Molecular genetics of skeletal muscle channelopathies.

Abstract

Skeletal muscle channelopathies are genetic disorders associated with variants in genes encoding ion channels and related proteins expressed in skeletal muscle. Most commonly, these involve genes encoding voltage-gated ion channels (VGICs) that regulate sarcolemmal excitability, including CLCN1 for ClC-1, SCN4A for the Nav1.4 α subunit, CACNA1S for the Cav1.1 α subunit, and KCNJ2 for Kir2.1. Skeletal muscle channelopathies primarily manifest with two clinical symptoms: myotonia, characterized by delayed muscle relaxation, and paralysis and classified into two disease types: non-dystrophic myotonia and periodic paralysis. Recent advances in the clinical application of next-generation sequencing have improved diagnostic rate and provided epidemiological evidence of the diseases. Furthermore, atypical phenotypes have been identified, indicating that skeletal muscle channelopathies present a broad clinical spectrum. This review provides an updated overview of the clinical and genetic aspects of skeletal muscle channelopathies and discusses key issues that require further investigation.