SCN4A

SCN4A is a human gene that encodes the alpha subunit (Nav1.4) of the skeletal muscle voltage-gated sodium channel. Nav1.4 forms the pore responsible for the rapid influx of sodium ions during the initiation and propagation of action potentials in skeletal muscle, which is essential for normal muscle excitability and contraction. The protein is expressed predominantly in skeletal muscle fibers and contributes to the fast upstroke of the action potential. The channel has the typical four-domain (I–IV) structure with six transmembrane segments per domain, including voltage-sensing S4 segments and an intracellular loop that mediates fast inactivation.

Mutations in SCN4A are associated with a spectrum of neuromuscular disorders that feature myotonia and episodic weakness. The spectrum includes paramyotonia congenita and sodium-channel myotonia, as well as periodic paralyses such as hypokalemic periodic paralysis type 2 and, less commonly, hyperkalemic periodic paralysis. Inheritance is usually autosomal dominant, though the phenotypic expression can vary among individuals.

Pathophysiology: Many pathogenic SCN4A variants cause gain-of-function effects, including increased persistent or resurgent sodium current or altered fast inactivation. These changes can lead to skeletal muscle hyperexcitability and myotonia, or, depending on the mutation’s impact on excitability, episodic weakness or paralysis during attacks.

Diagnosis is based on clinical evaluation and genetic testing, with electromyography potentially showing myotonia and provocative tests revealing weakness under certain conditions. Treatment is tailored to the phenotype and may include mexiletine to reduce myotonia and other sodium-channel–modulating therapies; acetazolamide and lifestyle adjustments can help some individuals with periodic paralysis. Management is individualized and may involve genetic counseling.