Genetics for Pediatricians

Prévia do material em texto

Remedica genetics series
Pediatricians
Genetics for 
Mohnish Suri
Ian D Young
Series Editor
Eli Hatchwell
Genetics for Pediatricians
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Genetic testing plays an important role in the investigation of almost
every child who presents with one of the many common inherited
disorders. It can be difficult for even the most conscientious
practitioner to keep abreast of developments and to appreciate 
both the significance and the relevance of some of the major
discoveries of recent years. So, it is with the busy general
pediatrician in mind that this contemporary account of the 
molecular aspects of pediatric disorders has been prepared. 
“This text is designed to be readily accessible, and effectively
blends clinical features with molecular and clinical genetics. 
It will provide a valuable bridge between standard pediatric 
sources and Internet-provided databases. Suri and Young are 
highly respected clinical geneticists with vast experience in 
the pediatric applications of their speciality. They are also
accomplished communicators – they recognize the challenges 
of clinical syndrome identification, and the necessity to balance
diagnostic enthusiasm with restraint when it comes to selecting
from an ever-expanding repertoire of investigations, many 
of which generate both personal and financial pressures.”
Derek Johnston
Children’s Department, University Hospital, Queen’s Medical 
Centre, Nottingham, UK
“Pediatricians will find this easy-to-read book a major step forward
in their clinical practice. It should be of interest to working
pediatricians who need help in diagnosing syndromes and in
understanding the molecular tests that are needed for diagnosis. 
It wisely does not attempt to discuss every single genetic condition
that exists, but confines itself to the important conditions.”
Jo Sibert
Head of Department and Professor of Child Health, Department of
Child Health, University of Wales School of Medicine, Cardiff, UK
9 781901 346633
ISBN 1-901346-63-3
R
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Genetics for Pediatricians
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The Remedica Genetics for… Series
Genetics for Cardiologists
Genetics for Dermatologists
Genetics for Endocrinologists
Genetics for Hematologists
Genetics for Oncologists
Genetics for Ophthalmologists
Genetics for Orthopedic Surgeons
Genetics for Pediatricians
Genetics for Pulmonologists
Genetics for Rheumatologists
Published by Remedica Publishing
32–38 Osnaburgh Street, London, NW1 3ND, UK
20 N Wacker Drive, Suite 1642, Chicago, IL 60606, USA
E-mail: books@remedica.com
www.remedica.com
Publisher: Andrew Ward
In-house editors: Thomas Moberly and James Griffin
© 2004 Remedica Publishing
While every effort is made by the publishers and authors to see that no inaccurate or misleading data, opinions, or
statements appear in this book, they wish to make it clear that the material contained in the publication represents 
a summary of the independent evaluations and opinions of the authors and contributors. As a consequence, the authors,
publishers, and any sponsoring company accept no responsibility for the consequences of any such inaccurate or
misleading data, opinions, or statements. Neither do they endorse the content of the publication or the use of any 
drug or device in a way that lies outside its current licensed application in any territory.
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 63 3
ISSN 1472 4618
British Library Cataloguing-in Publication Data
A catalogue record for this book is available from the British Library.
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Genetics for Pediatricians
Mohnish Suri 
Department of Clinical Genetics
City Hospital
Nottingham
UK
Ian D Young
Department of Clinical Genetics
Leicester Royal Infirmary
Leicester
UK
Series Editor
Eli Hatchwell
Investigator
Cold Spring Harbor Laboratory
USA
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To our wives and parents. 
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Genetics for Pediatricians 
Introduction to the 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
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.
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Introduction
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. Online Mendelian Inheritance in Man. The Online 
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. National Coalition for Health Professional Education in Genetics.
An organization designed to prepare health professionals for the
genomics revolution. http://www.nchpeg.org/
Finally, a series of articles from the New England Journal of Medicine,
entitled Genomic Medicine, has been made available free of charge at
http://www.nejm.org.
Eli Hatchwell
Cold Spring Harbor Laboratory
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Genetics for Pediatricians 
Preface
There can be very few areas of medicine in which progress has been
achieved at such a rapid pace as molecular genetics. Almost every
common single-gene disorder has succumbedto the march of scientific
progress to the extent that genetic testing now plays an important role in
the investigation of almost every child who presents with one of the many
common inherited disorders which make a major contribution to pediatric
morbidity and mortality throughout the world. The rate of progress is
such that it can be difficult for even the most conscientious practitioner 
to keep abreast of developments and to appreciate both the significance
and the relevance of some of the major discoveries of recent years.
It is with the busy general pediatrician in mind that this contemporary
account of the molecular aspects of pediatric disorders has been
prepared. The number of conditions which have been mapped or in
which the causative gene has been isolated is vast. Thus in order to
ensure that this text is of manageable proportions, coverage has been
restricted to the more common single-gene disorders which are likely to
be encountered in general pediatric practice. “Small print” obscurities
and the many inborn errors for which comprehensive biochemical
testing is available have generally been omitted. Instead attention 
has been focused on the more common conditions in which molecular
analysis can play an important role in diagnosis or in the management 
of a child and his or her family. In some instances, notably with eye 
and skin disorders, we have also omitted rare disorders which fall 
within the remit of other specialties, particularly when these have
received detailed coverage in other books in this series.
In addition to providing a unique insight into the cause of so many
previously unexplained disorders, recent advances in molecular
genetics have also demonstrated that, far from being straightforward,
Mendelian inheritance and its contribution to genetic disease can be
remarkably complex. Thus a “simple” disorder such as cystic fibrosis
has proved to be extremely heterogeneous both clinically and at the
molecular level, with over 1,000 different mutations reported at the
main disease locus. Indeed, for many conditions such as cystic fibrosis
and β-thalassemia, mutational heterogeneity has proved to be the
norm. Entities such as nonsyndromal sensorineural hearing loss illustrate
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Preface
that locus heterogeneity can also be extremely important. Further
examples of etiologic complexity are provided by the Bardet–Biedl
syndrome, which shows not only locus heterogeneity but also the
curious phenomenon of triallelic inheritance, and by Hirschsprung
disease, for which the concept of synergistic heterozygosity has started
to shed light on how genes at several loci can interact to contribute to
what is commonly referred to as oligogenic or polygenic inheritance.
And if this was not enough, research on pediatric disorders such as 
the fragile X syndrome and the Angelman/Prader–Willi syndromes has
identified “new” genetic mechanisms such as triplet repeat instability
with anticipation, and imprinting/uniparental disomy, respectively. 
So as well as providing a useful up-to-date account of molecular
pathogenesis, we hope that this text will also help readers become
better acquainted with some of the new and exciting developments that
have characterized molecular genetic research over the last few years.
In writing this book we would like to offer our thanks to colleagues who
have provided photographs, and to Mrs Diane Castledine for secretarial
assistance. Above all we would like to express our gratitude to, and
admiration for, the many children and families who, over the years, 
have taught us so much more than they could possibly have learned
from us.
Mohnish Suri
Ian D Young
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Genetics for Pediatricians 
Contents
1. Progressive Ataxias and Neurologic Disorders 1
Ataxia–Telangiectasia 2
Duchenne Muscular Dystrophy 4
Facioscapulohumeral Muscular Dystrophy 7
Friedreich Ataxia 8
Hereditary Motor and Sensory Neuropathy 10
Limb-girdle Muscular Dystrophy 18
Myotonic Dystrophy 23
Spinal Muscular Atrophy 27
2. Cerebral Malformations and Mental Retardation Syndromes 29
Angelman Syndrome 30
Fragile X Syndrome 34
Holoprosencephaly 36
Hunter Syndrome 40
Huntington Disease 41
Lesch–Nyhan Syndrome 43
Lissencephaly 45
Lowe Syndrome 52
Neuronal Ceroid Lipofuscinosis 53
Pelizaeus–Merzbacher Syndrome 57
Prader–Willi Syndrome 59
Rett Syndrome 61
X-linked Adrenoleukodystrophy 62
X-linked α-Thalassemia and Mental Retardation Syndrome 64
X-linked Hydrocephalus 66
3. Disorders of Vision 69
Aniridia 70
Bardet–Biedl Syndrome 72
Juvenile Retinoschisis 74
Leber Congenital Amaurosis 75
Norrie Disease 79
Rieger Syndrome 80
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Contents
4. Hearing Disorders 83
Nonsyndromal Hearing Loss 84
Hearing Loss due to Connexin 26 Gene Defect 85
Pendred Syndrome 86
Usher Syndrome 87
Waardenburg Syndrome 90
5. Neurocutaneous Disorders and Childhood Cancer 93
Multiple Endocrine Neoplasia Type 2 94
Neurofibromatosis Type 1 96
Retinoblastoma 98
Tuberous Sclerosis 101
von Hippel–Lindau Disease 103
6. Connective Tissue and Skeletal Disorders 107
Achondroplasia 108
Ehlers–Danlos Syndrome 110
Hereditary Multiple Exostoses 115
Marfan Syndrome 117
Osteogenesis Imperfecta 119
Pseudoachondroplasia 124
Stickler Syndrome 125
7. Cardio-respiratory Disorders 129
Barth Syndrome 130
Cystic Fibrosis 131
DiGeorge/Shprintzen Syndrome 133
Holt–Oram Syndrome 135
Laterality Defects 137
Noonan Syndrome 138
Primary Ciliary Dyskinesia 139
Williams Syndrome 141
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Genetics for Pediatricians 
8. Craniofacial Disorders 143
Apert Syndrome 144
Crouzon Syndrome 146
Greig Syndrome 148
Pfeiffer Syndrome 149
Rubinstein–Taybi Syndrome 151
Saethre–Chotzen Syndrome 152
Sotos Syndrome 153
Treacher Collins Syndrome 154
Van der Woude Syndrome 155
9. Endocrine Disorders 157
Androgen Insensitivity Syndrome 158
Congenital Adrenal Hyperplasia 160
Diabetes Insipidus 163
Growth Hormone Deficiency 164
Growth Hormone Receptor Defects 166
Panhypopituitarism 167
Pseudohypoparathyroidism 169
10. Gastrointestinal and Hepatic Diseases 173
Alagille Syndrome 174
α1-Antitrypsin Deficiency 175
Hirschsprung Disease 177
11. Hematologic Disorders 181
Fanconi Anemia 182
Glucose-6-Phosphate Dehydrogenase Deficiency 183
Hemophilia A 185
Hemophilia B 187
Hereditary Elliptocytosis 189
Hereditary Spherocytosis 190
Sickle Cell Anemia 193
α-Thalassemia 194
β-Thalassemia 197
von Willebrand Disease 198
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Contents
12. Immunologic Disorders 201
Bruton Agammaglobulinemia 202
Chronic Granulomatous Disease 203
Severe Combined Immunodeficiency 205
Wiskott–Aldrich Syndrome 207
13. Metabolic Disorders 209
Medium Chain Acyl-CoA Dehydrogenase Deficiency 210
Menkes Disease 211
Ornithine Transcarbamylase Deficiency 212
Phenylketonuria 214
Wilson Disease 215
14. Renal Disorders 217
Alport Syndrome 218
Beckwith–Wiedemann Syndrome 220
Cystinosis 224
Orofaciodigital Syndrome Type I 225
Polycystic Kidney Disease 226
15. Abbreviations 229
16. Glossary 235
17. Index 285
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1. Progressive Ataxias and Neurologic Disorders
Ataxia–Telangiectasia 2
Duchenne Muscular Dystrophy 4
Facioscapulohumeral Muscular Dystrophy 7
Friedreich Ataxia 8
Hereditary Motor and Sensory Neuropathy 10
Limb-girdle Muscular Dystrophy 18
Myotonic Dystrophy 23
Spinal Muscular Atrophy 27
1
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Ataxia–Telangiectasia2
Ataxia–Telangiectasia
(also known as: AT; Louis-Bar syndrome)
MIM 208900
Clinical features AT is a neurocutaneous syndrome. Patients present with progressive
truncal and gait ataxia, unusual head movements, choreoathetosis, and
oculomotor apraxia in both horizontal and vertical gaze. Other features
include motor developmental delay, dysarthria, and mask-like facies.
Telangiectasia appears over the bulbar conjunctiva, face,and ears from
the age of 3–4 years (see Figure 1). Many children have a history of
recurrent respiratory infections, and 30%–40% of patients develop 
a malignancy. These include T-cell leukemias and B-cell lymphomas 
in children and epithelial tumors (such as breast and ovarian cancer) 
in adults. Patients with AT usually survive into their twenties, although
longer survival periods have been documented. Investigations show
elevated levels of α-fetoprotein and carcinoembryonic antigen 
and reduced levels of immunoglobulin (Ig)G2, IgA, and IgE.
Chromosome analysis can show reciprocal balanced translocations
involving the short arm of chromosome 7 and the long arm of
chromosome 14, or the short arm of chromosome 2 and the 
long arm of chromosome 22.
Age of onset Most children present with ataxia between the ages of 1 and 3 years.
Epidemiology The population incidence is estimated to be about 1 in 40,000 to 
1 in 100,000 live births. About 1% of the general population are
believed to be carriers (heterozygotes).
Inheritance Autosomal recessive
Chromosomal 11q22.3
location
Gene ATM (ataxia–telangiectasia mutated)
Mutational Over 400 mutations have been described. These include small and large
spectrum deletions and insertions, as well as nonsense, missense, and splice-site
mutations. About 65%–70% of mutations result in protein truncation,
and these mutations produce no detectable protein. The remaining 
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Progressive Ataxias and Neurologic Disorders 3
mutations result in the production of a normal-sized protein that is
nonfunctional. Almost all nonconsanguineous patients are compound
heterozygotes, ie, they have different mutations in their two ATM alleles.
Molecular ATM has 66 exons and encodes a protein with 3,056 amino acids.
pathogenesis The ATM protein is ubiquitously expressed and has homology to yeast
and mammalian phosphatidylinositol-3 kinases, which are involved in
signal transduction, cell cycle control, and DNA repair. It is believed that
the ATM protein phosphorylates several other proteins, including p53,
ABL, BRCA1, TERF1, RAD9, and nibrin (the protein product of the gene
for Nijmegen breakage syndrome, MIM 251260), after cell exposure to
ionizing radiation. This delays the progression of the cell through the cell
cycle at the G1/S checkpoint, allowing the cell to repair DNA damage
before entering the S phase. Without ATM protein the cell would be able
to progress to the S phase without repairing the DNA damage sustained
by radiation exposure, which could predispose to the development of
cancer. The molecular pathogenesis of the neurocutaneous phenotype 
of AT is unknown.
Genetic diagnosis The diagnosis can be confirmed by demonstrating increased 
and counseling chromosomal breakage in cultured lymphocytes after X-irradiation 
and reduced or absent expression of ATM protein in lymphocytes.
Genetic testing is only available on a research basis.
Figure 1. Telangiectasia over the
bulbar conjunctiva in a child with
ataxia–telangiectasia.
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Duchenne Muscular Dystrophy4
Counseling is on the basis of autosomal recessive inheritance. 
Carrier females (particularly those who carry a missense mutation) 
are at increased risk of developing breast cancer. Missense mutations 
in ATM are believed to be associated with an increased cancer risk 
as a result of a dominant-negative effect.
Prenatal diagnosis is possible by linkage analysis or by ATM mutation
analysis if mutations have been identified previously in an affected 
child from the family. Prenatal diagnosis has been attempted by
amniocentesis followed by X-irradiation of cultured amniocytes 
to look for chromosomal breakage, but this method of prenatal 
diagnosis is unreliable.
Duchenne Muscular Dystrophy
(also known as: DMD)
MIM 310200
Clinical features This condition mainly affects males, who present with delayed
motor-developmental milestones, proximal muscle weakness with
pseudohypertrophy of some muscles, particularly the calves (see
Figure 2), and cardiomyopathy. The muscle weakness is progressive. 
In classical cases, loss of ambulation occurs before the age of 12 years
and death occurs in the twenties. Intermediate forms of DMD exist 
in which progression is slower, with loss of ambulation occurring
between 11 and 16 years of age. Learning difficulties are seen in
approximately 60% of patients. Death is usually due to respiratory
infection or cardiomyopathy. About 2.5% of female carriers are
symptomatic (manifesting carriers).
Figure 2. Calf hypertrophy in a boy with Duchenne muscular dystrophy.
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Progressive Ataxias and Neurologic Disorders 5
Age of onset Usually in the first year of life, although diagnosis is often delayed.
Epidemiology This is the most common form of muscular dystrophy, affecting 
1 in 3,500 live-born males. The prevalence of symptomatic carriers 
in the female population is estimated to be 1 in 100,000.
Inheritance X-linked recessive
Chromosomal Xp21.2
location
Gene DMD (dystrophin)
Mutational An intragenic deletion that involves one or more exons is present in
spectrum 65%–70% of patients. There are two deletion hotspots, one between
exons 2 and 20 and the other between exons 44 and 53. Intragenic
duplications are seen in 5%–6% of cases. The remainder of cases
involve point mutations (nonsense, missense, and splice-site
mutations), which are distributed across the whole gene.
Molecular DMD is the largest known gene in the human genome. It is 2.4 Mb 
pathogenesis in size and composed of 79 exons. It encodes a large, rod-shaped
cytoskeletal protein made up of 3,685 amino acids. The dystrophin
protein has an actin-binding domain, two calpain-homology domains,
22 spectrin repeats, one WW domain (a short domain of about 40 amino
acids that contains two tryptophan residues that are spaced 20–23 amino
acids apart – the term WW derives from the two tryptophan residues, 
as the single letter code for tryptophan is W) and one ZZ-type zinc finger
domain. The gene is subject to alternative splicing, and there are at 
least four isoforms of dystrophin. These include a muscle (M) isoform, 
a brain (B) isoform, and a cerebellar Purkinje (CP) isoform. 
Dystrophin is expressed in several tissues and plays an important role 
in anchoring the cytoskeleton to the plasma membrane. In muscle,
dystrophin links the sarcolemmal cytoskeleton to the extracellular matrix.
It is thought to protect the sarcolemma during muscular contractions.
Mutations that result in the DMD phenotype are associated with protein
truncation or loss of the translational reading frame. These mutations
result in the absence of dystrophin. 
Mutations that maintain the translational reading frame result in the
phenotype of Becker muscular dystrophy (MIM 300376). These
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Duchenne Muscular Dystrophy6
mutations result in the production of a shortened and only partially
functional protein. Patients with Becker muscular dystrophy have
clinical features similar to those of DMD, but the condition is milder,
progression is slower, and survival is prolonged. 
Mutations in the 5́ end of DMD and in-frame deletions in exons 48 
and 49 can also cause X-linked dilated cardiomyopathy (MIM 302045).
Mutations in the 5́ end of DMD result in failure to transcribe the M
isoform in skeletal and cardiac muscle. However, the absence of this
isoform in skeletal muscle can be compensated for by up-regulation of
the B and CP isoforms. This does not appear to be the case in cardiac
muscle, where the lack of dystrophin expression results in cardiomyopathy.
The mechanism by which in-frame deletions in exons 48 and 49 
cause X-linked dilated cardiomyopathy is not understood, but it 
has been suggested that intron 48 might contain sequences that 
are necessary for the expression of dystrophin in cardiac muscle.
Genetic diagnosis The diagnosis of DMDis based on clinical features, markedly 
and counseling elevated plasma creatine kinase (CK) levels, muscle biopsy (with
immunohistochemistry using monoclonal antibodies to dystrophin), 
and mutation testing. Routine genetic testing can only detect intragenic
deletions and duplications. Testing for point mutations in DMD is only
undertaken in a few specialized research laboratories and is best
performed on dystrophin mRNA extracted from a fresh or frozen 
muscle biopsy.
Genetic counseling is on an X-linked recessive basis. Female relatives 
of affected males who have an intragenic deletion or duplication can be
offered carrier testing. Carrier females have a 50% chance of having an
affected son, and can be offered a reliable genetic prenatal test for this
condition by chorionic villus sampling.
There is a two-thirds chance that the mother of a sporadic case 
(single affected male with no family history) is a carrier. The mother 
of a sporadic case can also have somatic or gonadal mosaicism for the
DMD mutation. Therefore, there is a 10%–15% recurrence risk of DMD
in a subsequent pregnancy for the mother of a sporadic case. In DMD
families in which the DMD mutation cannot be identified, carrier testing
involves linkage analysis and serial plasma CK assays. Linkage analysis 
using intragenic and flanking markers can also be used for prenatal
diagnosis in these families.
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Progressive Ataxias and Neurologic Disorders 7
Facioscapulohumeral Muscular Dystrophy
(also known as: FSHMD)
MIM 158900 (type 1A)
158901 (type 1B)
Clinical features This is a slowly progressive muscular dystrophy. The affected patient
usually presents with facial weakness, shoulder-girdle weakness and
wasting, and scapular winging. Later, there is involvement of feet 
and hip-girdle dorsiflexors. There is often striking wasting of the neck
muscles and the muscles of the upper arm. Retinal vasculopathy and
high-frequency sensorineural hearing loss are also recognized features.
Age of onset Late childhood or adolescence.
Epidemiology The incidence of FSHMD is approximately 1 in 20,000.
Inheritance Autosomal dominant
Chromosomal Type 1A: 4q35
location Type 1B: unknown
Gene Unknown (both types)
Mutational Most cases of FSHMD are type 1A. Although the gene for this
spectrum condition has not yet been identified, almost all patients have a
chromosomal rearrangement in the subtelomeric region of the long 
arm of chromosome 4 (4q35). This region contains a polymorphic
3.3-kb repeat element termed D4Z4. In the general population, the
number of D4Z4 repeats varies from 10 to more than 100. Affected
individuals have a deletion in this region that reduces the number 
of D4Z4 repeats to less than 10. This reduction is the basis of 
a diagnostic molecular genetic test for FSHMD type 1A.
Molecular Unknown. It has been suggested that deletion of the D4Z4 repeat 
pathogenesis sequences could interfere with the expression of a gene located some
distance away on the long arm of chromosome 4 by a “position effect”.
Recent work suggests that an element within the D4Z4 repeat sequence
specifically binds a multiprotein complex that mediates transcriptional
repression of genes at 4q35. Deletion of D4Z4 sequences below a certain
number could result in a reduction in the number of repressor complexes.
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Friedreich Ataxia8
This could decrease or abolish the transcriptional repression of 4q35
genes, with overexpression of one or more of these genes resulting 
in the FSHMD phenotype.
Genetic diagnosis Genetic testing is routinely available and enables a diagnosis to 
and counseling be made in most cases. Counseling is on the basis of autosomal
dominant inheritance. About 30% of patients represent new mutations.
The condition demonstrates 95% penetrance by the age of 20 years,
although penetrance is lower in females. Anticipation has been
described in some families. Prenatal testing can be done by 
genetic testing or, in suitable families, by linkage analysis.
Friedreich Ataxia
MIM 229300 (Friedreich ataxia 1)
601992 (Friedreich ataxia 2)
Clinical features This is the most common cause of cerebellar ataxia in childhood.
Affected children present with dysarthria and progressive ataxia of 
their gait. Neurologic examination demonstrates weakness of the 
lower limbs, absent knee and ankle jerks, extensor plantar reflexes,
decreased position and vibration sense in legs, positive Romberg 
sign, and pes cavus. Other features include scoliosis, diabetes 
mellitus, optic atrophy, and deafness. Nerve conduction studies 
show reduced or absent sensory action potentials, but normal
motor-nerve conduction velocities. Echocardiograms show 
features of hypertrophic cardiomyopathy in 70% of patients.
Age of onset Usually between 5 and 15 years of age. Almost all cases present 
before the age of 25 years, although onset after this age has also 
been described (late-onset form).
Epidemiology The estimated population prevalence is 1–2 per 50,000. The carrier
(heterozygote) frequency is between 1 in 60 and 1 in 110.
Inheritance Autosomal recessive
Chromosomal Friedreich ataxia 1: 9q13
location Friedreich ataxia 2: 9p11–p23
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Progressive Ataxias and Neurologic Disorders 9
Gene Friedreich ataxia 1: FRDA (frataxin)
Friedreich ataxia 2: unknown
Mutational FRDA has seven exons that are subject to alternative splicing. The major
spectrum protein product of this gene is the 210-amino-acid protein frataxin. 
This is encoded by exons 1–4 spliced to exon 5A. The majority of
patients (~96%) are homozygous for an expansion of a GAA triplet
repeat motif in the first intron of the gene. The normal number of 
GAA triplet repeats is 9–22. In affected individuals the size range is
66–1,700 repeats, with most patients having 600–1,200 repeats. 
The remaining patients are compound heterozygotes for a pathogenic
GAA repeat expansion in one FRDA allele and an inactivating mutation
(nonsense or frame-shift) in the other allele.
Molecular Frataxin is located in the inner mitochondrial membrane, where it plays
pathogenesis an important role in oxidative phosphorylation and iron homeostasis.
The GAA repeat expansion interferes with the transcription of FRDA,
resulting in frataxin deficiency. This is associated with a defect of
mitochondrial oxidative phosphorylation and accumulation of iron
within the mitochondria. Thus, Friedreich ataxia is essentially a
mitochondrial disorder and this is reflected in its clinical features.
Genetic diagnosis Genetic testing is available from diagnostic laboratories. However,
and counseling it is limited to testing for the pathogenic GAA repeat expansion.
Counseling is on the basis of autosomal recessive inheritance. 
The sibling recurrence risk is 25%, but there can be marked 
variability in the expression of the condition in members of the 
same family. This can manifest as a different age of onset and/or 
a difference in the rate of progression.
Carrier testing and prenatal diagnosis are available in families where
molecular genetic analysis has confirmed that the affected individual 
is homozygous for a GAA repeat expansion.
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 9
Hereditary Motor and Sensory Neuropathy10
Hereditary Motor and Sensory Neuropathy
(also known as: HMSN; Charcot–Marie–Tooth disease; peroneal muscular atrophy)
The hereditary motor and sensory neuropathies are a clinically and genetically heterogeneous
group of disorders. Four main clinical phenotypes can be recognized: classical HMSN,
Dejerine–Sottas syndrome, congenital hypomyelinating neuropathy (CHN), and hereditary
neuropathy with liability to pressure palsies (HNPP). Each of these phenotypes is discussed 
in turn. Table 1 summarizes the classification, distinguishing clinical features, inheritance
patterns, and molecular genetics of the various forms of HMSN.
MIM See Table 1.
Clinical FeaturesClassical HMSN/HMSN I & II
Patients with classical HMSN present with distal weakness and wasting of
the legs, often associated with pes cavus and loss of ankle jerks. Sensory
symptoms are usually mild and include paresthesia of the hands and feet.
The condition progresses at a variable rate to involve the small muscles of
the hands and proximal parts of the lower limbs. Classical HMSN patients
can be divided into two groups based on their nerve conduction velocities
(NCVs). Patients with HMSN I have a demyelinating neuropathy with
reduced NCVs (patients over the age of 2 years have a motor NCV of
<38 m/s in the median nerve). Patients with HMSN II have an axonal form
of neuropathy, with normal or only slightly reduced NCVs (patients over
the age of 2 years have a motor NCV of >38 m/s in the median nerve).
Dejerine–Sottas syndrome/HMSN III
The Dejerine–Sottas syndrome phenotype is more severe than that of
classical HMSN, and patients with this condition present with hypotonia,
generalized muscle weakness, motor developmental delay, ataxia, and
areflexia. They often have palpable peripheral nerves. Muscle weakness
tends to progress more rapidly than in classical HMSN, and patients are
often nonambulatory by adolescence. However, the condition is quite
variable in its severity and progression. Nerve conduction studies show
very low NCVs (often <10 m/s), in association with demyelination 
with onion-bulb formation or hypomyelination on sural nerve biopsy.
HMSN IV
Autosomal recessive forms of HMSN I are designated HMSN IV. 
The phenotype is similar to that of HMSN I, but HMSN IV tends to
present earlier and progress more rapidly. NCVs are usually <20 m/s.
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 10
Progressive Ataxias and Neurologic Disorders 11
Congenital hypomyelinating neuropathy
This is the most severe form of HMSN. Affected children present in
infancy with severe hypotonia, generalized weakness, and areflexia. 
The condition can mimic spinal muscular atrophy, though nerve
conduction studies show very slow or unrecordable NCVs and sural
nerve biopsy shows amyelination or hypomyelination of nerve fibers.
Affected children can have respiratory and swallowing difficulties, 
and an arthrogryposis-like presentation has also been described. 
CHN can take a lethal course, causing early death, though 
improvement has been described in some children.
Hereditary neuropathy with liability to pressure palsies
This is the mildest form of HMSN. Affected individuals present with
recurrent peroneal- and ulnar-nerve pressure palsies, from which they
often make a complete recovery. Nerve conduction studies show slightly
reduced NCVs, with prolonged distal motor latencies of median and
peroneal nerves. Sural nerve biopsy shows sausage-shaped swellings of
the myelin sheath of nerve fibers. These swellings are called tomaculae.
Age of onset HMSN I and II usually present in the first decade of life, but onset can
also occur in adult life.
HMSN III usually presents in the first 2 years of life.
HMSN IV usually presents in the first decade of life.
CHN usually presents at birth or during early infancy.
HNPP usually presents in adult life.
Epidemiology The population prevalence of all forms of HMSN is about 1 in 2,500.
Inheritance, See Table 1.
chromosomal 
location, gene, and 
mutational spectrum
Molecular PMP22 is composed of four exons. It is expressed in Schwann cells
pathogenesis and encodes a 160-amino-acid integral membrane protein called
peripheral myelin protein 22. This protein is involved in the formation
and compaction of myelin in peripheral nerves. Mutations in PMP22
cause HMSN I, HMSN III, and HNPP. Duplication of PMP22 is believed 
to cause HMSN IA by a dosage effect. It has been suggested that
overexpression of PMP22 could cause the protein to accumulate 
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 11
Hereditary Motor and Sensory Neuropathy12
in the late Golgi-cell membrane compartment of Schwann cells, which
could interfere with normal myelin assembly. Deletions of PMP22 cause
HNPP as a result of haploinsufficiency. Point mutations in PMP22
are associated with a more severe phenotype than duplications of this 
gene, and are believed to cause HMSN by a dominant-negative effect
(ie, the mutant protein interferes with the function of the normal 
protein produced by the normal allele of this gene).
MPZ has seven exons and encodes a 248-amino-acid integral
membrane protein called myelin protein zero. This protein has 
a large extracellular domain containing an immunoglobulin V-type 
fold, a single transmembrane segment, and a short cytoplasmic
C-terminal end. Myelin protein zero is a major structural component 
of the myelin of peripheral nerves and is involved in the formation 
and compaction of myelin. Mutations in this gene can cause HMSN I, 
II, III, and CHN by interfering with the function of the protein in the
myelin sheath of peripheral nerves.
LITAF is a widely expressed gene with four exons that encodes a
161-amino-acid protein called lipopolysaccharide-induced tumor
necrosis factor-α factor. This protein plays an important role in the
regulation of tumor necrosis factor-α and could play a role in protein
degradation pathways. Missense mutations in this gene cause 
HMSN IC, but the precise molecular mechanism is unknown.
EGR2 has two exons and encodes a transcription factor protein (early
growth response 2) with 476 amino acids. This protein is involved 
in the differentiation and maintenance of Schwann cells by regulating
transcription of MPZ and PRX. Mutations in EGR2 can cause HMSN I,
HMSN III, and CHN.
NEFL contains four exons. It encodes the neurofilament protein 
(light polypeptide) that has 543 amino acids. This protein is one of 
three components of neurofilaments. Neurofilaments are cytoplasmic
intermediate filaments of neurons. They are believed to play a role 
in the maturation of regenerating myelinated nerve fibers, and mutations
in NEFL could lead to HMSN IF and IIE by interfering with this function.
CX32 (or GJB1) is a small gene with only two exons. It is expressed in
myelinated peripheral nerves and codes for connexin 32, a gap-junction
protein with 283 amino acids. Gap junctions are involved in cell–cell
communication. Mutations in CX32 result in an X-linked dominant form 
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 12
Progressive Ataxias and Neurologic Disorders 13
C
la
ss
ifi
ca
tio
n 
M
IM
D
is
tin
gu
is
hi
ng
In
he
rit
an
ce
C
hr
om
os
om
al
 
G
en
e
P
ro
du
ct
M
ut
at
io
na
l s
pe
ct
ru
m
cl
in
ic
al
 fe
at
ur
es
lo
ca
tio
n
H
M
SN
 IA
 
1
1
8
2
2
0
 
Sl
ow
 N
C
Vs
 
A
ut
os
om
al
 
1
7
p1
1
.2
P
M
P
2
2
Pe
rip
he
ra
l m
ye
lin
A
 1
.5
-M
b 
du
pl
ic
at
io
n 
of
 
do
m
in
an
t
pr
ot
ei
n 
2
2
1
7
p1
1
.2
 in
cl
ud
in
g 
P
M
P
2
2
is
 th
e 
m
os
t c
om
m
on
ca
us
e 
of
 H
M
SN
 IA
. P
oi
nt
m
ut
at
io
ns
 in
 th
is
 g
en
e
ha
ve
 a
ls
o 
be
en
 id
en
tif
ie
d,
in
cl
ud
in
g 
m
is
se
ns
e 
an
d
fr
am
e-
sh
ift
 m
ut
at
io
ns
H
M
SN
 IB
 
1
1
8
2
0
0
 
Sl
ow
 N
C
Vs
 
A
ut
os
om
al
 
1
q2
2
 
M
P
Z
M
ye
lin
 p
ro
te
in
 z
er
o
M
is
se
ns
e 
m
ut
at
io
ns
do
m
in
an
t 
H
M
SN
 IC
 
6
0
1
0
9
8
Sl
ow
 N
C
Vs
A
ut
os
om
al
 
1
6
p1
2
–p
1
3
.3
LI
TA
F
Li
po
po
ly
sa
cc
ha
rid
e-
M
is
se
ns
e 
m
ut
at
io
ns
do
m
in
an
t
in
du
ce
d 
tu
m
or
ne
cr
os
is
 fa
ct
or
-α
 fa
ct
or
H
M
SN
 ID
 
6
0
7
6
7
8
 
Ve
ry
 s
lo
w
 N
C
Vs
 
A
ut
os
om
al
1
0
q2
1
.1
–q
2
2
.1
EG
R
2
Ea
rly
 g
ro
w
th
 
M
is
se
ns
e 
m
ut
at
io
n 
do
m
in
an
t
re
sp
on
se
 2
(A
rg
4
0
9
Tr
p)
H
M
SN
 IF
 
6
0
7
7
3
4
Sl
ow
 N
C
Vs
, o
ns
et
A
ut
os
om
al
8
p2
1
N
EF
L
N
eu
ro
fil
am
en
t
In
-f
ra
m
e 
de
le
tio
n 
or
 
in
 in
fa
nc
y 
or
 e
ar
ly
do
m
in
an
t
pr
ot
ei
n,
 li
gh
t
m
is
se
ns
e 
m
ut
at
io
n 
ch
ild
ho
od
po
ly
pe
pt
id
e
(P
ro
8A
rg
)
H
M
SN
 X
 
3
0
2
8
0
0
M
al
es
 a
re
 m
or
e
X-
lin
ke
d 
 
Xq
1
3
.1
C
X3
2
C
on
ne
xi
n 
3
2
M
is
se
ns
e 
m
ut
at
io
ns
 
se
ve
re
ly
 a
ffe
ct
ed
 
do
m
in
an
t
ac
co
un
t f
or
 ~
7
5
%
 o
f a
ll
th
an
 fe
m
al
es
. M
al
es
:
m
ut
at
io
ns
. N
on
se
ns
e 
an
d
sl
ow
 N
C
Vs
. F
em
al
es
: 
fr
am
e-
sh
ift
 m
ut
at
io
ns
, a
s
no
rm
al
 o
r s
lo
w
 N
C
Vs
w
el
l a
s 
in
-f
ra
m
e 
de
le
tio
ns
 
an
d 
in
se
rt
io
ns
 h
av
e 
al
so
be
en
 id
en
tif
ie
d
H
M
SN
 II
A
 
1
1
8
2
1
0
 
N
or
m
al
 o
r s
lig
ht
ly
 
A
ut
os
om
al
1
p3
6
.2
K
IF
1
B
K
in
es
in
 fa
m
ily
 
M
is
se
ns
e 
m
ut
at
io
ns
re
du
ce
d 
N
C
Vs
do
m
in
an
t
m
em
be
r 1
B
H
M
SN
 II
B
 
6
0
0
8
8
2
U
lc
er
o-
m
ut
ila
tin
g 
A
ut
os
om
al
3
q2
1
R
A
B
7
R
A
S-
re
la
te
d 
G
TP
-
M
is
se
ns
e 
m
ut
at
io
ns
fe
at
ur
es
, n
or
m
al
 o
r 
do
m
in
an
t
bi
nd
in
g 
pr
ot
ei
n 
7
sl
ig
ht
ly
 re
du
ce
d 
N
C
Vs
H
M
SN
 II
B
1
 
6
0
5
5
8
8
Sl
ow
 N
C
Vs
A
ut
os
om
al
1
q2
1
.2
LM
N
A
La
m
in
 A
/C
M
is
se
ns
e 
m
ut
at
io
n
re
ce
ss
iv
e
(A
rg
2
9
8
C
ys
)
H
M
SN
 II
C
 
6
0
6
0
7
1
W
ea
kn
es
s 
of
 v
oc
al
 c
or
d
A
ut
os
om
al
U
nk
no
w
n
U
nk
no
w
n
U
nk
no
w
n
U
nk
no
w
n
an
d 
in
te
rc
os
ta
l m
us
cl
es
,
do
m
in
an
t
no
rm
al
 N
C
Vs
H
M
SN
 II
D
 
6
0
1
4
7
2
W
ea
kn
es
s 
an
d 
w
as
tin
g
A
ut
os
om
al
7
p1
5
G
A
R
S
G
ly
cy
l-t
R
N
A
M
is
se
ns
e 
m
ut
at
io
ns
of
 h
an
d 
at
 o
ns
et
,
do
m
in
an
t
sy
nt
he
ta
se
no
rm
al
 N
C
Vs
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 13
Hereditary Motor and Sensory Neuropathy14
C
la
ss
ifi
ca
tio
n 
M
IM
D
is
tin
gu
is
hi
ng
In
he
rit
an
ce
C
hr
om
os
om
al
 
G
en
e
P
ro
du
ct
M
ut
at
io
na
l s
pe
ct
ru
m
cl
in
ic
al
 fe
at
ur
es
lo
ca
tio
n
H
M
SN
 II
E 
6
0
7
6
8
4
N
or
m
al
 o
r s
lig
ht
ly
 
A
ut
os
om
al
8
p2
1
N
EF
L
N
eu
ro
fil
am
en
t p
ro
te
in
,
M
is
se
ns
e 
m
ut
at
io
ns
re
du
ce
d 
N
C
Vs
do
m
in
an
t
lig
ht
 p
ol
yp
ep
tid
e 
M
SN
 II
F 
6
0
6
5
9
5
N
or
m
al
 N
C
Vs
 
A
ut
os
om
al
7
q1
1
–q
2
1
U
nk
no
w
n
U
nk
no
w
n
U
nk
no
w
n
do
m
in
an
t
H
M
SN
 II
G
 
6
0
7
7
0
6
N
or
m
al
 o
r s
lig
ht
ly
A
ut
os
om
al
8
q1
3
–q
2
1
.1
G
D
A
P
1
G
an
gl
io
si
de
-in
du
ce
d 
N
on
se
ns
e 
m
ut
at
io
ns
re
du
ce
d 
N
C
Vs
 w
ith
 
re
ce
ss
iv
e
di
ffe
re
nt
ia
tio
n-
vo
ca
l c
or
d 
pa
re
si
s
as
so
ci
at
ed
 p
ro
te
in
 1
H
M
SN
 II
H
 
6
0
7
7
3
1
 
–
A
ut
os
om
al
8
q2
1
.3
U
nk
no
w
n
U
nk
no
w
n
U
nk
no
w
n
re
ce
ss
iv
e
H
M
SN
 II
 I 
6
0
7
6
7
7
N
or
m
al
 o
r s
lig
ht
ly
 
A
ut
os
om
al
1
q2
2
M
P
Z
M
ye
lin
 p
ro
te
in
 z
er
o
M
is
se
ns
e 
m
ut
at
io
ns
 (t
w
o
re
du
ce
d 
N
C
Vs
do
m
in
an
t
pa
tie
nt
s 
ha
d 
th
re
e 
di
ffe
re
nt
m
is
se
ns
e 
m
ut
at
io
ns
 in
th
e 
sa
m
e 
al
le
le
)
H
M
SN
 II
J 
6
0
7
7
3
6
N
or
m
al
 o
r s
lig
ht
ly
 
A
ut
os
om
al
1
q2
2
M
P
Z
M
ye
lin
 p
ro
te
in
 z
er
o
M
is
se
ns
e 
m
ut
at
io
ns
re
du
ce
d 
N
C
Vs
 w
ith
do
m
in
an
t
(T
hr
1
2
4
M
et
 o
r A
sp
7
5
Va
l)
pa
pi
lla
ry
 a
bn
or
m
al
iti
es
an
d 
de
af
ne
ss
H
M
SN
 II
K
 
6
0
7
8
3
1
Sl
ig
ht
ly
 re
du
ce
d 
N
C
Vs
A
ut
os
om
al
8
q1
3
–q
2
1
.1
G
D
A
P
1
G
an
gl
io
si
de
-in
du
ce
d
H
om
oz
yg
os
ity
 fo
r 
w
ith
 o
ns
et
 in
 e
ar
ly
 
re
ce
ss
iv
e
di
ffe
re
nt
ia
tio
n-
Se
r1
9
4
St
op
ch
ild
ho
od
as
so
ci
at
ed
 p
ro
te
in
 1
m
ut
at
io
n
H
M
SN
 II
I/
1
4
5
9
0
0
Se
e 
te
xt
 
A
ut
os
om
al
1
7
p1
1
.2
P
M
P
2
2
Pe
rip
he
ra
l m
ye
lin
M
is
se
ns
e 
an
d
D
ej
er
in
e–
So
tt
as
do
m
in
an
t
pr
ot
ei
n 
2
2
 
fr
am
e-
sh
ift
 m
ut
at
io
n
sy
nd
ro
m
e
A
ut
os
om
al
1
q2
2
 
M
P
Z
M
ye
lin
 p
ro
te
in
 z
er
o 
M
is
se
ns
e 
m
ut
at
io
ns
 
do
m
in
an
t
A
ut
os
om
al
1
0
q2
1
.1
–q
2
2
.1
EG
R
2
Ea
rly
 g
ro
w
th
 
M
is
se
ns
e 
m
ut
at
io
n
do
m
in
an
t
re
sp
on
se
 2
(A
rg
3
5
9
Tr
p)
A
ut
os
om
al
1
7
p1
1
.2
P
M
P
2
2
Pe
rip
he
ra
l m
ye
lin
1
.5
-M
b 
du
pl
ic
at
io
n 
of
re
ce
ss
iv
e 
pr
ot
ei
n 
2
2
 
1
7
p1
1
.2
, i
nc
lu
di
ng
 
P
M
P
2
2
in
 b
ot
h 
al
le
le
s 
or
du
pl
ic
at
io
n 
of
 o
ne
 a
lle
le
 
an
d 
a 
po
in
t m
ut
at
io
n
(u
su
al
ly
 a
 m
is
se
ns
e 
m
ut
at
io
n)
 in
 th
e 
ot
he
r a
lle
le
A
ut
os
om
al
1
9
q1
3
.1
–q
1
3
.2
P
R
X
Pe
ria
xi
n 
N
on
se
ns
e 
an
d 
re
ce
ss
iv
e 
fr
am
e-
sh
ift
 m
ut
at
io
ns
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 14
C
la
ss
ifi
ca
tio
n 
M
IM
D
is
tin
gu
is
hi
ng
In
he
rit
an
ce
C
hr
om
os
om
al
 
G
en
e
P
ro
du
ct
M
ut
at
io
na
l s
pe
ct
ru
m
cl
in
ic
al
 fe
at
ur
es
lo
ca
tio
n
H
M
SN
 IV
A
 
2
1
4
4
0
0
B
ot
h 
a 
de
m
ye
lin
at
in
g 
A
ut
os
om
al
8
q1
3
–q
2
1
.1
G
D
A
P
1
G
an
gl
io
si
de
-in
du
ce
d
D
em
ye
lin
at
in
g 
ty
pe
:
an
d 
an
 a
xo
na
l f
or
m
re
ce
ss
iv
e
di
ffe
re
nt
ia
tio
n-
no
ns
en
se
 a
nd
ar
e 
re
co
gn
iz
ed
. 
as
so
ci
at
ed
m
is
se
ns
e 
m
ut
at
io
ns
A
xo
na
l t
yp
e:
 
pr
ot
ei
n 
1
A
xo
na
l t
yp
e:
pa
tie
nt
s 
ca
n 
ha
ve
 
no
ns
en
se
, m
is
se
ns
e,
 a
nd
vo
ca
l c
or
d 
pa
re
si
s
fr
am
e-
sh
ift
 m
ut
at
io
ns
H
M
SN
 IV
B
1
 
6
0
1
3
8
2
Sl
ow
 N
C
Vs
A
ut
os
om
al
1
1
q2
2
M
TM
R
2
M
yo
tu
bu
la
rin
-r
el
at
ed
N
on
se
ns
e,
 fr
am
e-
sh
ift
,
re
ce
ss
iv
e
pr
ot
ei
n 
2
an
d 
sp
lic
e-
si
te
 m
ut
at
io
ns
H
M
SN
 IV
B
2
 
6
0
4
5
6
3
Sl
ow
 N
C
Vs
A
ut
os
om
al
1
1
p1
5
S
B
F2
SE
T-
bi
nd
in
g 
fa
ct
or
 2
 
N
on
se
ns
e 
m
ut
at
io
ns
re
ce
ss
iv
e
an
d 
in
-f
ra
m
e 
de
le
tio
n
H
M
SN
 IV
C
 
6
0
1
5
9
6
Sl
ow
 N
C
Vs
A
ut
os
om
al
5
q3
2
U
nk
no
w
n
U
nk
no
w
n
U
nk
no
w
n
re
ce
ss
iv
e
H
M
SN
 IV
D
/ 
6
0
1
4
5
5
O
ns
et
 in
 fi
rs
t d
ec
ad
e,
A
ut
os
om
al
8
q2
4
.3
N
D
R
G
1
N
-m
yc
 d
ow
ns
tr
ea
m
-
N
on
se
ns
e 
m
ut
at
io
n
H
M
SN
 L
 
ea
rly
-o
ns
et
 d
ea
fn
es
s,
 
re
ce
ss
iv
e
re
gu
la
te
d 
ge
ne
 1
(A
rg
1
4
8
St
op
) 
(s
ee
 te
xt
)
sl
ow
 N
C
Vs
pr
ot
ei
n
H
N
P
P
 
1
6
2
5
0
0
Se
e 
te
xt
A
ut
os
om
al
1
7
p1
1
.2
P
M
P
2
2
Pe
rip
he
ra
l m
ye
lin
 
O
ve
r 8
5
%
 o
f p
at
ie
nt
s 
do
m
in
an
t
pr
ot
ei
n 
2
2
 
ha
ve
 a
 1
.5
-M
b 
de
le
tio
n 
of
 1
7
p1
1
.2
, i
nc
lu
di
ng
P
M
P
2
2
. T
he
 re
m
ai
nd
er
ha
ve
 fr
am
e-
sh
ift
 o
r s
pl
ic
e-
si
te
 m
ut
at
io
ns
 th
at
 re
su
lt 
in
lo
ss
 o
f f
un
ct
io
n 
of
 th
e 
ge
ne
C
H
N
 
6
0
5
2
5
3
Se
e 
te
xt
 
A
ut
os
om
al
1
q2
2
M
P
Z
M
ye
lin
 p
ro
te
in
 z
er
o
N
on
se
ns
e 
m
ut
at
io
n
do
m
in
an
t
A
ut
os
om
al
1
0
q2
1
.1
–q
2
2
.1
EG
R
2
Ea
rly
 g
ro
w
th
D
ou
bl
e 
m
is
se
ns
e 
m
ut
at
io
n
do
m
in
an
t
re
sp
on
se
 2
 
(o
n 
sa
m
e 
al
le
le
)
A
ut
os
om
al
 
1
0
q2
1
.1
–q
2
2
.1
EG
R
2
 
Ea
rly
 g
ro
w
th
 
M
is
se
ns
e 
m
ut
at
io
n
re
ce
ss
iv
e 
re
sp
on
se
 2
 
Ta
bl
e 
1
.H
er
ed
ita
ry
 m
ot
or
 a
nd
 s
en
so
ry
 n
eu
ro
pa
th
ie
s 
(H
M
SN
s)
: c
la
ss
ifi
ca
tio
ns
, i
nh
er
ita
nc
e 
pa
tt
er
ns
, a
nd
 m
ol
ec
ul
ar
 g
en
et
ic
s.
 C
H
N
: c
on
ge
ni
ta
l h
yp
om
ye
lin
at
in
g
ne
ur
op
at
hy
; H
N
P
P:
 h
er
ed
ita
ry
 n
eu
ro
pa
th
y 
w
ith
 li
ab
ili
ty
 to
 p
re
ss
ur
e 
pa
ls
ie
s;
 N
C
V:
 n
er
ve
 c
on
du
ct
io
n 
ve
lo
ci
ty
.
Progressive Ataxias and Neurologic Disorders 15
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 15
HereditaryMotor and Sensory Neuropathy16
of HMSN. Mutant protein may have an increased tendency to form
conducting hemichannels compared with normal protein. This could
prevent the normal functioning of Schwann cells and neurons by
increasing their membrane permeability.
KIF1B has 47 exons and encodes an N-terminal-type motor protein 
with 1,816 amino acids. It acts as a motor for the anterograde transport
of mitochondria. A mutation in this gene could result in the production 
of a mutant protein without any motor activity. The precise mechanism
by which a mutation in this gene causes HMSN IIA is unknown.
RAB7 has six exons and encodes a ubiquitously expressed protein 
with 207 amino acids called RAS-associated protein 7. This is a small
GTPase, which is a member of the RAS-related GTP-binding protein
family. It is believed to be involved in vesicular transport of proteins. 
It is not understood how mutations in this gene result in HMSN IIB.
LMNA has 10 exons and codes for two proteins by alternative splicing 
of its exons. The gene products include lamin A and lamin C. Both
proteins are components of the nuclear lamina. The mechanisms by
which mutations in this gene cause HMSN IIB1 are not understood.
Mutations in LMNA can cause several other conditions (see LGMD 
entry, p.18).
GARS has 17 exons and encodes glycyl-tRNA synthetase. This is 
an enzyme with 685 amino acids that catalyses the esterification 
of glycine to its cognate tRNA during protein synthesis. Missense
mutations in GARS cause HMSN IID and an autosomal dominant 
form of distal spinal muscular atrophy (type V, MIM 600794) by 
an unknown mechanism.
GDAP1 has six exons and codes for ganglioside-induced differentiation-
associated protein. This has 358 amino acids and may be involved in
the signal transduction pathway in neuronal development. The precise
mechanism by which mutations in GDAP1 cause HMSN IIG, IIK, and
IVA is not understood.
PRX contains six exons and produces two mRNA transcripts. One
transcript produces L-periaxin and the other S-periaxin. Both proteins
are expressed in Schwann cells and interact with the C-termini of
plasma membrane proteins and with cytoskeletal proteins, and are
required for the maintenance of peripheral nerve myelin. Mutations 
in this gene cause a form of HMSN III.
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 16
Progressive Ataxias and Neurologic Disorders 17
MTMR2 is composed of 15 exons. Its protein product, myotubularin-
related protein 2, has 643 amino acids and is ubiquitously expressed.
It is a dual-specificity phosphatase with homology to myotubularin. 
It is not understood how mutations in this gene cause HMSN IVB1.
SBF2 is a large gene with 43 exons. Its protein product, SET-binding
factor 2, has 1,849 amino acids and is a member of the pseudophosphatase
branch of myotubularin-related proteins. It is expressed in fetal brain,
spinal cord, and peripheral nerves and is involved in the differentiation
of Schwann cells during myelination. Mutations in SBF2 cause HMSN IVB2.
NDRG1 has 16 exons. Its protein product has 394 amino acids and 
is ubiquitously expressed. It appears to be expressed at particularly 
high levels in Schwann cells. NDRG1 protein is involved in growth 
arrest and cell differentiation, and it appears to have a role in Schwann
cell signaling that is necessary for axonal survival. Mutations in NDRG1
cause HMSN IVD (this condition is also called HMSN, Lom type, or
HMSN L because it only affects members of the Gypsy community 
of Lom in Bulgaria).
Genetic diagnosis PMP22, MPZ, and CX32 mutation analysis is available from several 
and counseling diagnostic laboratories. However, testing for mutations in the other
genes is not routinely available at this time. All autosomal dominant 
and sporadic cases of HMSN I should be tested for mutations in 
PMP22 and MPZ. Patients from X-linked dominant HMSN families,
sporadic male cases with HMSN I, and sporadic female cases with
HMSN II should also be tested for mutations in CX32.
Detailed pedigree analysis can often establish the mode of inheritance 
of HMSN in a family and allow accurate genetic advice to be given to
other family members. HMSN I can show remarkable interfamilial and
intrafamilial variability of expression. Therefore, parents of an apparently
sporadic case should be carefully examined and offered nerve conduction
studies to determine whether one parent is mildly affected. Predictive
testing can be offered to at-risk members of families in which a mutation
has been identified.
Counseling in HNPP families is carried out on an autosomal-
dominant basis.
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 17
Limb-girdle Muscular Dystrophy18
Limb-girdle Muscular Dystrophy
(also known as: LGMD)
The LGMDs are a group of hereditary muscle disorders that predominantly affect the shoulder
and pelvic girdles. There are several autosomal dominant (LGMD1) and autosomal recessive
(LGMD2) forms with remarkable locus heterogeneity. Table 2 summarizes the classification,
distinguishing clinical features, inheritance pattern, and molecular genetics of the various
forms of LGMD.
MIM See Table 2.
Clinical features The LGMDs are a clinically and genetically heterogeneous group 
of disorders. Affected individuals present with proximal weakness 
of the upper and lower limbs.
Age of onset See Table 2.
Epidemiology LGMDs affect all populations, but their incidence varies in different
populations. Autosomal dominant forms only account for about 10% of
cases. Mutations in one of the sarcoglycan genes (sarcoglycanopathies)
can be seen in 8%–25% of patients with LGMD. In most populations 
the most frequently seen form of LGMD is LGMD2A, which accounts 
for 40%–45% of cases. However, LGMD2I is probably the most
common form of LGMD in the UK.
Inheritance, See Table 2.
chromosomal
location,
and gene 
Molecular TTID is composed of 10 exons and codes for a structural muscle protein 
pathogenesis with 498 amino acids called titin immunoglobulin domain protein or
myotilin. This is a thin, filament-associated, Z-disc protein that binds to
α-actinin, F-actin, and filamin c. It cross-links actin filaments and controls
sarcomere assembly, and is believed to play an important role in the
stabilization and anchorage of thin filaments. Mutations in TTID probably
cause LGMD by interfering with the proper organization of Z-discs.
LMNA contains 10 exons and encodes two proteins as a result of
alternative splicing of its exons. These proteins include lamin A 
(664 amino acids) and lamin C (572 amino acids). Both lamins 
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 18
Progressive Ataxias and Neurologic Disorders 19
are nuclear envelope proteins. How mutations in LMNA cause LGMD 
is not known. Mutations in LMNA have also been described in several
other conditions, including an autosomal dominant form of dilated
cardiomyopathy (type 1A, MIM 115200), an autosomal dominant form
of Emery–Dreifuss muscular dystrophy (MIM 181350), Dunnigan type
partial lipodystrophy (MIM 151660), an autosomal recessive form of
HMSN (HMSN IIB1, MIM 605588 – see p.13), and two dysmorphic
syndromes associated with premature ageing: Hutchinson-Gilford
syndrome or progeria (MIM 176670) and mandibuloacral dysplasia
(MIM 248370).
CAV3 contains three exons and encodes caveolin 3, which has
131 amino acids. Caveolin 3 is the muscle-specific form of the caveolin
protein family. Caveolins are the main protein components of caveolae
(50–100 nm invaginations of plasma membranes). Mutations in CAV3
act in a dominant-negative manner by interfering with oligomerization 
of caveolin 3. This disrupts caveolae formation in the sarcolemmal
membrane. Caveolin 3 interacts with dysferlin at the surface of the
sarcolemmal membrane, and is also involved in normal expression 
of α-dystroglycan at the sarcolemmal surface. Caveolin 3 deficiency
could therefore result in muscular dystrophy by interfering with the
normal expression of dysferlin and α-dystroglycan.
CAPN3 has 24 exonsand encodes an 821-amino-acid protein called
calpain 3. This is a muscle-specific, calcium-dependent protease.
It appears to have a role in controlling the levels of muscle-specific
transcription factors, though the precise role of calpain 3 in muscle 
and the mechanism by which a deficiency of this protein causes
muscular dystrophy are unknown.
DYSF is a large gene with 55 exons. It encodes dysferlin, a 2,080 
amino-acid protein that localizes to the sarcolemmal membrane and
co-immunoprecipitates with caveolin 3 in skeletal muscle. It is expressed
very early in human development. Studies in mice have shown that
dysferlin has an essential role in the resealing of the sarcolemma in
response to injury. Therefore, mutations in DYSF probably cause
muscular degeneration by disrupting the muscle membrane repair
machinery. Mutations in DYSF have also been identified in Miyoshi
myopathy, an autosomal recessive distal myopathy (MIM 254130).
SGCA has eight exons and encodes α-sarcoglycan (also called 50-kDa
dystrophin-associated glycoprotein [DAG]), which has 387 amino acids.
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 19
Limb-girdle Muscular Dystrophy
C
la
ss
ifi
ca
tio
n 
M
IM
D
is
tin
ct
iv
e
A
ge
 o
f
In
he
rit
an
ce
C
hr
om
os
om
al
G
en
e
P
ro
te
in
 p
ro
du
ct
 
M
ut
at
io
na
l s
pe
ct
ru
m
 
cl
in
ic
al
on
se
t
lo
ca
tio
n
fe
at
ur
es
LG
M
D
1
A
 
1
5
9
0
0
0
D
ys
ar
th
ria
1
8
–3
5
 y
ea
rs
A
ut
os
om
al
5
q3
1
TT
ID
Ti
tin
 im
m
un
og
lo
bu
lin
-M
is
se
ns
e 
m
ut
at
io
ns
do
m
in
an
t
do
m
ai
n 
pr
ot
ei
n 
or
m
yo
til
in
LG
M
D
1
B
 
1
5
9
0
0
1
C
ar
di
ac
 in
vo
lv
em
en
t,
4
–3
8
 y
ea
rs
A
ut
os
om
al
1
q2
1
.2
LM
N
A
La
m
in
 A
/C
 
M
is
se
ns
e 
an
d 
sp
lic
e-
si
te
 
pa
rt
ic
ul
ar
ly
 c
ar
di
ac
do
m
in
an
t
m
ut
at
io
ns
, 3
-b
p 
de
le
tio
n
co
nd
uc
tio
n 
de
fe
ct
s
LG
M
D
1
C
 
6
0
1
2
5
3
M
us
cl
e 
cr
am
ps
,
~
5
 y
ea
rs
A
ut
os
om
al
3
p2
5
C
AV
3
C
av
eo
lin
 3
M
is
se
ns
e 
m
ut
at
io
ns
ca
lf 
hy
pe
rt
ro
ph
y,
do
m
in
an
t
an
d 
9
-b
p 
de
le
tio
n
m
od
er
at
el
y 
el
ev
at
ed
C
K
 le
ve
ls
 
LG
M
D
1
D
6
0
3
5
1
1
N
on
e
A
du
lth
oo
d
A
ut
os
om
al
7
q
U
nk
no
w
n
U
nk
no
w
n
U
nk
no
w
n
do
m
in
an
t
LG
M
D
 w
ith
6
0
2
0
6
7
D
ila
te
d
1
5
–2
0
 y
ea
rs
A
ut
os
om
al
6
q2
3
U
nk
no
w
n
U
nk
no
w
n
U
nk
no
w
n
di
la
te
d
ca
rd
io
m
yo
pa
th
y
do
m
in
an
t
ca
rd
io
m
yo
pa
th
y
w
ith
 c
ar
di
ac
 
co
nd
uc
tio
n
de
fe
ct
s
LG
M
D
2
A
 
2
5
3
6
0
0
C
on
tr
ac
tu
re
s 
of
 
8
–1
5
 y
ea
rs
A
ut
os
om
al
15
q1
5.
1–
q2
1.
1
C
A
P
N
3
C
al
pa
in
 3
M
is
se
ns
e 
an
d 
sp
lic
e-
si
te
te
nd
o-
A
ch
ill
es
 a
nd
re
ce
ss
iv
e
m
ut
at
io
ns
, s
m
al
l d
el
et
io
ns
ot
he
r s
ite
s,
 s
ca
pu
la
r
an
d 
in
se
rt
io
ns
w
in
gi
ng
, h
ip
 
ab
du
ct
or
s 
sp
ar
ed
LG
M
D
2
B
 
6
0
3
0
0
9
In
ab
ili
ty
 to
 w
al
k 
on
La
te
 te
en
s
A
ut
os
om
al
2
p1
3
.1
–p
1
3
.3
D
YS
F
D
ys
fe
rli
n
M
is
se
ns
e,
 fr
am
e-
sh
ift
, 
tip
to
e,
 c
al
f a
tr
op
hy
,
re
ce
ss
iv
e
an
d 
sp
lic
e-
si
te
 m
ut
at
io
ns
m
ar
ke
dl
y 
el
ev
at
ed
 
C
K
 le
ve
ls
LG
M
D
2
C
 
2
5
3
7
0
0
C
al
f h
yp
er
tr
op
hy
C
hi
ld
ho
od
A
ut
os
om
al
1
3
q1
2
 
S
G
C
G
γ-
Sa
rc
og
ly
ca
n
Sm
al
l d
el
et
io
ns
re
ce
ss
iv
e
LG
M
D
2
D
 
6
0
0
1
1
9
 
To
e-
w
al
ki
ng
, m
us
cl
e 
3
–1
5
 y
ea
rs
A
ut
os
om
al
1
7
q1
2
–q
2
1
.3
3
S
G
C
A
α-
Sa
rc
og
ly
ca
n 
N
on
se
ns
e,
 m
is
se
ns
e,
 
cr
am
ps
, s
ca
pu
la
r
re
ce
ss
iv
e
an
d 
sp
lic
e-
si
te
 m
ut
at
io
ns
, 
w
in
gi
ng
, c
al
f
du
pl
ic
at
io
ns
. E
xo
n
3
hy
pe
rt
ro
ph
y 
m
ut
at
io
na
l h
ot
sp
ot
. 
A
rg
7
7
C
ys
 m
ut
at
io
n 
ac
co
un
ts
fo
r ~
4
0
%
 o
f a
ll 
m
ut
at
io
ns
20
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 20
Progressive Ataxias and Neurologic Disorders 21
C
la
ss
ifi
ca
tio
n 
M
IM
D
is
tin
ct
iv
e
A
ge
 o
f
In
he
rit
an
ce
C
hr
om
os
om
al
G
en
e
P
ro
te
in
 p
ro
du
ct
 
M
ut
at
io
na
l s
pe
ct
ru
m
 
cl
in
ic
al
on
se
t
lo
ca
tio
n
fe
at
ur
es
LG
M
D
2
E 
6
0
4
2
8
6
N
on
e
C
hi
ld
ho
od
A
ut
os
om
al
4
q1
2
S
G
C
B
β-
Sa
rc
og
ly
ca
n
M
is
se
ns
e 
an
d 
pr
ot
ei
n-
re
ce
ss
iv
e
tr
un
ca
tin
g 
m
ut
at
io
ns
 
LG
M
D
2
F 
6
0
1
2
8
7
C
ar
di
om
yo
pa
th
y,
4
–1
0
 y
ea
rs
 
A
ut
os
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P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 21
Limb-girdle Muscular Dystrophy22
SGCB has only six exons and encodes a protein with 318 amino acids,
which is called β-sarcoglycan (43-kDa DAG). SGCD has nine exons 
and encodes δ-sarcoglycan (35-kDa DAG), which has 290 amino acids.
SGCG is composed of eight exons and codes for γ-sarcoglycan (35-kDa
DAG). This protein also has 290 amino acids. The sarcoglycans are
transmembrane proteins that are an important component of the
dystrophin–glycoprotein complex at the sarcolemmal membrane. 
The components of this complex link dystrophin inside the sarcolemma
to the laminin α2 chain of merosin and other proteins in the extracellular
matrix. The dystrophin–glycoprotein complex is believed to play a
critical role in maintaining the integrity of the sarcolemmal membrane,
particularly during muscle contraction. Therefore, absence or deficiency
of the critical components of this complex can result in the phenotype 
of muscular dystrophy. Heterozygous mutations in SGCD can also 
cause one form of dilated cardiomyopathy type 1L (MIM 606685).
TCAP is a small gene with only two exons. It encodes a structural
sarcomeric protein called titin cap or telethonin. This protein has 
167 amino acids and localizes to the Z-disc of adult skeletal muscle.
TRIM32 has two exons and encodes a protein with 653 amino acids. 
Its protein product, TRIM 32 protein, is thought to be an E3ubiquitin
ligase. The mechanism by which mutations in this gene result in the
LGMD phenotype is unknown.
FKRP is composed of four exons and encodes fukutin-related protein,
which has 495 amino acids. Fukutin-related protein is probably a
Golgi-resident glycosyltransferase that is involved in the glycosylation 
of α-dystroglycan. This protein links the dystrophin–glycoprotein
complex to various extracellular proteins, including the laminin α2 
chain of merosin, neurexin, and agrin. Deficiency of fukutin-related
protein probably results in muscular dystrophy due to aberrant
glycosylation of α-dystroglycan.
Genetic diagnosis The diagnosis of LGMD is made by the combination of clinical features,
and counseling immunohistochemistry on a muscle biopsy sample, and molecular genetic
analysis. Immunohistochemistry and genetic testing are only available
from a few specialized laboratories. Interpretation of the results of muscle
immunohistochemistry is difficult and should only be carried out by
laboratories experienced in the use of this technique. It is important to
rule out facioscapulohumeral muscular dystropy and Emery–Dreifuss
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 22
Progressive Ataxias and Neurologic Disorders 23
muscular dystrophy in families that appear to have an autosomal
dominant form of LGMD. In large families with an autosomal recessive
form of LGMD, linkage analysis might allow the precise form of LGMD 
to be identified. However, this should always be confirmed by muscle
immunohistochemistry or mutation analysis of the relevant gene.
Because of the genetic heterogeneity of LGMD, genetic counseling is
difficult. Accurate genetic counseling and prenatal diagnosis are only
possible in families where a definitive diagnosis can be made by muscle
immunohistochemistry and genetic testing. Accurate counseling is 
also possible in large families with several affected members, where 
it is possible to determine the precise mode of inheritance (autosomal
recessive or dominant). Isolated cases of LGMD could represent an
autosomal recessive form of LGMD or a new autosomal dominant mutation.
Myotonic Dystrophy
(also known as: MD; dystrophia myotonica; Steinert disease. 
Includes proximal myotonic myopathy [PROMM])
MIM 160900 (MD1)
602668 (MD2)
600109 (PROMM)
Clinical features Four forms of MD1 can be recognized based on age of onset and clinical
features. These include a mild form, an adult or classical form, a congenital
form, and a childhood or juvenile form. Patients with mild MD usually
present with presenile cataracts. The classical form of MD is a multisystem
disorder. Symptoms include: muscle weakness and wasting, grip and
percussion myotonia, cardiac arrhythmias that can present as syncope 
or sudden death, gastrointestinal problems, cataracts, an increased
incidence of diabetes mellitus, and testicular atrophy in males. 
The distribution of muscle weakness and wasting is characteristic and 
is responsible for the well-recognized facial features of this condition.
These include frontal balding, ptosis, facial weakness, bitemporal
narrowing (due to wasting of the temporalis muscles), wasting of the jaw
muscles, and a slender neck due to wasting of the sternomastoids. Early
appearance and progression of male pattern baldness is also a feature.
Distal limb muscles tend to be affected earlier than proximal muscles.
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 23
Myotonic Dystrophy24
Congenital MD is the most severe form of this disease and is the result 
of anticipation. It can present antenatally as reduced fetal movements
and polyhydramnios, or in the neonatal period as severe hypotonia,
respiratory distress (often requiring ventilation), feeding difficulties,
facial weakness, cardiac problems (cardiomyopathy or arrhythmias),
and talipes or arthrogryposis. A chest X-ray will often show thin ribs.
Many patients with congenital MD die in childhood. Survivors show
delayed development and have learning difficulties and characteristic
facies (facial diplegia, an open-mouthed appearance with a tented 
upper lip, and a prominent, everted lower lip). 
A childhood or juvenile form of this condition has also been described.
These patients usually present between 1 and 10 years of age with
speech and language delay and learning difficulties, although some
patients present with muscle weakness and myotonia at school age.
MD2 and PROMM are probably a single entity as they have similar
clinical features and are allelic or have very closely linked genes.
Patients with these conditions present with slowly progressive proximal
muscle weakness, mild myotonia, cardiac arrhythmias, and late-onset
cataracts. White matter changes have been described in some families.
Features that help to distinguish these conditions from the classical form
of MD1 include the absence of facial weakness and the characteristic
facial features that are seen in patients with classical MD, absent 
or minimal distal limb weakness, and the presence of myalgia.
Age of onset The mild form of MD1 presents in late adult life, the classical form
presents in late adolescence or early adult life, the congenital form
presents antenatally or in the neonatal period, and the childhood 
or juvenile form presents in early childhood.
MD2 and PROMM present in adulthood.
Epidemiology MD1 has an estimated incidence of 1 in 8,000. It appears to be
particularly prevalent in the Saguenay-Lac-St-Jean region of Canada,
where its prevalence is 1 in 475.
MD2 and PROMM are rare disorders. Their population incidence 
and prevalence are unknown.
Inheritance MD1: autosomal dominant
MD2/PROMM: autosomal dominant
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 24
Progressive Ataxias and Neurologic Disorders 25
Chromosome MD1: 19q13.3
location MD2/PROMM: 3q13.3–q24
Genes MD1: DMPK (dystrophia myotonica protein kinase)
MD2/PROMM: ZNF9 (zinc finger protein 9)
Mutational MD1 is caused by the expansion of a CTG triplet repeat motif in
spectrum the 3́ -untranslated region of the last exon of DMPK. In the general
population, the number of CTG repeats varies from 5 to 37. Affected
individuals have more than 50 repeats and there appears to be a
correlation between the number of repeats and the severity of the
phenotype. Repeat sizes of 50–100 are associated with the mild form 
of MD, whereas repeat sizes of between 500 and 1,500 result in the
congenital MD phenotype. Expansions of between 100 and 500 are
usually associated with classical MD, but it is not possible to predict 
the age of onset or the severity of disease in this group of patients.
The CTG repeat shows meiotic instability and its size tends to increase 
in successive generations. This is responsible for the phenomenon of
anticipation, in which the phenotype of a disease increases in severity 
in successive generations. Maternal transmission can be associated 
with a large expansion in the CTG repeat number, whereas paternal
transmission is usually associated with a modest expansion of the 
repeat or, in some cases, a decrease in the number of repeats. Thus,
congenital MD, which is caused by very large CTG repeat expansions, 
is almost always maternally transmitted. In contrast, the childhood 
or juvenile form of MD is more frequently paternally transmitted.
Patients with MD2/PROMM have an expansion of a CCTG repeat 
motif in the first intron of ZNF9. Affected individuals have between 
75 and 11,000 repeats, with an average of 5,000.
Molecular DMPK has 15 exons and produces two main protein isoforms of 71 kDa
pathogenesis and 80 kDa as a result of alternative splicing. Both of these isoforms are
predominantly expressed in skeletal and cardiac muscle. The precise
mechanism by which the CTG repeat expansion causes MD1 is unknown.
Interest has focused on the possibility that the allele with the CTG repeat
expansion produces mRNA that inappropriately binds to proteins via
CUG repeats (thymidine is replaced by uridine in RNA). One particular
protein (CUG-binding protein)is involved in processing mRNA from
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 25
Myotonic Dystrophy26
several other genes, including cardiac troponin T. Binding of CUG-binding
protein to the mRNA product of the DMPK allele with the CTG repeat
expansion could interfere with its ability to process the mRNAs of
several other genes, and altered expression of these genes could 
result in the MD1 phenotype. Thus, the CTG repeat expansion 
in DMPK would appear to be a gain-of-function mutation.
ZNF9 has five exons and encodes a protein with 177 amino acids. 
This protein has seven zinc-finger domains and is believed to be an
RNA-binding protein. Mutant ZNF9 mRNA accumulates in the nucleus 
and probably results in the MD2/PROMM phenotype in a manner
analogous to the expansions in the DMPK gene that cause MD1.
Genetic diagnosis Genetic testing for MD1 is widely available, so all patients with MD 
and counseling should have genetic testing to confirm the diagnosis. Patients whose
clinical features are suggestive of MD but who test negative for the 
CTG repeat expansion in DMPK are likely to have MD2/PROMM or an
alternative myotonic disorder. Counseling is on the basis of autosomal
dominant inheritance. Women with MD1 should be told that their
children could be affected with congenital MD as a result of anticipation.
Women who have neuromuscular disease or who have previously had 
an affected child with congenital MD are particularly at risk of having 
a baby with congenital MD. Patients with MD should be told that they 
are at risk of developing cardiac arrhythmias, cataracts, and diabetes
mellitus, and they should be under the care of a physician. They should
also be told about the complications of general anesthesia, including
malignant hyperthermia and postanesthetic apnea. Patients should 
be asked to carry an alert card or bracelet. Presymptomatic/predictive
genetic testing can be offered to those from families where a CTG repeat
expansion has been previously documented in an affected individual 
(and who therefore have a 50% risk of being affected). Prenatal diagnosis
is also available by testing DNA extracted from either a chorionic villus
sample or cultured amniocytes for the CTG repeat expansion.
Genetic testing for MD2/PROMM is only available on a research basis.
Counseling is as for autosomal dominant inheritance. Anticipation 
does occur, but is milder than that seen in MD1.
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 26
Progressive Ataxias and Neurologic Disorders 27
Spinal Muscular Atrophy
(also known as: SMA)
MIM 253300 (SMA type I/Werdnig–Hoffmann disease)
253550 (SMA type II)
253400 (SMA type III/Kugelberg–Welander syndrome)
Clinical features Children with SMA present with generalized muscle weakness and wasting,
hypotonia, and areflexia. The muscle weakness begins proximally, 
and characteristically involves the intercostal muscles and later the
diaphragm, but spares the extraocular muscles and facial muscles.
Fasciculation of the tongue and other muscles is a helpful diagnostic
clue. Childhood SMA is classified into three types based on age of onset,
extent of motor development, and prognosis. The most severe form is
SMA type I. Children with this condition never learn to sit and usually
die by the age of 2 years. Patients with SMA type II learn to sit without
support, but never learn to walk unaided. The prognosis is variable, with
some patients dying in childhood and others surviving to adulthood.
Patients with SMA type III are able to walk independently. They have
slowly progressive muscle weakness, and survive into adulthood.
Diagnosis can be confirmed by electromyography (which shows a
neurogenic pattern) and by muscle biopsy (which shows grouped
atrophy of both type I and II fibers, with hypertrophy of type I fibers).
Age of onset SMA type I: before 3 months
SMA type II: 3–18 months
SMA type III: after 18 months
Epidemiology The incidence of all forms of SMA is about 1 in 10,000 live births. 
SMA has been described in all ethnic groups. The heterozygote (carrier)
frequency is about 1 in 50.
Inheritance All forms of childhood SMA are inherited in an autosomal recessive
manner. However, a small proportion (~2%) of those with type II or III
may have a form inherited in an autosomal dominant manner.
Chromosomal 5q12.2–q13.3
location
Gene SMN1 (survival of motor neuron 1)
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 27
Spinal Muscular Atrophy28
Mutational There are two copies of the SMN gene: a telomeric copy (SMN1) 
spectrum and a centromeric copy (SMN2). There are only minor differences in 
the coding sequence of these two genes. Both genes are expressed, 
but SMN1 produces much higher levels of the functional full-length
transcript than SMN2. Because of the homology between these two
genes, gene conversion events are frequent, resulting in the conversion
of SMN1 to SMN2.
The vast majority of patients with SMA (~96%) are homozygous for a
deletion or gene conversion of SMN1. A small number of patients (~4%)
are compound heterozygotes with a deletion or gene conversion affecting
one SMN1 allele and a different mutation in the other allele. Other
mutations in SMN1 are rare, but can include point mutations (mostly
missense mutations and splice-site mutations) and frame-shift mutations.
The presence of multiple copies of SMN2 in patients homozygous for 
a deletion or gene conversion of SMN1 can modify the phenotype and
lead to less severe disease (SMA types II or III). Other genetic modifiers
of the phenotype have also been described (eg, splicing mechanisms 
of the SMN2 gene and deletion of the H4F5 gene that lies upstream 
of SMN1).
Molecular The protein product of the SMN1 and SMN2 genes is expressed in 
pathogenesis several areas, including the central nervous system, skeletal muscle,
heart, liver, kidneys, lungs, thymus, and pancreas. Within the central
nervous system it is expressed in the anterior horn cells of the spinal
cord. The SMN protein is localized to the cytoplasm and nucleus. 
In the nucleus it is localized in small, discrete, dot-like structures called
“gems”. It interacts with several small nuclear ribonucleoproteins and
appears to have an important role in the generation of the pre-mRNA
splicing machinery, and, therefore, in mRNA processing in the cell.
Although SMN1 is ubiquitously expressed, loss of function of this 
gene only results in degeneration of spinal motor neurons because 
these cells are believed to need high levels of SMN protein to survive.
Genetic diagnosis Genetic testing for SMA is routinely available. Carrier testing for 
and counseling SMA is also available from diagnostic laboratories. Counseling is 
on an autosomal recessive basis. Prenatal diagnosis can be offered 
to parents of children with SMA in whom the diagnosis has been
confirmed by genetic testing.
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 28
2. Cerebral Malformations and Mental
Retardation Syndromes
Angelman Syndrome 30
Fragile X Syndrome 34
Holoprosencephaly 36
Hunter Syndrome 40
Huntington Disease 41
Lesch–Nyhan Syndrome 43
Lissencephaly 45
Lowe Syndrome 52
Neuronal Ceroid Lipofuscinosis 53
Pelizaeus–Merzbacher Syndrome 57
Prader–Willi Syndrome 59
Rett Syndrome 61
X-linked Adrenoleukodystrophy 62
X-linked α-Thalassemia and Mental Retardation Syndrome 64
X-linked Hydrocephalus 66
2
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 29
Angelman Syndrome30
Angelman Syndrome
(also known as: AS; happy puppet syndrome)
MIM 105830
Clinical features Affected children show severe developmental delay with very limited
speech, ataxia, and easily provoked laughter; they have a happy
demeanor and excitable personality. Convulsions occur in 80%, 
usually with onset in early childhood. Other common features include
microcephaly, drooling, prognathism, hypopigmentation, and a scoliosis
(this can progress and require surgical correction). Life expectancy 
is relatively normal.
Age of onset