Functional consequences of a KCNT1 variant associated with status dystonicus and early-onset infantile encephalopathy

Ann Clin Transl Neurol. 2019 Sep;6(9):1606-1615. doi: 10.1002/acn3.50847. Epub 2019 Jul 15.

Abstract

Objective: We identified a novel de novo KCNT1 variant in a patient with early-infantile epileptic encephalopathy (EIEE) and status dystonicus, a life-threatening movement disorder. We determined the functional consequences of this variant on the encoded KNa 1.1 channel to investigate the molecular mechanisms responsible for this disorder.

Methods: A retrospective case review of the proband is presented. We performed manual and automated electrophysiologic analyses of the KCNT1-L437F variant expressed heterologously in Chinese hamster ovary (CHO) cells in the presence of channel activators/blockers.

Results: The KCNT1-L437F variant, identified in a patient with refractory EIEE and status dystonicus, confers a gain-of-function channel phenotype characterized by instantaneous, voltage-dependent activation. Channel openers do not further increase L437F channel function, suggesting maximal activation, whereas channel blockers similarly block wild-type and variant channels. We further demonstrated that KCNT1 current can be measured on a high-throughput automated electrophysiology platform with potential value for future screening of novel and repurposed pharmacotherapies.

Interpretation: A novel pathogenic variant in KCNT1 associated with early-onset, medication-refractory epilepsy and dystonia causes gain-of-function with rapid activation kinetics. Our findings extend the genotype-phenotype relationships of KCNT1 variants to include severe dystonia.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain / diagnostic imaging
  • Child
  • Child, Preschool
  • Dystonia / diagnostic imaging
  • Dystonia / genetics*
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Phenotype
  • Potassium Channels, Sodium-Activated / genetics*
  • Spasms, Infantile / diagnostic imaging
  • Spasms, Infantile / genetics*

Substances

  • KCNT1 protein, human
  • Nerve Tissue Proteins
  • Potassium Channels, Sodium-Activated

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy