For example, the index case may be a baby with Down syndrome. Can be termed propositus (if male) or proposita (if female).
Insertion
Interruption of a chromosomal sequence as a result of insertion of material from elsewhere in the genome (either a different chromosome, or elsewhere from the same chromosome). Such insertions may result in abnormal phenotypes either because of direct interruption of a gene (uncommon), or because of the resulting imbalance (i.e. increased dosage) when the chromosomes that contain the normal counterparts of the inserted sequence are also present.
Intron
A non-coding DNA sequence that ‘interrupts’ the protein-coding sequences of a gene; intron sequences are transcribed into messenger RNA (mRNA) but are cut out before the mRNA is translated into a protein (this process is known as splicing). Introns may contain sequences involved in regulating expression of a gene. Unlike the
Glossary
303
exon, the intron is the nucleotide sequence in a gene that is not represented in the amino acid sequence of the final gene product. Inversion
A structural abnormality of a chromosome in which a segment is reversed, as compared to the normal orientation of the segment. An inversion may result in the reversal of a segment that lies entirely on one chromosome arm (paracentric) or one that spans (i.e. contains) the centromere (pericentric). While individuals who possess an inversion are likely to be genetically balanced (and therefore usually phenotypically normal), they are at increased risk of producing unbalanced offspring because of problems at meiosis with pairing of the inversion chromosome with its normal homologue. Both deletions and duplications may result, with concomitant congenital abnormalities related to genomic imbalance, or miscarriage if the imbalance is lethal.
K Karyotype
A photomicrograph of an individual’s chromosomes arranged in a standard format showing the number, size, and shape of each chromosome type, and any abnormalities of chromosome number or morphology (see Figure 10).
Kilobase (kb)
1000 base pairs of DNA.
Knudson hypothesis
See tumor suppressor gene
L Linkage
304
Co-inheritance of DNA sequences/phenotypes as a result of physical proximity on a chromosome. Before the advent of molecular genetics, linkage was often studied with regard to proteins, enzymes or cellular characteristics. An early study demonstrated linkage between the Duffy blood group and a form of autosomal dominant congenital cataract (both are now known to reside at 1q21.1). Phenotypes may Genetics for Ophthalmologists
Figure 10. Schematic of a normal human (male) karyotype. (ISCN 550 ideogram produced by the MRC Human Genetics Unit, Edinburgh, reproduced with permission.)
also be linked in this manner (i.e. families manifesting two distinct Mendelian disorders). During the recombination phase of meiosis, genetic material is exchanged (equally) between two homologous chromosomes. Genes/ DNA sequences that are located physically close to each other are unlikely to be separated during recombination. Sequences that lie far apart on the same chromosome are more likely to be separated. For sequences that reside on different chromosomes, segregation will always be random, so that there will be a 50% chance of 2 markers being co-inherited. Linkage analysis
Glossary
An algorithm designed to map (i.e. physically locate) an unknown gene (associated with the phenotype of interest) to a chromosomal 305
region. Linkage analysis has been the mainstay of diseaseassociated gene identification for some years. The general availability of large numbers of DNA markers that are variable in the population (polymorphisms), and which therefore permit allele discrimination, has made linkage analysis a relatively rapid and dependable approach (see Figure 11). However, the method relies on the ascertainment of large families manifesting Mendelian disorders. Relatively little phenotypic heterogeneity is tolerated, as a single misassigned individual (believed to be unaffected despite being a gene carrier) in a pedigree may completely invalidate the results. Genetic heterogeneity is another problem, not within families (usually) but between families. Thus, conditions that result in identical phenotypes despite being associated with mutations within different genes (e.g. tuberous sclerosis) are often hard to study. Linkage analysis typically follows a standard algorithm: 1. Large families with a given disorder are ascertained. Detailed clinical evaluation results in assignment of affected vs. unaffected individuals. 2. Large numbers of polymorphic DNA markers that span the genome are analyzed in all individuals (affected and unaffected). 3. The results are analyzed statistically, in the hope that one of the markers used will have demonstrably been co-inherited with the phenotype in question more often than would be predicted by chance. The LOD score (logarithm of the odds) gives an indication of the likelihood of the result being significant (and not having occurred simply as a result of chance co-inheritance of the given marker with the condition). Linkage disequilibrium
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Association of particular DNA sequences with each other, more often than is likely by chance alone (see Figure 12). Of particular relevance to inbred populations (e.g. Finland), where specific disease mutations are found to reside in close proximity to specific variants of DNA markers, as a result of the founder effect. Genetics for Ophthalmologists
5kb 2kb
2kb
5kb 2kb
5kb 2kb
5kb 2kb
2kb
5kb 2kb
2kb
2kb
2kb
In the example above, note that the (affected) mother has a 5 kb band in addition to a 2 kb band. All the unaffected individuals have the small band only, all those who are affected have the large band. The unaffected individuals must have the mother’s 2 kb fragment rather than her 5 kb fragment, and the affected individuals must have inherited the 5 kb band from the mother (as the father does not have one)—note that those individuals who only show the 2 kb band still have two alleles (one from each parent), they are just the same size and so cannot be differentiated. Thus, it appears that the 5 kb band is segregating with the disorder. The results in a family such as this are suggestive but further similar results in other families would be required for a sufficiently high LOD score.
X
2kb
X
3kb
X
Probe
The probe recognizes a DNA sequence adjacent to a restriction site (see arrow) that is polymorphic (present on some chromosomes but not others). When such a site is present, the DNA is cleaved at that point and the probe detects a 2 kb fragment. When absent, the DNA is not cleaved and the probe detects a fragment of size (2 + 3) kb = 5 kb. X refers to the points at which the restriction enzyme will cleave the DNA. The recognition sequence for most restriction enzymes is very stringent—change in just one nucleotide will result in failure of cleavage. Most RFLPs result from the presence of a single nucleotide polymorphism that has altered the restriction site. Figure 11. Schematic demonstrating the use of restriction fragment length polymorphisms (RFLPs) in linkage analysis.
Linkage map
A map of genetic markers as determined by genetic analysis (i.e. recombination analysis). May differ markedly from a map determined by actual physical relationships of genetic markers, because of the variability of recombination.
Locus
The position of a gene/DNA sequence on the genetic map. Allelic genes/sequences are situated at identical loci in homologous chromosomes.
Glossary
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Marker A
Marker B
–
+
–
–
+
+
+
–
Mutant allele
Many generations
+
–
–
–
Mutant allele
Mutant allele
A gene is physically very close to marker B and further from marker A. Markers A and B, both on the same chromosome, can exist in one of two forms : +/-. Thus there are 4 possible haplotypes, as shown. If the founder mutation in the gene occurred as shown, then it is likely that even after many generations the mutant allele will segregate with the – form of marker B, as recombination is unlikely to have occurred between the two. However, since marker A is further away, the gene will now often segregate with the – form of marker A, which was not present on the original chromosome. The likelihood of recombination between the gene and marker A will depend on the physical distance between them, and on rates of recombination. It is possible that the gene would show a lesser but still significant degree of linkage disequilibrium with marker A. Figure 12. Schematic demonstrating the concept of linkage disequilibrium.
Locus heterogeneity
Mutations at different loci cause similar phenotypes.
LOD (Logarithm of the Odds) score
A statistical test of linkage. Used to determine whether a result is likely to have occurred by chance or to truly reflect linkage. The LOD score is the logarithm (base 10) of the likelihood that the linkage is meaningful. A LOD score of 3 implies that there is only a 1:1000 chance that the results have occurred by chance (i.e. the result would be likely to occur once by chance in 1000 simultaneous
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studies addressing the same question). This is taken as proof of linkage (see Figure 11). Lyonisation
The inactivation of n-1 X chromosomes on a random basis in an individual with n X chromosomes. Named after Mary Lyon, this mechanism ensures dosage compensation of genes encoded by the X chromosome. X chromosome inactivation does not occur in normal males who possess only one X chromosome but does occur in one of the two X chromosomes of normal females. In males who possess more than one X chromosome (i.e. XXY, XXXY, etc.), the rule is the same and only one X chromosome remains active. X-inactivation occurs in early embryonic development and is random in each cell. The inactivation pattern in each cell is faithfully maintained in all daughter cells. Therefore, females are genetic mosaics, in that they possess two populations of cells with respect to the X chromosome: one population has one X active, while in the other population the other X is active. This is relevant to the expression of X-linked disease in females.
M Meiosis
The process of cell division by which male and female gametes (germ cells) are produced. Meiosis has two main roles. The first is recombination (during meiosis I). The second is reduction division. Human beings have 46 chromosomes, and each is conceived as a result of the union of two germ cells; therefore, it is reasonable to suppose that each germ cell will contain only 23 chromosomes (i.e. the haploid number). If not, then the first generation would have 92 chromosomes, the second 184, etc. Thus, at meiosis I, the number of chromosomes is reduced from 46 to 23.
Mendelian inheritance
Refers to a particular pattern of inheritance, obeying simple rules: each somatic cell contains 2 genes for every characteristic and each pair of genes divides independently of all other pairs at meiosis.
Glossary
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Mendelian Inheritance in Man (MIM/OMIM)
A catalogue of human Mendelian disorders, initiated in book form by Dr Victor McKusick of Johns Hopkins Hospital in Baltimore, USA. The original catalogue (produced in the mid-1960s) listed approximately 1500 conditions. By December 1998, this number had risen to 10,000, at the time of writing (November 2001) the figure had reached 13,118. With the advent of the Internet, MIM is now available as an online resource, free of charge (OMIM – Online Mendelian Inheritance in Man). The URL for this site is: http://www.ncbi.nlm.nih.gov/omim/. The online version is updated regularly, far faster than is possible for the print version, therefore, new gene discoveries are quickly assimilated into the database. OMIM lists disorders according to their mode of inheritance: 1 - - - - (100000- ) Autosomal dominant (entries created before May 15, 1994) 2 - - - - (200000- ) Autosomal recessive (entries created before May 15, 1994) 3 - - - - (300000- ) X-linked loci or phenotypes 4 - - - - (400000- ) Y-linked loci or phenotypes 5 - - - - (500000- ) Mitochondrial loci or phenotypes 6 - - - - (600000- ) Autosomal loci/phenotypes (entries created after May 15, 1994). Full explanations of the best way to search the catalogue are available at the home page for OMIM.
Messenger RNA (mRNA)
The template for protein synthesis, carries genetic information from the nucleus to the ribosomes where the code is translated into protein. Genetic information flows: DNA → RNA → protein.
Methylation
See DNA methylation
Microdeletion
Structural chromosome abnormality involving the loss of a segment that is not detectable using conventional (even high resolution)
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cytogenetic analysis. Microdeletions usually involve 1–3 Mb of sequence (the resolution of cytogenetic analysis rarely is better than 10 Mb). Most microdeletions are heterozygous, although some individuals/families have been described with homozygous microdeletions. See also contiguous gene syndrome. Microduplication
Structural chromosome abnormality involving the gain of a segment that may involve long sequences (commonly 1–3 Mb), which are, nevertheless, undetectable using conventional cytogenetic analysis. Patients with microduplications have 3 copies of all sequences within the duplicated segment, as compared to 2 copies in normal individuals. See also contiguous gene syndrome.
Microsatellites
DNA sequences composed of short tandem repeats (STRs), such as di- and trinucleotide repeats, distributed widely throughout the genome with varying numbers of copies of the repeating units. Microsatellites are very valuable as genetic markers for mapping human genes.
Missense mutation
Single base substitution resulting in a codon that specifies a different amino acid than the wild-type.
Mitochondrial disease/disorder
Ambiguous term referring to disorders resulting from abnormalities of mitochondrial function. Two separate possibilities should be considered. 1. Mutations in the mitochondrial genome (see Figure 13). Such disorders will manifest an inheritance pattern that mirrors the manner in which mitochondria are inherited. Therefore, a mother will transmit a mitochondrial mutation to all her offspring (all of whom will be affected, albeit to a variable degree). A father will not transmit the disorder to any of his offspring. 2. Mutations in nuclear encoded genes that adversely affect mitochondrial function. The mitochondrial genome does not code for all the genes required for its maintenance, many are encoded in the
Glossary
311
Figure 13. Mitochondrial inheritance. This pedigree relates to mutations in the mitochondrial genome.
nuclear genome. However, the inheritance patterns will differ markedly from the category described in the first option, and will be indistinguishable from standard Mendelian disorders. Each mitochondrion possesses between 2–10 copies of its genome, and there are approximately 100 mitochondria in each cell. Therefore, each cell possesses 200–1000 copies of the mitochondrial genome. Heteroplasmy refers to the variability in sequence of this large number of genomes—even individuals with mitochondrial genome mutations are likely to have wild-type alleles. Variability in the proportion of molecules that are wild-type may have some bearing on the clinical variability often seen in such disorders. Mitochondrial DNA
The DNA in the circular chromosome of mitochondria. Mitochondrial DNA is present in multiple copies per cell and mutates more rapidly than genomic (nuclear) DNA.
Mitosis
Cell division occurring in somatic cells, resulting in two daughter cells that are genetically identical to the parent cell.
Monogenic trait
Causally associated with a single gene (see Mendelian trait).
Monosomy
Absence of one of a pair of chromosomes.
Monozygotic
Arising from a single zygote or fertilized egg. Monozygotic twins are genetically identical.
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Mosaicism or mosaic
Refers to the presence of two or more distinct cell lines, all derived from the same zygote. Such cell lines differ from each other as a result of DNA content/sequence. Mosaicism arises when the genetic alteration occurs post-fertilization (post-zygotic). The important features that need to be considered in mosaicism are: The proportion of cells that are ‘abnormal’. In general, the greater the proportion of cells that are abnormal, the greater the severity of the associated phenotype. The specific tissues that contain high levels of the abnormal cell line(s). This variable will clearly also be relevant to the manifestation of any phenotype. An individual may have a mutation bearing cell line in a tissue where the mutation is largely irrelevant to the normal functioning of that tissue, with a concomitant reduction in phenotypic sequelae. Mosaicism may be functional, as in normal females who are mosaic for activity of the two X chromosomes (see Lyonisation). Mosaicism may occasionally be observed directly. X-linked skin disorders, such as incontinentia pigmenti, often manifest mosaic changes in the skin of a female, such that abnormal skin is observed alternately with normal skin, often in streaks (Blaschko’s lines), which delineate developmental histories of cells.
Multifactorial inheritance
A type of hereditary pattern resulting from a complex interplay of genetic and environmental factors.
Mutation
Any heritable change in DNA sequence.
N Non-disjunction
Glossary
Failure of two homologous chromosomes to pull apart during meiosis I, or two chromatids of a chromosome to separate in meiosis II or mitosis. The result is that both are transmitted to one daughter cell, while the other daughter cell receives neither.
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Non-dynamic (stable) mutations
Stably inherited mutations, in contradistinction to dynamic mutations, which display variability from generation to generation. Includes all types of stable mutation (single base substitution, small deletions/ insertions, microduplications and microdeletions).
Non-penetrance
Failure of expression of a phenotype in the presence of the relevant genotype.
Nonsense mutation
A single base substitution resulting in the creation of a stop codon (see Figure 14).
Northern blot
Hybridization of a radio-labeled RNA/DNA probe to an immobilized RNA sequence. So called in order to differentiate it from Southern blotting which was described first. Neither has any relationship to points on the compass. Southern blotting was named after its inventor Ed Southern (currently Professor of Biochemistry at Oxford University, UK).
Nucleotide
A basic unit of DNA or RNA consisting of a nitrogenous base— adenine, guanine, thymine or cytosine in DNA, and adenine, guanine, uracil or cytosine in RNA. A nucleotide is composed of a phosphate molecule, and a sugar molecule—deoxyribose in DNA and ribose in RNA. Many thousands or millions of nucleotides link to form a DNA or RNA molecule.
O Obligate carrier
See obligate heterozygote
Obligate heterozygote (obligate carrier)
An individual who, on the basis of pedigree analysis, must carry the mutant allele.
Oncogene
A gene that, when over expressed, causes neoplasia. In contrast to tumor suppressor genes, which result in tumorigenesis when their activity is reduced.
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G G
A C T
G T C
C T C
T G A
G
Collagen IIa1 sequence
Mutant (protein)
ACT Thr
GTC Val
CTC Leu
TGA STOP
Normal (protein)
ACT Thr
GTC Val
CTC Leu
TGC Cys
Figure 14. Nonsense mutation. This example shows a sequence graph of collagen II (alpha 1) in a patient with Stickler syndrome, an autosomal dominant condition. The sequence is of genomic DNA and shows both normal and abnormal sequences (the patient is heterozygous for the mutation). The base marked with an arrow has been changed from C to A. When translated the codon is changed from TGC (cysteine) to TGA (stop). The premature stop codon in the collagen gene results in Stickler syndrome.
P p
Short arm of a chromosome (from the French petit) (see Figure 4).
Palindromic sequence
A DNA sequence that contains the same 5’ to 3’ sequence on both strands. Most restriction enzymes recognize palindromic sequences. An example is 5’ – AGATCT – 3’, which would read 3’ – TCTAGA – 5’ on the complementary strand. This is the recognition site of BglII.
Pedigree
A schematic for a family indicating relationships to the proband and how a particular disease or trait has been inherited (see Figure 15).
Penetrance
An all-or-none phenomenon related to the proportion of individuals with the relevant genotype for a disease who actually manifest
Glossary
315
4
Male, female - unaffected
Abortion/stillbirth
Sex not known
Twins
Male, female - affected
Monozygotic twins
4 unaffected females
Heterozygote (AR)
Deceased, affected female
Heterozygote (X-linked)
Consanguineous marriage
Propositus/proband
Figure 15. Symbols commonly used in pedigree drawing.
the phenotype. Note the difference between penetrance and variable expressivity. Phenotype
Observed disease/abnormality/trait. An all-embracing term that does not necessarily imply pathology. A particular phenotype may be the result of genotype, the environment or both.
Physical map
A map of the locations of identifiable landmarks on DNA, such as specific DNA sequences or genes, where distance is measured in base pairs. For any genome, the highest resolution map is the complete nucleotide sequence of the chromosomes. A physical map should be distinguished from a genetic map, which depends on recombination frequencies.
Plasmid
Found largely in bacterial and protozoan cells, plasmids are autonomously replicating, extrachromosomal, circular DNA molecules that are distinct from the normal bacterial genome and are often used as vectors in recombinant DNA technologies. They
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are not essential for cell survival under non-selective conditions, but can be incorporated into the genome and are transferred between cells if they encode a protein that would enhance survival under selective conditions (e.g. an enzyme that breaks down a specific antibiotic). Pleiotropy
Diverse effects of a single gene on many organ systems (e.g. the mutation in Marfan’s syndrome results in lens dislocation, aortic root dilatation and other pathologies).
Ploidy
The number of sets of chromosomes in a cell. Human cells may be haploid (23 chromosomes, as in mature sperm or ova), diploid (46 chromosomes, seen in normal somatic cells) or triploid (69 chromosomes, seen in abnormal somatic cells, which results in severe congenital abnormalities).
Point mutation
Single base substitution.
Polygenic disease
Disease (or trait) that results from the simultaneous interaction of multiple gene mutations, each of which contributes to the eventual phenotype. Generally, each mutation in isolation is likely to have a relatively minor effect on the phenotype. Such disorders are not inherited in a Mendelian fashion. Examples include hypertension, obesity and diabetes.
Polymerase chain reaction (PCR)
A molecular technique for amplifying DNA sequences in vitro (see Figure 16). The DNA to be copied is denatured to its single strand form and two synthetic oligonucleotide primers are annealed to complementary regions of the target DNA in the presence of excess deoxynucleotides and a heat-stable DNA polymerase. The power of PCR lies in the exponential nature of amplification, which results from repeated cycling of the ‘copying’ process. Thus, a single molecule will be copied in the first cycle, resulting in 2 molecules. In the second cycle, each of these will also be copied, resulting in 4 copies. In theory, after n cycles, there will be 2n molecules for
Glossary
317
3'
5'
5'
3' 95°C
DENATURATION
3'
5' P1
P2
1st Cycle
5'
3'
3'
5'
5'
3'
3'
5'
5'
3'
2nd Cycle
P2
P1
Genomic doublestranded DNA Temperature is lowered to ~50°C to permit annealing of primers to their complementary DNA sequence Temperature is elevated to the optimal heat (~72°C) for the thermophilic polymerase, resulting in primer extension
Denaturation and annealing of primers
3'
Figure 16. Schematic illustrating the technique of polymerase chain reaction (PCR).
each starting molecule. In practice, this theoretical limit is rarely reached, mainly for technical reasons. PCR has become a standard technique in molecular biology research as well as routine diagnostics. Polymorphism
May be applied to phenotype or genotype. The presence in a population of two or more distinct variants, such that the frequency of the rarest is at least 1% (more than can be explained by recurrent mutation alone). A genetic locus is polymorphic if its sequence exists in at least two forms in the population.
Premutation
Any DNA mutation that has little, if any, phenotypic consequence but predisposes future generations to the development of full mutations with phenotypic sequelae. Particularly relevant in the analysis of diseases associated with dynamic mutations.
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Proband (propositus) – index case
The first individual to present with a disorder through which a pedigree can be ascertained.
Probe
General term for a molecule used to make a measurement. In molecular genetics, a probe is a piece of DNA or RNA that is labeled and used to detect its complementary sequence (e.g. Southern blotting).
Promoter region
The non-coding sequence upstream (5’) of a gene where RNA polymerase binds. Gene expression is controlled by the promoter region both in terms of level and tissue specificity.
Protease
An enzyme that digests other proteins by cleaving them into small fragments; proteases may have broad specificity or only cleave a particular site on a protein or set of proteins.
Protease inhibitor
A chemical that can inhibit the activity of a protease. Most proteases have a corresponding specific protease inhibitor.
Proto-oncogene
A misleading term that refers to genes that are usually involved in signaling and cell development, and are often expressed in actively dividing cells. Certain mutations in such genes may result in malignant transformation, with the mutated genes being described as oncogenes. The term proto-oncogene is misleading because it implies that such genes were selected for by evolution in order that, upon mutation, cancers would result because of oncogenic activation. A similar problem arises with the term tumor suppressor gene.
Pseudogene
Near copies of true genes. Pseudogenes share sequence homology with true genes but are inactive as a result of multiple mutations over a long period of time.
Purine
A nitrogen-containing, double-ring, basic compound occurring in nucleic acids. The purines in DNA and RNA are adenine and guanine.
Glossary
319
Pyrimidine
A nitrogen-containing, single-ring, basic compound that occurs in nucleic acids. The pyrimidines in DNA are cytosine and thymine, and cytosine and uracil in RNA.
Q q
Long arm of a chromosome (see Figure 4).
R Re-annealing
see hybridization
Recessive (traits, diseases)
Manifest only in homozygotes. For the X chromosome, recessivity applies to males who carry only one (mutant) allele. Females who carry X-linked mutations are generally heterozygotes and, barring unfortunate X-inactivation, do not manifest X-linked recessive phenotypes.
Reciprocal translocation The exchange of material between two non-homologous chromosomes. Recombination
The creation of new combinations of linked genes as a result of crossing over at meiosis (see Figure 6).
Recurrence risk
The chance that a genetic disease, already present in a member of a family, will recur in that family and affect another individual.
Restriction enzyme
Endonuclease that cleaves double-stranded (ds) DNA at specific sequences. For example, the enzyme BglII recognizes the sequence AGATCT, and cleaves after the first A on both strands. Most restriction endonucleases recognize sequences that are palindromic— the complementary sequence to AGATCT, read in the same orientation, is also AGATCT. The term ‘restriction’ refers to the function of these enzymes in nature. The organism that synthesizes a given restriction
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enzyme (e.g. BglII) does so in order to ‘kill’ foreign DNA— ‘restricting’ the potential of foreign DNA that has become integrated to adversely affect the cell. The organism protects its own DNA from the restriction enzyme by simultaneously synthesizing a specific methylase that recognizes the same sequence and modifies one of the bases, such that the restriction enzyme is no longer able to cleave. Thus, for every restriction enzyme, it is likely that a corresponding methylase exists, although in practice only a relatively small number of these have been isolated. Restriction fragment length polymorphism (RFLP)
A restriction fragment is the length of DNA generated when DNA is cleaved by a restriction enzyme. Restriction fragment length varies when a mutation occurs within a restriction enzyme sequence. Most commonly the polymorphism is a single base substitution but it may also be a variation in length of a DNA sequence due to variable number tandem repeats (VNTRs). The analysis of the fragment lengths after DNA is cut by restriction enzymes is a valuable tool for establishing familial relationships and is often used in forensic analysis of blood, hair or semen (see Figure 11).
Restriction map
A DNA sequence map, indicating the position of restriction sites.
Reverse genetics
Identification of the causative gene for a disorder, based purely on molecular genetic techniques, when no knowledge of the function of the gene exists (the case for most genetic disorders).
Reverse transcriptase
Catalyses the synthesis of DNA from a single-stranded RNA template. Contradicted the central dogma of genetics (DNA → RNA → protein) and earned its discoverers the Nobel Prize in 1975.
RNA (ribonucleic acid)
Glossary
RNA molecules differ from DNA molecules in that they contain a ribose sugar instead of deoxyribose. There are a variety of types of RNA (including messenger RNA, transfer RNA and ribosomal RNA) and they work together to transfer information from DNA to the protein-forming units of the cell.
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Robertsonian translocation
A translocation between two acrocentric chromosomes, resulting from centric fusion. The short arms and satellites (chromosome segments separated from the main body of the chromosome by a constriction and containing highly repetitive DNA) are lost.
S Second hit hypothesis
See tumor suppressor gene
Sex chromosomes
Refers to the X and Y chromosomes. All normal individuals possess 46 chromosomes, of which 44 are autosomes and 2 are sex chromosomes. An individual’s sex is determined by his/her complement of sex chromosomes. Essentially, the presence of a Y chromosome results in the male phenotype. Males have an X and a Y chromosome, while females possess two X chromosomes. The Y chromosome is small and contains relatively few genes, concerned almost exclusively with sex determination and/or sperm formation. By contrast, the X chromosome is a large chromosome that possesses many hundreds of genes.
Sex-limited trait
A trait/disorder that is almost exclusively limited to one sex and often results from mutations in autosomal genes. A good example of a sexlimited trait is breast cancer. While males are affected by breast cancer, it is much less common (~1%) than in women. Females are more prone to breast cancer than males not only because they possess significantly more breast tissue but also because their hormonal milieu is significantly different. In many cases, early onset bilateral breast cancer is associated with mutations either in BRCA1 or BRCA2, both autosomal genes. An example of a sex-limited trait in males is male pattern baldness, which is extremely rare in pre-menopausal women. The inheritance of male pattern baldness is consistent with autosomal dominant, not sex-linked dominant, inheritance.
Sex-linked dominant
See X-linked dominant
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Sex-linked recessive
See X-linked recessive
Sibship
All the sibs in a family.
Silent mutation
One that has no (apparent) phenotypic effect.
Single gene disorder
A disorder resulting from a mutation on one gene.
Somatic cell
Any cell of a multicellular organism not involved in the production of gametes.
Southern blot
Hybridization with a radio-labeled RNA/DNA probe to an immobilized DNA sequence (see Figure 17). Named after Ed Southern (currently Professor of Biochemistry at Oxford University, UK), the technique has spawned the nomenclature for other types of blot (Northern blots for RNA and Western blots for proteins).
Figure 17. Southern blotting.
Glossary
323
Splicing
Removal of introns from precursor RNA to produce messenger RNA. The process involves recognition of intron-exon junctions and specific removal of intronic sequences, coupled with re-connection of the two strands of DNA that formerly flanked the intron.
Start codon
The AUG codon of messenger RNA recognized by the ribosome to begin protein production.
Stop codon
The codons UAA, UGA, or UAG on messenger RNA (mRNA) (see Table 2). Since no transfer RNA molecules exist that possess anticodons to these sequences, they cannot be translated. When they occur in frame on an mRNA molecule, protein synthesis stops and the ribosome releases the mRNA and the protein.
T Telomere
End of a chromosome. The telomere is a specialized structure involved in replicating and stabilizing linear DNA molecules.
Teratogen
Any external agent/factor that increases the probability of congenital malformations. A teratogen may be a drug, whether prescribed or illicit, or an environmental effect, such as high temperature. The classical example is thalidomide, a drug originally prescribed for morning sickness, which resulted in very high rates of congenital malformation in exposed fetuses (especially limb defects).
Termination codon
See stop codon
Thymine (T)
One of the bases making up DNA and RNA (pairs with adenine).
Transcription
Synthesis of single-stranded RNA from a double-stranded DNA template (see Figure 18).
Transfer RNA (tRNA)
An RNA molecule that possesses an anticodon sequence (complementary to the codon in mRNA) and the amino acid which
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RNA polymerase
CTC
Sense strand
DNA 3' CUC GAG
Antisense strand
5' RNA
Figure 18. Schematic demonstrating the process of transcription. The sense strand has the sequence CTC (coding for leucine). RNA is generated by pairing with the antisense strand, which has the sequence GAG (the complement of CTC). The RNA produced is the complement of GAG, CUC (essentially the same as CTC, uracil replaces thymine in RNA).
that codon specifies. When the ribosome ‘reads’ the mRNA codon, the tRNA with the corresponding anticodon and amino acid is recruited for protein synthesis. The tRNA ‘gives up’ its amino acid to the production of the protein. Translation
Glossary
Protein synthesis directed by a specific messenger RNA (mRNA), (see Figure 19). The information in mature mRNA is converted at the ribosome into the linear arrangement of amino acids that constitutes a protein. The mRNA consists of a series of trinucleotide sequences, known as codons. The start codon is AUG, which specifies that methionine should be inserted. For each codon, except for the stop codons that specify the end of translation, a transfer RNA (tRNA) molecule exists that possesses an anticodon sequence (complementary to the codon in mRNA) and the amino acid which that codon specifies. The process of translation results in the sequential addition of amino acids to the growing polypeptide chain. When translation is complete, the protein is released from the ribosome/mRNA complex and may then undergo post-translational modification, in addition to folding into its final, active, conformational shape. 325
Growing polypeptide chain
LEU tRNA with anticodon GAG, charged with Leucine
Amino (NH2) terminus of protein
GAG CUCGUC 5'
3' mRNA
Ribosome
Ribosome moves to next codon
Figure 19. Schematic of the process of translation. Messenger RNA (mRNA) is translated at the ribosome into a growing polypeptide chain. For each codon, there is a transfer RNA molecule with the anticodon and the appropriate amino acid. Here, the amino acid leucine is shown being added to the polypeptide. The next codon is GUC, specifying valine. Translation happens in a 5’ to 3’ direction along the mRNA molecule. When the stop codon is reached, the polypeptide chain is released from the ribosome.
Translocation
Exchange of chromosomal material between 2 or more nonhomologous chromosomes. Translocations may be balanced or unbalanced. Unbalanced translocations are those that are observed in association with either a loss of genetic material, a gain, or both. As with other causes of genomic imbalance, there are usually phenotypic consequences, in particular mental retardation. Balanced translocations are usually associated with a normal phenotype but increase the risk of genomic imbalance in offspring, with expected consequences (either severe phenotypes or lethality). Translocations are described by incorporating information about the chromosomes involved (usually but not always two) and the positions on the chromosomes at which the breaks have occurred. Thus t(11;X)(p13;q27.3) refers to an apparently balanced translocation involving chromosome 11 and X, in which the break on 11 is at 11p13 and the break on the X is at Xq27.3
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Triplet repeats
Tandem repeats in DNA that comprise many copies of a basic trinucleotide sequence. Of particular relevance to disorders associated with dynamic mutations, such as Huntington’s chorea (HC). HC is associated with a pathological expansion of a CAG repeat within the coding region of the huntingtin gene. This repeat codes for a tract of polyglutamines in the resultant protein, and it is believed that the increase in length of the polyglutamine tract in affected individuals is toxic to cells, resulting in specific neuronal damage.
Trisomy
Possessing three copies of a particular chromosome instead of two.
Tumor suppressor genes
Genes that act to inhibit/control unrestrained growth as part of normal development. The terminology is misleading, implying that these genes function to inhibit tumor formation. The classical tumor suppressor gene is the Rb gene, which is inactivated in retinoblastoma. Unlike oncogenes, where a mutation at one allele is sufficient for malignant transformation in a cell (since mutations in oncogenes result in increased activity, which is unmitigated by the normal allele), both copies of a tumor suppressor gene must be inactivated in a cell for malignant transformation to proceed. Therefore, at the cellular level, tumor suppressor genes behave recessively. However, at the organismal level they behave as dominants, and an individual who possesses a mutation in only one Rb allele still has an extremely high probability of developing bilateral retinoblastomas. The explanation for this phenomenon was first put forward by Knudson and has come to be known as the Knudson hypothesis (also known as the second hit hypothesis). An individual who has a germ-line mutation in one Rb allele (and the same argument may be applied to any tumor suppressor gene) will have the mutation in every cell in his/her body. It is believed that the rate of spontaneous somatic mutation (defined functionally, in terms of loss of function of that gene by whatever mechanism) is of the order of one in a million per gene per cell division. Given that there are many more than one million retinal cells in each eye, and many cell divisions involved in retinal development, the chance that the second (wild-type) Rb
Glossary
327
allele will suffer a somatic mutation is extremely high. In a cell that has acquired a ‘second hit’, there will now be no functional copies of the Rb gene, as the other allele is already mutated (germ-line mutation). Such a cell will have completely lost its ability to control cell growth and will eventually manifest as a retinoblastoma. The same mechanism occurs in many other tumors, the tissue affected being related to the tissue specificity of expression of the relevant tumor suppressor gene.
U Unequal crossing over
Occurs between similar sequences on chromosomes that are not properly aligned. It is common where specific repeats are found and is the basis of many microdeletion/microduplication syndromes (see Figure 20).
Uniparental disomy (UPD)
In the vast majority of individuals, each chromosome of a pair is derived from a different parent. However, UPD occurs when an offspring receives both copies of a particular chromosome from only one of its parents. UPD of some chromosomes results in recognizable phenotypes whereas for other chromosomes there do not appear to be any phenotypic sequelae. One example of UPD is Prader-Willi syndrome (PWS), which can occur if an individual inherits both copies of chromosome 15 from their mother.
Uniparental heterodisomy
Uniparental disomy in which the two homologues inherited from the same parent are not identical. If the parent has chromosomes A,B the child will also have A,B.
Uniparental isodisomy
Uniparental disomy in which the two homologues inherited from the same parent are identical (i.e. duplicates). So, if the parent has chromosomes A,B then the child will have either A,A or B,B.
Uracil (U)
A nitrogenous base found in RNA but not in DNA, uracil is capable of forming a base pair with adenine.
328
Genetics for Ophthalmologists
A1
B1
A2
B2
C1
Repeats 1 and 2 represent identical repeated sequences in different positions on the chromosome. These are likely to have no function.
C2 Equal (normal) recombination at meiosis
A1
B1
A2
A1 A2
B1
B2
C2
Product 1 Duplication of region B and all genes within it A2
C2
B2 C1 Meiotic exchange (crossing over)
C1 Unequal (abnormal) recombination at meiosis B2
B1
C1
Product 2 Deletion of region B and all genes within it A1
C2
Figure 20. Schematic demonstrating (i) normal homologous recombination and (ii) homologous unequal recombination, resulting in a deletion and a duplication chromosome.
V Variable expressivity
Variable expression of a phenotype: not all-or-none (as is the case with penetrance). Individuals with identical mutations may manifest variable severity of symptoms, or symptoms that appear in one organ and not in another.
Variable number of Certain DNA sequences possess tandem arrays of repeated tandem repeats (VNTR) sequences. Generally, the longer the array (i.e. the greater the number of copies of a given repeat), the more unstable the sequence, with a consequent wide variability between alleles (both within an individual and between individuals). Because of their variability, VNTRs are extremely useful for genetic studies as they allow for different alleles to be distinguished.
Glossary
329
W Western blot
Like a Southern or Northern blot but for proteins, using a labeled antibody as a probe.
X X-autosome translocation Translocation between the X chromosome and an autosome. X chromosome
See sex chromosomes
X-chromosome inactivation
See Lyonisation
X-linked
Relating to the X chromosome/associated with genes on the X chromosome.
X-linked recessive (XLR) X-linked disorder in which the phenotype is manifest in homozygous/hemizygous individuals (see Figures 21a and 21b). In practice, it is hemizygous males that are affected by X-linked recessive disorders, such as Duchenne’s muscular dystrophy (DMD). Females are rarely affected by XLR disorders, although a number of mechanisms have been described that predispose females to being affected, despite being heterozygous. X-linked dominant (XLD)
X-linked disorder that manifests in the heterozygote. XLD disorders result in manifestation of the phenotype in females and males (see Figure 22). However, because males are hemizygous, they are more severely affected as a rule. In some cases, the XLD disorder results in male lethality.
Y Y chromosome
330
See sex chromosomes
Genetics for Ophthalmologists
Figure 21a. X-linked recessive inheritance – A. Most X-linked disorders manifest recessively, in that heterozygous females (carriers) are unaffected and males, who are hemizygous (possess only one X chromosome) are affected. In this example, a carrier mother has transmitted the disorder to three of her sons. One of her daughters is also a carrier. On average, 50% of the male offspring of a carrier mother will be affected (having inherited the mutated X chromosome), and 50% will be unaffected. Similarly, 50% of daughters will be carriers and 50% will not be carriers. None of the female offspring will be affected but the carriers will carry the same risks to their offspring as their mother. The classical example of this type of inheritance is Duchenne’s muscular dystrophy.
Figure 21b. X-linked recessive inheritance – B. In this example the father is affected. Because all his sons must have inherited their Y chromosome from him and their X chromosome from their normal mother, none will be affected. Since all his daughters must have inherited his X chromosome, all will be carriers but none affected. For this type of inheritance, it is clearly necessary that males reach reproductive age and are fertile—this is not the case with Duchenne’s muscular dystrophy, which is usually fatal by the teenage years in boys. Emery-Dreifuss muscular dystrophy is a good example of this form of inheritance, as males are likely to live long enough to reproduce.
Figure 22. X-linked dominant inheritance. In X-linked dominant inheritance, the heterozygous female and hemizygous male are affected, however, the males are usually more severely affected than the females. In many cases, X-linked dominant disorders are lethal in males, resulting either in miscarriage or neonatal/infantile death. On average, 50% of all males of an affected mother will inherit the gene and be severely affected; 50% of males will be completely normal. Fifty percent of female offspring will have the same phenotype as their affected mother and the other 50% will be normal and carry no extra risk for their offspring. An example of this type of inheritance is incontinentia pigmenti, a disorder that is almost always lethal in males (males are usually lost during pregnancy).
Glossary
331
Z Zippering
A process by which complementary DNA strands that have annealed over a short length undergo rapid full annealing along their whole length. DNA annealing is believed to occur in 2 main stages. A chance encounter of two strands that are complementary results in a short region of double stranded DNA, which if perfectly matched, stabilizes the two single strands so that further re-annealing of their specific sequences proceeds extremely rapidly. The initial stage is known as nucleation, while the second stage is called zippering.
Zygote
Diploid cell resulting from the union of male and female haploid gametes.
332
Genetics for Ophthalmologists
12 12. Abbreviations
334
AAAS
achalasia-addisonianism-alacrima syndrome
ABCC6
ATP-binding cassette, subfamily C, member 6
ABCR
ATP-binding cassette transporter, retina-specific
ACHM
achromatopsia
AD
autosomal dominant
adRP
autosomal dominant retinitis pigmentosa
AIPL1
arylhydrocarbon-interacting receptor protein-like 1
ALMS1
Alström syndrome
AP3B1
adaptin beta-3a
APC
adenomatous polyposis of the colon
AQPO
aquaporin O
AR
autosomal recessive
ARCC
autosomal recessive congenital cataracts
ARMD
age-related macular degeneration
arRP
autosomal recessive retinitis pigmentosa
ASMD
anterior segment mesenchymal dysgenesis
ASOD
anterior segment ocular dysgenesis
BBS
Bardet-Biedl syndrome
BCNS
basal cell nevus syndrome
BIGH3
beta-Ig-H3
BPES
blepharophimosis, ptosis and epicanthus inversus
CAL
café-au-lait
CBS
cystathionine beta synthase
CFEOM
congenital fibrosis of extraocular muscles
CHM
choroideremia
CHRPE
congenital hypertrophic lesions of the retinal pigment epithelium
Genetics for Ophthalmologists
Abbreviations
CHS1
Chediak-Higashi syndrome
CHST6
carbohydrate sulfotransferase 6
CKN
Cockayne syndrome
CLN3
ceroid lipofuscinosis type 3
CNGA3
cyclic nucleotide-gated cation channel, alpha subunit
CNGB3
cyclic nucleotide-gated cation channel, beta subunit
CNS
central nervous system
COD3
cone dystrophy 3
COH1
Cohen syndrome
COL8A2
collagen type VIII, alpha 2
CPD IV
cerebelloparenchymal disorder IV
CRALBP
cellular retinaldehyde-binding protein
CRD
cone-rod dystrophy
CREBBP
CREB-binding protein
CRYBA1
αB1 crystallin
CRYBB2
βB2 crystalin
CRYG3
γ3 crystallin
CRYGD
γD crystallin
CSNB
congenital stationary night blindness
CTNS
cystinosin
CVS
chorionic villus sampling
CX
connexin
CXR
chest x-ray
CYP1B1
cytochrome P450B1
DHRD
Doyne honeycomb retinal dystrophy
DMPK
dystrophia myotonica protein kinase
DNA
deoxyribonucleic acid
335
336
DOA
dominant optic atrophy
ECG
electrocardiogram
EFEMP1
EGF-containing fibrillin-like extracellular matrix protein 1
EGF
epidermal growth factor
ELOVL4
elongation of very long-chain fatty acids-like gene 4
EOG
electro-oculogram
ERG
electroretinogram
ES
embryonic stem
ESCS
enhanced S-cone syndrome
EVR1
exudative vitreoretinopathy 1
FAP
familial adenomatous polyposis
FBN1
fibrillin 1
FECD
Fuchs’ endothelial corneal dystrophy
FEOM
fibrosis of extraocular muscles
FEVR
familial exudative vitreoretinopathy
FOXC1
forkhead box C1
FOXE3
forkhead box E3
FOXL2
forkhead transcription factor
FTL
ferritin light chain
GALK
galactokinase
GALT
galactosidase galactose-1-phosphate uridyltransferase
GI
gastrointestinal
GLUT-1
glucose transporter-1
GPCR
G protein-coupled receptor
GPDS
glaucoma-related pigment dispersion syndrome
GRT
giant retinal tears
GUCA1A
guanylate cyclase activator 1A
Genetics for Ophthalmologists
Abbreviations
GUCY2D
guanylate cyclase 2D
HESX1
homeobox gene expressed in ES cells
HEXA
hexosaminidase A
HEXB
hexosaminidase B
HIF-1
hypoxia-inducible factor-1
HPS
Hermansky-Pudlak syndrome
ICE
iridocorneal endothelial
IGDA
iridogoniodysgenesis anomaly
IP2
incontinentia pigmenti type II
IRE
iron responsive element
IRID1
iridogoniodysgenesis type I
IRP
iron responsive protein
JBTS
Joubert syndrome
KRT12
keratin 12
KRT3
keratin 3
kDa
kilo Dalton
KERA
keratocan
KNO
Knobloch syndrome
KSPG
keratan sulfate proteoglycans
KSS
Kearns-Sayre syndrome
LCA
Leber congenital amaurosis
LCD
lattice corneal dystrophy
LHON
leber hereditary optic neuropathy
LMX1B
LIM homeo box transcription factor 1, beta
LRR
leucine-rich repeat
LYST
lysosomal trafficking regulator
MASS
Mitral valve prolapse, mild Aortic root dilatation, Skin involvement striae and Skeletal findings
337
338
MELAS
mitochondrial encephalopathy, lactic acidosis and stroke
MFS
Marfan syndrome
MIM
Mendelian inheritance in man
MIP
major intrinsic protein
MKKS
McKusick-Kaufman Syndrome
MLVT
malattia leventinese
MPS
mucopolysaccharidoses
MRI
magnetic resonance imaging
MRP6
multidrug resistance protein 6
mtDNA
mitochondrial DNA
MYO7A
myosin VIIa
MYOC
myocilin
NARP
neuropathy, ataxia and retinitis pigmentosa
NBCCS
nevoid basal cell carcinoma syndrome
NEMO
NFκB essential modulator
NF1
neurofibromatosis type I
NF2
neurofibromatosis type II
NHS
Nance-Horan syndrome
NPS
nail-patella syndrome
NR2E3
nuclear receptor subfamily 2, group E, member 3
OA1
ocular albinism type 1
OAT
ornithine aminotransferase
OCA
oculocutaneous albinism
ONCR
optic nerve coloboma with renal disease
ONH
optic nerve hypoplasia
OPA1
optic atrophy 1
P
pink-eye gene,
PAX2
paired box gene 2 Genetics for Ophthalmologists
PAX6
paired box gene 6
PHYH
phytanoyl-CoA hydroxylase
PKD
polycystic kidney disease
PITX2
paired-like homeodomain transcription factor 2
PITX3
paired-like homeodomain transcription factor 3
POAG
primary open angle glaucoma
PPCD
posterior polymorphous dystrophy
PPRPE
preserved para-arteriolar retinal pigment
PTCH
patched gene
pVHL
VHL protein
PXE
pseudoxanthoma elasticum
Rab-GGTase Rab geranylgeranyl transferase
Abbreviations
RB
retinoblastoma
RDH5
retinol dehydrogenase 5
RDS
retinal degeneration slow
REP-1
Rab escort protein 1
RHO
rhodopsin
RHOK
rhodopsin kinase
RLBP1
retinaldehyde-binding protein 1
RNA
ribonucleic acid
ROM1
rod outer segment protein 1
RP
retinitis pigmentosa
RPA
retinitis punctata albescens
RPE65
retinal pigment epithelium-specific protein, 65 kDa
RPX
Rathke pouch homeobox
RRD
rhegmatogenous retinal detachment
rRNA
ribosomal ribonucleic acid
RS1
X-linked retinoschisis 339
340
RSTS
Rubinstein-Taybi syndrome
SAG
S-antigen
SCH
schwannomin
SFD
Sorsby pseudoinflammatory fundus dystrophy
SLRP
small leucine-rich proteoglycan
SOD
septo-optic dysplasia
SRNVM
subretinal neovascular membrane
STGD
Stargardt disease
STL
Stickler syndrome
TGFBI
transforming growth factor, beta-induced
TGF-β
transforming growth factor beta
TIGR
trabecular meshwork-induced glucocorticoid response
TIMP3
tissue inhibitor of metalloproteinase 3
tRNA
transfer RNA
TRP1
tyrosine-related protein 1
TSC
tuberous sclerosis complex
TYR
tyrosinase
UBO
unidentified bright object
VA
visual acuity
VEGF
vascular endothelial growth factor
VHL
von Hippel-Lindau syndrome
VMD
vitelliform macular dystrophy
WAGR
Wilms’ tumor, Aniridia, Genitourinary abnormalities and mental Retardation
WBC
white blood cell
WFS
Wolfram syndrome
XLRP
X-linked retinitis pigmentosa
Genetics for Ophthalmologists
13 13. Index
ABCA4 (ATP-binding cassette, subfamily A, member 4) 88–9, 99–101, 110, 134 ABCC6 (ATP-binding cassette, subfamily C, member 6) 89, 94 N-acetylgalactosamine-4-sulfatase (ARSB) 236 achalasia–addisonianism–alacrima (AAAS) syndrome 268–9 achromatopsia 82–3 aculeiform cataract 32–3 adaptin beta-3a (AP3B1) 209–10 adenomatous polyposis of colon 244–6 adnexal developmental defects 267–77 age-related macular degeneration (ARMD) 88–9 AIPL1 (arylhydrocarbon-interacting receptor protein-like 1) 115, 118 alacrima 268–9 albinism (OCA) 202–6, 211–2 Allgrove syndrome 268–9 alpha subunit of rod transducin (GNAT1) 142 Alström syndrome 147–8 amyloidosis Finnish-type/Meretoja-type 20–2 lattice corneal dystrophy, type I 18–9 primary subepithelial 7 amyloidosis V 20–2 Anderson–Fabry disease 215–6 aniridia 65–7 anophthalmos 274–5 anterior polar cataract 34 anterior segment ocular (mesenchymal) dysgenesis (ASOD) 68–9 AP3B1 (adaptin beta-3a) 209 APC (adenomatous polyposis of colon) 244–6 aquaporin O (AQPO) 41 arachnodactyly 53 ARMD (age-related macular degeneration) 88 arrestin (SAG S-antigen) 134 ARSB (N-acetylgalactosamine-4-sulfatase) 236 arthro-ophthalmopathy, progressive 180–4 arylhydrocarbon-interacting receptor protein-like 1 (AIPL1) 118 ATP-binding cassette, subfamily A, member 4 (ABCA4) 88–9, 99–100, 134 ATP-binding cassette, subfamily C, member 6 (ABCC6) 89, 94 Avellino-type corneal dystrophy 14–7 Axenfeld anomalies 68, 72, 77 Bardet–Biedl syndrome 149–52 basal cell nevus syndrome 247–50 Batten disease 231–3 BBS2, BBS4 151–2 Best macular dystrophy 104–6 beta-Ig-H3/transforming growth factor (BIGH/TGFB1) 10–9 bicoid-related homeobox-containing gene 78 BIGH3-related dystrophies 4 10–9
342
Genetics for Ophthalmologists
Blaschko’s lines 173 blepharophimosis, ptosis and epicanthus inversus 270–1 Bloch–Sulzberger syndrome 172–4 blue cone monochromatic color blindness 84–5 Bowman’s layer dystrophy type I 10–1 type II 12–3 buphthalmos 58–60 cadherin-like gene CDH23 166 calcium channel alpha-1 subunit (CACNA1F) 142 carbohydrate sulfotransferase-6 (CHST6) 24 cataract 28–44 aculeiform 32–3 autosomal dominant (ADCC) 29 autosomal recessive (ARCC) 30 cerulean (blue-dot) 36–7 congenital zonular with sutural opacities 38 Coppock-like 39–40 embryonic nuclear 39–40 hyperferritinemia–cataract syndrome 45 Lowe (oculocerebrorenal) syndrome 46–8 myotonic dystrophy 49–51 polymorphic and lamellar 41 posterior polar 42 syndromic 45–51 X-linked with Hutchinsonian teeth 35 Lowe syndrome 46–8 zonular pulverulent 43–4 cataract–dental syndrome 35 CBBM (blue cone monochromatic color blindness) 84–5 CEH10 homeodomain-containing homolog (CHX10) 276 cellular retinaldehyde-binding protein 1 (CRBP1) 120 central areolar choroidal dystrophy (CACD) 127–9 cerebellar vermis agenesis 158 cerebelloparenchymal disorder IV (CPDIV) 158 ceroid lipofuscinosis type-3 231–3 CFEOM (congenital fibrosis of extraocular muscles) 272–3 Chediak–Higashi syndrome 207–8 choroid, and retina, gyrate atrophy 226–7 choroidal dystrophy, central areolar 127–9 choroidal sclerosis (choroideremia) 107–9 choroiditis, Doyne honeycomb retinal dystrophy 90–1 CHRPEs, retinal pigment epithelium 244 CHX10 (CEH10 homeodomain-containing homolog) 276 CLN3 (ceroid lipofuscinosis type-3) 231–3 CNGA1 134
Index
343
Cockayne syndrome 153–5 COD(3) 86–7 Cohen syndrome 156–7 collagens type II,alpha1 (COL2A1) 183 type VIII,alpha2 (COL8A2) 26 type XI,alpha1 (COL11A1) 183 type XVIII,alpha1 (COL18A1) 175 coloboma with renal disease (ONCR) 194–5 color blindness, blue cone monochromatic 84–5 cone dystrophies 82–7 cone–rod dystrophy 110–1 cone–rod homeobox (CRX) 119 connexins (CX) 43–4 Coppock-like cataract 39–40 CORD1–9 110 CORD3 (Stargardt disease) 98–101 cornea plana 5–6 corneal amyloidosis, primary subepithelial 7 corneal dystrophies 3–26 CDBI 10–1 CDBII 12–3 chromosomal localization 4 Fuchs’ endothelial 25–6 Granular 14–7 Groenouw type I 14–7 Groenouw type II 23–4 honeycomb 12–3 inheritance pattern 4 lattice 18–22 corneal shape abnormalities 2–6 CRD (cone-rod dystrophy) 110–1 CREB-binding protein (CREBPP) 79–80 Criswick–Schepens syndrome 170–1 crumbs homolog 1 (CRB1) 134, 135 CRX 126 crystallins (CRY) 29, 30 alphaA (CRYAA) 276 alphaB (CRYAB) 42 betaA1 (CRYBA1) 36 betaB2 (CRYBB2) 36, 39, 276 gamma (CRYG) 40 gammaD (CRYGD) 32 CSNB1–3 141 cyclic nucleotide-gated cation channel alpha subunit (CNGA3) 82 beta subunit (CNGB3) 82 cystathionine beta-synthase (CBS) 228–30
344
Genetics for Ophthalmologists
cystinosin (CTNS) 237–8 cytochrome P450B1 (CYP1B1) 2, 59 de Morsier syndrome 196–8 deafness 199–200 diabetes mellitus, diabetes insipidus, optic atrophy and deafness (DIDMOAD) 199–200 digenic retinitis pigmentosa 137 dominant optic atrophy, type-1 188–9 Doyne honeycomb retinal dystrophy (choroiditis) 90–1 Drosophila homologs crumbs 1 (CRB1) 134, 135 patched (PTCH) 250 drusen, radial 90–1 dystrophia myotonica protein kinase (DMPK) 49–51 ectopia lentis 52–6 EGF-containing fibrillin-like extracellular matrix protein-1 (EFEMP1) 89, 91 elongation of VLC fatty acids-like gene 4 (ELOVL4) 89, 103 embryonic nuclear cataract 39–40 endothelial 25–6 enhanced S–cone syndrome 112–3 epicanthus inversus 270–1 ERCC6, ERCC8 154 exudative vitreoretinopathy EVR1 170–1 X-linked (EVR2) 177–9 Fabry disease 215–6 familial adenomatous polyposis (FAP) 244–6 familial iridogoniodysplasia 72–3 FECD (Fuchs’ endothelial corneal dystrophy) 25–6 ferritin light chain (FLC) 45 fibrillin 1 (FBN1) 55 fibrillin-like extracellular matrix protein-1 (EFEMP1) 89, 91 fibrosis of extraocular muscles (FEOM1, FEOM2) 272–3 fifth phakomatosis 247–50 Finnish-type amyloidosis 20–2 forkhead box C1 (FOXC1) 72 forkhead box E3 (FOXE3) 68 forkhead transcription factor (FOXL2) 271 Franceschetti sign 114 Fuchs’ endothelial corneal dystrophy 25–6 fundus albipunctatus 144–5 fundus flavimaculatus 98–101, 102–3 galactose-1-phosphate uridyltransferase (GALT) deficiency 219–21 galactosemia 219–21 cataract 47
Index
345
galactokinase deficiency 217–8 galactosidase alpha (GLA) 216 galactosidase beta (GLB1) 236 GALNS (galactosamine-6-sulfate sulfatase) 236 Gardner syndrome 244–6 gelatinous drop-like corneal dystrophy 7 gelsolin 21 geographic granular dystrophy 10–1 glaucoma 57–80 primary 58–64 congenital glaucoma 58–60 juvenile open angle 61–2 open angle glaucoma 63–4 secondary 65–80 glaucoma-related pigment dispersion syndrome 70–1 GM2 gangliosidosis type I 222–5 type II 222–5 GNAT1 (alpha subunit of rod transducin) 142 Goldmann–Favre syndrome 112 Gorlin–Golz syndrome 247–50 granular corneal dystrophy 14–7 granular dystrophy, geographic 10–1 green cone pigment, including deuteranopia 84 Groenouw corneal dystrophy type I 14–7 type II 23–4 Grönblad–Strandberg syndrome 92–5 GTPases, Rab escort proteins 108 guanylate cyclase 2D (GUCY2D) 116 activator 1A (GUCAA1A) 7 gyrate atrophy of choroid and retina 226–7 harmonin 165 heparan sulfate proteoglycans 76 Hermansky–Pudlak syndrome 209–10 hexosaminidase A/B deficiency, HEXA, HEXB 222–5 von Hippel–Lindau syndrome 264–5 homeobox gene expressed in ES cells (HESX1) 197 homocystinuria 228–30 honeycomb corneal dystrophy 12–3 honeycomb degeneration of retina 90–1 HPS 209–10 Hunter syndrome 234–6 Hurler syndrome 234–6 Hutchinsonian teeth, X-linked cataract 35 hyperferritinemia–cataract syndrome 45
346
Genetics for Ophthalmologists
IDS (iduronate sulfatase) 236 IDUA (alpha-L-iduronidase) 236 incontinentia pigmenti type II (IP2) 172–4 infantile nephropathic cystinosis 237–8 inherited retinal disease 81–167 iridogoniodysgenesis 72–3, 77–8 anomaly (IGDA) 72–3 with somatic anomalies 77–8 type I 72–3 type II 77–8 iris hypoplasia 77–8 isolated ectopia lentis 52–6 isolated microphthalmos 274–5 Joubert–Bolthauser syndrome 158 juvenile familial corneal dystrophy 8–9 juvenile neuronal ceroid lipofuscinosis, type-3 231–3 juvenile optic atrophy 188–9 juvenile-onset primary open angle glaucoma (JOAG) 61–2 Kearns–Sayre syndrome 160 keratan sulfate, carbohydrate sulfotransferase-6 (CHST6) 24 keratan sulfate proteoglycans (KSPGs) 6 keratocan (KERA 5) 276 Kjer-type optic atrophy 188–9 Knobloch syndrome 175–6 Krukenberg spindles 70 lattice corneal dystrophy type I 18–9 type II 20–2 Leber congenital amaurosis (LCA) 114–9 Leber hereditary optic atrophy/neuropathy 190–3 lens, anatomy 29 lens disorders 27–56 lens subluxation 53–6 homocystinuria 228–30 Lester sign 75 LIM homeobox transcription factor 1beta (LMX1B) 74 LIM2 30 Lowe (oculocerebrorenal) syndrome 46–8 LRAT 134 lysosomal trafficking regulator (LYST) 207 McKusick–Kaufman syndrome 152 macular corneal dystrophy 23–4 macular dystrophies 88–106 macular pattern dystrophy, deafness and diabetes 161
Index
347
MAF 2, 276 major intrinsic protein of lens fiber membrane (MIP) 41 Malattia Leventinese (MLVT) 90–1 malignancy (increased risk) 241–65 Knudson’s two-hit hypothesis 242 Marfan syndrome 52–6 Maroteux–Lamy syndrome 234–6 MASS phenotype 56 MCDC (macular corneal dystrophy 23–4 Meesmann corneal dystrophy 8–9 membrane component, chr-1, surface marker-1 (M1S1) 7 Meretoja-type amyloidosis 20–2 merlin 255 MERTK 134 mesenchymal dysgenesis, anterior segment 68–9 metabolic disorders 213–40 MFS1 (Marfan syndrome) 52–6 microphthalmos, isolated 274–5 mitochondrial disease and retinopathy 159–62 mitochondrial genes, LHON 190–3 MKKS (McKusick–Kaufman syndrome) 152 Morquio syndrome 234–6 de Morsier syndrome 196–8 mucopolysaccharidoses 234–6 multidrug resistance protein 6 (MRP6) 94 myocilin (MYOC) 62–4 myosin VIIa 165 myotonic dystrophy 49–51 nail dystrophy 174 nail–patella syndrome 74–6 Nance–Horan sydrome (NHS) 35 nanophthalmos 274–5 NARP (neuropathy, ataxia and retinitis pigmentosa) 162 NDP (Norrie disease) 177–9 nephropathic cystinosis 237–8 Nettleship–Falls type ocular albinism 211–2 neurofibromatosis type I 251–3 type II 254–6 neurofibromin (NF1) 253 neuronal ceroid lipofuscinosis, juvenile type-3 231–3 neuropathy, ataxia and retinitis pigmentosa 162 nevoid basal cell carcinoma syndrome (NBCCS) 247–50 NFκB essential modulator (NEMO) 174 night blindness 141–4 Norrie disease 177–9 NRL 126
348
Genetics for Ophthalmologists
nuclear receptor subfamily 2, group E, member 3 (NR2E3) 112 nyctalopin (NYX) 142 OA1, X-linked albinism 211–2 OAT (ornithine aminotransferase) 226–7 occipital encephalocoele 175–6 OCRL (oculocerebrorenal syndrome) 46–8 ocular albinism, type-1 211–2 ocular/adnexal developmental defects 267–7 oculocerebrorenal syndrome 46–8 oculocutaneous albinism 202–6 Oguchi disease 145–6 onychoosteodysplasia 74–6 OPA1 (optic atrophy type 1) 188–9 open-angle glaucoma type 1a (GLCIA) 61–2 optic atrophy 187–200 DIDMOAD 199–200 optic nerve coloboma with renal disease (ONCR) 194–5 ornithine aminotransferase (OAT) deficiency 226–7 paired box gene 2 (PAX2) 192 paired box gene 6 (PAX6) 66 paired-like homeodomain transcription factors (PITX2) 78 (PITX3) 68 patched homolog (PTCH) 250 patellar aplasia 74–6 PCDH15 166 PDE6A 134 PDE6B 134, 142 peripherin/RDS-related RP 87, 127–9 Peters’ anomaly 68, 77 phytanoyl-CoA hydroxylase (PHYH) 240 pigment dispersion syndrome (pigmentary glaucoma) 70–1 pigmentation defects 201–12 red and green cone pigment 84 pink-eye (P) gene 205 polymorphic and lamellar cataract 41 posterior polar cataract 42 posterior polymorphous dystrophy (PPCD) 25–6 primary subepithelial corneal amyloidosis 7 progressive arthro-ophthalmopathy 180–4 progressive cone dystrophy 86–7, 127 progressive rod–cone dystrophies 122–40 PROML1 134 PRPC8 126 pseudoxanthoma elasticum (PXE) 92–5 ptosis and epicanthus inversus 270–1
Index
349
Rab escort protein 1 (REP-1) 108 radial drusen 90–1 Rathke pouch homeobox (RPX) 197 RB1 (retinoblastoma) 257–60 RBP4 134 RDH5 (retinol dehydrogenase 5) 143 RDS/peripherin (RDS) 87, 89, 126, 129 von Recklinghausen disease 251–3 red cone pigment, including protanopia 84 Refsum disease 239–40 Reis–Buckler’s corneal dystrophy 10–1 renal–coloboma syndrome 194–5 RetGC1 116 retina, and choroid, gyrate atrophy 226–7 retinal degeneration slow (RDS) 87, 89, 126, 129 retinal detachment 175–6 retinal dystrophies 81–167 cone 82–7 macular 88–106 miscellaneous 107–21 mitochondrial diseases 159–62 progressive rod–cone 122–40 stationary night blindness 141–4 syndromic 147–67 retinal pigment epithelium, congenital hypertrophic lesions (CHRPEs) 244 retinal pigment epithelium-specific protein (RPE65) 117, 134 retinaldehyde-binding protein 1 (RBP1) 120 retinitis pigmentosa 122–40 autosomal dominant 125–6 genes 125–6 autosomal recessive 132–6 genes 134 digenic 137 peripherin/RDS 127–9 PPRPE type 135–6 rhodopsin-related 130–1 stationary night blindness 141–6 type-12 (RP12) 135–6 X-linked 138–40 genes 139 retinitis punctata albescens 120–1, 127 retinoblastoma 257–60 retinol dehydrogenase 5 (RDH5) 143 retinoschisis, X-linked 185–6 RGR 134 RHO (rhodopsin-related RP) 130–1, 142 RHOK (rhodopsin kinase) 146 Rieger anomalies 68, 72
350
Genetics for Ophthalmologists
Rieger syndrome 72, 77–8 RLBP1 134 rod, see also cone–rod rod monochromatism 82–3 rod outer segment protein 1 (ROM1) 137 rod transducin, alpha subunit (GNAT1) 142 ROM/RDS 126, 137 RP1 126 RP2 139 RPA (retinitis punctata albescens) 120–1 RPE65 (retinal pigment epithelium-specific protein) 117–8, 134 RPGR 139 RPGRIP1 (RPGR-interacting protein) 118 RPX (Rathke pouch homeobox) 197 RSI X-linked retinoschisis 185–6 Rubinstein–Taybi syndrome 79–80 SAG (S-antigen) 134 Sandhoff disease (hexosaminidase B deficiency) 222–5 SCH (schwannomin) 255 Scheie syndrome 234–6 septo–optic dysplasia 196–8 SFD (Sorsby pseudoinflammatory fundus dystrophy) 96–7 SIX5 51 small leucine-rich proteoglycans (SLRPs) 6 Sorsby pseudoinflammatory fundus dystrophy 96–7 Stargardt disease 98–103 autosomal dominant 102–3 autosomal recessive 98–101 stationary night blindness 141–6 Stickler syndrome 180–4 stromal 21–4 subretinal neovascular membranes (SRNVMs) 94 Tay–Sachs disease (hexosaminidase A deficiency) 222–5 Thiel–Behnke corneal dystrophy 12–3 tissue inhibitor of metalloproteinase 3 (TIMP3) 89, 97 trabecular meshwork-induced glucocorticoid response (TIGR) 62 trinucleotide repeat (CTG) regions 50 triple-A syndrome 268–9 tuberous sclerosis complex (TSC1, TSC2) 261–3 TULP1 134 tumor predisposition 242–3 tumor suppressor genes Knudson’s two-hit hypothesis 242 RB1 (retinoblastoma) 257–60 tyrosinase (TYR), OCA1 202–6 tyrosine-related protein (TYP1), OCA3 205–6
Index
351
Usher syndrome 163–7 USH2A/usherin 134, 164 USH genes 164 VHL (von Hippel–Lindau) 264–5 vitelliform dystrophy (RDS-related) 127–8 vitelliform macular dystrophy (VMD2) 104–6 vitreoretinal disorders 169–86 VMD2 89,104–6 Vogt–Spielmeyer (Batten) disease 231–3 von Hippel–Lindau syndrome 264–5 von Recklinghausen disease 251–3 VSX1 2, 4, 25 WAGR (Wilms’ tumor, aniridia, genitourinary defects and retardation) 67 WFS1 (wolframin) 199–200 Wolfram syndrome 199–200 X-linked disorders anophthalmos 274–5 cataract with Hutchinsonian teeth 35 familial exudative vitreoretinopathy (EVR2) 177–9 Hunter syndrome 234–6 ocular albinism 211–2 retinitis pigmentosa 138–40 retinoschisis 185–6 zonular cataract, with sutural opacities 38 zonular pulverulent cataract 43–4
352
Genetics for Ophthalmologists
