De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies

Neurology. 2009 Sep 29;73(13):1046-53. doi: 10.1212/WNL.0b013e3181b9cebc.


Background: Mutations of voltage-gated sodium channel alpha(II) gene, SCN2A, have been described in a wide spectrum of epilepsies. While inherited SCN2A mutations have been identified in multiple mild epilepsy cases, a de novo SCN2A-R102X mutation, which we previously reported in a patient with sporadic intractable childhood localization-related epilepsy, remains unique. To validate the involvement of de novo SCN2A mutations in the etiology of intractable epilepsies, we sought to identify additional instances.

Methods: We performed mutational analyses on SCN2A in 116 patients with severe myoclonic epilepsy in infancy, infantile spasms, and other types of intractable childhood partial and generalized epilepsies and did whole-cell patch-clamp recordings on Na(v)1.2 channels containing identified mutations.

Results: We discovered 2 additional de novo SCN2A mutations. One mutation, SCN2A-E1211K, was identified in a patient with sporadic infantile spasms. SCN2A-E1211K produced channels with altered electrophysiologic properties compatible with both augmented (an approximately 18-mV hyperpolarizing shift in the voltage dependence of activation) and reduced (an approximately 22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation) channel activities. The other de novo mutation, SCN2A-I1473M, was identified in a patient with sporadic neonatal epileptic encephalopathy. SCN2A-I1473M caused an approximately 14-mV hyperpolarizing shift in the voltage dependence of activation.

Conclusions: The identified de novo mutations SCN2A-E1211K, -I1473M, and -R102X indicate that SCN2A is an etiologic candidate underlying a variety of intractable childhood epilepsies. The phenotypic variations among patients might be due to the different electrophysiologic properties of mutant channels.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Conserved Sequence
  • DNA Mutational Analysis
  • Epilepsies, Myoclonic / genetics*
  • Epilepsies, Myoclonic / physiopathology*
  • Fatal Outcome
  • Female
  • Haplotypes
  • Humans
  • Infant, Newborn
  • Kidney / cytology
  • Male
  • Mutation, Missense*
  • NAV1.2 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / physiology
  • Patch-Clamp Techniques
  • Protein Structure, Tertiary
  • Severity of Illness Index*
  • Sodium Channels / chemistry
  • Sodium Channels / genetics*
  • Sodium Channels / physiology
  • Spasms, Infantile / genetics
  • Spasms, Infantile / physiopathology
  • Transfection
  • Young Adult


  • NAV1.2 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • SCN2A protein, human
  • Sodium Channels