Molecular Genetics of the Myotonias

Abstract The nondystrophic myotonias and myotonic dystrophy encompass the inherited causes of myotonia. The nondystrophic myotonias, including myotonia congenita ( CLCN1 mutations) and paramyotonia congenita or sodium channel myotonia ( SCN4A mutations), result from altered chloride or sodium channel function causing membrane hyperexcitability. In contrast, myotonic dystrophy type 1 ( DMPK CTG expansion) and type 2 ( CNBP CCTG expansion) are multisystemic repeat expansion disorders driven by toxic RNA gain‐of‐function. Expanded repeat‐containing RNAs sequester MBNL proteins and dysregulate CELF1, leading to widespread mis‐splicing, including of CLCN1 , which contributes to myotonia. Somatic instability, anticipation and repeat interruptions influence disease severity in DM1, whereas DM2 lacks congenital forms and shows less intergenerational expansion. Coexisting CLCN1 or SCN4A variants can modify the phenotype in nondystrophic myotonia and myotonic dystrophy. Understanding these molecular mechanisms enhances diagnostic accuracy, variant interpretation and targeted therapeutic development for skeletal muscle channelopathies and myotonic dystrophies. Key Concepts Myotonia is delayed skeletal muscle relaxation after contraction. Inherited myotonias fall into two main groups: nondystrophic myotonias, confined to muscle, and myotonic dystrophies (type 1 and type 2), which are multisystemic. Nondystrophic myotonias are skeletal muscle channelopathies caused by mutations in voltage‐gated ion channel genes regulating sarcolemmal excitability. Myotonia congenita results from loss‐of‐function mutations in CLCN1 , reducing chloride conductance and causing membrane hyperexcitability. Paramyotonia congenita and sodium channel myotonia arise from gain‐of‐function SCN4A mutations that increase persistent sodium currents. Myotonic dystrophy type 1 and type 2 are repeat expansion disorders of DMPK (CTG expansion) and CNBP (CCTG expansion), respectively. Myotonic dystrophy type 1 demonstrates anticipation . Myotonic dystrophy pathogenesis involves toxic RNA gain‐of‐function, with expanded CUG/CCUG RNAs forming nuclear foci that sequester MBNL and dysregulate CELF1. Mis‐splicing of target transcripts contributes to the classic symptoms of myotonic dystrophy, for example, CLCN1 underlying myotonia or RYR1 and CACNA1S underlying muscle weakness. Accurate diagnosis of myotonic disorders requires awareness of their genetic and phenotypic complexity. Comprehensive testing, including repeat expansion analysis and next‐generation sequencing panels, alongside specialist genetic counselling, is important for precise classification and management.