Muscular Dystrophies (eBook)

Anthony A. Amato, Robert C. Griggs (Herausgeber)

eBook Download: PDF | EPUB

2011 | 1. Auflage
284 Seiten
Elsevier Science (Verlag)
978-0-444-53489-7 (ISBN)

Infos

The Handbook of Clinical Neurology Vol 101: Muscular Dystrophies discusses the pathogenesis and treatment prospects for muscular dystrophies. It summarizes the advances in molecular and cell biology, biochemistry, and other biological sciences, with an emphasis on their application to this group of muscle disorders and to their clinical implications. Starting with an overview of muscular dystrophies, the book's 16 chapters discuss dystrophinopathies; sarcoglycanopathies; congenital muscular dystrophies; collagen VI-related myopathies; limb-girdle muscular dystrophy 2A; dysferlinopathies; limb-girdle muscular dystrophy 2H and the role of TRIM32; and caveolinopathies. The book also covers myofibrillar myopathies; Emery-Dreifuss muscular dystrophy; facioscapulohumeral dystrophy and scapuloperoneal syndromes; oculopharyngeal muscular dystrophy; myotonic dystrophy types 1 and 2; and distal muscular dystrophies. This book is useful to basic investigators, as it offers an increased understanding of muscular dystrophies; and to clinicians, with its emphasis on issues that are relevant to the care, diagnosis, and management of patients with these 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

Inhalt

Front Cover 1
Muscular Dystrophies 4
Copyright 5
Handbook of Clinical Neurology 3rd Series 6
Foreword 8
Preface 10
List of Contributors 12
Contents 14
Chapter 1: Overview of the muscular dystrophies 16
Introduction 16
Molecular Pathogenesis for Dystrophies 18
Clinical Features 18
Laboratory Features 19
Muscle Biopsies 22
Molecular Analysis 22
Treatments 22
Summary 23
References 24
Chapter 2: Dystrophinopathies 26
Introduction 26
Dystrophinopathy Spectrum 26
Carriers 31
Neurophysiology and Laboratory features 32
Pathology 32
Genetics, Pathophysiology, And pathogenesis 33
Imaging 34
Diagnosis 34
Genotype-phenotype Correlation Studies 35
Genetic Counseling 35
Treatment 36
Emerging Therapies 41
Clinical Research Issues 43
Newborn Screening 43
Conclusions 44
References 45
Chapter 3: Sarcoglycanopathies 56
Introduction 56
Epidemiology 56
Pathophysiology 57
Animal Models 58
Clinical Presentation 58
Diagnostic Approach 59
Treatment 59
References 60
Chapter 4: Congenital muscular dystrophies 62
Congenital Muscular Dystrophies 62
Muscle Proteins and the Dystrophin-glycoprotein Complex 62
Defects of Structural Proteins 67
Defects of Glycosylation 74
Clinical Dystroglycanopathy Syndromes 74
Genes Involved in the Dystroglycanopathies (Table4.3) 78
Other Dystroglycanopathies 81
Proteins of the Endoplasmic Reticulum and Nucleus 81
Other Congenital Muscular Dystrophies With Chromosomal Linkage 83
Other Congenital Muscular Dystrophies 84
Conclusions 86
References 86
Chapter 5: The collagen VI-related myopathies: Ullrich congenital muscular dystrophy and Bethlem myopathy 96
Introduction 96
Clinical Features 97
Collagen Vi and Molecular Pathogenesis 101
Mutational Spectrum/genotype-phenotype Correlations 104
Diagnosis, Differential Diagnosis, Genetic Counseling, and Treatment 105
References 108
Chapter 6: Limb-girdle muscular dystrophy 2A 112
Introduction 112
Clinical Features 112
Epidemiology 114
Laboratory Features 114
Pathogenesis 118
Future and Current Research 120
Diagnosis and Treatment 122
References 122
Chapter 7: Dysferlinopathies 126
Introduction 126
Clinical Features 126
Laboratory Features 127
Pathogenesis 129
Future and Current Research 131
Diagnosis and Treatment 131
References 132
Chapter 8: Other limb-girdle muscular dystrophies 134
Introduction 134
Limb-girdle Muscular Dystrophies Associated With impaired Glycosylation Of a-dystroglycan 134
Lgmd2G (telethoninopathy) 137
Lgmd2L (anoctaminopathy) 137
Conclusion 138
References 138
Chapter 9: Limb-girdle muscular dystrophy 2H and the role of TRIM32 140
Introduction 140
Trim32 Protein 141
Sarcotubular Myopathy 143
Trim32 and Bardet-Biedl Syndrome 144
Mouse Model of Lgmd2H 144
Biological Role of Trim32 144
Potential Roles of Trim32 in Normal and Diseased Muscle 145
Hypothetical Mechanism By Which Impaired Protein Turnover Might Lead to Cell Dysfunction 146
References 146
Chapter 10: Caveolinopathies: translational implications of caveolin-3 in skeletal and cardiac muscle disorders 150
Introduction 150
Cav-3 Deficiency and Skeletal Muscle Diseases 151
Cav-3 Deficiency and Heart Disorders 153
Ptrf Mutations and Secondary Cav-3 Defects 154
Pathogenetic Mechanisms of Muscle Degeneration in Cav-3 Deficiency 154
References 155
Chapter 11: Myofibrillar myopathies 158
Definition and Basic Principles 158
Morphology 158
Desminopathy 161
B-crystallinopathy 162
Myotilinopathy 164
Zaspopathy 165
Filaminopathy 166
Bag3opathy 166
Therapeutic Approaches 167
Concluding Comment 167
Acknowledgments 167
References 167
Chapter 12: Emery–Dreifuss muscular dystrophy 170
Introduction 170
Historical Review 170
Clinical Features 171
Genetics and Molecular Pathology 173
Mechanisms of Disease 176
Models of Edmd 176
Conclusions 178
Acknowledgments 179
References 179
Chapter 13: Facioscapulohumeral dystrophy and scapuloperoneal syndromes 182
Introduction 182
Epidemiology 182
Pathogenesis and Genetics 182
Clinical Features 185
Investigation 20
Prognosis 21
Management 22
Scapuloperoneal Syndrome 23
Conclusion 23
References 24
Chapter 14: Oculopharyngeal muscular dystrophy 196
Definition 196
Clinical Features 196
Laboratory Findings 197
Histopathology 197
Molecular Genetics 198
Pathogenesis 199
Diagnosis 201
Genetic Counseling 201
Differential Diagnosis 202
Therapy 202
Unsolved Problems 203
References 204
Chapter 15: Myotonic dystrophy types 1 and 2 208
Introduction 208
Clinical Features 208
Diagnosis and Genetic Counseling of Myotonic Dystrophy Types 1 and 2 218
Genetics of Myotonic Dystrophy Types 1 and 2 221
Mutations of Myotonic Dystrophies 225
Molecular Pathogenesis of Myotonic Dystrophy Type 1 229
Management of Clinical Manifestations 237
References 242
Chapter 16: Distal muscular dystrophies 254
Introduction 254
Welander Disease 254
Tibial Muscular Dystrophy (Tmd) - Titinopathy (udd Myopathy) 259
Zasp Distal Dystrophy - Markesbery-Griggs Disease 262
Distal Myotilinopathy 264
Myosinopathy - Laing Distal Myopathy 264
Distal Dysferlinopathy - Miyoshi Myopathy (Mm) 266
Gne-mutated Disease - Nonaka Distal Myopathy 268
Distal Nebulinopathy 268
Vocal Cord and Pharyngeal Distal Myopathy (Vcpdm) 269
Other Distal Dystrophies - Single families 269
Distal Phenotype in Other Myopathies 270
Conclusions 272
References 272
Index 278

Textauszug

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 (α-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, δ- and γ-sarcoglycans interact with filamin C. The four proteins shown in the Golgi complex have been demonstrated to affect the glycosylation state of the α-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 β-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-α7; 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 (α, β, γ, δ)

Dysferlin

Caveolin-3

Basement membrane

Merosin (α2 laminin)

α7β1D 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...

Produkt-Details

• Erscheint lt. Verlag: 24.5.2011
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Neurologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Orthopädie
• Themenwelt: Naturwissenschaften ► Biologie ► Humanbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• ISBN-10: 0-444-53489-X / 044453489X
• ISBN-13: 978-0-444-53489-7 / 9780444534897