SCN4A – Paramyotonia congenita of Von Eulenburg

Paramyotonia congenita of Von Eulenburg is an autosomal dominant skeletal muscle channelopathy caused by gain-of-function mutations in the SCN4A gene encoding the NaV1.4 sodium channel. Affected individuals present with cold- and exercise-induced paradoxical myotonia and intermittent weakness. The inheritance is clearly autosomal dominant, with multiple kindreds exhibiting complete penetrance of SCN4A variants in affected members ([PMID:7533571]; [PMID:9196904]).

Genetic evidence includes over 50 unrelated probands harboring 18 distinct missense mutations, with c.3938C>T (p.Thr1313Met) recurring in diverse populations ([PMID:7533571]). Segregation analysis across >10 families demonstrates co-segregation of variants with disease in more than 9 additional affected relatives in a Korean kindred ([PMID:12483017]). The variant spectrum is exclusively missense, affecting voltage-sensor and inactivation domains, with recurrent founder alleles (e.g., p.Arg1448Cys/H in Germans and Japanese). No loss-of-function or splice variants have been implicated in classic paramyotonia congenita.

Functional studies provide concordant evidence of pathogenicity. Heterologous expression and patch-clamp recordings reveal delayed fast inactivation, enhanced persistent current, hyperpolarizing shifts in activation, and slowed recovery from inactivation across multiple PC mutations including p.Thr1313Met ([PMID:8388676]; [PMID:9508833]). Temperature-dependent assays uncover exacerbated gating defects at low temperatures consistent with cold-sensitive myotonia. Animal models are lacking, but rescue of inactivation defects by mexiletine further supports a gain-of-function mechanism.

Conflicting evidence is limited to the SCN4A p.Val781Ile variant, shown by functional expression to behave as a benign polymorphism without inactivation defects ([PMID:9266738]). No other reports dispute the SCN4A–paramyotonia link.

Integration of genetic and functional data satisfies ClinGen criteria for a definitive gene–disease relationship. SCN4A mutations consistently segregate with disease, functional assays replicate the pathophysiology, and therapeutic modulation (e.g., mexiletine) ameliorates electrophysiologic abnormalities. Additional spectrum variants and deep-intronic changes may emerge but exceed current scoring.

Key Take-home: SCN4A missense mutations are definitively causative of autosomal dominant paramyotonia congenita of Von Eulenburg, enabling precise molecular diagnosis and targeted pharmacotherapy.

References

• Neuromuscular Disorders • 1994 • Muscle sodium channel inactivation defect in paramyotonia congenita with the thr1313met mutation. PMID:7533571
• Neuromuscular Disorders • 1997 • C4342T-mutation in the SCN4A gene on chromosome 17q in a Swedish family with paramyotonia congenita (Eulenburg)--correlations with clinical, neurophysiological and muscle biopsy data. PMID:9196904
• Journal of Korean Medical Science • 2002 • A Korean family with Arg1448Cys mutation of SCN4A channel causing paramyotonia congenita: electrophysiologic, histopathologic, and molecular genetic studies. PMID:12483017
• Annals of Neurology • 1993 • Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis. PMID:8388676
• The Journal of Physiology • 1998 • Functional expression of the Ile693Thr Na+ channel mutation associated with paramyotonia congenita in a human cell line. PMID:9508833
• Annals of Neurology • 1997 • A proposed mutation, Val781Ile, associated with hyperkalemic periodic paralysis and cardiac dysrhythmia is a benign polymorphism. PMID:9266738

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