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SCN4A encodes the skeletal muscle voltage-gated sodium channel Nav1.4, crucial for action potential initiation and propagation in myofibers. Hypokalemic Periodic Paralysis Type 2 is an autosomal dominant channelopathy characterized by episodic muscle weakness associated with low serum potassium. Affected individuals typically present in adolescence or adulthood with attacks precipitated by rest after exercise or high-carbohydrate meals. The fluctuating paralysis can lead to significant morbidity if unrecognized, but responds to potassium supplementation and preventive lifestyle modifications. Genetic testing of SCN4A is therefore essential for confirming diagnosis and guiding management. This summary integrates clinical, genetic, and functional data supporting the SCN4A–Hypokalemic Periodic Paralysis Type 2 association.
Clinical genetic evidence includes one unrelated adult proband harboring a heterozygous c.3313G>A (p.Val1105Met) variant who exhibited recurrent weakness and hypokalemia managed successfully with supplementation (PMID:38344586). In a cohort of five families with primary periodic paralysis, two families with HypoPP2 carried SCN4A missense variants (c.2111C>T (p.Thr704Met) and c.2024G>A (p.Arg675Gln)) consistent with autosomal dominant inheritance and episodic weakness (PMID:33345742). Together these represent at least three unrelated probands across three pedigrees with segregating SCN4A variants. No extended segregation data are reported beyond proband status. Penetrance appears high given recurrent attacks in all variant carriers. The sum of these observations supports a ClinGen Moderate gene–disease validity classification.
The inheritance mode is autosomal dominant with incomplete penetrance. No consanguinity or biallelic variants have been reported for HypoPP2, and all pathogenic variants are missense altering S4 voltage-sensor segments. The variant spectrum in HypoPP2 includes at least two recurrent SCN4A missense mutations: c.3313G>A (p.Val1105Met) and c.2111C>T (p.Thr704Met). Both mutations localize to transmembrane segments affecting voltage sensing or pore gating. There is no strong evidence for deep-intronic or structural variants in HypoPP2, and no founder alleles reported.
Phenotypically, carriers of HypoPP2 variants manifest episodic flaccid paralysis with concomitant hypokalemia (HP:0002900) and muscle weakness/paralysis (HP:0003470). Attacks last hours to days and are reversible with potassium correction. Between episodes, muscle strength is typically normal. The prevalence of HypoPP2 is estimated at ~1 in 100,000, but precise carrier frequencies for SCN4A missense alleles are not well defined.
Functional studies of HypoPP2-associated SCN4A mutants affecting S4 voltage-sensor arginine residues have demonstrated enhanced fast and slow inactivation in HEK cells, reducing channel availability and promoting membrane depolarization under low-K+ conditions (PMID:11912116). These biophysical defects create gating pore currents or alter voltage-sensor movement, providing a clear loss-of-function mechanism. Although direct patch-clamp data for Val1105Met and Thr704Met are pending, analogous effects for other HypoPP2 mutations support a shared pathomechanism.
In summary, multiple unrelated SCN4A missense variants cause autosomal dominant Hypokalemic Periodic Paralysis Type 2 by disturbing voltage-sensor gating, leading to episodic muscle hypoexcitability under hypokalemic conditions. Genetic confirmation enables targeted potassium therapy, lifestyle advice, and genetic counseling. Additional large-scale segregation and population data would further solidify this association, but current evidence is sufficient for clinical utility in diagnosis and management.
Gene–Disease AssociationModerateThree unrelated probands across three families with AD SCN4A missense variants; consistent episodic hypokalemic paralysis phenotype Genetic EvidenceModerateAt least 3 probands with c.3313G>A and c.2111C>T in unrelated families; autosomal dominant segregation Functional EvidenceModerateElectrophysiological studies of HypoPP2 arginine sensor mutants show enhanced fast/slow inactivation and gating pore currents ([PMID:11912116]) |