Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

Key Points Congenital myopathies are clinically and genetically heterogeneous conditions characterized by muscle weakness and distinctive structural abnormalities in muscle biopsy samples Clinically, congenital myopathies have a stable or slowly progressive course, and the severity varies depending on the causative mutation More than 20 genes have been implicated in congenital myopathies The most commonly affected genes encode proteins involved in skeletal muscle Ca 2+ homeostasis, excitation–contraction coupling and thin–thick filament assembly and interactions Management of congenital myopathies is largely supportive, although experimental therapeutic approaches are reaching the clinical trial stage The congenital myopathies are a group of early-onset neuromuscular disorders characterized by muscle weakness and distinctive structural abnormalities in skeletal muscle. In this Review, the authors summarize the genetic, clinical and pathological features of the main congenital myopathies and discuss current and future approaches to treatment and management. The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories. However, these entities seem to belong to a much wider phenotypic spectrum. To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca 2+ homeostasis, excitation–contraction coupling, thin–thick filament assembly and interactions, and other mechanisms. RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds. At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage.