Genetics of Movement Disorders (eBook)

Front Cover 1
Genetics of Movement Disorders 4
Copyright Page 5
Contents 8
Contributors 16
Foreword 20
Preface 22
Chapter 1. Introduction to Medical Genetics and Methods of DNA Testing 24
I. Concepts and Terminology 25
II. Patterns of Inheritance 25
III. Molecular Genetic Tools 34
IV. Molecular Genetic Testing 37
V. Animal Models 38
VI. Web-Based Information for Genetic Diagnosis and Testing 39
References 40
Chapter 2. Inherited Ataxias: An Introduction 42
I. Classification 42
II. Recently Identified Ataxias 45
III. Worldwide Prevalence 46
IV. Mechanisms of Disease 48
V. Genotype/Phenotype Correlations and Modifying Loci 52
VI. Progression and Treatment 53
References 53
Chapter 3. Spinocerebellar Ataxia 1 (SCA1) 58
I. Summary 58
II. SCAl—The Phenotype 58
III. The SCA1 Gene 59
IV. Models of Disease 61
V. Treatment 64
References 64
Chapter 4. Spinocerebellar Ataxia 2 (SCA2) 68
I. Summary 68
II. Phenotype 68
III. Normal and Abnormal Gene Function 70
IV. Diagnosis 73
V. Neurophysiology 74
VI. Neuroimaging 74
VII. Neuropathology 74
VIII. Animal Models 74
IX. Genotype/Phenotype/Modifying Alleles 75
X. Treatment 76
References 76
Chapter 5. Spinocerebellar Ataxia 3—Machado-joseph Disease (SCA3) 80
I. Historical Introduction 80
II. Prevalence of MJD 81
III. Phenotype 81
IV. Diagnosis 83
V. Neuropathology 84
VI. Molecular Genetics 85
VII. Phenotype-Genotype Correlation 85
VIII. Pathogenic Mechanisms and Models 86
IX. Treatment 88
References 88
Chapter 6. Spinocerebellar Ataxia Type 4 (SCA4) 94
I. Summary 94
II. Phenotype 94
III. Gene Locus 94
IV. Diagnostic and Ancillary Tests 95
V. Neuropathology 95
VI. ADCCA or Pure Cerebellar Ataxia Linked to SCA4 Locus 95
References 96
Chapter 7. Spinocerebellar Ataxia 5 (SCA5) 98
I. Introduction 98
II. Anticipation 100
III. Genetic and Physical Mapping 100
IV. Repeat Expansion Detection and Rapid Cloning 101
V. Clinical Features 101
VI. Neuroimaging and Neuropathology 102
VII. Conclusions 102
References 103
Chapter 8. Spinocerebellar Ataxia 6 (SCA6) 104
I. Introduction 104
II. Clinical Features 104
III. Genetics 104
IV. Diagnosis 105
V Molecular Pathogenesis 105
VI. Neuropathology 106
VII. Animal Models 106
VIII. Treatment 106
References 106
Chapter 9. Spinocerebellar Ataxia 7 (SCA7) 108
I. Summary 108
II. Phenotype 108
III. Gene 109
IV. Diagnostic and Ancillary Tests 110
V Neuroimaging 111
VI. Neuropathology 111
VII. Cellular and Animal Models of Disease 112
VIII. Genotype/Phenotype Correlations/Modifying Alleles 113
IX. Treatment 114
X. Conclusion 114
References 115
Chapter 10. Spinocerebellar Ataxia 8 (SCA8) 118
I. Summary 118
II. Phenotype 118
III. Gene 119
IV. Diagnostic and Ancillary Tests 120
V. Cellular and Animal Models of Disease 121
VI. Genotype/Phenotype Correlation and Modifying Alleles 121
VII. Treatment 124
References 124
Chapter 11. Spinocerebellar Ataxia 10 (SCA10) 126
I. Summary 126
II. Phenotype 126
III. The SCA 10 Gene 127
IV. Instability of the Expanded ATTCT Repeat 131
V. Diagnosis 131
VI. Genotype-Phenotype Correlation 133
VII. Population Genetics 134
VIII. Models and Disease Mechanism of the ATTCT Expansion 134
IX. Treatment 136
References 136
Chapter 12. Spinocerebellar Ataxia 11 (SCA11) 140
I. Summary 140
II. Phenotype 140
III. Gene 141
IV. Neuroimaging and Ancillary Tests 142
References 142
Chapter 13. Spinocerebellar Ataxia 12 (SCA12) 144
I. Introduction 144
II. Phenotype of SCA12 145
III. Normal and Abnormal Gene Function 146
IV. Diagnosis 151
V. Treatment 153
References 153
Chapter 14. Spinocerebellar Ataxia 13, 14, and 16 156
I. Summary 156
II. Phenotype 157
III. Gene 157
IV. Diagnostic and Ancillary Tests 159
V. Neuroimaging 159
VI. Neuropathology 159
VII. Cellular and Animal Models of Disease 160
VIII. Genotype/Phenotype Correlation/Modifying Alleles 160
IX. Treatment 160
References 160
Chapter 15. Spinocerebellar Ataxia 17 (SCA17) 162
I. Summary 162
II. Phenotype 162
III. Gene 163
IV. Diagnosis 163
V. Neuropathology 163
VI. Neuroimaging 163
VII. Cellular and Animal Models of Disease 163
VIII. Treatment 163
References 163
Chapter 16. Dentatorubral-Pallidoluysian Atrophy (DRPLA) 166
I. Phenotype 166
II. Molecular Genetics of DRPLA 167
III. Diagnostic and Ancillary Tests 168
IV. Cellular and Animal Models of Disease 169
V. Treatment 171
References 171
Chapter 17. Ataxia in Prion Diseases 174
I. The PRNP Gene and Protein Products 174
II. Phenotypes 176
III. Diagnostic and Ancillary Tests 182
IV. Cellular and Animal Models of Disease 183
V. Treatment and Management 184
References 184
Chapter 18. Friedreich Ataxia 188
I. Summary 188
II. Phenotype 188
III. Gene 192
IV. Diagnostic and Ancillary Tests 193
V. Pathology 196
VI. Cellular and Animal Models of Disease 197
VII. Genotype/Phenotype Correlations/Modifying Alleles 197
VIII. Treatment 197
References 198
Chapter 19. Familial Ataxia with Isolated Vitamin E Deficiency (AVED) 202
I. Introduction 202
II. Phenotype 203
III. Gene 204
IV. Diagnostic and Ancillary Tests 206
V. Cellular and Animal Models of the Disease 207
VI. Genotype/Phenotype Correlations—Modifying Alleles 208
VII. Treatment 208
References 208
Chapter 20. Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS/SACS)—No Longer a Local Disease 212
I. Phenotype 212
II. Gene 214
III. Diagnostic and Ancillary Tests 214
IV. Neuroimaging 215
V. Neuropathology 215
VI. Genotype/Phenotype Correlations 215
References 216
Chapter 21. Ataxia-Telangiectasia 218
I. Phenotype 218
II. ATM Gene and Function Based on Human Data 220
III. Biochemical Targets of ATM Kinase Activity 220
IV. Diagnosis 221
V. Cellular and Animal Models of the Disease 221
VI. Animal Models of A-T 223
VII. Genotype/Phenotype Correlations 224
VIII. Treatment 225
IX. Syndromes Related to A-T 225
References 225
Chapter 22. Episodic and Intermittent Ataxias 228
I. Clinical Features 228
II. Genetics 230
III. Diagnosis 231
IV. In Vitro and In Vivo Models 232
V. Treatment 233
References 234
Chapter 23. Multiple System Atrophy 236
I. Introduction 236
II. Clinical Features 237
III. Diagnosis of MSA 240
IV. Neuroimaging 243
V. Pathology of MSA 246
VI. Epidemiology and Environmental Risk Factors 247
VII. Genetics 248
VIII. Management and Treatment 249
References 249
Chapter 24. Metabolic and Mitochondrial Ataxias 254
I. Ataxia in Mitochondrial Disorders 254
II. Ataxia in Lipid Disorders 260
III. Ataxia in Lysosomal Disorders 263
IV Ataxias Associated with Other Metabolic Disorders 267
References 271
Chapter 25. Diagnostic Evaluation of Ataxic Patients 276
I. Defining the Neurologic Phenotype in Patients with Ataxia as the Primary Symptom 277
II. Determining whether the Disease is Genetic 286
References 290
Chapter 26. Parkinson's Disease: Genetic Epidemiology and Overview 296
I. Introduction 296
II. The Clinical and Pathological Features of Parkinson's Disease 297
III. Diagnosis of Parkinson's Disease 297
IV. The Treatment of Parkinson's Disease 298
V. Challenges Investigating the Etiology of Parkinson's Disease 298
VI. Studies of Familial Aggregation 299
VII. Twin Studies 303
VIII. Single Gene Associations 304
IX. Conclusion 306
References 306
Chapter 27. PARK1 and a-Synuclein: A New Era in Parkinson's Research 310
I. Introduction 310
II. The Contursi Kindred 311
III. The Clinical Phenotype of the A53T Mutation 312
IV. Parkinsonism Due to a A30P Mutation 314
V. Gene Function 315
VI. Aggregation of a-Synuclein 317
VII. Diagnosis 321
VIII. Neuroimaging 321
IX. Animal Models of a-Synucleinopathies 321
X. Is the A53T Phenotype Parkinson's Disease? 322
XI. Treatment 323
XII. Conclusions 323
References 323
Chapter 28. Parkin Mutations (Park2) 328
I. Introduction 328
II. Gene 329
III. Diagnostic and Ancillary Tests 331
IV. Neuroimaging 334
V. Neuropathology 334
VI. Cellular and Animal Models 335
VII. Genotype and Phenotype Correlations/Modifying Alleles 335
VIII. Treatment 335
References 335
Chapter 29. PARK3, Ubiquitin Hydrolase-L1 and Other PD Loci 338
I. PARK3 338
II. PARK4 339
III. PARK5 340
IV. PARK6 340
V. PARK7 342
VI. PARK8 and PARK9 342
VII. Other Linked PD Loci 342
References 344
Chapter 30. tau Genetics in Frontotemporal Lobe Dementia, Progressive Supranuclear Palsy, and Corticobasal Degeneration 348
I. Introduction 348
II. Anatomy of the tau Gene 349
III. tau Genetics and Molecular Function 352
IV Clinical Phenotypes Caused by tau Gene Mutations 354
V. Clinical Genetics in FTD, PSP, and CBD 356
VI. tau Genetics and Transgenic Models of Disease 358
VII. Treatment 358
References 359
Chapter 31. Wilson Disease 364
I. Introduction 364
II. Phenotype 364
III. Normal and Abnormal Gene Function 366
IV Diagnosis 369
V. Neuroimaging 369
VI. Pathologic Anatomy 371
VII. Animal Models 371
VIII. Treatment 371
References 373
Chapter 32. Essential Tremor 376
I. Phenotype 376
II. Gene 378
III. Diagnostic and Ancillary Tests 379
IV Neuroimaging 379
V. Neuropathology 380
VI. Cellular and Animal Models of Disease 380
VII. Genotype/Phenotype Correlations/Modifying Alleles 381
VIII. Treatment 381
References 383
Chapter 33. Molecular Biology of Huntington's Disease (HD) and HD-Like Disorders 388
I. Summary 388
II. Symptomatology of HD 389
III. Neuropathology 389
IV. Neuroimaging 389
V. Genetics of HD 390
VI. Diagnostic and Predictive Testing 391
VII. Gene, Normal Gene, and Abnormal Gene Function 392
VIII. Huntingtin Aggregates 393
IX. Cell Death in HD 395
X. Early Changes in Gene Expression 397
XI. Excitotoxicity and Impaired Energy Production 397
XII. Animal Models 398
XIII. Genotype/Phenotype/Modifying Alleles 398
XIV. Treatment 399
XV. HD-Like Disorders 399
References 400
Chapter 34. Paroxysmal Dyskinesias 408
I. Historical Aspects and Classification 408
II. Pathophysiology 413
III. Future Directions 414
IV. Concluding Summary 414
References 415
Chapter 35. Primary Dystonias 418
I. Autosomal Dominant Dystonias 420
II. Autosomal Recessive Dystonias 423
III. X-Linked Recessive Dystonias 423
IV. Animal Models of Dystonia 425
References 426
Chapter 36. DYT1 Dystonia 430
I. Summary 430
II. Phenotype 430
III. Gene 432
IV. Diagnostic and Ancillary Tests 436
V. Neuroimaging 436
VI. Neuropathology 436
VII. Cellular and Animal Models of Disease 437
VIII. Treatment 437
References 438
Chapter 37. Dopa-Responsive Dystonia 442
I. Introduction 442
II. Phenotype and Treatment 443
III. Causative Gene 443
IV. Diagnosis 445
V. Genotype/Phenotype Correlation 446
VI. Mechanism of Dominant Inheritance 447
VII. The Mechanism of Neuronal Selectivity—A Study with an Animal Model of Biopterin Deficiency 447
References 449
Chapter 38. Hallervorden-Spatz Syndrom 452
I. Introduction 452
II. Phenotype 452
III. Gene 456
IV. Diagnostic and Ancillary Tests 457
V. Cellular and Animal Models of Disease 460
VI. Genotype/Phenotype Correlations/Modifying Alleles 460
VII. Treatment 461
References 462
Chapter 39. Genetics of Familial Idiopathic Basal Ganglia Calcification (FIBGC) 466
I. Clinical Phenotype 466
II. Genetics 467
III. Diagnostic and Ancillary Tests 467
IV. Neuroimaging 469
V. Neuropathology 470
VI. Pathogenesis and Models of Disease 470
VII. Genotype-Phenotype Correlations 471
VIII. Treatment 471
References 471
Chapter 40. Myoclonus and Myodonus-Dystonias 474
I. Summary 474
II. Phenotype 475
III. Gene(s) 483
IV. Diagnostic and Ancillary Tests 487
V. Neuroimaging 488
VI. Neuropathology 488
VII. Cellular and Animal Models of Disease 488
VIII. Genotype/Phenotype Correlations 488
IX. Treatment 492
References 493
Chapter 41. Mitochondrial Mutations in Parkinson's Disease and Dystonias 496
I. Mitochondrial Genetics 497
II. Parkinson's Disease 497
III. Dystonia 503
IV. Treatment Implications 505
V. Conclusions 506
References 506
Chapter 42. Genetics of Gilles de la Tourette Syndrome 514
I. The GTS Phenotype 514
II. GTS is Heritable 515
III. Segregation Analyses of GTS Family Data 516
IV. The Search for Genes in GTS 517
V. Cytogenetic and Molecular Cytogenetic Approaches 519
VI. Neuroimaging 520
VII. Treatment 520
VIII. Summary and Future Prospects 520
References 521
Chapter 43. The Genetics of Restless Legs Syndrome 526
I. Introduction 526
II. Clinical Features 526
III. Prevalence and Progression 527
IV. Genetic Studies 527
V. Diagnosis 529
VI. Neuroimaging and Neurophysiological Studies 530
VII. Treatment 530
VIII. Summary 531
References 531
Chapter 44. Other Adult-Onset Movement Disorders with a Genetic Basis 534
I. Inborn Errors of Metabolism 534
II. Disorders of Heavy Metal Metabolism 541
III. Movement Disorders Associated with Hematological Disease 543
IV. Other Rare Disorders 554
V Summary 556
References 556
Chapter 45. Ethical Issues in Genetic Testing for Movement Disorders 564
I. Introduction 564
II. Understanding the Role of Molecular Diagnostics in the Management of Neurological Disorders 565
III. Ethical Principles 568
IV. Conclusions 572
References 572
Index 574