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SCN4A, encoding the Nav1.4 voltage-gated sodium channel, is implicated in autosomal dominant myotonia permanens, a non-dystrophic myotonia characterized by continuous muscle stiffness. Initial reports identified a c.3917G>A (p.Gly1306Glu) variant in two sporadic patients and a three-generation family segregating with disease (PMID:16832098). A second independent kindred harbors a novel c.3473C>T (p.Pro1158Leu) variant in a child with severe myotonia and muscle hypertrophy (PMID:27164696). In total, four probands across three families support a strong gene–disease relationship.
Segregation of c.3917G>A with myotonia in a pedigree with three affected relatives confirms autosomal dominant inheritance and full penetrance in this family (PMID:16832098). Genetic testing has consistently detected missense gain-of-function alleles in unrelated individuals, fulfilling ClinGen criteria for strong genetic evidence.
Functional characterization of p.Pro1158Leu in tsA201 cells demonstrates slowed current decay, a rightward shift in the voltage dependence of fast inactivation, and increased persistent sodium current, directly correlating with the clinical myotonia phenotype (PMID:27164696). Pharmacologic profiling revealed reduced mexiletine sensitivity but preserved flecainide inhibition, guiding tailored therapy.
The pathogenic mechanism is a gain-of-function defect, whereby impaired fast inactivation of Nav1.4 leads to sustained inward sodium currents and muscle hyperexcitability. No contradictory studies have been reported, and experimental findings align across independent assays and patient phenotypes.
Together, the genetic and functional data firmly establish SCN4A mutations as a cause of myotonia permanens, enabling precise molecular diagnosis and informing personalized pharmacotherapy. Key take-home: SCN4A testing is critical for confirming myotonia permanens and selecting optimal sodium-channel blockers.
Gene–Disease AssociationStrongFour probands in three families with autosomal dominant inheritance and functional concordance ([PMID:16832098], [PMID:27164696]) Genetic EvidenceStrongCase-level data from 4 probands and segregation in a multi-generation pedigree Functional EvidenceModeratePatch-clamp studies of p.Pro1158Leu and p.Gly1306Glu show impaired fast inactivation, persistent current, and pharmacologic rescue |