Inherited Neuromuscular Diseases (eBook)

Preface 6
Contents 8
Contributors 10
1 Pathology and Diagnosis of Muscular Dystrophies 15
1.1 Introduction 15
1.2 Diagnosis of Muscular Dystrophies 18
1.2.1 Protein Studies 18
1.2.2 Molecular Genetics 22
References 22
2 Standards of Care for Duchenne Muscular Dystrophy: Brief Treat-NMD Recommendations 26
2.1 Introduction 26
2.2 Diagnosis of DMD 27
2.3 Neurology 28
2.4 GI-Nutrition 29
2.5 Respiratory Care 30
2.6 Cardiac Care 31
2.7 Orthopaedics 32
2.8 Psychosocial 32
2.9 Rehabilitation 32
2.10 Oral Care 33
Further Reading 34
3 Genetics and Pathogenesis of Distal Muscular Dystrophies 35
3.1 Introduction 35
3.2 Late Adult Onset Distal Dystrophies 36
3.2.1 Welander Myopathy 36
3.2.1.1 Clinical Features 36
3.2.1.2 Laboratory Findings 36
3.2.1.3 Molecular Genetics 39
3.2.2 Tibial Muscular Dystrophy (TMD, UDD Myopathy) 39
3.2.2.1 Clinical Features 39
3.2.2.2 Laboratory Findings 39
3.2.2.3 Molecular Genetics 40
3.2.2.4 Molecular Pathogenesis 40
3.2.3 Zaspopathy (Markesbery-Griggs Distal Myopathy) 40
3.2.3.1 Clinical Features 40
3.2.3.2 Laboratory Findings 41
3.2.3.3 Molecular Genetics 41
3.2.3.4 Molecular Pathomechanism 41
3.2.4 Distal Myotilinopathy 41
3.2.4.1 Clinical Features 41
3.2.4.2 Laboratory Findings 41
3.2.4.3 Molecular Genetics 42
3.2.5 Molecular Pathomechanisms in Distal Dystrophies with Myofibrillar Myopathy 42
3.3 Early Adult-Onset Distal Myopathies 42
3.3.1 Distal Myopathy with Rimmed Vacuoles (DRMV, Nonaka Myopathy) 43
3.3.1.1 Clinical Features 43
3.3.1.2 Laboratory Findings 43
3.3.1.3 Molecular Genetics 43
3.3.1.4 Molecular Pathogenesis 43
3.3.2 Miyoshi Distal Myopathy 44
3.3.2.1 Clinical Features 44
3.3.2.2 Laboratory Findings 44
3.3.2.3 Molecular Genetics 44
3.3.2.4 Molecular Pathomechanisms 45
3.4 Early Onset Distal Myopathies 45
3.4.1 Laing Distal Myopathy (MPD1) 45
3.4.1.1 Clinical Features 45
3.4.1.2 Laboratory Findings 45
3.4.1.3 Molecular Genetics 45
3.4.2 Distal Nebulin Myopathy 46
3.4.2.1 Clinical Features 46
3.4.2.2 Laboratory Findings 46
3.4.2.3 Molecular Genetics 46
3.5 Distal Dystrophies with Other Molecular Cause 46
3.5.1 Distal Myopathy with Vocal Cord and Pharyngeal Weakness (VCPDM, MPD2) 46
3.5.2 Dynaminopathy 46
3.5.3 VCP Mutated Distal Myopathy 47
3.5.4 Distal Caveolinopathy 47
3.5.5 19p13 Linked Distal Phenotype 47
3.5.6 Australian Distal Myopathy 47
3.5.7 Finnish Adult Onset Distal Dystrophy (MPD3) 47
3.6 Conclusion 47
References 48
4 Phenotype Variations in Early Onset Pompe Disease: Diagnosis and Treatment Results with Myozyme 51
4.1 Introduction 51
4.2 Incidence 52
4.3 Symtomatology 52
4.3.1 Infantile-Onset Pompe Disease 52
4.3.2 Late-Onset Disease, Whose Symptoms Appear After the First Year of Age 52
4.4 Evolution 53
4.5 Diagnosis 54
4.6 Genetics 54
4.7 Treatment 55
4.7.1 Non Specific or Symptomatic Treatment 55
4.7.2 Enzimatic Replacement Therapy (ERT) 55
4.8 Conclusion 57
References 58
5 Diseases of the Human Mitochondrial Oxidative Phosphorylation System 59
5.1 Introduction 59
5.2 Mitochondrial Genetic System 61
5.3 Mitochondrial Genetics 63
5.3.1 Maternal Inheritance 63
5.3.2 Polyplasmy 63
5.3.3 Mitotic Segregation 63
5.3.4 Threshold Effect 63
5.3.5 High Mutational Rate 64
5.4 Diseases Caused by Mutations in mtDNA 64
5.5 New mtDNA Point Mutations: Pathogenicity Criteria 69
5.5.1 The Mutation must Be Present in Patients and Absent in Controls 70
5.5.2 The Mutation Must Be Found in Different Mitochondrial Genetic Backgrounds 70
5.5.3 The Percentage of the Mutation Must Correlate with the Phenotype 70
5.5.4 The Mutation Should Be the Best mtDNA Candidate Variant to Be Pathologic 71
5.5.5 The Mutation Must Affect Highly Evolutionarily Conserved Nucleotides 71
5.5.6 The Mutation Must Affect Functionally Important Domains 71
5.5.7 Transfer of the mtDNA with a Mutation to Other Cell Lines Must Be Accompanied By Transfer of the Cellular and Molecular Defect: Transmitochondrial Cybrids as a Model to Confirm the Pathogenicity of a New Mutation. 71
5.6 mtDNA Haplogrupos and Diseases 72
5.7 Oxphos Disorders Without mtDNA Mutations 73
5.8 Oxphos Defects Due to Environmental Factors 74
5.9 mtDNA in Multifactorial Disorders 75
5.10 Conclusions 75
References 76
6 Mitochondrial Diseases: A Cross-Talk Between Mitochondrial and Nuclear Genomes 80
6.1 Introduction 80
6.2 Genetics and Pathophysiology 81
6.2.1 Stability and the Integrity of mtDNA: Pathophysiological Aspects 81
6.2.1.1 Clinical Manifestations 82
6.2.1.2 Etiology 85
6.2.1.3 Pathogenesis and Pathophysiology 89
6.3 Diagnostic Considerations 91
References 92
7 Mitochondrial Disorders Due to Nuclear OXPHOS Gene Defects 96
7.1 Introduction 96
7.2 Nuclear Gene Defects of Structural or Assembly Genes of the OXPHOS System 97
7.2.1 Complex I Deficiency 97
7.2.1.1 Mutations in Complex I Nuclear Structural Genes 101
7.2.1.2 Mutations in Complex I Assembly Factors 102
7.2.2 Complex II Deficiency 103
7.2.3 Complex III Deficiency 104
7.2.3.1 Mutations in Complex III Nuclear Structural Genes 104
7.2.3.2 Mutations in BCS1L 104
7.2.4 Complex IV Deficiency 105
7.2.4.1 Mutations in Complex IV Nuclear Structural Subunits 106
7.2.4.2 Mutations in Complex IV Assembly Factors 106
7.2.5 Complex V Deficiency 107
7.3 Nuclear Gene Defects in the Biogenesis of Protein Constituents of the OXPHOS System 108
7.3.1 Defects in the Mitochondrial Translation Machinery 108
7.3.2 Defects in Mitochondrial Protein Import 110
7.3.3 Defects in Mitochondrial Fe-S Cluster Biosynthesis 111
7.3.4 Defects in Mitochondrial Protein Metabolism 112
7.4 Nuclear Gene Defects in the Biogenesis of Non-Protein Constituents of the OXPHOS System 112
7.4.1 Coenzyme Q10 Deficiency 113
7.4.2 Barth Syndrome 113
7.5 Nuclear Gene Defects of Mitochondrial Dynamics 114
References 116
8 Coenzyme Q10 Deficiencies in Neuromuscular Diseases 128
8.1 Introduction 128
8.2 CoQ Biosynthesis Pathway 129
8.3 Primary CoQ Deficiencies 131
8.3.1 Clinical and Biochemical Diagnosis 131
8.3.2 Molecular Studies of CoQ Biosynthesis 133
8.3.2.1 Mutations in COQ2 Gene (MIM #609825) 133
8.3.2.2 Mutations in PDSS1 and PDSS2 Subunits of Prenyldiphosphate Synthase 133
8.3.2.3 Mutations in COQ8 Gene (MIM #606980) 134
8.4 Secondary CoQ Deficiency in Mitochondrial Disorders 135
8.5 Therapy of CoQ Deficient Patients 136
8.6 Concluding Remarks 137
References 137
9 The Role of Mitochondrial Network Dynamics in the Pathogenesis of Charcot-Marie-Tooth Disease 140
9.1 Introduction 141
9.2 Fusion and Fission in Mitochondrial Dynamics 142
9.3 Mitochondrial Dynamics and Charcot-Marie-Tooth Neuropathies 143
9.4 Mitochondrial Dynamics and Neurodegeneration 145
References 146
10 Pathogenesis and Treatment of Mitochondrial Disorders 149
10.1 Classification of the Mitochondrial Diseases 150
10.2 Pathogenic Mechanisms in Mitochondrial Diseases 159
10.3 Therapeutic Strategies 165
References 172
11 Biology of Peripheral Inherited Neuropathies: Schwann Cell Axonal Interactions 181
11.1 Introduction 181
11.2 Axonal Signals Regulate Myelination 182
11.3 Demyelinating Schwann Cells Disrupt Axons 183
11.4 CMT1A and Axonal Degeneration 184
11.5 MPZ, CMT1B and Length Dependent Gliopathies 185
11.6 H10P Causes a Dying Back Gliopathy and Accumulation of Proteinaceous Material Within the Intralaminar Space But Not Demyelination 186
11.7 Myelin in R69C Heterozygous Mice Refractory to Axonal Signaling 186
11.8 GDAP1 Mutations and the Role of Ubiquitously Expressed Genes in Axo-Glial Interactions 187
11.9 Fig4 Mutations Alter Neurons and Schwann Cells Independently 188
11.10 Summary 188
References 189
12 Phenotype and Clinical Evolution of Charcot-Marie-Tooth Disease Type 1A Duplication 192
12.1 Introduction 192
12.2 Genetic, Electrophysiologic, Pathologic and Neuroimaging Data 193
12.3 Classic CMT1A Phenotype 196
12.3.1 Initial Symptoms 197
12.3.2 Progression of Disease 199
12.4 Evolution of Mild Phenotype of Secondary Cases in Infancy and Early Childhood 199
12.4.1 Pathophysiology 202
12.5 Proximal Lower-Limb Involvement 203
12.6 Minimal CMT1A-Adult Phenotype 204
References 207
13 Genotypes Sensory Phenotypes in 2 New X-Linked Neuropathies (CMTX3 and dSMAX) and Dominant CMT/HMN Overlap Syndromes 210
13.1 Introduction 210
13.2 X-Linked Syndromes 211
13.2.1 CMTX3 211
13.2.2 Distal X-Linked HMN (Distal X-Linked SMA, dSMAX) 212
13.2.3 Dominant Neuropathies 212
13.2.3.1 HMN1, OMIM 182960 212
13.2.3.2 Other Dominant Motor Neuropathy Syndromes 213
13.2.3.3 Known Genes Causing Motor Neuropathies 213
13.2.3.4 Unknown Genes Causing Motor Neuropathies 214
13.3 Discussion 214
References 215
14 Natural History and Treatment of Peripheral Inherited Neuropathies 216
14.1 Introduction 217
14.2 CMT Subtype Frequency 217
14.3 Phenotypes 217
14.3.1 Disease Severity Depends on CMT Type 217
14.3.2 Phenotypic Variability 218
14.4 Natural History Studies 219
14.4.1 Outcome Measures 219
14.4.1.1 CMT Neuropathy Score (CMTNS) 220
14.4.1.2 Other Outcome Measures in CMT 221
14.5 Treatment of Charcot-Marie-Tooth Disease 222
14.5.1 Rehabilitative Treatment 223
14.5.2 Orthotics 223
14.5.3 Respiratory Failure 224
14.5.4 Surgical Treatment 224
14.5.5 Symptomatic Drug Therapy 225
14.5.6 Specific Drug Therapy 225
14.5.6.1 Animal Models and Clinical Trials 226
References 228
15 Spinal Muscular Atrophy During Human Development: Where Are the Early Pathogenic Findings? 234
15.1 Introduction to SMA 234
15.2 Therapeutic Prospective in SMA 236
15.3 The Neuromuscular System During Development 237
15.4 SMA During Human Development 238
15.4.1 Histologic Observations 238
15.4.2 DNA Fragmentation 239
15.4.3 SMN Expression 239
15.4.4 Ultrasound Evaluation 240
15.5 SMA as a Developmental Disorder 240
References 241
16 Spinal Muscular Atrophy 245
16.1 Clinical Aspects 245
16.2 Genetic Basis of SMA 246
16.3 SMN: A Multifunctional Protein 247
16.4 SMA Pathogenesis 248
16.5 Therapeutic Strategies in SMA 250
16.6 Conclusion 251
References 252
17 Friedreich Ataxia: An Update on Animal Models, Frataxin Function and Therapies 255
17.1 Introduction 255
17.2 Friedreich Ataxia Gene and Molecular Pathology 256
17.3 Animal Models in Friedreich Ataxia 256
17.4 The Function of Frataxin 258
17.4.1 Frataxin and the Homeostasis of Mitochondrial Iron 259
17.4.2 Frataxin as an Iron-Storage Protein 259
17.4.3 Frataxin as a Chaperone for Iron 260
17.4.4 Frataxin as a Regulatory of Oxidative Phosphorylation 261
17.5 Therapies for Friedreich Ataxia 261
17.5.1 Antioxidant Therapy 262
17.5.2 Iron Chelators Therapy 262
17.5.3 Therapy with Metalloporphyrins 263
17.5.4 Therapy to Increase Frataxin Expression 263
References 264
18 Genetics and Pathogenesis of Inherited Ataxias and Spastic Paraplegias 270
18.1 Inherited Ataxias 270
18.1.1 Autosomal Recessive Cerebellar Ataxias 271
18.1.1.1 Congenital Ataxias 271
18.1.1.2 Metabolic Ataxias 274
18.1.1.3 DNA Repair Defects 275
18.1.1.4 Degenerative Ataxias 277
18.1.2 Autosomal Dominant Cerebellar Ataxias 278
18.1.2.1 Common Features of Spinocerebellar Ataxias 279
18.1.2.2 Insights into Pathogenesis 282
18.1.3 X-Linked Cerebellar Ataxias 286
18.2 Hereditary Spastic Paraplegias: Definition and Classification 287
18.2.1 Pure HSP Forms 288
18.2.2 Complex HSP Forms 290
18.2.3 Pathogenic Mechanisms 292
References 294
Index 304