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

Arch Neurol. 1999 Jun;56(6):692-6. doi: 10.1001/archneur.56.6.692.


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 alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Chromosome Mapping
  • Cold Temperature
  • Exons
  • Female
  • Genetic Linkage
  • Humans
  • Japan
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Muscle, Skeletal / metabolism*
  • Mutation, Missense*
  • Myotonia Congenita / genetics*
  • NAV1.4 Voltage-Gated Sodium Channel
  • Pedigree
  • Phenotype
  • Polymerase Chain Reaction
  • Protein Structure, Secondary
  • Sodium Channels / chemistry
  • Sodium Channels / genetics*


  • NAV1.4 Voltage-Gated Sodium Channel
  • SCN4A protein, human
  • Sodium Channels