Table Of ContentDuchenne Muscular
Dystrophy
Oxford Monographs on Medical Genetics
General editors:
Judith G. Hall
Peter S. Harper
Louanne Hudgins
Evan Eichler
Charles J. Epstein (deceased 2011)
Arno G. Motulsky (resigned 2011)
35. H. Ostrer: Non-Mendelian Genetics in Humans
36. E. Traboulsi: Genetic Factors in Human Disease
37. G. L. Semenza: Transcription Factors and Human Disease
38. L. Pinsky, R. P. Erickson, and R. N. Schimke: Genetic Disorders of Human Sexual Development
39. R. E. Stevenson, C. E. Schwartz, and R. J. Schroer: X-Linked Mental Retardation
40. M. J. Khoury, W. Burke, and E. J. Thomson: Genetics and Public Health in the 21st Century
41. J. Weil: Psychosocial Genetic Counseling
42. R. J. Gorlin, M. M. Cohen, Jr., and R. C. M. Hennekam: Syndromes of the Head and Neck, Fourth
Edition
43. M. M. Cohen, Jr., G. Neri, and R. Weksberg: Overgrowth Syndromes
44. R. A. King, J. I. Rotter, and A. G. Motulsky: The Genetic Basis of Common Diseases, Second Edition
45. G. P. Bates, P. S. Harper, and L. Jones: Huntington’s Disease, Third Edition
46. R. J. M. Gardner and G. R. Sutherland: Chromosome Abnormalities and Genetic Counseling, Third
Edition
47. I. J. Holt: Genetics of Mitochondrial Disease
48. F. Flinter, E. Maher, and A. Saggar-Malik: The Genetics of Renal Disease
49. C. J. Epstein, R. P. Erickson, and A. Wynshaw-Boris: Inborn Errors of Development: The Molecular
Basis of Clinical Disorders of Morphogenesis
50. H. V. Toriello, W. Reardon, and R. J. Gorlin: Hereditary Hearing Loss and Its Syndromes, Second
Edition
51. P. S. Harper: Landmarks in Medical Genetics
52. R. E. Stevenson and J. G. Hall: Human Malformations and Related Anomalies, Second Edition
53. D. Kumar and S. D. Weatherall: Genomics and Clinical Medicine
54. C. J. Epstein, R. P. Erickson, and A. Wynshaw-Boris: Inborn Errors of Development: The Molecular
Basis of Clinical Disorders of Morphogenesis, Second Edition
55. W. Weber: Pharmacogenetics, Second Edition
56. P. L. Beales, I. S. Farooqi, and S. O’Rahilly: The Genetics of Obesity Syndromes
57. P. S. Harper: A Short History of Medical Genetics
58. R. C. M. Hennekam, I. D. Krantz, and J. E. Allanson: Gorlin’s Syndromes of the Head and Neck, Fifth
Edition
59. D. Kumar and P. Elliot: Principles and Practices of Cardiovascular Genetics
60. V. P. Sybert: Genetic Skin Disorders, Second Edition
61. R. J. M. Gardner, G. R. Sutherland, and L. C. Shaffer: Chromosome Abnormalities and Genetic
Counseling, Fourth Edition
62. D. Kumar: Genomics and Health in the Developing World
63. P. S. Harper: A Short History of Medical Genetics, Second Edition (online)
64. G. Bates, S. Tabrizi, and L. Jones: Huntington’s Disease, Fourth Edition
65. D. Kumar and C. Eng: Genomic Medicine: Principles and Practice, Second Edition
66. B. Lee and F. Scaglia: Inborn Errors of Metabolism
67. A. E. H. Emery, F. Muntoni, and R. C. M. Quinlivan: Duchenne Muscular Dystrophy, Fourth Edition
Duchenne Muscular
Dystrophy
FOURTH EDITION
Alan E H Emery
Francesco Muntoni
Rosaline Quinlivan
1
1
Great Clarendon Street, Oxford, OX2 6DP,
United Kingdom
Oxford University Press is a department of the University of Oxford.
It furthers the University’s objective of excellence in research, scholarship,
and education by publishing worldwide. Oxford is a registered trade mark of
Oxford University Press in the UK and in certain other countries
© Oxford University Press 2015
The moral rights of the authors have been asserted
Third Edition published in 2003
Fourth Edition published in 2015
Impression: 1
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, without the
prior permission in writing of Oxford University Press, or as expressly permitted
by law, by licence or under terms agreed with the appropriate reprographics
rights organization. Enquiries concerning reproduction outside the scope of the
above should be sent to the Rights Department, Oxford University Press, at the
address above
You must not circulate this work in any other form
and you must impose this same condition on any acquirer
Published in the United States of America by Oxford University Press
198 Madison Avenue, New York, NY 10016, United States of America
British Library Cataloguing in Publication Data
Data available
Library of Congress Control Number: 2014954274
ISBN 978–0–19968148–8
Printed and bound by
CPI Group (UK) Ltd, Croydon, CR0 4YY
Oxford University Press makes no representation, express or implied, that the
drug dosages in this book are correct. Readers must therefore always check
the product information and clinical procedures with the most up-to-date
published product information and data sheets provided by the manufacturers
and the most recent codes of conduct and safety regulations. The authors and
the publishers do not accept responsibility or legal liability for any errors in the
text or for the misuse or misapplication of material in this work. Except where
otherwise stated, drug dosages and recommendations are for the non-pregnant
adult who is not breast-feeding
Links to third party websites are provided by Oxford in good faith and
for information only. Oxford disclaims any responsibility for the materials
contained in any third party website referenced in this work.
Preface
The first edition of this book was published in 1987, at the time the gene for
Duchenne muscular dystrophy had been localized to the short arm of the
X chromosome. However, shortly after publication, the gene itself was isolated
and cloned, and its product dystrophin identified. This revolution in the history
of the subject precipitated the production of a revised edition the following
year! Over the subsequent 25 years, the subject has advanced considerably.
There now seems a real possibility of some form of effective gene therapy in the
not too distant future. Furthermore, these studies have subsequently been ap-
plied to other conditions, with the result that now some 50 different forms of
dystrophy have been identified, and, in most of these disorders, the responsible
gene and its protein product are now known.
In the preparation of this book, we should like to thank our various colleagues
for information and help. In this regard, we are particularly grateful to Professor
Caroline Sewry from Great Ormond Street Hospital for her help on specific as-
pects related to muscle pathology, to Dr Valeria Ricotti and Dr Adnan Manzur
also from Great Ormond Street Hospital, to Dr Anna Mayhew from Newcastle
University, and to all the colleagues of the UK North Star Network for their
contribution to the longitudinal data collection on more than 600 DMD boys
followed in the UK (<http://www.muscular-dystrophy.org/how_we_help_you/
for_professionals/clinical_databases>). The support of the Muscular Dystrophy
Campaign towards the North Star Network is also gratefully acknowledged, as
the support of both the MRC Translational Research Centre and Great Ormond
Street Hospital Biomedical Research Centre towards the activities of R. Q.
and F. M.
We should also like to thank Caroline Smith of Oxford University Press for
her professional and tireless help in the editing of this new edition.
We have endeavoured on occasions to draw attention to areas which may in-
dicate possible paths for future research. However, as in previous editions, we
have emphasized developments particularly relevant to the diagnosis, manage-
ment, and treatment of Duchenne muscular dystrophy.
Oxford/Exeter, A. E. H. E.
London, F. M. and R. Q.
Reproduced courtesy of the Wellcome Library, London under Creative Commons Attribution
Licence CC BY 4.0.
Contents
Symbols and abbreviations viii
1 Introduction to Duchenne muscular dystrophy 1
2 History of the disease 6
3 Clinical features 29
4 Confirmation of the diagnosis 52
5 Differential diagnosis 82
6 Involvement of tissues other than skeletal muscle 98
7 Biochemistry of Duchenne muscular dystrophy 117
8 Genetics 138
9 Molecular pathology 148
10 Pathogenesis 169
11 Prevention 185
12 Genetic counselling 213
13 Management 222
Appendix 1 Egen Klassifikation Scale Version 2 (EK2) 276
Appendix 2 The North Star Ambulatory Assessment 281
Appendix 3 Muscular Dystrophy Associations and Groups in
Various Countries (2013) 288
Index 299
Symbols and abbreviations
α alpha DAPC dystrophin-associated
β beta glycoprotein complex
δ delta der derived
γ gamma DEXA dual-energy X-ray
absorptiometry
µ mu
DMD Duchenne muscular dystrophy
θ theta
DNA deoxyribonucleic acid
~ approximately
ECG electrocardiogram
º degree
EEG electroencephalography
= equal to
EK Egen Klassifikation
≤ equal to or less than
EMG electromyography
< less than
ENMC European Neuromuscular
> more than
Centre
± plus or minus
FIGE field inversion gel
® registered trademark electrophoresis
FVC forced vital capacity
AAV adeno-associated virus g gram
ACE angiotensin-converting enzyme GABA gamma-aminobutyric acid
ADHD attention-deficit/hyperactivity GOT glutamic–oxaloacetic
disorder transaminase
ADP adenosine diphosphate GPT glutamic–pyruvic transaminase
AMP adenosine monophosphate HFDR high-frequency deletion
ATP adenosine triphosphate region
bFGF basic fibroblast growth factor HFMD hypertrophic feline muscular
BMD Becker muscular dystrophy dystrophy
bp base pair HLA human leucocyte antigen
Ca2+ calcium ion Ig immunoglobulin
[Ca2+] free intracellular calcium IGF insulin-like growth factor
i
CAMS children and adolescent mental IGF-1 insulin-like growth factor-1
health services IGFBP insulin growth factor-binding
cDNA complementary protein
deoxyribonucleic acid IQ intelligence quotient
CK creatine kinase IU international unit
cM centimorgan IV intravenous
CMD congenital muscular K+ potassium ion
dystrophy KAFO knee–ankle–foot orthosis
CT computerized tomography kb kilobase
Da dalton kDa kilodalton
SYMBOLS AND ABBREVIATIONS ix
kg kilogram NSAA North Star Ambulatory
L litre Assessment
LAMA2 laminin alpha 2 ORF open reading frame
LDH lactate dehydrogenase OTC ornithine transcarbamylase
LGMD limb-girdle muscular p probability
dystrophy pCO carbon dioxide tension
2
MAPH multiplex amplifiable probe PCR polymerase chain reaction
hybridization PERT phenol-enhanced reassociation
MAPK mitogen-activated protein technique
kinase PET positron emission
mb megabase tomography
MDC1A muscular dystrophy congenital PFGE pulsed-field gel electrophoresis
lA PK pyruvate kinase
mg milligram pO arterial oxygen tension
2
Mg2+ magnesium ion PTT protein truncation test
MHC major histocompatibility r correlation coefficient
complex
RFLP restriction fragment length
MLPA multiplex ligation-dependent polymorphism
probe amplification
RNA ribonucleic acid
mm millimetre
SAPK-3 stress-activated protein kinase-3
MMP matrix metalloproteinase
SCARMD severe childhood autosomal
MRC Medical Research Council recessive muscular dystrophy
MRI magnetic resonance imaging SCK serum creatine kinase
mRNA messenger ribonucleic acid SD standard deviation
MRS magnetic resonance SMA spinal muscular atrophy
spectroscopy
SNP single nucleotide
MW molecular weight polymorphism
MZ monozygotic SPECT single-photon emission
N number computerized tomography
Na+ sodium ion SSCP single-strand conformation
NADP nicotinamide adenine polymorphism
dinucleotide phosphate TGF transforming growth factor
NICE National Institute for Health TRP transient receptor potential
and Care Excellence U unit
NIPPV nasal intermittent positive UK United Kingdom
pressure ventilation
US United States
NIV non-invasive ventilation
WFA Wheelchair Football
NMR nuclear magnetic resonance Association
nNOS neuronal nitric oxide Xce X chromosome-controlling
synthase element
NO nitric oxide XLDCM X-linked dilated
NOS nitric oxide synthase cardiomyopathy
