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A Novel Mutation in the Gene for the Adult Skeletal Muscle Sodium Channel  -Subunit (SCN4A) That Causes Paramyotonia Congenita of von Eulenburg
Ryogen Sasaki, MD;
Hiroki Takano, MD, PhD;
Keiko Kamakura, MD;
Kenichi Kaida, MD;
Akira Hirata, MD;
Masaaki Saito, MD;
Hajime Tanaka, MD;
Shigeki Kuzuhara, MD;
Shoji Tsuji, MD, PhD
Arch Neurol. 1999;56:692-696.
Background Paramyotonia congenita (PMC) of von Eulenburg is an autosomal dominant muscular disease characterized by exercise- and cold-induced myotonia and weakness. To date, 18 missense mutations in the adult skeletal muscle sodium channel  -subunit (SCN4A) gene have been identified to cause a spectrum of muscular diseases, including PMC of von Eulenburg, PMC without cold paralysis, potassium-aggravating myotonia, and hyperkalemic periodic paralysis. However, no obvious correlations can be made between the location or nature of amino acid substitutions in SCN4A and its clinical phenotypes.
Objective To describe clinical and genetic features of a family with PMC of von Eulenburg.
Results A Japanese family with cold-induced myotonia and weakness was diagnosed as having PMC of von Eulenburg. This phenotype was identified to be caused by a novel mutation that substituted a glutamic acid residue for a highly 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.
From the Department of Neurology, Brain Research Institute, Niigata University, Niigata (Drs Sasaki, Takano, Saito, Tanaka, and Tsuji); Department of Neurology, Mie University School of Medicine, Tsushi (Drs Sasaki and Kuzuhara); and Third Department of Internal Medicine, National Defense Medical College, Tokorozawa (Drs Kamakura, Kaida, and Hirata), Japan.
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