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Neuromuscular Disorders of Infancy, Childhood, and Adolescence

A Clinician's Approach

2nd Edition - November 25, 2014

Editors: Basil T. Darras, H. Royden Jones Jr., Monique M. Ryan, Darryl C. De Vivo

Hardback ISBN:

9 7 8 - 0 - 1 2 - 4 1 7 0 4 4 - 5

eBook ISBN:

9 7 8 - 0 - 1 2 - 4 1 7 1 2 7 - 5

Neuromuscular disorders are diagnosed across the lifespan and create many challenges especially with infants, children and adolescents. This new edition of the definitive… Read more

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Neuromuscular disorders are diagnosed across the lifespan and create many challenges especially with infants, children and adolescents. This new edition of the definitive reference, edited by the established world renowned authorities on the science, diagnosis and treatment of neuromuscular disorders in childhood is a timely and needed resource for all clinicians and researchers studying neuromuscular disorders, especially in childhood. The Second Edition is completely revised to remain current with advances in the field and to insure this remains the standard reference for clinical neurologists and clinical research neurologists. The Second Edition retains comprehensive coverage while shortening the total chapter count to be an even more manageable and effective reference.

Dedication

About the Cover Images

Foreword

Preface to the Second Edition

Preface to the First Edition

List of Contributors

Part I: Clinical and Laboratory Approach to the Infant and Child with a Neuromuscular Problem

Chapter 1. Introduction: Historical Perspectives

Introduction
Traditional Diagnostic Tests
Modern Diagnostic Testing
Clinical Classification
Clinical Approach
Presenting Complaints
Conclusion
References

Chapter 2. Genetics of Neuromuscular Disorders

Introduction
Patterns of Genetic Transmission
Pedigree Analysis and Risk Assessment
Chromosomes and Chromosomal Abnormalities
Genetic Imprinting
Molecular Genetics
Gene Mutations and Modes of Inheritance
Developments in Molecular Diagnostics
Methods of Molecular Genetic Diagnostics
Comparison Between Panels and Whole Exome Sequencing
Secondary Findings
Clinical Indications for Genetic Testing
Approach to Genetic Evaluation
Potential Barriers to Testing
Attitudes Towards Genetic Testing
Recurrence Risk in Families and Reproductive Options
Treatment of Genetic Disorders
References

Chapter 3. Electromyography in Pediatrics

Introduction
Dealing with Misconceptions
Normative Data
Techniques
Investigation Strategies
Final Words
References

Chapter 4. Muscle Biopsy for Diagnosis of Neuromuscular and Metabolic Diseases

Introduction
Tissue Selection and Preparation
Ontogenesis of Striated Muscle
Cellular Death and Regeneration
Denervation, Disuse, and Hypotrophy
Muscle Biopsy in Specific Myopathies
Myofibrillar Myopathies
Glycogenoses
Lipid Storage Myopathies
Inflammatory Myopathies
References

Chapter 5. Nerve Biopsy

Introduction
Techniques
Complications
Age-Related Differences in Sural Nerve Morphology
Biopsy Findings in Relevant Diseases
Conclusion
References

Part II: Infantile Hypotonia and Arthrogryposis

Chapter 6. Neonatal Hypotonia

Introduction
History and General Examination
Neonatal Neuromuscular Examination
Distinguishing Features of Motor System Disorders
Conclusion
References

Chapter 7. Arthrogryposis

Introduction
Historical Background
Epidemiology
Pathogenesis
Clinical Features
Genotype/Phenotype Correlation
Arthrogryposis Associated with Maternal Illnesses
Therapy
Prognosis
Relatively Common Specific Conditions Associated with Multiple Congenital Contractures
Chromosomal Anomalies
Maternal Antibodies with and Without Myasthenia Gravis
Acknowledgments
References

Part III: Motor Neuron Disorders

Chapter 8. Spinal Muscular Atrophies

Introduction
Epidemiology
Clinical Characteristics
Genetics
Other Diagnostic Tests
Molecular Function of SMN
Differential Diagnosis
The Pathology of SMA
Animal Models
Treatment
Care of the Patient with SMA
Conclusion
Acknowledgments
References

Chapter 9. Juvenile Amyotrophic Lateral Sclerosis

Introduction
Nosology of Motor Neuron Diseases
Discussion of Table 9.1
Management
Genetic Counseling
Conclusions
References

Chapter 10. Infectious or Acquired Motor Neuron Diseases

Infantile Poliomyelitis
Vaccine-Associated Poliomyelitis
Tetanus: A Combined Perspective from South Africa and North America
Rabies
References

Chapter 11. The Stiff-man Syndrome in Children and Adolescents

Introduction
Historical Perspective
Epidemiology
Pathophysiology
Neurological Presentation
Coexisting Autoimmune Diseases
Oncological Findings
Differential Diagnosis
Testing
Treatment
Prognosis
Conclusion
References

Part IV: Peripheral Nerve Disorders

Chapter 12. Radiculopathies and Plexopathies

Anatomy
Diagnostic Procedures
Cervical Radiculopathies
Lumbosacral Radiculopathies
Plexopathies
References

Chapter 13. Congenital and Acquired Facial Palsies

Introduction
Evaluation of the Facial Nerve in Children
Congenital Facial Palsies
Acquired Facial Palsies
References

Chapter 14. Mononeuropathies

Introduction
Assessment and Evaluation of Peripheral Nerve Lesions in Childhood
Upper Extremity Mononeuropathies
Lower Extremity Mononeuropathies
References

Chapter 15. Overview of Pediatric Peripheral Neuropathies

Introduction
Approach to Evaluating Childhood Neuropathies
Pediatric Electrodiagnostic Testing
Trauma
Nerve Biopsy
Neuroimaging in Childhood Polyneuropathies
References

Chapter 16. Congenital and Early Infantile Neuropathies

Introduction
Etiology
Clinical Presentation and Approach to Peripheral Neuropathies in Early Infancy
Genetic Demyelinating Neuropathies with Infantile Onset
Demyelinating Neuropathies of Infancy Associated with Central Nervous System Involvement
Genetic Axonal Neuropathies with Infantile Onset
Conclusion
Acknowledgments
References

Chapter 17. Hereditary Neuropathies in Late Childhood and Adolescence

Definition and Nomenclature
Epidemiology
Pathobiology
Clinical Manifestations
Neurophysiology
Genetic Testing and Diagnostic Strategies
Specific Forms of CMT
Differential Diagnosis
Treatment Strategies
Summary
References

Chapter 18. Hereditary Sensory and Autonomic Neuropathies

Introduction
Hsan Type I
Hsan Type II
Hsan Type III
Hsan Type IV
Hsan Type V
Diagnosis of an Hsan
Therapeutic Interventions
References

Chapter 19. Peripheral Neuropathy in Inherited Metabolic Disease

Introduction
Lysosomal Storage Diseases
Peroxisomal Storage Diseases
Diseases of Lipids and Lipoproteins
Glycogen Storage Disease
Amino Acid Disease
Mitochondrial Diseases
Other Inherited Metabolic Diseases
References

Chapter 20. Acute Polyneuropathies

Introduction
Guillain-Barré Syndrome
Tick Paralysis
References

Chapter 21. Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Epidemiology
Pathogenesis
Clinical Features
Differential Diagnosis
Laboratory Studies
Electrophysiologic Testing
Nerve Biopsy
Neuroimaging
Treatment
Prognosis
References

Chapter 22. Neuropathies Secondary to Systemic Disorders

Introduction
Critical Illness Polyneuropathy
Renal Disorders
Endocrine Disorders
Vitamin Deficiency States
Malignancies and Reticuloses
Connective Tissue Disorders
Miscellaneous Systemic Disorders
References

Chapter 23. Toxic Neuropathies

Introduction
General Features of Toxic Neuropathies
Selected Toxic Neuropathies
Conclusion
References

Chapter 24. Hansen’s Disease (Leprosy): Leprous Neuropathy

Introduction
Skin Manifestations
Leprosy Neuropathy
Diagnosis
Pathophysiology of Nerve Damage
Treatment
References

Part V: Neuromuscular Junction Disorders

Chapter 25. Acquired Presynaptic Neuromuscular Junction Disorders: Infant Botulism and Lambert-Eaton Myasthenic Syndrome

Infant Botulism
Lambert-Eaton Myasthenic Syndrome
Summary
References

Chapter 26. Congenital Myasthenic Syndromes

Introduction
Diagnosis
Classification
Presynaptic Congenital Myasthenic Syndrome
Synaptic Basal Lamina Associated CMS
Postsynaptic CMS
Currently Available Therapies
References

Chapter 27. Juvenile and Neonatal Myasthenia Gravis

Background
Pathophysiology
Clinical Presentation
Diagnostic Testing
Medical Therapies
Surgical Therapies
Neonatal Myasthenia Gravis and the Fetal Acetylcholine Receptor Inactivation Syndrome
Prognosis
Conclusions
References

Part VI: Myopathies

Chapter 28. Congenital and Other Structural Myopathies

Nemaline Myopathy
Core Myopathies
Multiminicore Disease
Congenital Fiber Type Disproportion
Centronuclear Myopathies
Titinopathies
Myofibrillar Myopathies
Hyaline Body Myopathy
Autophagic Vacuolar Myopathies
Treatment of Congenital Myopathies
Novel Therapeutic Strategies
Drug Discovery
References

Chapter 29. Congenital Muscular Dystrophies

Introduction
Merosin-Deficient CMD
Dystroglycanopathies
CMD With Collagen VI Deficiency (Ullrich Disease)

SEPN1

LAMIN A/C-Related CMD
Differential Diagnosis
Therapeutic Approaches
Acknowledgments
References

Chapter 30. Dystrophinopathies

Introduction
Etiology and Pathogenesis
Incidence and Prevalence
Clinical Presentation
Differential Diagnosis
Diagnostic Testing
Treatment and Management
References

Chapter 31. Clinical Management of Dystrophinopathies: A Systematic Approach

Introduction
Duchenne Muscular Dystrophy
Other Dystrophinopathies: Becker Muscular Dystrophy and Manifesting Carriers of DMD/BMD
Conclusions
References

Chapter 32. Facioscapulohumeral Dystrophy

Introduction
Clinical Features
Extramuscular Manifestations
Infantile FSHD
FSHD Variants
Scapulohumeral Dystrophy Phenotype with Facial Sparing
Differential Diagnosis
Laboratory Tests
Management
Prognosis
Genetics
References

Chapter 33. Distal Myopathies

Early Onset Distal Myopathies
Juvenile Onset Distal Myopathies
References

Chapter 34. Limb-girdle Muscular Dystrophies

Introduction
Autosomal Recessive Limb-Girdle Muscular Dystrophies
Autosomal Dominant LIMB-Girdle Muscular Dystrophies
Other Muscular Dystrophies that May Present as LGMD
Summary and Approach to Patients
References

Chapter 35. Emery-Dreifuss Muscular Dystrophy: Nuclear Envelopathies

Introduction
Historical Background
Molecular Biology
Pathogenesis
Clinical Features
Differential Diagnosis
Genotype-Phenotype Correlation
Laboratory Investigations
Therapy
Prognosis
Acknowledgments
References

Chapter 36. Myopathies of Systemic Disease

Introduction
Hyperthyroidism
Hypothyroidism
Parathyroid Disease
Cushing’s Syndrome
Uremia
Osteomalacia
Hypokalemia
Hypernatremia
Primary Hyperparathyroidism
Human Immunodeficiency Virus
Lyme Disease
Sepsis/Intensive Care Unit Myopathies
Medication-Related Myopathies
Inflammatory Myopathies Associated with Systemic Disorders
Eosinophilic Myopathic Syndromes
References

Chapter 37. Myotonic Dystrophy

Clinical Presentation and Phenotypes
Molecular Genetics
Diagnostic Approach
Management
References

Chapter 38. Muscle Channelopathies: Myotonias and Periodic Paralyses

Introduction
Electrophysiology of Clinical Weakness and Paralysis
Myotonias
Paramyotonia
Periodic Paralyses
Acknowledgments
References

Chapter 39. Glycogen Storage Diseases of Muscle

Introduction and Background
Forearm Ischemic Exercise Test
Defects of Glycogenolysis
Defects of Glycolysis
Defects of Glycogen Synthesis
Defects of Lysosomal Glycolysis
References

Chapter 40. Lipid Storage Myopathies Due to Fatty Acid Oxidation Defects

Historical Background
Pathophysiology
Clinical and Biochemical Features of Identified Defects
Differentiating Laboratory Features
Diagnostic Approaches and Screening Methods
Treatment
Genetics and Presymptomatic Recognition
Conclusion
Acknowledgments
References

Chapter 41. Mitochondrial Encephalomyopathies

Introduction
Diseases Due to mtDNA Mutations
Diagnostic Approach
Therapeutic Approaches
References

Chapter 42. Juvenile Dermatomyositis and Other Inflammatory Myopathies in Children

Introduction
The Epidemiology of the Major Pediatric Inflammatory Myopathies
Pathogenesis/Genetic Data
Course and Therapy
Other Less Common Forms of Inflammatory Myopathy
Conclusion
References

Part VII: Special Clinical Problems

Chapter 43. Neuromuscular Problems of the Critically Ill Neonate and Child

Introduction
Acute Neuromuscular Crises in the Infant
Acute Neuromuscular Crises in the Toddler and the Older Child
Critical Illness Neuromuscular Disorders
Conclusions
References

Chapter 44. Intensive Care Management, Including Cardiorespiratory Care

Historical Background
Intensive Care
Ethics
Normal Physiology
Pathophysiology
Evaluation
Treatment
References

Chapter 45. Malignant Hyperthermia: An Inherited Disorder of Muscle Calcium Metabolism

Malignant Hyperthermia—Deaths in General Anesthesia
Muscular Hypermetabolism by Rampant Ca²⁺
Anesthesia-Related Muscle Spasms
Awake Episodes
MH and Childhood
Functional Diagnostics—In Vitro Contracture Test
Genetic Diagnostics
Creatine Phosphokinase
Histological Findings and Core Formation
Associated Syndromes and MH-Like Episodes
Clinical Considerations
References

Chapter 46. Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

General Principles
The Extraocular Lower Motor Unit
Examination Approach to Extraocular Movement Disorders
Cranial Nerve Palsies
Congenital Ptosis Syndromes
Congenital Cranial Dysinnervation Disorders
Synkinesis Syndromes
Ophthalmoplegia in Pediatric Neuromuscular Disease
References

Chapter 47. Oromotor Dysfunction in Neuromuscular Disorders: Evaluation and Treatment

Introduction
Oromotor Dysfunction Due to Neuromuscular Disorders
Neuromuscular Disorders with Associated Oromotor Dysfunction
OMS Dysfunction Assessment
Treatment of Oromotor Dysfunction Due to a Neuromuscular Disorder
References

Chapter 48. Complex Regional Pain Syndromes I and II (Reflex Sympathetic Dystrophy, Causalgia)

Introduction
Incidence and Prevalence
Pathophysiology
Diagnosis
Treatment
Prognosis
References

Chapter 49. Friedreich Ataxia

Introduction
Epidemiology
Pathology
Clinical Aspects
Differential Diagnosis
Molecular Genetics
New Approaches to Treatment
References

Chapter 50. Dominantly Inherited Spinocerebellar Syndromes

Introduction
SCAs Caused by Polyglutamine Expansions
SCAs Caused by Other (Nonpolyglutamine) Repeat Expansions
SCAs Caused By Missense Mutations
SCAs of Unknown Cause
Episodic Ataxias
Clinical Case Descriptions
Diagnosis
Therapy
Acknowledgments
References

Part VIII: General Therapeutic Principles

Chapter 51. Principles and Practice of Molecular Therapies

Introduction
Newborn Screening for Muscular Dystrophy: The Key to Making a Therapeutic Difference
Gene Repair through Exon Skipping and Mutation Suppression
Ignoring Stop Codons Using Small Molecules
Gene Replacement Strategies Targeting Specific Muscular Dystrophies
Vascular Delivery to Improve Clinical Outcomes
Therapeutic Enhancement Using Surrogate Genes
Strategies responsive to Immunity of AAV and/or Transgene
Summary
Acknowledgments
References

Chapter 52. Orthopedic Management

Introduction
Spinal Muscular Atrophy
Hereditary Sensory and Motor Neuropathies
Friedreich Ataxia
Duchenne Muscular Dystrophy
Becker Muscular Dystrophy
Congenital Myotonic Dystrophy
Congenital Myopathies
Arthrogryposis
Cerebral Palsy
References

Chapter 53. Rehabilitation of the Child with a Neuromuscular Disorder

Introduction
Rehabilitation Goals and Programs
Rehabilitation Therapies
Assistive Devices
Assistive Technology
Alternative Therapies
Conclusion
References

Chapter 54. Outcome Measures in Neuromuscular Diseases

Introduction: What are Outcome Measures?
Outcome Measures in Different Stages of Therapeutics Development
Clinical Outcome Measures
Potential Biomarkers
Patient Reported Outcome Measures
Conclusions
References

Index

Basil T. Darras

Dr. Basil T. Darras is Associate Neurologist-in-Chief and Chief of the Division of Clinical Neurology at Boston Children’s Hospital, and the Joseph J. Volpe Professor of Neurology at Harvard Medical School. Dr. Darras is a pediatric neurologist with advanced training and certification in human genetics and neuromuscular medicine. At Boston Children’s he serves as Director of the Neuromuscular Program, which includes one of the oldest and most active muscular dystrophy clinics in the country and where he specializes in the care of children with neuromuscular conditions originating from inherited or acquired conditions of the motor unit. He has published over 140 original reports in peer-reviewed journals and over 70 chapters, reviews and editorials; his major publications and specific research interests have focused on the molecular genetics, diagnostics, and therapeutics of Duchenne and Becker muscular dystrophies and spinal muscular atrophy, and on defining the indications for new diagnostic methodologies in the evaluation of children with pediatric neuromuscular diseases. Basic research, carried out in collaboration with scientists in the research laboratories of Boston Children’s and other institutions, focuses on the description of novel mutations in patients with neuromuscular diseases and the application of new technologies to explore the pathogenesis and treatment of congenital myopathies and muscular dystrophies. Dr. Darras is site PI for the consortium conducting Pediatric Neuromuscular Clinical Research in Spinal Muscular Atrophy, and site PI/PD for the NeuroNEXT NINDS Program. He is currently involved in multiple clinical trials of novel genetic interventions for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy.

Affiliations and expertise

Children's Hospital, Boston, MA, USA

H. Royden Jones Jr.

Dr. H. Royden Jones was Chair of the Department of Neurology at Lahey Hospital and Medical Center, Burlington, Massachusetts; Director of the Electromyography Laboratory at Boston Children’s Hospital; and Clinical Professor of Neurology at Harvard Medical School. Dr. Jones completed residencies in Internal Medicine and Neurology and a fellowship in neurological physiology at the Mayo Clinic. He served over 3 years in the United States Army as Chief of Neurology at 5th General Hospital, Bad Cannstatt, Germany. Dr. Jones was Board certified in neurology, clinical neurophysiology, and neuromuscular medicine. Upon completion of his training he joined the Lahey Clinic in 1972. In 1977 he also joined the neurology department at Boston Children’s Hospital, founding the electromyography laboratory in 1979. Pediatric EMG became his major clinical research interest. Dr. Jones was co-editor of three major textbooks on childhood clinical neurophysiology and neuromuscular disorders. He was a co-founder of the biennial International Paediatric EMG Conference based at Great Ormond Street Children’s Hospital, London, England. Recognized as one of the top neurologists in the U.S., Dr. Jones was an author and editor of several Netter publications including two editions of Netter’s Neurology, The Netter Collection of Medical Illustrations: Nervous System, Volume 7, Part I (Brain) and Part II (Spinal Cord and Peripheral Motor and Sensory Systems), 2nd Editions (volumes in the Netter Green Book Collection). Dr. Jones authored and edited several other Netter publications and contributed over 200 peer-reviewed papers and book chapters. Dr. Jones served 8 years as a director of the American Board of Psychiatry and Neurology, becoming Chair of its Neurology Council in 2004. In 2007 he received the Distinguished Physician Award from the American Association of Neuromuscular and Electrodiagnostic Medicine. Lahey Clinic’s Medical Staff Association recognized Dr. Jones in 2010 with its highest honor—the Frank Lahey Award for “commitment to the values of Dr. Frank Lahey: respect, teamwork, excellence, commitment to personal best.” Dr. Jones was named Outstanding Teacher in Pediatric Neurology 2012 – 2013 by the Department of Neurology, Boston Children’s Hospital, Harvard Medical School. He also received an award in recognition of his many years of dedicated teaching at Tufts University School of Medicine.

Affiliations and expertise

Children's Hospital, Boston, MA, USA

Monique M. Ryan

Associate Professor Monique Ryan is a paediatric neurologist in the Children’s Neurosciences Centre, Royal Children’s Hospital, Melbourne Australia, where she is head of the neuromuscular clinical research program and multidisciplinary Neuromuscular Clinic. This clinic oversees the care of more than 500 children with neuromuscular disorders. A/Prof Ryan’s research interests include natural history studies of paediatric neuropathies and clinical trials of new therapies for muscle diseases, neuropathies and myasthenic syndromes of childhood. Her group undertook the landmark initial study of treatment of paediatric Charcot-Marie-Tooth disease type 1A with ascorbic acid, the first randomized, double-blind placebo-controlled therapeutic trial in paediatric CMT. Other research trials previously or currently undertaken at RCH include trials of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy, a number of studies addressing the natural history of various forms of paediatric CMT, and studies identifying new genes for CMT. A/Prof Ryan is a member of several international neuromuscular research consortia, a board member of CINRG and a member of the extended TREAT-NMD therapeutic advisory committee.

Affiliations and expertise

Royal Children's Hospital, Parkville, Victoria, Australia

Darryl C. De Vivo

Dr. Darryl C. De Vivo is the Sidney Carter Professor of Neurology, Professor of Pediatrics, and Director Emeritus (1979-2000) of the Pediatric Neurology Service at the Columbia University Medical Center in New York City. He also serves as the Associate Chairman for Pediatric Neurosciences and Developmental Neurobiology, the Founding Director of the Colleen Giblin Research Laboratories for Pediatric Neurology, and the Co-Director of the Center for Motor Neuron Biology and Disease (MNC). Dr. De Vivo was a Director for Neurology and President of the American Board of Psychiatry and Neurology, Secretary of the American Academy of Neurology, and President of the Child Neurology Society. He completed postgraduate training in medicine at the University of Virginia Medical School, and residency training in medicine, pediatrics, and neurology at the Massachusetts Memorial Hospital and the Massachusetts General Hospital, and at the National Institutes of Health where he was a Clinical Associate in Neurology. Dr. De Vivo receives federal and non-federal funding, and serves as the Director for the Pediatric Neuromuscular Clinical Research Network (PNCRN) in Spinal Muscular Atrophy. He has published more than 400 original articles and reviews, lectures extensively in the U.S. and abroad, and serves on several editorial boards and advisory committees. He was honored in 2014 by the American Academy of Neurology as the recipient of the Sidney Carter Award in Pediatric Neurology. He has devoted part of his professional career to the study of neuromuscular diseases. In 1967, he studied at the NINDS as a clinical associate under W. King Engel. In 1975, he and Michael Brooke established the Jerry Lewis Neuromuscular Disease Center at Washington University School of Medicine. In 1979, Dr. De Vivo established the Pediatric Neuromuscular Disease Center at the Columbia University Medical Center, and in 2004, with support from the New York-based SMA Foundation, the Center was expanded to include the SMA Clinical Research Center, an intramural affiliate of the MNC. Recently, the PNCRN, established in 2004, has been expanded to six academic sites at Columbia, Harvard, Penn, Rochester, Nemours/Orlando and Stanford. This network is dedicated to the acceleration of clinical trials in search of effective treatments for SMA.

Affiliations and expertise

Columbia University Medical Center, New York, NY, USA