A novel mutation in the gene for the adult skeletal muscle sodium channel alpha-subunit (SCN4A) that causes paramyotonia congenita of von Eulenburg

Background: Paramyotonia congenita (PMC) of yon Eulenburg is an autosomal d ominant muscular disease characterized by exercise- and cold-induced myoton ia and weakness. To date, 18 missense mutations in the adult skeletal muscl e sodium channel ol-subunit (SCN4A) gene have been identified to cause a sp ectrum of muscular diseases, including PMC of von Eulenburg, PMC without co ld paralysis, potassium-aggravating myotonia, and hyperkalemic periodic par alysis. However, no obvious correlations can be made between the location o r nature of amino acid substitutions in SCN4A and its clinical phenotypes. Objective: To describe clinical and genetic features a family with PMC of v on Eulenburg. Results: A Japanese family with cold-induced myotonia and weakness was diag nosed as having PMC of von Eulenburg. This phenotype was identified to be c aused by a novel mutation that substituted a glutamic acid residue for a hi ghly conserved glycine residue in the fourth transmembrane segment (S4) of domain IV. This predicted a decrease in positive-charge specific for the S4 . Conclusion: In addition to the G1456E identified in this study, 4 mutations that cause a decrease in positive charge in the S4/D4 are associated with the phenotype of PMC of von Eulenburg. This provides an important genotype- phenotype correlation in sodium channelopathies.