SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype

Neuromuscul Disord. 2015 Apr;25(4):301-7. doi: 10.1016/j.nmd.2015.01.006. Epub 2015 Jan 21.


In myotonic dystrophy type 2 (DM2), an association has been reported between early and severe myotonia and recessive chloride channel (CLCN1) mutations. No DM2 cases have been described with sodium channel gene (SCN4A) mutations. The aim is to describe a DM2 patient with severe and early onset myotonia and co-occurrence of a novel missense mutation in SNC4A. A 26-year-old patient complaining of hand cramps and difficulty relaxing her hands after activity was evaluated at our department. Neurophysiology and genetic analysis for DM1, DM2, CLCN1 and SCN4A mutations were performed. Genetic testing was positive for DM2 (2650 CCTG repeat) and for a variant c.215C>T (p.Pro72Leu) in the SCN4A gene. The variation affects the cytoplasmic N terminus domain of Nav1.4, where mutations have never been reported. The biophysical properties of the mutant Nav1.4 channels were evaluated by whole-cell voltage-clamp analysis of heterologously expressed mutant channel in tsA201 cells. Electrophysiological studies of the P72L variant showed a hyperpolarizing shift (-5 mV) of the voltage dependence of activation that may increase cell excitability. This case suggests that SCN4A mutations may enhance the myotonic phenotype of DM2 patients and should be screened for atypical cases with severe myotonia.

Keywords: Myotonia; Myotonic dystrophy type 2; N-terminus; SCN4A.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Line
  • Chloride Channels / genetics
  • DNA Mutational Analysis
  • Electric Stimulation
  • Female
  • Humans
  • Membrane Potentials / genetics
  • Membrane Potentials / physiology
  • Mutation*
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / physiopathology
  • Myotonin-Protein Kinase / genetics
  • NAV1.4 Voltage-Gated Sodium Channel / genetics*
  • NAV1.4 Voltage-Gated Sodium Channel / metabolism
  • Patch-Clamp Techniques
  • RNA-Binding Proteins / genetics
  • Transfection


  • CLC-1 channel
  • CNBP protein, human
  • Chloride Channels
  • DMPK protein, human
  • NAV1.4 Voltage-Gated Sodium Channel
  • RNA-Binding Proteins
  • SCN4A protein, human
  • Myotonin-Protein Kinase