Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function

Epilepsia. 2021 Jun;62(6):e82-e87. doi: 10.1111/epi.16913. Epub 2021 Apr 26.


We identified nine patients from four unrelated families harboring three biallelic variants in SCN1B (NM_001037.5: c.136C>T; p.[Arg46Cys], c.178C>T; p.[Arg60Cys], and c.472G>A; p.[Val158Met]). All subjects presented with early infantile epileptic encephalopathy 52 (EIEE52), a rare, severe developmental and epileptic encephalopathy featuring infantile onset refractory seizures followed by developmental stagnation or regression. Because SCN1B influences neuronal excitability through modulation of voltage-gated sodium (NaV ) channel function, we examined the effects of human SCN1BR46C (β1R46C ), SCN1BR60C (β1R60C ), and SCN1BV158M (β1V158M ) on the three predominant brain NaV channel subtypes NaV 1.1 (SCN1A), NaV 1.2 (SCN2A), and NaV 1.6 (SCN8A). We observed a shift toward more depolarizing potentials of conductance-voltage relationships (NaV 1.2/β1R46C , NaV 1.2/β1R60C , NaV 1.6/β1R46C , NaV 1.6/β1R60C , and NaV 1.6/β1V158M ) and channel availability (NaV 1.1/β1R46C , NaV 1.1/β1V158M , NaV 1.2/β1R46C , NaV 1.2/β1R60C , and NaV 1.6/β1V158M ), and detected a slower recovery from fast inactivation for NaV 1.1/β1V158M . Combined with modeling data indicating perturbation-induced structural changes in β1, these results suggest that the SCN1B variants reported here can disrupt normal NaV channel function in the brain, which may contribute to EIEE52.

Keywords: SCN1B; EIEE52; developmental and epileptic encephalopathy; early infantile epileptic encephalopathy 52; voltage-gated sodium channel.

Publication types

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

MeSH terms

  • Child
  • Child, Preschool
  • Chromosome Mapping
  • DNA / genetics
  • Drug Resistant Epilepsy / etiology
  • Electroencephalography
  • Exome
  • Female
  • Genetic Variation
  • Humans
  • Infant
  • Male
  • Models, Molecular
  • Mutation, Missense / genetics
  • Pedigree
  • Seizures / etiology
  • Spasms, Infantile / genetics*
  • Voltage-Gated Sodium Channel beta-1 Subunit / genetics*
  • Voltage-Gated Sodium Channels / genetics*
  • Voltage-Gated Sodium Channels / metabolism*


  • SCN1B protein, human
  • Voltage-Gated Sodium Channel beta-1 Subunit
  • Voltage-Gated Sodium Channels
  • DNA

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy