SCN4A
Sodium Voltage-Gated Channel Alpha Subunit 4
Gene Summary
RefSeq / NCBIVoltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]
Clinical Phenotype
Multiple allelic disorders of Nav1.4: paramyotonia congenita (PMC), hyperkalemic periodic paralysis (HyperPP), hypokalemic periodic paralysis type 2 (HypoPP2), and potassium-aggravated myotonia. Episodic weakness and/or myotonia, often cold or exercise triggered.
Molecular Mechanism
Nav1.4 is the primary voltage-gated sodium channel in skeletal muscle. Gain-of-function mutations impair inactivation, leading to prolonged depolarization (myotonia). Some mutations cause depolarization-induced paradoxical Na⁺ influx during hypokalemia, causing flaccid weakness in periodic paralysis.
Clinical Hallmarks & Key Evidence
Paramyotonia congenita is paradoxically worsened by exercise (myotonia increases with repeated contractions) — the reverse of 'warm-up' seen in myotonic dystrophy.
Streib EW. Muscle Nerve. 1987;10(4):312-20.
Cold exposure is a classic trigger for both myotonia and weakness in SCN4A disease — patients often report facial stiffness in cold air or after eating cold food.
Jurkat-Rott K, Lehmann-Horn F. Muscle Nerve. 2007;35(1):4-22.
Mexiletine, a sodium channel blocker, is the first-line pharmacotherapy for symptomatic SCN4A myotonia, reducing both stiffness and episodes of weakness.
Statland JM et al. JAMA Neurol. 2012;69(3):1) 400-407.
Associated Conditions
External Resources
Related Genes
Gene data compiled from the Washington University Neuromuscular Disease Center, NCBI Gene, and OMIM. For clinical use, always refer to primary sources.