Muscular Dystrophies

Handbook of Clinical Neurology Vol.101 (Series Editors: Aminoff, Boller and Swaab)
1. Auflage 2011
ISBN: 978-0-444-53489-7
Verlag: Elsevier Reference Monographs
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 282 Seiten

This volume provides clinicians and scientists with the latest information concerning the muscular dystrophies, paying special attention to the way advancements in molecular and cell biology, biochemistry, and other biological sciences provide comprehensive insights into a group of disorders that have only been studied for the past two decades. Information on both pathogenesis and prospects for treatment are covered, with an emphasis on clinical implications, both now and in the foreseeable future. Clinical wisdom is combined with invaluable perspectives from the most highly experienced physicians, experts, and scientists to bring an authoritative and complete examination of the muscular dystrophies, their diagnosis, and treatments protocols. Insights from this handbook will both enhance and forward efforts for practitioners who care for, and manage, patients with this group of disorders.
* Valuable insights into the muscular dystrophies, including treatment, diagnosis, and care and patient management
* A comprehensive compilation of the combined wisdom of the most highly regarded physicians, experts, and scientists studying the muscular dystrophies
* An evaluation of the way advances in molecular and cell biology, biochemistry, and other biological sciences continue to advance the study of these disorders

Autoren/Hrsg.

Inhaltsverzeichnis

1;Front Cover;1
2;Muscular Dystrophies;4
3;Copyright;5
4;Handbook of Clinical Neurology 3rd Series;6
5;Foreword;8
6;Preface;10
7;List of Contributors;12
8;Contents;14
9;Chapter 1: Overview of the muscular dystrophies;16
9.1;Introduction;16
9.2;Molecular Pathogenesis for Dystrophies;18
9.3;Clinical Features;18
9.4;Laboratory Features;19
9.5;Muscle Biopsies;22
9.6;Molecular Analysis;22
9.7;Treatments;22
9.8;Summary;23
9.9;References;24
10;Chapter 2: Dystrophinopathies;26
10.1;Introduction;26
10.2;Dystrophinopathy Spectrum;26
10.3;Carriers;31
10.4;Neurophysiology and Laboratory features;32
10.5;Pathology;32
10.6;Genetics, Pathophysiology, And pathogenesis;33
10.7;Imaging;34
10.8;Diagnosis;34
10.9;Genotype-phenotype Correlation Studies;35
10.10;Genetic Counseling;35
10.11;Treatment;36
10.12;Emerging Therapies;41
10.13;Clinical Research Issues;43
10.14;Newborn Screening;43
10.15;Conclusions;44
10.16;References;45
11;Chapter 3: Sarcoglycanopathies;56
11.1;Introduction;56
11.2;Epidemiology;56
11.3;Pathophysiology;57
11.4;Animal Models;58
11.5;Clinical Presentation;58
11.6;Diagnostic Approach;59
11.7;Treatment;59
11.8;References;60
12;Chapter 4: Congenital muscular dystrophies;62
12.1;Congenital Muscular Dystrophies;62
12.2;Muscle Proteins and the Dystrophin-glycoprotein Complex;62
12.3;Defects of Structural Proteins;67
12.4;Defects of Glycosylation;74
12.5;Clinical Dystroglycanopathy Syndromes;74
12.6;Genes Involved in the Dystroglycanopathies (Table4.3);78
12.7;Other Dystroglycanopathies;81
12.8;Proteins of the Endoplasmic Reticulum and Nucleus;81
12.9;Other Congenital Muscular Dystrophies With Chromosomal Linkage;83
12.10;Other Congenital Muscular Dystrophies;84
12.11;Conclusions;86
12.12;References;86
13;Chapter 5: The collagen VI-related myopathies: Ullrich congenital muscular dystrophy and Bethlem myopathy;96
13.1;Introduction;96
13.2;Clinical Features;97
13.3;Collagen Vi and Molecular Pathogenesis;101
13.4;Mutational Spectrum/genotype-phenotype Correlations;104
13.5;Diagnosis, Differential Diagnosis, Genetic Counseling, and Treatment;105
13.6;References;108
14;Chapter 6: Limb-girdle muscular dystrophy 2A;112
14.1;Introduction;112
14.2;Clinical Features;112
14.3;Epidemiology;114
14.4;Laboratory Features;114
14.5;Pathogenesis;118
14.6;Future and Current Research;120
14.7;Diagnosis and Treatment;122
14.8;References;122
15;Chapter 7: Dysferlinopathies;126
15.1;Introduction;126
15.2;Clinical Features;126
15.3;Laboratory Features;127
15.4;Pathogenesis;129
15.5;Future and Current Research;131
15.6;Diagnosis and Treatment;131
15.7;References;132
16;Chapter 8: Other limb-girdle muscular dystrophies;134
16.1;Introduction;134
16.2;Limb-girdle Muscular Dystrophies Associated With impaired Glycosylation Of a-dystroglycan;134
16.3;Lgmd2G (telethoninopathy);137
16.4;Lgmd2L (anoctaminopathy);137
16.5;Conclusion;138
16.6;References;138
17;Chapter 9: Limb-girdle muscular dystrophy 2H and the role of TRIM32;140
17.1;Introduction;140
17.2;Trim32 Protein;141
17.3;Sarcotubular Myopathy;143
17.4;Trim32 and Bardet-Biedl Syndrome;144
17.5;Mouse Model of Lgmd2H;144
17.6;Biological Role of Trim32;144
17.7;Potential Roles of Trim32 in Normal and Diseased Muscle;145
17.8;Hypothetical Mechanism By Which Impaired Protein Turnover Might Lead to Cell Dysfunction;146
17.9;References;146
18;Chapter 10: Caveolinopathies: translational implications of caveolin-3 in skeletal and cardiac muscle disorders;150
18.1;Introduction;150
18.2;Cav-3 Deficiency and Skeletal Muscle Diseases;151
18.3;Cav-3 Deficiency and Heart Disorders;153
18.4;Ptrf Mutations and Secondary Cav-3 Defects;154
18.5;Pathogenetic Mechanisms of Muscle Degeneration in Cav-3 Deficiency;154
18.6;References;155
19;Chapter 11: Myofibrillar myopathies;158
19.1;Definition and Basic Principles;158
19.2;Morphology;158
19.3;Desminopathy;161
19.4;B-crystallinopathy;162
19.5;Myotilinopathy;164
19.6;Zaspopathy;165
19.7;Filaminopathy;166
19.8;Bag3opathy;166
19.9;Therapeutic Approaches;167
19.10;Concluding Comment;167
19.11;Acknowledgments;167
19.12;References;167
20;Chapter 12: Emery–Dreifuss muscular dystrophy;170
20.1;Introduction;170
20.2;Historical Review;170
20.3;Clinical Features;171
20.4;Genetics and Molecular Pathology;173
20.5;Mechanisms of Disease;176
20.6;Models of Edmd;176
20.7;Conclusions;178
20.8;Acknowledgments;179
20.9;References;179
21;Chapter 13: Facioscapulohumeral dystrophy and scapuloperoneal syndromes;182
21.1;Introduction;182
21.2;Epidemiology;182
21.3;Pathogenesis and Genetics;182
21.4;Clinical Features;185
21.5;Investigation;20
21.6;Prognosis;21
21.7;Management;22
21.8;Scapuloperoneal Syndrome;23
21.9;Conclusion;23
21.10;References;24
22;Chapter 14: Oculopharyngeal muscular dystrophy;196
22.1;Definition;196
22.2;Clinical Features;196
22.3;Laboratory Findings;197
22.4;Histopathology;197
22.5;Molecular Genetics;198
22.6;Pathogenesis;199
22.7;Diagnosis;201
22.8;Genetic Counseling;201
22.9;Differential Diagnosis;202
22.10;Therapy;202
22.11;Unsolved Problems;203
22.12;References;204
23;Chapter 15: Myotonic dystrophy types 1 and 2;208
23.1;Introduction;208
23.2;Clinical Features;208
23.3;Diagnosis and Genetic Counseling of Myotonic Dystrophy Types 1 and 2;218
23.4;Genetics of Myotonic Dystrophy Types 1 and 2;221
23.5;Mutations of Myotonic Dystrophies;225
23.6;Molecular Pathogenesis of Myotonic Dystrophy Type 1;229
23.7;Management of Clinical Manifestations;237
23.8;References;242
24;Chapter 16: Distal muscular dystrophies;254
24.1;Introduction;254
24.2;Welander Disease;254
24.3;Tibial Muscular Dystrophy (Tmd) - Titinopathy (udd Myopathy);259
24.4;Zasp Distal Dystrophy - Markesbery-Griggs Disease;262
24.5;Distal Myotilinopathy;264
24.6;Myosinopathy - Laing Distal Myopathy;264
24.7;Distal Dysferlinopathy - Miyoshi Myopathy (Mm);266
24.8;Gne-mutated Disease - Nonaka Distal Myopathy;268
24.9;Distal Nebulinopathy;268
24.10;Vocal Cord and Pharyngeal Distal Myopathy (Vcpdm);269
24.11;Other Distal Dystrophies - Single families;269
24.12;Distal Phenotype in Other Myopathies;270
24.13;Conclusions;272
24.14;References;272
25;Index;278

Leseproben

Handbook of Clinical Neurology, Vol. 101, No. Suppl C, 2011 ISSN: 0072-9752 doi: 10.1016/B978-0-08-045031-5.00001-3 Chapter 1Overview of the muscular dystrophies Anthony A. Amato1*E-mail address:[e-mail], Robert C. Griggs2 1 Department of Neurology, Neuromuscular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA *Correspondence to: Anthony Amato, M.D., Harvard Medical School, Brigham and Women’s Hospital, Department of Neurology, Neuromuscular Division, 75 Francis St., Boston, MA 02115–6110, USA. Tel: [phone], Fax: [phone], Abstract The muscular dystrophies are a clinically and genetically heterogeneous group of myopathies typically associated with progressive weakness. Weakness may be noted at birth or develop in late adult life. Some patients manifest with myalgias, rhabdomyolysis, or only raised serum creatine kinase levels without any symptoms or signs of weakness. The muscular dystrophies can be inherited in an X-linked, autosomal recessive, or autosomal dominant fashion and can result from mutations affecting structural proteins localizable to the sarcolemmal proteins, nuclear membrane, basement membrane, sarcomere, or nonstructural enzymatic proteins. This chapter provided a brief overview of the muscular dystrophies before later chapters discuss the individual subtypes in greater detail. Introduction
Classification
Historically, the muscular dystrophies have been defined as progressive myopathies in which muscle biopsies demonstrate replacement of muscle fibers by adipose and connective tissue. The clinical onset of the dystrophy may be evident at birth, as in congenital muscular dystrophies, or may not develop until late adulthood. The dystrophies were felt to differ from congenital myopathies by the presence of specific ultrastructural abnormalities apparent in muscle biopsies in the latter (e.g., nemaline rods, cores, or minicores). However, with advances in molecular genetics the distinction between what constitutes a muscular dystrophy and a congenital myopathy has become blurred. For example, myofibrillar abnormalities and inclusions such as nemaline rods, cytoplasmic bodies, and reducing bodies that initially led to categorization as a congenital myopathy have been noted in disorders known to carry similar genetic defects that have been considered forms of dystrophy. Dystrophies have been classified according to age of onset, mode of inheritance, and pattern of weakness (Table 1.1). For example, those that present at birth have been termed congenital muscular dystrophies (MDC). Dystrophies have also been named based on the patterns of muscle involvement, including limb-girdle muscular dystrophy (LGMD), facioscapulohumeral dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), distal myopathy/dystrophies, and scapuloperoneal dystrophy. Within the distal muscular dystrophies, subclassifications have been based on inheritance pattern, age of onset, and the specific muscle groups initially affected; for example, the Markesbery–Griggs, Udd, and Laing types of distal myopathy have preferential involvement of the anterior tibial muscles, Miyoshi myopathy the gastrocnemius, and Welander myopathy the extensor forearm muscles. Dystrophies associated with proximal greater than distal weakness are called limb-girdle dystrophies (LGMD). The LGMD, inherited in an autosomal dominant fashion, are termed LGMD type 1 (LGMD1), whereas autosomal recessive dystrophies are called LGMD2. Further subclassifications of the LGMDs are based on genotype differences (e.g., LGMD1A, LGMD1B). Table 1.1 Genetic classification of the muscular dystrophies There are problems with this traditional classification of muscular dystrophies. We now know that most of the genetic defects previously found to be associated with congenital muscular dystrophy can all be associated with milder, adult-onset dystrophy (see Table 1.1). In addition, clinical heterogeneity is sometimes evident within family members with specific mutations such that some may manifest with a limb-girdle pattern of weakness, whereas other members in the family have distal weakness (e.g., Miyoshi myopathy, anterior tibial myopathy, LGMD2B are all associated with dysferlin mutations). Thus, it may be more appropriate to classify the dystrophies by the genetic defect (e.g., dysferlinopathies, calpainopathy) and to understand the specific clinical phenotype, including age of onset and patterns of weakness that may be associated with the specific disorders. However, the classic terminology (e.g., LGMD) is so ingrained that it is likely to persist until a new generation of clinical investigators armed with the explanations for divergent phenotypes writes its textbooks. Molecular pathogenesis for dystrophies
The muscular dystrophies can be caused by mutations that encode for sarcolemmal, basement membrane, sarcomeric, nuclear structural proteins, or enzymes (Figures 1.1 and 1.2, Table 1.2). Further, some disorders are caused by mutations that affect splicing of mRNA (e.g., the myotonic dystrophies) or by yet still unknown mechanisms (e.g., FSHD). The pathogenesis of the various forms of muscular dystrophy will be discussed in subsequent chapters. Figure 1.1 Sarcolemmal membrane and enzymatic proteins. This schematic shows the location of various sarcolemmal and enzymatic proteins associated with muscular dystrophies. The diseases caused by these molecules when mutated are shown in boxes. Dystrophin, via its interaction with the dystroglycan complex, connects the actin cytoskeleton to the extracellular matrix. Intracellularly, it interacts with dystrobrevin (a-DTN) and syntrophins (Syn) (shown in blue). Extracellularly, the sarcoglycan complex (orange) interacts with biglycan, which connects this complex to the dystroglycan complex and the extracellular matrix collagen. Intracellularly, d- and ?-sarcoglycans interact with filamin C. The four proteins shown in the Golgi complex have been demonstrated to affect the glycosylation state of the a-dystroglycan and mediate its binding to the extracellular matrix. Fukutin and fukutin-related protein (FKRP) have been shown to localize to the medial Golgi. The localization of POMT1 (protein O-mannosyltransferase), POMGnT1 (protein O-linked mannose ß-1,2-N-acetylglucosaminyltransferase), and LARGE (another putative glycosyltransferase) is unknown but believed to be in the Golgi complex as these enzymes are involved in the glycosylation process. BMD, Becker muscular dystrophy; DMD, Duchenne muscular dystrophy; ITGA7, integrin-a7; LGMD, limb-girdle muscular dystrophy; MDC, congenital muscular dystrophy; MEB, muscle–eye–brain; SEPN, selenoprotein N; TRIM, E3 ubiquitin ligase. (From Amato AA, Russell J (2008) p. 530. Neuromuscular Disease. McGraw-Hill, New York, with permission.) Figure 1.2 Sarcomeric and nuclear proteins involved in the muscular dystrophies. The schematic for the sarcomere and the nucleus showing the localization of the proteins involved in muscular dystrophies. The diseases they give rise to are shown in boxes. EDMD, Emery–Dreifuss muscular dystrophy; h-IBMPFD, hereditary inclusion body myopathy with Paget disease of bone; IBM, inclusion body myopathy; LGMD, limb-girdle muscular dystrophy; MD, muscular dystrophy; OPMD, oculopharyngeal muscular dystrophy; PABN, polyadenylate binding nuclear protein; VCP, valosin-containing protein; ZASP, Z-band alternately spliced PDZ motif-containing protein. (From Amato AA, Russell J (2008) p. 531. Neuromuscular Disease. McGraw-Hill, New York, with permission.) Table 1.2 Molecular defects associated with muscular dystrophies Mechanism Protein or enzyme affected Sarcolemmal Dystrophin Sarcoglycans (a, ß, ?, d) Dysferlin Caveolin-3 Basement membrane Merosin (a2 laminin) a7ß1D integrin Collagen 6A1, 6A2, 6A3 Sarcomeric Myotilin Titin Telethonin Z-band alternately spliced PDZ motif-containing protein (ZASP) Filamin C Desmin Myosin heavy chains FHL1 (four and a half LIM domain protein 1) Nuclear Emerin Lamin A/C Nesprin 1 and 2 Poly(A) binding protein 2 (PABP2) Valosin-containing protein...