An Introduction to the Muscular Dystrophies

Abstract

Muscular dystrophies refer to a clinically and genetically heterogenous group of primary progressive diseases of skeletal muscle with variable extramuscular manifestations. This heterogeneity makes their classification difficult and attempts at classification have evolved over time. Their classification was originally based on the pattern of weakness, mode of inheritance and age of onset. Advances in molecular genetics over the past few decades have enriched the understanding of these disorders and transformed the classification to incorporate genetic information. For example, limb-girdle muscular dystrophy (LGMD) now encompasses more than 30 different subtypes of genetically distinct muscular dystrophies. It is also evident that the clinical and pathological phenotypic spectrum of each causative gene is variable. Adding to the complexity is the convergence of multiple genotypes into similar phenotypes. The diagnosis of these disorders has been revolutionized by the commercial availability of next generation sequencing (NGS), which allows the sequencing of several genes simultaneously, including efficient whole exome or whole genome sequencing. However, patients suspected to have disorders of repeat expansion (myotonic dystrophies, oculopharyngeal muscular dystrophy and oculopharyngodistal myopathies) or repeat contraction (facioscapulohumeral muscular dystrophies) should undergo specific genetic tests for these disorders as the initial test, since many NGS platforms do not detect repeat disorders. For most other muscular dystrophies, NGS has reduced the time and cost of genetic testing and has, for most part, replaced muscle biopsy as the initial diagnostic modality. In patients whom genetic testing is negative or inconclusive, muscle biopsy remains pivotal in guiding the diagnostic evaluation or validating the pathogenicity of variants of unknown significance (VUS) uncovered by genetic testing. In recent years, muscle imaging has shown to be a promising ancillary tool for diagnosis and as a biomarker of disease severity. With emerging disease specific radiological patterns of muscle involvement, muscle imaging may assist in the interpretation of VUS. The development of valid and reliable outcome measures in muscular dystrophy continues to be an area of active research. A multidisciplinary team remains the mainstay of patient management, which is mostly supportive. However, breakthroughs in genetic therapies for Duchene muscular dystrophy may have paved the way for future discovery of disease-modifying therapies for other muscular dystrophies.