Workshop report

117th ENMC Workshop: Ventilatory Support in Congenital Neuromuscular Disorders — Congenital Myopathies, Congenital Muscular Dystrophies, Congenital Myotonic Dystrophy and SMA (II) 4–6 April 2003, Naarden, The Netherlands

Sleep disordered breathing (SDB) is prevalent among children with neuromuscular disorders (NMD). The combination of respiratory muscle weakness, altered drive, and chest wall distortion due to scoliosis make sleep a stressful state in this population. Symptomatology can range from absent to snoring, nocturnal awakenings, morning headaches, and excessive daytime sleepiness. Sequelae of untreated SDB includes cardiovascular effects, metabolic derangements, and neurocognitive concerns which can be compounded by those innate to the NMD. The clinician should have a low threshold for obtaining polysomnography and recognize the nuances of individual disorders due to disproportionately impacted muscle groups such as hypoventilation in ambulating patients from diaphragm weakness. Non-invasive or invasive ventilation are the mainstay of treatment. In this review we explore the diagnosis and treatment of SDB in children with various NMD.

Spinal muscular atrophy (SMA) is caused by biallelic mutations in the SMN1 (survival motor neuron 1) gene on chromosome 5q13.2, which leads to a progressive degeneration of alpha motor neurons in the spinal cord and in motor nerve nuclei in the caudal brainstem. It is characterized by progressive proximally accentuated muscle weakness with loss of already acquired motor skills, areflexia and, depending on the phenotype, varying degrees of weakness of the respiratory and bulbar muscles. Over the past decade, disease-modifying therapies have become available based on splicing modulation of the SMN2 with SMN1 gene replacement, which if initiated significantly modifies the natural course of the disease. Newborn screening for SMA has been implemented in an increasing number of centers; however, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage.

Weakness of limb and respiratory muscles that occurs in the course of critical illness has become an increasingly common and serious complication of adult and pediatric intensive care unit patients and a cause of prolonged ventilatory support, morbidity, and prolonged hospitalization. Two motor disorders that occur singly or together, namely critical illness polyneuropathy and critical illness myopathy, cause weakness of limb and of breathing muscles, making it difficult to be weaned from ventilatory support, commencing rehabilitation, and extending the length of stay in the intensive care unit, with higher rates of morbidity and mortality. Recovery can take weeks or months and in severe cases, and may be incomplete or absent. Recent findings suggest an improved prognosis of critical illness myopathy compared to polyneuropathy. Prevention and treatment are therefore very important. Its management requires an integrated team approach commencing with neurologic consultation, creatine kinase (CK) measurement, detailed electrodiagnostic, respiratory and neuroimaging studies, and potentially muscle biopsy to elucidate the etiopathogenesis of the weakness in the peripheral and/or central nervous system, for which there may be a variety of causes. These tenets of care are being applied to new cases and survivors of the coronavirus-2 disease pandemic of 2019. This chapter provides an update to the understanding and approach to critical illness motor disorders.

The congenital myopathies are inherited muscle disorders characterized clinically by hypotonia and weakness, usually from birth, with a static or slowly progressive clinical course. Historically, the congenital myopathies have been classified according to major morphological features seen on muscle biopsy as nemaline myopathy, central core disease, centronuclear or myotubular myopathy, and congenital fiber type disproportion. However, in the past two decades, the genetic basis of these different forms of congenital myopathy has been further elucidated with the result being improved correlation with histological and genetic characteristics. However, these notions have been challenged for three reasons. First, many of the congenital myopathies can be caused by mutations in more than one gene that suggests an impact of genetic heterogeneity. Second, mutations in the same gene can cause different muscle pathologies. Third, the same genetic mutation may lead to different pathological features in members of the same family or in the same individual at different ages. This chapter provides a clinical overview of the congenital myopathies and a clinically useful guide to its genetic basis recognizing the increasing reliance of exome, subexome, and genome sequencing studies as first-line analysis in many patients.

The nemaline myopathies constitute a large proportion of the congenital or structural myopathies. Common to all patients is muscle weakness and the presence in the muscle biopsy of nemaline rods. The causative genes are at least twelve, encoding structural or regulatory proteins of the thin filament, and the clinical picture as well as the histological appearance on muscle biopsy vary widely. Here, we suggest a renewed clinical classification to replace the original one, summarise what is known about the pathogenesis from mutations in each causative gene to the forms of nemaline myopathy described to date, and provide perspectives on pathogenetic mechanisms possibly open to therapeutic modalities.

Spinal muscular atrophy (SMA) and the congenital myopathies (CMs) typically present in neonatal, infantile, and early childhood ages with hypotonia and weakness. Organs that may be involved include heart, lungs, gastrointestinal tract, eyes, spine, and joints, especially in CMs. In this chapter, we discuss the clinical presentations of these disorders while highlighting the genetic and pathophysiologic variability. We review the advances in genetic testing and the development of targeted gene therapies that have altered the natural course of these disorders, in particular SMA. Importantly, we focus on supportive management by systems and screening for complications which remain key components of patient care and have a profound effect on quality of life.