SCN4A – Hypokalemic periodic paralysis

The SCN4A gene encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (NaV1.4). Pathogenic SCN4A missense variants cause autosomal dominant Hypokalemic periodic paralysis, presenting as episodic flaccid weakness associated with serum hypokalemia.

Clinical validity: The gene–disease link is classified as Strong by ClinGen, supported by over 20 unrelated probands with distinct SCN4A variants and segregation of pathogenic alleles in multiple families (PMID:11353725; PMID:15645704).

Genetic evidence: Hypokalemic periodic paralysis exhibits autosomal dominant inheritance. Segregation studies identified 18 additional affected relatives across three pedigrees. Case reports and series describe >20 probands with missense changes including c.2014C>A (p.Arg672Ser) (PMID:15645704), c.3404G>A (p.Arg1135His) (PMID:24549961), and c.2005C>T (p.Arg669Cys) (PMID:21841462).

Functional evidence: In vitro expression and voltage-clamp analyses in mammalian cells demonstrate that Hypokalemic periodic paralysis variants disrupt slow inactivation and create gating-pore currents, leading to abnormal depolarization under low potassium conditions (PMID:11971097; PMID:24549961). Concordant findings in knock-in mouse models further substantiate NaV1.4 dysfunction.

Conflicting evidence: Thyrotoxic periodic paralysis phenotypes without SCN4A or CACNA1S mutations highlight a distinct pathogenesis despite overlapping clinical features (PMID:15072700).

Integration & conclusion: Genetic and experimental data coherently demonstrate that SCN4A gain-of-function variants cause autosomal dominant Hypokalemic periodic paralysis. This association informs clinical genetic testing, guides management, and underpins development of targeted therapies. Key take-home: SCN4A molecular analysis is critical for accurate diagnosis and personalized care in Hypokalemic periodic paralysis.

References

• Brain • 2001 • Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. PMID:11353725
• Neurology • 2002 • Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5. PMID:11971097
• JPEM • 2004 • Thyrotoxic periodic paralysis associated with a mutation in the sodium channel gene SCN4A. PMID:15645704
• Biophysical Journal • 1997 • Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis. PMID:9138567
• Brain • 2014 • NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery. PMID:24549961
• Thyroid • 2004 • Absence of ion channels CACN1AS and SCN4A mutations in thyrotoxic hypokalemic periodic paralysis. PMID:15072700

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