Table Of ContentHANDBOOK OF CLINICAL
NEUROLOGY
Series Editors
MICHAEL J. AMINOFF, FRANC¸OIS BOLLER, AND DICK F. SWAAB
VOLUME 101
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ST LOUIS SYDNEY TORONTO 2011
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Foreword
ItiswithespecialpleasurethatwewelcomethisnewvolumeasanadditiontotheHandbookofClinicalNeurology.
ProfessorsRobertGriggsandAnthonyAmato,thevolumeeditors,haveassembledanimpressivegroupofinterna-
tionallyrecognizedauthoritiestoprovidecliniciansandscientistswiththelatestinformationconcerningthemuscu-
lar dystrophies. Cogent summaries are provided about advances in molecular and cell biology, biochemistry, and
other biological sciences, with particular regard to their application to this group of muscle disorders and to their
clinical implications, thereby providing comprehensive new insights to a group of disorders that have profound
effectsonpatientsandtheirfamilies.ComparisonwithearliervolumesoftheHandbookthathavecoveredrelated
topicswillindicatetheremarkablechangesthathaveoccurredinourconceptsofthesedisordersoverthelasttwo
decades.Suchadvancesclearlylaythefoundationforfuturetherapies.Wehopethatthisvolumewillappealtobasic
investigators by providing them with a greater understanding of the muscular dystrophies, and to clinicians by its
emphasisonaspectsthatareofrelevancetothecareofdiagnosisandmanagementofpatientswiththesedisorders.
We are grateful to the two volume editors, who are both renowned clinicians and investigators, and to the
numerousauthorswhomtheyassembled,forgivinggenerouslyoftheirtimeandexpertisetosummarizedevelop-
mentsintheirfieldandtherebyputtingtogetherthisoutstandingvolume.Asserieseditors,weeachreviewedallof
thechaptersincludedinthevolume,makingsuggestionsforimprovementasappropriate,butwewereenormously
impressedbytheirscholarlyappraisalofdevelopmentsinthefield.Inadditiontotheprintform,thevolumewillbe
available electronically on Elsevier’s Science Direct site. This will make it—and the other volumes of this third
series of the Handbook—more accessible to readers and will also facilitate search for specific information.
It is a pleasure, as always, to thank the team at Elsevier—and, in particular, Michael Houston and Michael
Parkinson in Edinburgh—for their unfailing and expert assistance in the development and production of this
volume.
Michael J. Aminoff
Franc¸ois Boller
Dick F. Swaab
Preface
In recent years, new discoveries concerning the muscular dystrophies have occurred at breath-taking speed. It is
only two decades since the first genetic cause of a muscular dystrophy was identified: dystrophin mutations as
a cause of Duchenne muscular dystrophy. Since that time, close to 50 genes have been found mutated in a mus-
cular dystrophy, and only a handful of disorders have not been categorized molecularly.
Unanticipated,however,hasbeenthecomplexityofthepathogenesisforeachgeneticallycharacterizeddisorder,
aswellasthepersistenceofunexplainedphenotypicheterogeneity.Moreover,although webothremainoptimistic
thatnewtherapeuticstrategieswillsoonprovidemajorimprovementinoneormoremusculardystrophies,thehurdles
remainhighandnewobstaclescontinuetoloomintoview.
Thisbookhasbeenorganizedanditsauthorsassembledtoprovidethelatestinformationonbothpathogenesisand
theprospectsfortreatment—integrated with theclinicalwisdom and perspectiveofhighly experiencedphysicians
whoarethego-toexpertsintheirsub-subspecialty.Eachchapterisauthoritativeandcomplete,butwithanemphasis
onwhatmattersclinicallynowandintheforeseeablefuture.Wethankthecontributorsfordoingamasterfuljobof
summarizingthestateoftheartintheirarea.
Robert C. Griggs
Anthony A. Amato
List of Contributors
A.A. Amato E. Gazzerro
Department of Neurology, Neuromuscular Division, Unit of Muscular and Neurodegenerative Diseases,
Brigham and Women’s Hospital, Harvard Medical G. Gaslini Institute, Genova, Italy
School, Boston, MA, USA
R.C. Griggs
T. Ashizawa Department of Neurology, University of Rochester
DepartmentofNeurology,McKnightBrainInstitute, School of Medicine, Rochester, NY, USA
UniversityofTexasMedicalBranch,Galveston,TX,USA
I. Illa
A. Bonetto Department of Neurology and Laboratory of
Unit of Muscular and Neurodegenerative Diseases, Experimental Neurology, Hospital de la Santa Creu i
G. Gaslini Institute, Genova, Italy Sant Pau and Universitat Auto`noma de Barcelona
(UAB), Barcelona, Spain
C.G. Bo¨nnemann
Neurogenetics Branch, Neuromuscular and
J. Kirschner
NeurogeneticDisordersofChildhoodSection,National
Department of Neuropediatrics and Muscle Disorders,
Institute of Neurological Disorders and Stroke/NIH,
University of Freiburg, Freiburg, Germany
Bethesda, MD, USA
E. Kudryashova
B. Brais
Department of Neurology, UCLA, Los Angeles,
Laboratory of Neurogenetics of Motion, Faculte´ de
CA, USA
Me´decine de l’Universite´ de Montre´al, Centre de
Recherche du CHUM, Hoˆpital Notre-Dame–CHUM,
H. Lochmu¨ller
Montre´al, Que´bec, Canada
Institute of Human Genetics, Newcastle University,
Newcastle upon Tyne, UK
R.H. Brown, Jr
Department of Neurology, University of
E. M. McNally
Massachusetts, Boston, MA, USA
Department of Medicine, Institute for Cardiovascular
Research, University of Chicago, Chicago, IL, USA
A.G. Engel
Department of Neurology and Neuromuscular Disease
ResearchLaboratory,MayoClinic,Rochester,MN,USA C. Minetti
Unit of Muscular and Neurodegenerative Diseases,
D.M. Escolar G. Gaslini Institute, Genova, Italy
Center for Genetic Muscle Disorders, Kennedy
Krieger Institute, Johns Hopkins School of Medicine, L.A. Morrison
Baltimore, MD, USA Department of Neurology, University of New Mexico,
Albuquerque, NM, USA
E. Gallardo
Department of Neurology and Laboratory of R.W. Orrell
Experimental Neurology, Hospital Universitari de la UniversityDepartmentofClinicalNeurosciences,UCL
Santa Creu i Sant Pau and Institut de Recerca HSCSP, Institute of Neurology, University College London,
Barcelona, Spain London, UK
xii LIST OF CONTRIBUTORS
M. Puckelwartz P.B. Shieh
Department of Medicine, University of Chicago, Department of Neurology, UCLA, Los Angeles,
Chicago, IL, USA CA, USA
A. Saenz S.E. Sparks
Grupo Neurogene´tica, Unidad Experimental, Hospital Clinical Genetics, Department of Pediatrics, Levine
Donostia, San Sebastian, Spain Children’s Hospital at Carolinas Medical Center,
Charlotte, NC, USA
P.S. Sarkar
Department of Neurology, University of Texas M.J. Spencer
Medical Branch, Galveston, TX, USA Department of Neurology, UCLA, Los Angeles,
CA, USA
D. Selcen
Department of Neurology and Neuromuscular Disease B. Udd
Research Laboratory, Mayo Clinic, Rochester, Department of Neurology, Tampere University and
MN, USA University Hospital, Tampere, Finland
HandbookofClinicalNeurology,Vol.101(3rdseries)
MuscularDystrophies
A.A.AmatoandR.C.Griggs,Editors
#2011ElsevierB.V.Allrightsreserved
Chapter 1
Overview of the muscular dystrophies
ANTHONYA.AMATO1*ANDROBERTC.GRIGGS2
1DepartmentofNeurology,Neuromuscular Division,BrighamandWomen’sHospital,
HarvardMedicalSchool,Boston,MA,USA
2DepartmentofNeurology, UniversityofRochesterSchoolofMedicine,Rochester,NY,USA
INTRODUCTION
muscle groups initially affected; for example, the
Markesbery–Griggs, Udd, and Laing types of distal
Classification
myopathy have preferential involvement of the ante-
Historically, the muscular dystrophies have been rior tibial muscles, Miyoshi myopathy the gastrocne-
defined as progressive myopathies in which muscle mius, and Welander myopathy the extensor forearm
biopsies demonstrate replacement of muscle fibers by muscles. Dystrophies associated with proximal greater
adipose and connective tissue. The clinical onset of than distal weakness are called limb-girdle dystrophies
the dystrophy may be evident at birth, as in congenital (LGMD). The LGMD, inherited in anautosomal domi-
muscular dystrophies, or may not develop until late nant fashion, are termed LGMD type 1 (LGMD1),
adulthood. The dystrophies were felt to differ from whereas autosomal recessive dystrophies are called
congenital myopathies by the presence of specific LGMD2. Further subclassifications of the LGMDs
ultrastructural abnormalities apparent in muscle biop- are based on genotype differences (e.g., LGMD1A,
sies in the latter (e.g., nemaline rods, cores, or mini- LGMD1B).
cores). However, with advances in molecular genetics There are problems with this traditional classifica-
the distinction between what constitutes a muscular tion of muscular dystrophies. We now know that most
dystrophy and a congenital myopathy has become of the genetic defects previously found to be asso-
blurred. For example, myofibrillar abnormalities and ciated with congenital muscular dystrophy can all be
inclusions such as nemaline rods, cytoplasmic bodies, associated with milder, adult-onset dystrophy (see
and reducing bodies that initially led to categorization Table 1.1). In addition, clinical heterogeneity is some-
asacongenital myopathy have been notedin disorders times evident within family members with specific
known to carry similar genetic defects that have been mutations such that some may manifest with a limb-
considered forms of dystrophy. girdle pattern of weakness, whereas other members in
Dystrophies have been classified according to age the family have distal weakness (e.g., Miyoshi myopa-
ofonset,modeofinheritance,andpatternofweakness thy, anterior tibial myopathy, LGMD2B are all
(Table 1.1). For example, those that present at birth associated with dysferlin mutations). Thus, it may be
have been termed congenital muscular dystrophies more appropriate to classify the dystrophies by the
(MDC). Dystrophies have also been named based on genetic defect (e.g., dysferlinopathies, calpainopathy)
the patterns of muscle involvement, including limb- and to understand the specific clinical phenotype,
girdle muscular dystrophy (LGMD), facioscapulohum- including age of onset and patterns of weakness
eral dystrophy (FSHD), oculopharyngeal muscular that may be associated with the specific disorders.
dystrophy (OPMD), distal myopathy/dystrophies, and However, the classic terminology (e.g., LGMD) is so
scapuloperoneal dystrophy. Within the distal muscular ingrainedthatitislikelytopersistuntilanewgeneration
dystrophies, subclassifications have been based on of clinical investigators armed with the explanations
inheritance pattern, age of onset, and the specific fordivergentphenotypeswritesitstextbooks.
*Correspondence to: Anthony Amato, M.D., Harvard Medical School, Brigham and Women’s Hospital, Department of
Neurology,NeuromuscularDivision,75FrancisSt.,Boston,MA02115–6110,USA.Tel:617732–5436,Fax:617730–2885,E-mail:
[email protected]
2 A.A. AMATO AND R.C. GRIGGS
Table1.1
Genetic classificationofthemusculardystrophies
Disease Inheritance Chromosome Affectedprotein
X-linkeddystrophies
Duchenne/Becker XR Xp21 Dystrophin
Emery–Dreifuss XR Xq28 Emerin
Scapuloperoneal/reducing XR Xq26.3 FourandahalfLIMdomain
bodymyopathy protein1(FHL1)
Limb-girdle dystrophies(LGMD)
LGMD1A AD 5q22.3–31.3 Myotilin
LGMD1B AD 1q11–21 LaminA/C
LGMD1C AD 3p25 Caveolin-3
LGMD1D AD 6q23 ?
LGMD1E AD 7q ?
LGMD2A AR 15q15.1–21.1 Calpain-3
LGMD2B* AR 2p13 Dysferlin
LGMD2C AR 13q12 g-Sarcoglycan
LGMD2D AR 17q12–21.3 a-Sarcoglycan
LGMD2E AR 4q12 b-Sarcoglycan
LGMD2F AR 5q33–34 d-Sarcoglycan
LGMD2G AR 17q11–12 Telethonin
LGMD2H AR 9q31–33 E3ubiquitin ligase(TRIM32)
LGMD2I AR 19q13 FKRP
LGMD2J AR 2q31 Titin
LGMD2K AR 9q31 POMT1
LGMD2L AR 11p14.3 Anoctamin-5
LGMD2M AR 9q31–33 Fukutin
LGMD2N AR 1p32 POMGnT1
LGMD2O AR 14q24 POMT1
Congenital musculardystrophies
(MDC)
MDC1A AR 6q22–23 Laminin-a2chain
a7Integrin-relatedMDC AR 12q13 a7Integrin
MCC/LGMD2I AR 19q13 FKRP
Fukuyama/LGMD2L AR 9q31–33 Fukutin
WWS/LGMDK AR 9q31 POMT1
MEBdisease/LGMD2M AR 1p32 POMGnT1
Rigidspinesyndrome AR 1p35–36 SelenoproteinN1
Ullrich/Bethlem AR/AD 21q22.3and2q37 Collagens6A1,6A2,6A3
Distal dystrophies/myopathies
Welander AD 2p13 ?
Udd AD 2q31 Titin
Markesbery–Griggs AD 10q22.3–23.2 ZASP
Nonaka AR 9p1–q1 GNE
Miyoshi1 AR 2p13 Dysferlin
Miyoshi2 AR 11p14.3 Anoctamin-5
Laing(MPD1) AD 14q11 MyHC-7
Distalmyopathywithvocal AD 5q31 Matrin-3
cordandpharyngeal
weakness(VCPDMor MPD2)
Otherdystrophies
Facioscapulohumeral AD 4q35 DUX4
Scapuloperonealdystrophy AD 2q35 Desmin
AD 14q11 MyHC-7
XR Xq26.3 FourandahalfLIMdomain
protein1(FHL1)
Emery–Dreifuss type3 AD 6q24 Nesprin-1
OVERVIEW OF THE MUSCULAR DYSTROPHIES 3
Table1.1
Continued
Disease Inheritance Chromosome Affectedprotein
Emery–Dreifuss type4 AD 14q23 Nesprin-2
Oculopharyngeal AD 14q11.2–13 PABP2
Myotonicdystrophy1 AD 19q13.3 DMPK
Myotonicdystrophy2 AD 3q21 ZNF9
Myofibrillarmyopathy AD 5q22.3–31.3 Myotilin
AD 10q22.3–23.2 ZASP
AD 7q32.1 FilaminC
AD 11q21–23 ab-Crystallin
AD/AR 2q35 Desmin
AR 1p36 SelenoproteinN1
AD 10q25–26 BAG3
HereditaryIBM
ARhereditaryIBM AR GNE
HereditaryIBMwithFTD AD VCP
andPagetdisease
HereditaryIBM3 AD MyHC-IIa
*LGMD2BandMiyoshidistaldystrophyaresamecondition.
AD, autosomal dominant; AR, autosomal recessive; BAG3, BCL2-associated AthanoGene 3; DMPK, myotonic dystrophy protein kinase;
IBM, inclusion body myopathy; FKRP, fukutin-relatedprotein; FTD, frontotemporal dementia; GNE, UDP-N-acetylglucosamine 2-epimerase/
N-acetylmannosamine kinase; MCC, multiple congenital contractures; MEB, muscle–eye–brain; MPD, myophosphorylase deficiency;
MyHC, myosin heavy chain; PABP, poly(A) binding protein; POMT1, protein O-mannosyltransferase gene; POMGnT1, protein O-mannose
b-1,2-N-acetylglucosaminyltransferase; TRIM32, tripartite motif-containing protein 32; VCP, valosin-containing protein; VCPDM, vocal cord
andpharyngealweaknesswithdistalmyopathy;WSS,Walker–Warburgsyndrome;XR,X-linkedrecessive;ZASP,Z-bandalternatelyspliced
PDZmotif-containingprotein;ZNF,zincfingerprotein9.
MOLECULARPATHOGENESISFOR and others with peculiar patterns of involvement
DYSTROPHIES (e.g., oculopharyngeal, facioscapulohumeral, scapulo-
peroneal) that narrow down the differential diagnoses.
The muscular dystrophies can be caused by mutations
It is important to look for facial weakness (FSHD),
that encode for sarcolemmal, basement membrane,
scapular winging (FSHD, LGMD2A), calf hypertrophy
sarcomeric, nuclear structural proteins, or enzymes
(dystrophinopathies, LGMD2C-F, LGMD2I), calf atro-
(Figures1.1 and1.2,Table 1.2).Further,somedisorders
phy (LGMD2B/Miyoshi), significant asymmetries in
are causedby mutations that affect splicing of mRNA
strength (FSHD), and rippling muscles (LGMD1C).
(e.g.,themyotonicdystrophies)orbyyetstillunknown
Muscles should be examined for myotonia that would
mechanisms(e.g.,FSHD).Thepathogenesisofthevar-
lead to consideration of myotonic dystrophy 1 or 2,
ious forms of muscular dystrophy will be discussed in
particularly if the patient has early cataracts, frontal
subsequent chapters.
balding, and temporal muscle wasting. Many patients
with severe weakness due to dystrophies develop con-
CLINICALFEATURES
tractures. However, contractures in muscles groups
Skeletal muscle weakness that are not significantly weak should lead to consi-
deration of Emery–Dreifuss muscular dystrophy or
The dystrophies are clinically heterogeneous. The most
Ullrich/Bethlem myopathy. Axial muscle weakness
important aspect when evaluating a patient with a
can lead to progressive scoliosis, particularly once the
possible dystrophy – or any neuromuscular condition
individual is wheelchair bound.
forthatmatter–istotrytodefinethepatternofmus-
cleweakness.Mostofthemusculardystrophieshavea
Other muscle involvement
“limb-girdle” pattern of weakness with proximal leg
and arm muscles being weaker than distal muscle The dystrophies affect more than just skeletal muscles.
groups. However, there is a group of disorders with Various dystrophies are associated with severe cardio-
more distal muscle involvement, as mentioned above, myopathy (Bushby et al., 2003; Norwood et al., 2007).
