Front Cover 1
Neuromuscular Disorders of Infancy, Childhood, and Adolescence 4
Copyright Page 5
Dedication 6
About the Cover images 7
Contents 8
Foreword 24
Preface to the Second Edition 26
Preface to the First Edition 28
List of Contributors 30
I. Clinical and Laboratory Approach to the Infant and Child with a Neuromuscular Problem 34
1 Introduction: Historical Perspectives 36
Introduction 36
Traditional Diagnostic Tests 36
Modern Diagnostic Testing 38
Clinical Classification 39
Clinical Approach 42
Presenting Complaints 44
Conclusion 48
References 48
2 Genetics of Neuromuscular Disorders 50
Introduction 50
Patterns of Genetic Transmission 50
Pedigree Analysis and Risk Assessment 50
Chromosomes and Chromosomal Abnormalities 53
Genetic Imprinting 53
Molecular Genetics 53
Gene Mutations and Modes of Inheritance 54
Developments in Molecular Diagnostics 55
Methods of Molecular Genetic Diagnostics 56
Positive Result 59
Negative Result 59
Comparison Between Panels and Whole Exome Sequencing 60
Secondary Findings 60
Clinical Indications for Genetic Testing 60
Approach to Genetic Evaluation 60
Potential Barriers to Testing 61
Attitudes Towards Genetic Testing 62
Recurrence Risk in Families and Reproductive Options 62
Treatment of Genetic Disorders 63
References 63
3 Electromyography in Pediatrics 65
Introduction 65
Dealing with Misconceptions 65
It Is too Painful 65
It Is too Difficult 67
EMG Has no Future in the Molecular Age 68
Normative Data 68
Techniques 70
Choice of Nerves 71
Investigation Strategies 72
Final Words 76
References 76
4 Muscle Biopsy for Diagnosis of Neuromuscular and Metabolic Diseases 79
Introduction 79
Tissue Selection and Preparation 79
Histopathological Aspects of Muscle Biopsy Preparation and Examination 80
Histological Examination 80
Histochemical Examination 80
Immunocytochemical Reactivities 81
Silver Impregnations 81
Transmission Electron Microscopy (EM) 81
Biochemical Assay of Respiratory Chain Complexes 82
Molecular Genetic Studies 82
Ontogenesis of Striated Muscle 82
Cellular Death And Regeneration 84
Denervation, Disuse, and Hypotrophy 85
Muscle Biopsy in Specific Myopathies 86
Muscular Dystrophies 86
Congenital Muscular Dystrophies 87
Myotonic Muscular Dystrophies 87
Congenital Myopathies 88
Congenital Muscle Fiber-Type Disproportion 88
Nemaline Myopathy 89
Central Core and Minicore/Multicore Myopathy 89
Centronuclear Myopathies 90
Segmental Amyoplasia 91
Muscular Dysgenesis (Proteus Syndrome Myopathy) 91
Myofibrillar Myopathies 91
Glycogenoses 92
Lipid Storage Myopathies 93
Mitochondrial Cytopathies 93
Inflammatory Myopathies 94
Dermatomyositis 95
Polymyositis 96
Autoimmune Necrotizing Myopathy 96
References 96
5 Nerve Biopsy 99
Introduction 99
Techniques 99
Light Microscopy Assessment 101
Transverse Sections 101
Teased Fibers 101
Electron Microscopy 102
Quantitative Analysis 102
Complications 103
Age-Related Differences in Sural Nerve Morphology 104
Biopsy Findings in Relevant Diseases 104
Conclusion 104
References 113
II. Infantile Hypotonia and Arthrogryposis 116
6 Neonatal Hypotonia 118
Introduction 118
History and General Examination 118
History 118
Physical Examination 118
Neonatal Neuromuscular Examination 119
Motor Examination 119
Tone and Posture 119
Motility and Power 120
Muscle Stretch Reflexes 120
Plantar Response 120
Primary Neonatal Reflexes 121
Moro Reflex 121
Palmar Grasp 121
Tonic Neck Response 121
Sensory Examination 121
Distinguishing Features of Motor System Disorders 121
Central Disorders 123
Anterior Horn Cell Disorders 123
Peripheral Nerve Disorders 124
Neuromuscular Junction Disorders 125
Muscle Disorders 125
Conclusion 127
References 127
7 Arthrogryposis 129
Introduction 129
Historical Background 129
Epidemiology 129
Pathogenesis 130
Clinical Features 131
Genotype/Phenotype Correlation 135
Arthrogryposis Associated with Maternal Illnesses 137
Therapy 137
Prognosis 139
Relatively Common Specific Conditions Associated with Multiple Congenital Contractures 139
Mainly Limb Involvement 139
Amyoplasia 139
Bony Fusions Leading to Apparent Congenital Contractures 140
Contractural Arachnodactyly 140
The Distal Arthrogryposes 140
Distal Arthrogryposis Type I 140
Gordon Syndrome (Distal Type IIA) 140
Distal Arthrogryposis Type 5 (IIB) 140
Limbs Plus Other Body Areas 140
Freeman-Sheldon Syndrome (Whistling Face Syndrome) and Sheldon-Hall Syndrome 140
Multiple Pterygium Syndromes 142
Escobar Type 142
Limbs Plus Central Nervous System Dysfunction 143
Lethal Multiple Pterygium Syndrome 143
Neu-Laxova Syndrome 143
Pena-Shokeir Phenotype 143
Chromosomal Anomalies 143
Maternal Antibodies with and Without Myasthenia Gravis 144
Acknowledgments 145
References 145
III. Motor Neuron Disorders 148
8 Spinal Muscular Atrophies 150
Introduction 150
Epidemiology 150
Clinical Characteristics 150
Type I SMA 151
Type II SMA 153
Type III SMA 153
Outliers 153
Other “Spinal Muscular Atrophies” 153
Genetics 154
The SMN Gene 154
Genetic Diagnosis 156
Newborn Screening 158
Other Diagnostic Tests 158
Molecular Function of SMN 158
Differential Diagnosis 159
Non-5q Spinal Muscular Atrophies 159
Congenital Neuropathies 162
Hexosaminidase A Deficiency 162
Juvenile Muscular Atrophy of Distal Upper Extremity (Hirayama Disease) 162
Other Disorders 163
The Pathology of SMA 163
Animal Models 163
Worm, Fly, and Fish Models of SMA 163
Murine Models of SMA—Additional Insights into Disease Pathology 165
Murine Models of SMA—Revealing the Cellular and Temporal Requirements of SMN 165
Treatment 166
Clinical Trials in SMA—Outcome Measures 166
Clinical Trials in SMA—Therapeutics 168
Agents That Upregulate SMN2 Gene Expression and Promote Exon 7 Inclusion 168
Small Molecules 168
Neuroprotective, SMN Protein Stabilization Agents 169
Other Small Molecules 169
Other Approaches 169
Antisense Oligonucleotides 169
Stem Cells 170
Gene Therapy 170
Care of the Patient with SMA 170
Pulmonary 171
Gastrointestinal 171
Nutrition 171
Orthopedic 171
Fatigue 172
Conclusion 172
Acknowledgments 172
References 172
9 Juvenile Amyotrophic Lateral Sclerosis 179
Introduction 179
Nosology of Motor Neuron Diseases 179
Molecular Classification of jALS—Syndromes of Juvenile ALS 180
Discussion of Table 9.1 180
ALS Overlap Disorders 180
ALS2 (Alsin) 180
ALS4 (Senataxin) 183
ALS5/SPG11 (Spatacsin) 183
ALS6 (Fused in Sarcoma/Translocated in Liposarcoma) 184
ALS16 (Sigma-1 Intracellular Receptor) and SPG18 (ERLIN2) 184
jALS Linked to Chromosome 6p25 and 21q22 184
Brown-Vialetto-Van Laere Syndrome 185
Ubiquilin1 185
Madras Motor Neuron Disease 185
Lower Motor Neuron Predominant Disorders 186
Berardinellie-Seip Congenital Lipodystrophy Type 2 Gene 186
DCTN1 186
HSPB1 186
Other dHMN Loci 186
Upper Motor Neuron Predominant Disorders 187
Juvenile-onset HSP with Lower Motor Neuron Involvement 187
SPG3A (Atlastin) 187
SPG4 (Spastin) 187
SPG20 (Spartin) 187
SPG39 (Patatin-like Phospholipase Domain-containing Protein 6, Also Known as Neuropathy Target Esterase) 187
Spastic Paraplegia, Optic Atrophy, and Neuropathy 188
SPG57 (Tyrosine-kinase Fused Gene) 188
SPG31 (Receptor Expression-enhancing Protein 1) 188
Miscellaneous Disorders 188
Management 189
Genetic Counseling 189
Conclusions 189
References 189
10 Infectious or Acquired Motor Neuron Diseases 193
Infantile Poliomyelitis 193
Historical Background 193
Epidemiology 194
Virology, Pathogenesis, and Genetics 194
Clinical Features 195
Postpolio Syndrome 196
Differential Diagnosis 198
Laboratory Evaluation 199
Blood, Cerebrospinal Fluid, and Urine Studies 199
Electromyography 199
Pathology 200
Therapy 200
Prognosis 200
Asthma-related Poliomyelitis Syndrome 200
Poliomyelitis in Patients with Immunodeficiency 201
Vaccine-Associated Poliomyelitis 201
Historical Background 201
Development of Poliovirus Vaccines 201
Impact of Poliovirus Vaccines 202
Epidemiology of Vaccine-Associated Paralytic Poliomyelitis 203
Laboratory Techniques 204
Viral Attenuation and Reversion to Virulence 204
Electrodiagnostic Abnormalities in Vaccine-Associated Poliomyelitis 204
Differential Diagnosis 204
Recommended Vaccination Strategies 204
Tetanus: A Combined Perspective from South Africa and North America 206
Etiology 206
Epidemiology 206
Pathogenesis 207
Clinical Features 207
Neonatal Tetanus 207
Non-neonatal Tetanus 208
Focal Tetanus 208
Cephalic Tetanus 208
Differential Diagnosis 209
Laboratory 209
Prevention 209
Wound Management 210
Management 210
Treatment 210
Ventilation 210
Immunoglobulins 210
Muscle Relaxation/Sedation 210
Antibiotics 210
Sympathetic Overactivity 211
Fluids 211
Active Immunization 211
Prognosis 211
Conclusion 211
Rabies 211
Etiology 211
Epidemiology 212
Pathogenesis 212
Clinical Features 212
Incubation Period 212
Prodrome Phase 212
Acute Neurologic Phase 212
Furious Rabies 212
Paralytic Rabies 212
Differential Diagnosis 213
Laboratory Analysis 214
Prevention 214
Preexposure 214
Postexposure 215
Management 215
Prognosis 216
References 216
11 The Stiff-man Syndrome in Children and Adolescents 221
Introduction 221
Historical Perspective 221
Epidemiology 222
Pathophysiology 222
Neurological Presentation 223
Coexisting Autoimmune Diseases 224
Oncological Findings 224
Differential Diagnosis 224
Testing 225
Neurophysiological Findings 225
Serological Testing 225
Treatment 225
Symptomatic Treatment 225
Immunotherapy 226
Prognosis 226
Conclusion 227
References 227
IV. Peripheral Nerve Disorders 230
12 Radiculopathies and Plexopathies 232
Anatomy 232
Diagnostic Procedures 232
Magnetic Resonance Imaging 232
Electromyography 232
Cervical Radiculopathies 233
Etiology 233
Clinical Presentation 234
Differential Diagnosis 235
Congenital Cervical Stenosis 235
Hirayama Disease 235
Motor Neuron Disease 235
Grisel Syndrome 236
Neurogenic Thoracic Outlet Syndrome 236
Lumbosacral Radiculopathies 236
Etiology 236
Clinical Presentation 236
Evaluation 237
Differential Diagnosis 237
Orthopedic Conditions 237
Intraspinal Lesions 237
Sacral and Pelvic Lesions 237
Treatment 237
Plexopathies 238
Brachial Plexopathies 238
Brachial Plexus Anatomy 238
Diagnostic Procedures 240
Imaging 240
Electrodiagnosis 240
Neonatal Brachial Plexus Lesions 242
Historical Aspects 242
Incidence and Risk Factors 242
Classification 243
Management of Neonatal Brachial Plexopathies 244
Nonsurgical 244
Surgical 245
Late plexus repair and rehabilitation 246
Prognosis 246
EMG and Prognosis 247
Prognosis and Indications for Surgery 247
Other Infantile Brachial Plexopathies 248
Brachial Plexopathies after the Neonatal Period 248
Hereditary Neuralgic Amyotrophy 248
Hereditary Neuropathy with Tendency to Pressure Palsies 249
Traumatic Brachial Plexopathies 249
Pressure Palsies 249
Child Abuse 249
Brachial Plexus Neoplasms 249
Idiopathic Neuralgic Amyotrophy 249
Lumbosacral Plexopathies 250
Anatomy 250
Evaluation of Pediatric Lumbosacral Plexopathies 250
Neonatal Lumbosacral Plexopathies 251
Lumbosacral Plexopathies after the Neonatal Period 251
Acute Lumbosacral Plexitis 252
Neoplasms of the Lumbosacral Plexus 252
References 252
13 Congenital and Acquired Facial Palsies 258
Introduction 258
Evaluation of the Facial Nerve in Children 258
Anatomy 258
Clinical Examination 259
Newborn and Young Infants 259
Older Children 259
Clinical-Anatomic Relationships 260
Complementary Investigations 260
Middle Ear and Auditory Investigations 260
Imaging Studies 260
Facial Nerve Conduction Studies and Electroneuronography 261
Needle Electromyography of Facial Muscles 261
Blink Responses 261
Congenital Facial Palsies 262
Perinatal Facial Nerve Injuries 262
Asymmetric Crying Facies 264
Orofacial Malformations with Cranial Nerve Palsies 264
Moebius Syndrome 265
Neuromuscular Disorders with Congenital Facial Diplegia 266
Congenital Facial Weakness Due to Neonatal Encephalopathy 267
Acquired Facial Palsies 268
Bell’s Palsy 268
Ramsay Hunt Syndrome 269
Lyme Disease 269
Otogenic Facial Palsy 270
Traumatic and Iatrogenic Facial Palsy 270
Recurrent Facial Palsy 271
Acquired Facial Diplegia 271
References 272
14 Mononeuropathies 276
Introduction 276
Assessment and Evaluation of Peripheral Nerve Lesions in Childhood 276
Upper Extremity Mononeuropathies 277
Median Nerve 277
Anatomy 277
Clinical Evaluation 277
Proximal Median Neuropathies 277
Distal Median Neuropathies 279
Evaluation 280
Treatment and Prognosis 280
Ulnar Nerve 281
Anatomy 281
Clinical Evaluation 281
Etiology 281
Evaluation 284
Treatment and Prognosis 284
Radial Nerve 284
Anatomy 284
Clinical Evaluation 284
Etiology 284
Evaluation 286
Treatment and Prognosis 287
Other Upper Extremity Nerves 287
Axillary Nerve 287
Long Thoracic Nerve 287
Musculocutaneous Nerve 287
Suprascapular Nerve 288
Spinal Accessory Nerve 288
Lower Extremity Mononeuropathies 288
Introduction 288
Sciatic Nerve 288
Anatomy 288
Clinical Presentation 288
Traumatic Sciatic Neuropathies 290
Compressive Sciatic Neuropathies 291
Ischemic Sciatic Neuropathies 291
Sciatic Nerve Neoplasms 291
Idiopathic Sciatic Neuropathies 292
Postviral Sciatic Neuropathies 292
Congenital and Infantile Sciatic Neuropathies 292
Evaluation 293
Treatment and Prognosis 293
Femoral Nerve 293
Anatomy 293
Clinical 295
Treatment and Prognosis 295
Lateral Femoral Cutaneous Nerve 295
Iliohypogastric, Ilioinguinal, and Genitofemoral Nerves 296
Obturator Nerve 297
Peroneal Nerve 297
Anatomy 297
Clinical Manifestations 297
Etiology 298
Compressive Peroneal Neuropathies 298
Entrapment Peroneal Neuropathies 298
Other Causes of Peroneal Neuropathy 299
Neonatal Peroneal Neuropathies 299
Evaluation 300
Treatment and Prognosis 300
Sural Nerve 300
Tibial Nerve 300
References 300
15 Overview of Pediatric Peripheral Neuropathies 307
Introduction 307
Peripheral Nerve Maturation 307
Approach to Evaluating Childhood Neuropathies 307
Confirm the Anatomical Site(s) Involved 307
Confirm Peripheral Nerve Type(s) and Fiber Size(s) Involved 309
Confirm Pattern of Peripheral Nerve Involvement 311
Confirm Rapidity of Disease Progression (Acute or Chronic) 311
Confirm Age at Symptom Onset 314
Confirm Electrodiagnostic Features 314
Confirm Associated Clinical Features 315
Pediatric Electrodiagnostic Testing 315
Nerve Conduction Studies 315
Electromyography 316
Trauma 317
Nerve Biopsy 318
Neuroimaging in Childhood Polyneuropathies 318
References 319
16 Congenital and Early Infantile Neuropathies 322
Introduction 322
Etiology 322
Clinical Presentation and Approach to Peripheral Neuropathies In Early Infancy 322
Clinical Presentation 322
Diagnostic Approach 323
Assessment and Management of Complications 326
Genetic Demyelinating Neuropathies with Infantile Onset 327
Demyelinating Forms of CMT with Early Onset 327
Terminology 327
Early Onset Neuropathies Due to PMP22 Mutations 328
Early Onset Neuropathies Due to MPZ Mutations 330
Early Onset Neuropathies Due to EGR2 Mutations 331
Early Onset Neuropathies Due to NEFL Mutations 332
Early Onset Neuropathies Due to GDAP1 Mutations 333
Early Onset Neuropathies Due to MTMR2 Mutations (CMT4B1) 333
Early Onset Neuropathies Due to SBF2 Mutations (CMT4B2) 334
Neuropathies Due to SBF1 Mutations (CMT4B3) 334
Early Onset Neuropathies Due to SH3TC2 Mutations (CMT4C) 334
Early Onset Neuropathies Due to PRX Mutations (CMT4F) 335
Early Onset Neuropathies Due to FGD4 Mutations (CMT4H) 335
Early Onset Neuropathies Due to FIG4 Mutations (CMT4J) 336
Early Onset Neuropathies Associated with GJB1 Mutations 336
Demyelinating Neuropathies of Infancy Associated With Central Nervous System Involvement 336
Demyelinating Neuropathies of Infancy Associated with CNS Hypomyelination 336
Hypomyelination and Congenital Cataract 336
SOX10 Related Conditions 336
Cockayne Syndrome 337
Congenital Cataracts Facial Dysmorphism Neuropathy Syndrome (CCFDN) 338
Genetic Axonal Neuropathies with Infantile Onset 338
Axonal Forms of CMT with Early Onset 338
Severe Early Onset Axonal Neuropathy Due to MFN2 Mutations 338
Infantile Neuropathies Due to TRPV4 Mutations 339
Early Onset Axonal Neuropathies Due to DYNC1H1 Mutations 339
Early Onset Axonal Neuropathy Due to TRIM2 Mutations 340
Lethal Neonatal Autosomal Recessive Axonal Sensorimotor Polyneuropathy 340
Early Onset Axonal Neuropathies with CNS Involvement 340
Giant Axonal Neuropathy 340
Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum 341
Infantile Neuroaxonal Dystrophy 341
Congenital Axonal Neuropathy and Encephalopathy 341
Spinal Muscular Atrophy and Motor Neuronopathies 341
Early Onset Axonal Neuropathies Associated with Mitochondrial Disorders 342
Immunologically Mediated Neuropathies 342
Guillain-Barré Syndrome 342
Chronic Inflammatory Demyelinating Polyneuropathy 342
Conclusion 342
Acknowledgments 342
References 342
17 Hereditary Neuropathies in Late Childhood and Adolescence 352
Definition and Nomenclature 352
Epidemiology 353
Pathobiology 353
Clinical Manifestations 355
Neurophysiology 357
Genetic Testing and Diagnostic Strategies 357
Very Slow MNCV (Less Than or Equal To 15m/s) 357
Slow MNCV (Greater Than 15 and Less Than or Equal To 35m/s) 357
Intermediate MNCV (Greater Than 35 and Less Than 45m/s) 358
Axonal MNCV (Greater Than 45m/s or Unobtainable CMAP) 358
Specific Forms of CMT 360
CMT1: Autosomal Dominant Demyelinating Neuropathies 360
CMT1A 360
CMT1B 361
CMT1C 361
CMT1D 361
CMT1E 361
CMT1F 362
HNPP 362
CMTX: X-linked CMT 362
CMT2: Autosomal Dominant Axonal Neuropathies 362
CMT2A 363
CMT2B 363
CMT2C 363
CMT2D 363
CMT2E 364
CMT2F 364
CMT2L 364
CMT2K 364
CMT2M 364
CMT2O 364
CMT4: Autosomal Recessive Neuropathies 364
CMT4A 364
CMT4B1 365
CMT4B2 365
CMT4C 365
CMT4F 365
CMT4J 365
CMT4: Autosomal Recessive Axonal Neuropathies Also Known as AR-CMT2 365
A: Lamin A/C 365
Intermediate CMT 365
dHMNs: Distal Hereditary Motor Neuropathies 366
dHMNs: Juvenile Onset 366
AD dHMN I 366
AR dHMN IV 366
AD dHMN V 367
AR dHMN-J 367
Differential Diagnosis 367
Treatment Strategies 367
Summary 368
References 368
18 Hereditary Sensory and Autonomic Neuropathies 373
Introduction 373
Hsan Type I 373
Molecular Genetics 373
Pathophysiology 374
Clinical Features 374
ATL1 374
RAB7 374
Hsan Type II 375
Molecular Genetics 375
HSAN 2A 375
HSAN 2B 375
HSAN 2C 375
Pathophysiology 375
Clinical Features 375
Hsan Type III 375
Molecular Genetics 375
Pathophysiology 376
Sensory Nervous System 376
Autonomic Nervous System 376
Clinical Features 377
Somatic Sensory and Motor Systems 377
Autonomic System 377
Gastrointestinal 377
Respiratory 377
Cardiovascular 378
The Eye 378
Cognition and Development 378
Musculoskeletal 378
Survival and Prognosis 378
Hsan Type IV 378
Molecular Genetics 378
Pathophysiology 379
Clinical Features 379
Sensory Nervous System 379
Autonomic Nervous System 379
Cognition 379
Hsan Type V 380
Molecular Genetics 380
Pathophysiology 380
Clinical Features 380
Diagnosis of an Hsan 381
Therapeutic Interventions 381
Management of Decreased Sensation 381
Management of Autonomic Dysfunction 383
Anhidrosis 383
Abnormal Swallowing 383
Respiratory Dysfunction 383
Hyperadrenergic Crises 383
Blood Pressure Lability 383
Emotional Lability and High Levels of Anxiety 383
References 383
19 Peripheral Neuropathy in Inherited Metabolic Disease 386
Introduction 386
Lysosomal Storage Diseases 386
Sphingolipidoses 386
Krabbe Disease: Globoid Cell Leukodystrophy (Galactosylceramide Lipidosis) 386
Clinical Characteristics 386
Pathology 389
Biochemistry 389
Molecular Defect 389
Management 389
Metachromatic Leukodystrophy (Sulfatide Lipidosis) 389
Clinical Characteristics 389
Pathology 389
Biochemistry 390
Molecular Defect 391
Management 391
Fabry Disease (Trihexosylceramide Lipidosis) 391
Clinical Characteristics 391
Cardiac Variant 391
Pathology 391
Biochemistry 391
Management 392
Mucopolysaccharidoses 392
Glycoproteinoses 392
Cherry Red Spot Myoclonus Syndrome (Sialidosis I) 393
Schindler Disease 393
Clinical Characteristics 393
Pathology 394
Peroxisomal Storage Diseases 395
Phytanic Acid Lipidosis (Refsum Disease Heredopathia Atactica Polyneuritiformis)
Clinical Characteristics 395
Pathology 395
Biochemistry 395
Molecular Defect 396
Management 396
Peripheral Neuropathy in Disorders of Peroxisome Biogenesis 396
X-linked Adrenoleukodystrophy 396
Clinical Characteristics of AMN 396
Pathology 397
Management 397
Hyperoxaluria 397
Diseases of Lipids and Lipoproteins 397
Cholestanol Lipidosis (Cerebrotendinous Xanthomatosis) 398
Management 398
Tangier Disease 398
Abetalipoproteinemia (Bassen-Kornzweig Disease) 399
Glycogen Storage Disease 399
Adult Polyglucosan Disease 399
Clinical Characteristics 399
Pathology 400
Biochemistry 400
Amino Acid Disease 400
Tyrosinemia 400
Management 400
Mitochondrial Diseases 401
Mitochondrial Trifunctional Protein and Long-Chain 3-Hydroxy-Acyl-CoA Dehydrogenase Deficiencies 401
Management 401
Leigh Disease (Subacute Necrotizing Encephalopathy) 401
Clinical Characteristics 402
Pathology 402
Biochemistry 402
Management 402
Neuropathy, Ataxia, and Retinitis Pigmentosa 402
Biochemistry 403
Other Inherited Metabolic Diseases 403
Acute Intermittent Porphyria 403
Management 403
References 404
20 Acute Polyneuropathies 412
Introduction 412
Guillain-Barré Syndrome 412
Clinical Findings 412
Clinical Variants of Guillain-Barré Syndrome 414
Acute Inflammatory Demyelinating Polyneuropathy 414
Acute Motor Axonal Neuropathy 414
Acute Motor-Sensory Axonal Neuropathy 415
Miller Fisher Syndrome and the Pharyngo-Cervical-Brachial Variant of GBS 415
Polyneuritis Cranialis 415
Pathophysiology 415
Investigations 416
Differential Diagnosis 418
Management 420
Outcome 421
Future Directions 422
Tick Paralysis 422
Epidemiology 422
Pathogenesis 422
Pathophysiology of Tick Paralysis 423
Clinical Features 424
Differential Diagnosis 424
Clinical Neurophysiology 425
Therapy 425
References 425
21 Chronic Inflammatory Demyelinating Polyradiculoneuropathy 431
Epidemiology 431
Pathogenesis 431
Clinical Features 432
Differential Diagnosis 434
Laboratory Studies 436
Electrophysiologic Testing 440
Nerve Biopsy 442
Neuroimaging 443
Treatment 443
Intravenous Immunoglobulin (IVIg) in Childhood CIDP 444
Corticosteroid Therapy in Childhood CIDP 444
Plasma Exchange in Childhood CIDP 445
Other Immunosuppressant Medications in Childhood CIDP 445
Prognosis 445
References 446
22 Neuropathies Secondary to Systemic Disorders 451
Introduction 451
Critical Illness Polyneuropathy 451
Renal Disorders 451
Chronic Renal Failure 451
Endocrine Disorders 453
Diabetes Mellitus 453
Multiple Endocrine Neoplasia Type 2B 454
Vitamin Deficiency States 454
Vitamin B1 (Thiamine) Deficiency 454
Vitamin B2 (Riboflavin) Deficiency 454
Vitamin B6 (Pyridoxine) Deficiency 454
Vitamin B12 (Cobalamin) Deficiency 455
Vitamin E Deficiency 455
Malignancies and Reticuloses 455
Lymphoma 456
Sensory Neuropathy 456
Sensorimotor Neuropathy 456
Paraneoplastic Neuropathies 456
Graft-versus-Host Disease 456
Neurofibromatosis 456
Sickle Cell Disease 457
Connective Tissue Disorders 457
Rheumatoid Arthritis 457
Systemic Lupus Erythematosus 457
Miscellaneous Systemic Disorders 458
Chronic Idiopathic Intestinal Pseudo-Obstruction 458
Sarcoidosis 458
Amyloidosis 458
References 459
23 Toxic Neuropathies 464
Introduction 464
General Features of Toxic Neuropathies 464
Clinical Features 464
Pathophysiology 464
Diagnosis 465
Treatment 465
Selected Toxic Neuropathies 465
Antineoplastic Agents 465
Antibacterial, Antiprotozoal, and Antiretroviral Drugs 466
Miscellaneous Medications 466
Insecticides, Rodenticides, and Heavy Metals 467
Poisonous Plants 469
Conclusion 469
References 469
24 Hansen’s Disease (Leprosy): Leprous Neuropathy 471
Introduction 471
Skin Manifestations 471
Leprosy Neuropathy 472
Characteristics of Leprosy Neuropathy 472
Diagnosis 473
Pathophysiology of Nerve Damage 473
Treatment 474
References 474
V. Neuromuscular Junction Disorders 476
25 Acquired Presynaptic Neuromuscular Junction Disorders 478
Infant Botulism 478
Clinical Concerns 478
Epidemiology 478
Pathogenesis 479
Differential Diagnosis and Evaluation 480
Therapy 482
Lambert-Eaton Myasthenic Syndrome 484
Clinical Concerns 484
Diagnostic Evaluations 484
Pathogenesis 485
Therapy 485
Summary 486
References 486
26 Congenital Myasthenic Syndromes 489
Introduction 489
Diagnosis 489
Generic Diagnosis 489
Genetic Diagnosis 489
Classification 490
Presynaptic Congenital Myasthenic Syndrome 491
Endplate Choline Acetyltransferase Deficiency (Congenital Myasthenic Syndrome with Episodic Apnea) 491
Paucity of Synaptic Vesicles Associated with Reduced Quantal Release 493
CMS Resembling the Lambert-Eaton Myasthenic Syndrome 493
Synaptic Basal Lamina Associated CMS 493
EP Acetylcholinesterase Deficiency 493
CMS Associated with ß2-Laminin Deficiency 495
Postsynaptic CMS 495
The Muscle Form of the Nicotinic Acetylcholine Receptor 495
Slow-Channel Syndrome 495
Fast-Channel Syndrome 496
Primary Acetylcholine Receptor Deficiency 497
Prenatal CMS Caused by Mutations in AChR Subunits and Other EP Specific Proteins 501
CMS Caused by Plectin Deficiency 501
Na-Channel Myasthenia 501
CMS Caused by Defects in Endplate Development or Maintenance 502
CMS Caused by Mutations in Rapsyn 503
CMS Caused by Mutations in Agrin 503
CMS Caused by Mutations in MuSK 503
CMS Caused by Mutations in Dok-7 505
CMS Caused by Congenital Defects in Glycosylation (CDG) 505
CMS Caused by Mutations in GFPT1 506
CMS Caused by Mutations in DPAGT1 507
Mutations in ALG2 and ALG14 509
CMS Associated with Centronuclear Myopathy 509
Currently Available Therapies 511
References 511
27 Juvenile and Neonatal Myasthenia Gravis 515
Background 515
Pathophysiology 515
Clinical Presentation 517
Diagnostic Testing 518
Antibody Testing 518
The Ice Test 519
The Edrophonium Test 519
Repetitive Stimulation 520
Single Fiber Electromyography 521
Imaging 521
Medical Therapies 521
General Approach to Treating Juvenile Myasthenia Gravis 521
Acetylcholinesterase Inhibition 522
Plasmapheresis 522
Intravenous Immunoglobulins 522
Corticosteroids 523
Steroid-sparing Agents 523
Surgical Therapies 524
Neonatal Myasthenia Gravis and the Fetal Acetylcholine Receptor Inactivation Syndrome 524
Prognosis 526
Conclusions 526
References 526
VI. Myopathies 530
28 Congenital and Other Structural Myopathies 532
Nemaline Myopathy 535
Classification 537
Clinical Features 538
Laboratory Investigations 541
Pathologic Features 541
Differential Diagnosis 543
Genetics 543
Core Myopathies 544
Clinical Features 544
Central Core Disease and Malignant Hyperthermia 546
Laboratory Investigations 546
Pathologic Features 546
Genetics 547
RYR1-related Myopathies 547
Multiminicore Disease 548
Clinical Features 548
Pathologic Features 548
Genetics 548
Congenital Fiber Type Disproportion 549
Centronuclear Myopathies 550
Clinical Features 550
Laboratory Investigations 553
Pathologic Features 553
Differential Diagnosis 554
Genetics 554
Titinopathies 554
Myofibrillar Myopathies 555
Clinical Features 555
Laboratory Investigations 555
Pathologic Features 555
Genetics 556
Desminopathies 556
BAG3opathies 556
AlphaB Crystallinopathies 556
Hyaline Body Myopathy 556
Clinical Features 557
Pathologic Features 557
Genetics 557
Autophagic Vacuolar Myopathies 557
Treatment of Congenital Myopathies 558
Prevention: Genetic Counseling and Prenatal Diagnosis 559
Monitoring 559
Risk Management 559
Surgical Procedures and Anesthetic Risks 559
Obstetric Complications 560
Symptomatic Therapy and Rehabilitation 560
Respiratory Care 560
Feeding Difficulties 560
Joint Contractures and Scoliosis 560
Exercise 561
Novel Therapeutic Strategies 561
Drug Discovery 561
References 561
29 Congenital Muscular Dystrophies 571
Introduction 571
Definition of CMD 571
Classification 571
Merosin-Deficient CMD 572
Dystroglycanopathies 575
CMD With Collagen VI Deficiency (Ullrich Disease) 577
SEPN1-Related CMD 579
LAMIN A/C-Related CMD 580
Differential Diagnosis 580
Therapeutic Approaches 581
Acknowledgments 581
References 581
30 Dystrophinopathies 584
Introduction 584
Historical Background 584
Etiology and Pathogenesis 585
DMD Gene 585
The Dystrophin Associated Protein Complex 585
DMD Gene Mutations 588
Exceptions to the Reading-Frame Rule: DMD Patients with In-Frame Deletions 590
Exceptions to the Reading-Frame Rule: BMD Patients with Out-of-Frame Deletions 590
Point Mutations 590
Dystrophin 590
Pathogenesis 590
Utrophin 592
Germline Mosaicism 592
Dystrophinopathies in Females 593
Incidence and Prevalence 593
Clinical Presentation 593
Duchenne Muscular Dystrophy 593
Clinical Features 593
Other Organ Involvement 598
Heart 598
Brain 598
Smooth Muscle 599
Skeleton 599
Adverse Anesthetic Reactions 599
Becker Muscular Dystrophy 599
“Outliers” or Intermediate Phenotype 600
DMD-associated Dilated Cardiomyopathy 600
Muscle Cramps with Myoglobinuria 601
Asymptomatic Elevation of Muscle Enzymes 601
Manifesting DMD/BMD Carrier Females 602
Differential Diagnosis 604
Limb-girdle Muscular Dystrophies 604
Acid Maltase Deficiency, Spinal Muscular Atrophy 604
Emery-Dreifuss Muscular Dystrophy 604
Congenital Muscular Dystrophies 604
Mitochondrial DNA Depletion Syndrome 604
Dermatomyositis 604
Elevation of Liver Enzymes 604
Dilated Cardiomyopathy 605
Diagnostic Testing 605
Serum Muscle Enzymes 605
Other Serum and Urine Abnormalities 607
Electromyography 607
Muscle Biopsy 607
Histopathological Findings 607
Dystrophin Immunostaining 609
Western Blot Analysis 609
Molecular Genetic Testing 611
Clinical Testing 612
Testing Strategies in Specific Populations 612
Genetic Counseling 613
Prenatal Testing 614
Treatment and Management 614
References 614
31 Clinical Management of Dystrophinopathies: A Systematic Approach 626
Introduction 626
Duchenne Muscular Dystrophy 626
Assessments 627
Pharmacological Interventions 632
Corticosteroids 632
Initiation of Corticosteroid Therapy 632
Steroid Formulations, Doses, and Regimes 633
Regimes—Equipoise 633
Nonambulant Patients 634
Administration 634
Side Effects 634
Weight Gain 636
Behavioral Problems 636
Growth 636
Bone Health 636
Gastrointestinal (GI) Problems 637
Delayed Puberty 637
Immune System 637
Emergencies 637
Other Pharmaceutical Interventions 637
Cardiac Management 637
Respiratory Management 639
Physiotherapy Input and Interventions 641
Spinal Management 642
Fracture Management 642
Nutritional, Swallowing, and Gastrointestinal Management 642
Surgical and Emergency Care Considerations 643
Cognitive and Speech Management 644
Psychological and Social Issues 644
Adults with DMD 644
Other Dystrophinopathies: Becker Muscular Dystrophy and Manifesting Carriers of DMD/BMD 645
Conclusions 646
References 646
32 Facioscapulohumeral Dystrophy 653
Introduction 653
Clinical Features 653
Extramuscular Manifestations 655
Infantile FSHD 655
FSHD Variants 656
Scapulohumeral Dystrophy Phenotype with Facial Sparing 656
Differential Diagnosis 656
Laboratory Tests 656
Management 657
Physical Therapy and Rehabilitation 657
Orthopedic/Surgical Interventions 657
Pain 657
Respiratory Function 657
Retinal Vascular Disease and Hearing Loss 657
Surveillance during Pregnancy 657
Prognosis 658
Genetics 658
References 660
33 Distal Myopathies 664
Early Onset Distal Myopathies 664
Laing Distal Myopathy (LDM, MPD1) 664
Clinical Phenotype 664
Molecular Genetics 664
Diagnostics 664
Therapy 664
Distal Nebulin Myopathy 665
Clinical Phenotype 665
Molecular Genetics 665
Distal Myopathy Caused by Mutations in KLHL9 665
Clinical Phenotype 665
Molecular Genetics 665
Distal Caveolinopathy 665
Juvenile Onset Distal Myopathies 665
Miyoshi Distal Myopathy 665
Clinical Phenotype 665
Molecular Genetics 666
Distal Anoctaminopathy 666
Clinical Phenotype 666
Molecular Genetics 666
References 666
34 Limb-girdle Muscular Dystrophies 668
Introduction 668
Historical Background and Definition 668
Genetic Nomenclature 668
Autosomal Recessive Limb-Girdle Muscular Dystrophies 669
Sarcoglycanopathies (LGMD 2C–F) 670
Pathophysiology 670
Dystrophin-associated proteins 670
Intracellular DAPs 670
Transmembrane DAPs: Dystroglycan complex 670
Transmembrane DAPs: Sarcoglycan complex 671
Genetics and Mutations 671
Clinical Features 672
Time course and distribution of motor symptoms 672
Cardiac features 672
Pulmonary features 673
Contractures and other signs and symptoms 673
Diagnosis 673
Treatment 675
LGMD 2I (Fukutin-related Protein Mutation) 675
Pathophysiology and Genetics 675
Clinical Features 675
Diagnosis 675
Treatment 675
Other a-Dystroglycanopathies 676
Calpainopathy (LGMD 2A) 676
Background and Epidemiology 676
Pathophysiology, Genetics, and Mutations 676
Clinical Features 676
Time course and distribution of motor symptoms 676
Cardiac features 678
Pulmonary features 678
Contractures and other signs and symptoms 678
Diagnosis 678
Treatment 678
Dysferlinopathy (LGMD 2B) 678
Pathophysiology 678
Genetics and Mutations 679
Clinical Features 679
Time course and distribution of motor symptoms 679
Cardiac and pulmonary features 680
Contractures and other signs and symptoms 680
Diagnosis 680
Treatment 680
Anoctaminopathy (LGMD 2L) 680
Pathophysiology, Genetics, and Mutations 680
Clinical Features 680
Cardiac and pulmonary features 681
Other Rare Autosomal Recessive Limb-girdle Muscular Dystrophies 681
Telethoninopathy (LGMD 2G) 681
Pathophysiology and genetics 681
Clinical features 681
Diagnosis 681
Treatment 681
LGMD 2H 681
Titinopathy (LGMD 2J) 682
Autosomal Dominant LIMB-Girdle Muscular Dystrophies 682
Autosomal Dominant LGMDs without Cardiac Involvement 682
Myotilinopathy (LGMD 1A) 682
Pathophysiology and mutations 682
Clinical features 682
Diagnosis 682
Treatment 683
Caveolinopathy (LGMD 1C) 683
Pathophysiology and genetics 683
Clinical features 683
Diagnosis 683
Treatment 683
LGMD 1E 683
Autosomal Dominant LGMDs with Cardiac Involvement 683
Laminopathy (LGMD 1B) 683
Pathophysiology and genetics 684
Clinical features 684
Cardiac features 684
Diagnosis 684
Treatment 684
Other Muscular Dystrophies that May Present as LGMD 684
Autosomal Recessive Conditions Presenting as LGMD 684
Partial Laminin a2 Deficiency 684
X-linked Recessive Conditions Presenting as LGMD 685
Autosomal Dominant Conditions that May Present as LGMD 685
Facioscapulohumeral Dystrophy 685
Myotonic Dystrophy Types 1 and 2 685
Collagen VI Related Dystrophies 685
Summary and Approach to Patients 686
Muscle Biopsy and Protein Studies 689
Molecular and Genetic Testing 689
References 689
35 Emery-Dreifuss Muscular Dystrophy: Nuclear Envelopathies 700
Introduction 700
Historical Background 700
Molecular Biology 701
X-linked EDMD 701
AD and AR EDMD 701
Pathogenesis 701
Clinical Features 703
Neuromuscular Features 703
Cardiac Features 704
Differential Diagnosis 704
Genotype-Phenotype Correlation 704
Laboratory Investigations 706
Serum Creatine Kinase 706
Electromyography 706
Histopathology and Immunohistochemistry 706
Radiological Studies of the Extremities 706
Genetic Testing 707
Cardiac Investigations 707
Therapy 707
Prognosis 708
Acknowledgments 708
References 708
36 Myopathies of Systemic Disease 712
Introduction 712
Hyperthyroidism 712
Hypothyroidism 713
Parathyroid Disease 713
Cushing’s Syndrome 713
Uremia 715
Osteomalacia 715
Hypokalemia 715
Licorice 715
Renal Tubular Acidosis 716
Hypernatremia 716
Primary Hyperparathyroidism 717
Human Immunodeficiency Virus 717
Lyme Disease 718
Sepsis/Intensive Care Unit Myopathies 718
Thick Filament Myopathy 718
Cachectic Myopathy 718
Acute Necrotizing Myopathy of Intensive Care 718
Hopkins’ Syndrome 718
Neutral Lipid Storage Disease 719
Medication-Related Myopathies 719
Corticosteroids 719
Amphotericin B 719
Didanosine 720
Chloroquine and Hydroxychloroquine 720
Clofibrate 720
Epsilon-aminocaproic Acid 720
Labetalol 721
Lovastatin 721
Other Medications 721
Inflammatory Myopathies Associated with Systemic Disorders 721
Inflammatory Myopathies and Malignancies 721
Rheumatoid Disease and Myopathy 724
Scleroderma–Myositis 725
Systemic Lupus Erythematosus–Myositis 725
Sjögren’s Syndrome–Myositis 725
Mixed Connective Tissue Disease–Myositis 725
Churg-Strauss Syndrome 725
Eosinophilic Myopathic Syndromes 726
Idiopathic Eosinophilic Myopathy 726
Eosinophilic Myopathy and Parasitic Infection 726
Toxic Oil Syndrome 726
Eosinophilia-Myalgia Syndrome 726
References 727
37 Myotonic Dystrophy 730
Clinical Presentation and Phenotypes 730
Brief Overview of History and Epidemiology 730
Mode of Inheritance and Prevalence 731
Clinical Presentation and Phenotypes 733
Myotonic Dystrophy Type 1 (Steinert’s Disease): Age of Onset and Clinical Presentation 733
Myotonic Dystrophy Type 2 (Proximal Myotonic Myopathy): Age of Onset and Clinical Presentation 738
Molecular Genetics 740
DM1: Normal Gene Product 740
DM2: Normal Gene Product 740
DM1 and DM2: Genotype-Phenotype Correlations 740
Disease Mechanisms for DM1 and DM2 741
DM1 and DM2 are RNA-mediated Diseases 741
Human Studies Supporting RNA-mediated Pathomechanism for DM1 and DM2 741
Animal Models 741
Current Human Research 742
Diagnostic Approach 743
Management 743
Standards of Care 743
Therapies under Investigation 744
References 746
38 Muscle Channelopathies: Myotonias and Periodic Paralyses 752
Introduction 752
Electrophysiology of Clinical Weakness and Paralysis 752
Myotonias 752
Clinical Presentation of Cl- Channel Myotonias Becker and Thomsen 752
Clinical Presentation of Na+ Channel Myotonias Fluctuans and Permanens 754
Myotonias: Diagnostic Approach 754
Myotonias: Differential Diagnoses 755
Myotonias: Therapeutic Interventions 756
Myotonias: Pathophysiology 756
Myotonias: Molecular Genetics 758
Paramyotonia 758
Clinical Presentation 758
Paramyotonia: Diagnostic Approach 758
Paramyotonia: Differential Diagnoses 759
Paramyotonia: Therapeutic Interventions 759
Paramyotonia: Pathophysiology 759
Paramyotonia: Molecular Genetics 759
Periodic Paralyses 759
Clinical Presentation of Hyperkalemic, Normokalemic and Hypokalemic Periodic Paralyses 759
Periodic Paralyses: Andersen-Tawil Syndrome 761
Thyrotoxic Hypokalemic Periodic Paralysis 761
Periodic Paralyses: Diagnostic Approach 762
Periodic Paralyses: Differential Diagnoses 762
Periodic Paralyses: Therapeutic Interventions 762
Periodic Paralyses: Pathophysiology 764
Periodic Paralyses: Molecular Genetics 764
Acknowledgments 765
References 765
39 Glycogen Storage Diseases of Muscle 768
Introduction and Background 768
Forearm Ischemic Exercise Test 769
Defects of Glycogenolysis 770
Phosphorylase Kinase Deficiency 770
Myophosphorylase Deficiency 771
Debranching Deficiency 773
A Pediatrician’s Perspective 774
Defects of Glycolysis 775
Phosphoglucomutase Deficiency 775
Phosphofructokinase Deficiency 775
Aldolase Deficiency 776
Phosphoglycerate Kinase Deficiency 776
Phosphoglycerate Mutase Deficiency 776
Beta-enolase Deficiency 777
Lactate Dehydrogenase Deficiency 777
A Pediatrician’s Perspective 777
Defects of Glycogen Synthesis 778
Muscle Glycogenin Deficiency 778
Muscle Glycogen Synthase Deficiency 779
Glycogen Branching Enzyme Deficiency 780
Other Polyglucosan Diseases 782
Lafora Progressive Myoclonus Epilepsy 782
Myopathy and Cardiomyopathy Due to Defective Ubiquitin Ligase RBCK1 783
Other Polyglucosan Disorders 783
A Pediatrician’s Perspective 783
Defects of Lysosomal Glycolysis 784
Acid a-Glucosidase Deficiency 784
A Pediatrician’s Perspective 787
References 787
40 Lipid Storage Myopathies Due to Fatty Acid Oxidation Defects 794
Historical Background 794
Pathophysiology 795
Normal Pathway of Fatty Acid Oxidation 795
The Regulation of Fatty Acid Oxidation 797
Alternative Pathways for Fatty Acid Metabolism 797
Central Role of Carnitine Metabolism 798
Fasting Adaptation 798
Increased Susceptibility of the Child 799
Clinical and Biochemical Features of Identified Defects 799
Common Features of Fatty Acid Oxidation Disorders 800
Metabolic Decompensation in Association with Fasting 800
Hypoketotic Hypoglycemia 800
Involvement of Fatty-acid Oxidation Dependent Tissues 800
Alterations in Plasma and Tissue Concentrations of Carnitine 801
Additional Laboratory Findings 801
Specific Features of Individual Genetic Defects 801
Differentiating Laboratory Features 808
Carnitine 809
Dicarboxylic Acids 810
Diagnostic Approaches and Screening Methods 811
History and Physical Examination 811
Total Carnitine Measurement 811
Urinary Organic Acids 811
Fasting Studies 811
Other Studies 812
Fatty Acid Oxidation Studies 812
Enzymatic Assays 812
Uptake Studies 812
Molecular Studies 814
Treatment 814
The Avoidance of Precipitating Factors 814
High-carbohydrate, Low-fat Diet 815
Uncooked Corn Starch 815
Specific Measures for Individual Fatty Acid Oxidation Disorders 815
Carnitine 815
Medium-chain Triglyceride Oil 816
Riboflavin 816
Specific Therapies for LCHAD/TFP Deficiency 816
Triheptanoin 817
Peroxisome Proliferators Activated Receptor (PPAR) Agonists 817
Gene Therapy Approach for VLCAD Deficiency 817
Genetics and Presymptomatic Recognition 817
Conclusion 818
Acknowledgments 819
References 819
41 Mitochondrial Encephalomyopathies 829
Introduction 829
Historical Background 829
Epidemiology 831
Classification 831
Pathogenesis and Genetics 832
Clinical Features 835
Diseases Due to mtDNA Mutations 836
Large-Scale Rearrangements of mtDNA 836
Major Deletions and Duplications 836
Kearns-Sayre Syndrome 836
Pearson’s Syndrome 836
Sporadic PEO with RRF 836
Point Mutations in mtDNA 837
Point Mutations in rRNA and tRNA Genes 837
Maternally Inherited PEO 838
Isolated Myopathy without PEO 838
Myoclonus Epilepsy with Ragged-red Fibers 838
Point Mutations in Protein-Coding Genes 839
NARP/MILS 839
Leber’s Hereditary Optic Neuropathy 839
Isolated Myopathies 839
Other Presentations 840
Diseases Due to Nuclear DNA Mutations 840
Direct Hits 840
Complex I 840
Complex II 840
Complex III 841
Coenzyme Q10 Deficiencies 841
Complex IV 841
Complex V 842
Indirect Hits 842
Complex I 842
Complex II 843
Complex III 843
Complex IV 843
Complex V 845
Defects of Mitochondrial Protein Importation 845
Defects of mtDNA Translation 845
Defects of the Mitochondrial Inner Membrane Lipid Milieu 846
Defects of Mitochondrial Dynamics 848
Defects of mtDNA Maintenance 848
Defects of the Replicating Machinery 849
Defects of the Intramitochondrial Deoxynucleoside Triphosphate (dNTP) Pool 849
Other Disorders of mtDNA Maintenance 851
Diagnostic Approach 851
Family History 851
Multisystem Disorders 851
Progressive External Ophthalmoplegia 851
Onset 852
Laboratory Exams 852
Muscle Biopsy 852
Biochemistry 853
Molecular Studies 854
Therapeutic Approaches 854
References 856
42 Juvenile Dermatomyositis and Other Inflammatory Myopathies in Children 867
Introduction 867
The Epidemiology of the Major Pediatric Inflammatory Myopathies 868
Pathogenesis/Genetic Data 873
Overview 873
Infectious Agents and JDM 873
Genetic Data 874
Clinical Features at Diagnosis 874
Cutaneous Findings 875
Musculoskeletal Symptoms 876
Cardiorespiratory Abnormalities 876
Pulmonary Fibrosis 876
Gastrointestinal Involvement 877
Genitourinary Function 877
Ophthalmologic Findings 877
Other Disease Manifestations 878
Juvenile Dermatomyositis with a Chronic Course 878
Lipodystrophy 878
Dystrophic Calcifications 878
Calcification—Differential Diagnosis 879
Disease Chronicity 879
Other Autoimmune Diseases 879
Laboratory Indicators of Juvenile Dermatomyositis 879
Magnetic Resonance Imaging 879
Muscle Enzymes 879
Electromyogram 882
Pathology 883
Muscle Biopsy 883
Skin Involvement 884
Immunologic Data 884
Humoral Immunity 884
Myositis Specific Antibodies 884
Myositis Associated Antibodies 885
Type 1 Interferons 885
T Cell Immunity 885
Complement 887
Cytokines and Chemokines 888
Neopterin 888
Acute Phase Reactants 888
Von Willebrand Factor Antigen 888
Bone Health 889
Vitamin D Levels 889
Bone Mineral Density 889
Course and Therapy 889
Disease Course 889
Evaluation Tools for Disease Activity and Chronicity 889
Therapy 890
Development of Consensus Driven Guidelines for Classification and Therapy 890
Oral Corticosteroids 890
Methotrexate 892
High-Dose Intravenous Intermittent (Pulse) Methylprednisolone 893
Hydroxychloroquine 893
Intravenous Immunoglobulin G (IVIg) 893
Treatment of Severe or Resistant IIM 894
Mycophenolate 894
Calcinurin inhibitors 894
Biologic Agents 894
Anti-TNFa Agents (Etanercept Infliximab)
Rituximab 894
Other Biologic Agents 894
Cyclophosphamide 894
Calcinosis 894
Vitamin D and Bone Health 895
Physical Therapy 895
Exercise Improves JDM Muscle Function 895
Physical Therapy for Flexion Contractures 895
Psychological Aspects of Juvenile Myositis 895
Other Less Common Forms of Inflammatory Myopathy 895
Myositis Associated with Connective Tissue Disease 895
Myositis Associated with Other Diseases 898
Laboratory Testing 898
Therapy 898
Focal Myositis 899
Inclusion Body Myositis 899
Orbital Myositis 899
Pathophysiology and Genetics 899
Clinical and Laboratory Findings 899
Laboratory Testing 900
Therapy 900
Rare Types of Localized Myositis in Children 900
Immune-Mediated Necrotizing Myopathy 900
Proliferative Myositis: Pathophysiology 900
Nodular Myositis: Pathophysiology 900
Eosinophilic Myositis/Fasciitis 900
Pathophysiology 900
Clinical Findings and Therapy 900
Cancer-Associated Myositis 901
Graft-vs.-Host Myositis 901
Conclusion 901
References 904
VII. Special Clinical Problems 916
43 Neuromuscular Problems of the Critically Ill Neonate and Child 918
Introduction 918
Acute Neuromuscular Crises in the Infant 919
Anterior Horn Cell 919
Peripheral Nerve 919
Neuromuscular Junction (NMJ) 921
Muscle 921
Acute Neuromuscular Crises in the Toddler and the Older Child 922
Anterior Horn Cell 922
Peripheral Nerve 922
Mononeuritis Multiplex (MNM) 926
Neuromuscular Junction Disorders in the Older Child 926
Muscle 926
Channelopathies 926
Dermatomyositis 928
Critical Illness Neuromuscular Disorders 928
Post-asthmatic Amyotrophy (Hopkins Syndrome) 928
Critical Illness Polyneuropathy 928
Persistent Neuromuscular Blockade 929
Acute Quadriplegic Myopathy 930
Acute Necrotizing Myopathy of Intensive Care 932
Conclusions 932
References 933
44 Intensive Care Management, Including Cardiorespiratory Care 937
Historical Background 937
Intensive Care 937
Ethics 937
Normal Physiology 938
Cardiac 938
Respiratory 938
Pathophysiology 938
Heart Failure 938
Cardiomyopathy 938
Arrhythmia 939
Respiratory Failure 940
Cardiopulmonary Interactions/Pulmonary Hypertension 940
Evaluation 940
Patient History 940
Physical Examination 940
Diagnostic Testing 940
Monitoring 940
Supplemental Monitoring 941
Input and Output 941
Laboratory 941
Imaging 941
Nutrition 942
Treatment 943
Pharmacologic 943
Pacemaker 943
Cardioversion 943
Cardiopulmonary Resuscitation 943
Mechanical Support 943
Cardiac Transplantation 944
Respiratory 944
Other Considerations 944
ICU Weakness 944
References 944
45 Malignant Hyperthermia: An Inherited Disorder of Muscle Calcium Metabolism 946
Malignant Hyperthermia—Deaths in General Anesthesia 946
Muscular Hypermetabolism by Rampant Ca2+ 946
Anesthesia-Related Muscle Spasms 948
Awake Episodes 948
MH and Childhood 948
Functional Diagnostics—In Vitro Contracture Test 949
Genetic Diagnostics 949
Creatine Phosphokinase 950
Histological Findings and Core Formation 950
Associated Syndromes and MH-Like Episodes 951
Clinical Considerations 952
References 953
46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles 955
General Principles 955
The Extraocular Lower Motor Unit 955
Examination Approach to Extraocular Movement Disorders 958
Examination 958
Lid Function 958
Pupil 958
Ocular Alignment 958
Ductions 958
Horizontal and Vertical Saccades 958
Cranial Nerve Palsies 959
Oculomotor Palsy (CN III) 959
Anatomy 959
Localizing Syndromes 959
Fundamental Signs and Symptoms 959
Etiology 960
Congenital CN III Palsies 960
Acquired CN III Palsies 960
Isolated Pupillary Dysfunction 960
Trochlear Palsy (CN IV) 962
Anatomy 962
Localizing Syndromes 963
Fundamental Signs and Symptoms 964
Etiology 964
Differential Diagnosis 964
Abducens Palsy (CN VI) 965
Anatomy 965
Localizing Syndromes 965
Fundamental Signs and Symptoms 965
Etiology 965
Congenital CN VI Palsies 966
Acquired CN VI Palsies 966
Differential Diagnosis 966
Investigations and Imaging of Cranial Nerve Palsies 966
Treatment and Prognosis of Cranial Nerve Palsies 967
General Principles 967
Oculomotor Palsy 967
Trochlear Palsy 967
Abducens Palsy 968
Congenital Ptosis Syndromes 968
Blepharoptosis 968
Isolated Congenital Ptosis 968
Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome 969
Congenital Cranial Dysinnervation Disorders 969
Duane Syndrome 969
Congenital Horizontal Gaze Palsy 970
Congenital Fibrosis of the Extraocular Muscles 971
Congenital Trochlear Palsy and Brown Syndrome 973
Moebius Syndrome 974
Synkinesis Syndromes 974
Ophthalmoplegia in Pediatric Neuromuscular Disease 975
Neuropathic Ocular Weakness 975
Congenital 975
Acquired 975
Neuromuscular Junction Disorders 975
Congenital Myasthenic Syndromes 975
Acquired Disorders of Neuromuscular Transmission 977
Myopathies 977
Congenital Myopathies 977
Muscular Dystrophies 978
Oculopharyngeal Muscular Dystrophy 979
Other Myopathies 979
Oculopharyngodistal Myopathy 979
Inclusion Body Myopathies 979
Endocrine Myopathies 979
Channelopathies 979
Mitochondrial Disorders 979
Arthrogryposis 980
Spinocerebellar Ataxias 980
References 981
47 Oromotor Dysfunction in Neuromuscular Disorders: Evaluation and Treatment 991
Introduction 991
Oromotor Dysfunction Due to Neuromuscular Disorders 993
Neuromuscular Disorders with Associated Oromotor Dysfunction 995
OMS Dysfunction Assessment 999
Treatment of Oromotor Dysfunction Due to a Neuromuscular Disorder 1001
References 1005
48 Complex Regional Pain Syndromes I and II (Reflex Sympathetic Dystrophy, Causalgia) 1009
Introduction 1009
Incidence and Prevalence 1009
Pathophysiology 1010
Diagnosis 1012
Treatment 1012
Patient Education 1012
Pharmacological Treatment 1013
Multidisciplinary Management 1013
Occupational and Physical Therapies 1013
Psychological Support 1014
Long-Term Care of CRPS 1014
Prognosis 1014
References 1014
49 Friedreich Ataxia 1017
Introduction 1017
Epidemiology 1017
Pathology 1017
Central Nervous System 1017
Heart 1018
Other Organs 1018
Clinical Aspects 1018
Onset 1018
Neurological Signs and Symptoms 1018
Heart Disease 1020
Diabetes Mellitus 1020
Other Clinical Manifestations 1021
Biochemical Investigations 1021
Neuroimaging 1021
Neurophysiological Investigations 1021
Variant Phenotypes: The Role of Molecular Testing 1021
Prognosis 1022
Differential Diagnosis 1022
Vitamin E Deficiency 1022
Sensory Axonal Neuropathy with Dysarthria and Ophthalmoplegia 1022
Autosomal Recessive Ataxias with Sensorimotor Axonal Neuropathy 1024
Other Progressive Metabolic Ataxias 1024
Mitochondrial Disorders 1024
Hereditary Spastic Paraplegia 1025
X-linked and Autosomal Dominant Diseases 1025
Ataxia with Hypogonadism 1025
Ataxia with Visual Loss 1025
Ataxia with Deafness 1026
Hereditary Motor and Sensory Neuropathies (HMSN) 1026
Molecular Genetics 1026
The GAA Expansion Mutation 1026
Size and Genetic Instability 1026
Genetic Epidemiology 1026
Pathogenic Mechanism of the GAA Expansion Mutation 1027
Genotype-phenotype Correlation for the GAA Expansion 1028
Point Mutations 1028
Frataxin Structure and Function 1028
Subcellular Localization 1028
The Function of Frataxin and FRDA Pathogenesis 1029
Animal and Cellular Models 1031
New Approaches to Treatment 1031
References 1032
50 Dominantly Inherited Spinocerebellar Syndromes 1036
Introduction 1036
SCAs Caused by Polyglutamine Expansions 1036
Spinocerebellar Ataxia Type 1 1039
Spinocerebellar Ataxia Type 2 1039
Spinocerebellar Ataxia Type 3 1040
Spinocerebellar Ataxia Type 6 1041
Spinocerebellar Ataxia Type 7 1041
Spinocerebellar Ataxia Type 17 1042
Dentatorubral-Pallidoluysian Atrophy 1042
SCAs Caused by Other (Nonpolyglutamine) Repeat Expansions 1042
Spinocerebellar Ataxia Type 8 1042
Spinocerebellar Ataxia Type 10 1043
Spinocerebellar Ataxia Type 12 1043
Spinocerebellar Ataxia Type 31 1043
Spinocerebellar Ataxia Type 36 1044
SCAs Caused By Missense Mutations 1044
Spinocerebellar Ataxia Type 5 1044
Spinocerebellar Ataxia Type 11 1044
Spinocerebellar Ataxia Type 13 1044
Spinocerebellar Ataxia Type 14 1045
Spinocerebellar Ataxia Type 15 1045
Spinocerebellar Ataxia Type 19 1045
Spinocerebellar Ataxia Type 23 1045
Spinocerebellar Ataxia Type 26 1045
Spinocerebellar Ataxia Type 27 1046
Spinocerebellar Ataxia Type 28 1046
Spinocerebellar Ataxia Type 35 1046
SCAs of Unknown Cause 1046
Spinocerebellar Ataxia Type 4 1046
Spinocerebellar Ataxia Type 18 1046
Spinocerebellar Ataxia Type 20 1047
Spinocerebellar Ataxia Type 21 1047
Spinocerebellar Ataxia Type 25 1047
Spinocerebellar Ataxia Type 30 1047
Spinocerebellar Ataxia Type 32 1047
Spinocerebellar Ataxia Type 34 1047
Episodic Ataxias 1047
Clinical Case Descriptions 1049
Case Discussions 1049
Diagnosis 1052
Therapy 1052
Acknowledgments 1053
References 1053
VIII. General Therapeutic Principles 1066
51 Principles and Practice of Molecular Therapies 1068
Introduction 1068
Newborn Screening for Muscular Dystrophy: The Key to Making a Therapeutic Difference 1068
Gene Repair through Exon Skipping and Mutation Suppression 1069
Exon Skipping Using Antisense Oligonucleotides 1069
Ignoring Stop Codons Using Small Molecules 1073
Aminoglycoside Therapy 1073
PTC124 (Ataluren®) 1073
Gene Replacement Strategies Targeting Specific Muscular Dystrophies 1074
Replacement of the DMD Gene for Duchenne Muscular Dystrophy 1074
Alpha-Sarcoglycan Gene Replacement for Limb Girdle Muscular Dystrophy 2D 1076
Dysferlin Gene Replacement for LGMD2B 1078
Vascular Delivery to Improve Clinical Outcomes 1079
Therapeutic Enhancement Using Surrogate Genes 1080
Follistatin Gene Therapy 1080
Combinational Therapy Using Follistatin and Micro-dystrophin 1080
Alpha7 Integrin Gene Therapy 1080
Strategies responsive to Immunity of AAV and/or Transgene 1081
Summary 1082
Acknowledgments 1082
References 1082
52 Orthopedic Management 1086
Introduction 1086
Spinal Muscular Atrophy 1086
Clinical Overview 1086
Scoliosis 1087
Special Considerations for SMA I 1088
Perioperative Considerations 1088
Hereditary Sensory and Motor Neuropathies 1088
Background 1088
Diagnosis and Presentation 1089
Foot and Lower Extremity 1089
Conservative Management 1089
Surgical Management 1089
Hip Dysplasia 1090
Scoliosis 1090
Upper Extremity 1090
Friedreich Ataxia 1090
Background 1090
Bracing in FA 1091
Surgical Intervention 1091
Pes Cavus 1091
Muscle Spasms 1092
Duchenne Muscular Dystrophy 1092
Extremity Contractures 1092
Spinal Deformity 1092
Becker Muscular Dystrophy 1093
Congenital Myotonic Dystrophy 1093
Congenital Myopathies 1094
Arthrogryposis 1094
Introduction 1094
Perinatal Fractures 1095
Clubfoot 1095
Knee Contractures 1096
Hip Deformities 1096
Upper Extremity Deformities 1097
Scoliosis 1097
Cerebral Palsy 1097
Introduction 1097
Scoliosis 1097
Hip Disorders 1098
References 1099
53 Rehabilitation of the Child with a Neuromuscular Disorder 1105
Introduction 1105
Rehabilitation Goals and Programs 1105
Rehabilitation Therapies 1106
Strength and Endurance 1106
Permit Weight Bearing 1106
Prolong Standing/Walking 1107
Orthopedic Deformities 1107
Minimize and Prevent Joint Contractures 1107
Cardiopulmonary Dysfunction 1107
Cognitive Impairment 1107
Assistive Devices 1107
Maximizing Functional Mobility 1107
Maximizing Independence for Activities of Daily Living 1108
Bracing 1108
Mobility Devices 1108
Adaptive Equipment 1109
Assistive Technology 1109
Alternative Therapies 1109
Conclusion 1109
References 1109
54 Outcome Measures in Neuromuscular Diseases 1111
Introduction: What are Outcome Measures? 1111
Outcome Measures in Different Stages of Therapeutics Development 1112
Clinical Outcome Measures 1112
Ambulatory: Walking, Endurance, Mobility 1113
Nonambulatory: Gross Motor Function Scales 1114
Upper Limb Function 1116
Respiratory Function 1117
Muscle Strength 1117
Potential Biomarkers 1118
Ultrasound 1118
Electrical Impedance Myography 1118
Motor Unit Number Estimation 1118
MR Imaging 1118
Patient Reported Outcome Measures 1119
Quality of Life and Caregiver Burden 1119
Conclusions 1119
References 1119
Index 1124