Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus

Jacy L. Wagnon, Niccolò E. Mencacci, Bryan S. Barker, Eric R. Wengert, Kailash P. Bhatia, Bettina Balint, Miryam Carecchio, Nicholas W. Wood, Manoj K. Patel, Miriam H. Meisler

Research output: Contribution to journalArticle

Abstract

Variants in the neuronal sodium channel gene SCN8A have been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain-of-function mutations that alter the biophysical properties of the channel. Complete loss-of-function variants of SCN8A have been identified in cases of isolated intellectual disability. We now report a novel heterozygous SCN8A variant, p.Pro1719Arg, in a small pedigree with five family members affected with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment. Functional analysis of the p.Pro1719Arg variant in transfected neuron-derived cells demonstrated greatly reduced Nav1.6 channel activity without altered gating properties. Hypomorphic alleles of Scn8a in the mouse are known to result in similar movement disorders. This study expands the phenotypic and functional spectrum of SCN8A variants to include inherited nonepileptic isolated myoclonus. SCN8A can be considered as a candidate gene for isolated movement disorders without seizures.

Original languageEnglish
Pages (from-to)965-969
Number of pages5
JournalHuman Mutation
Volume39
Issue number7
DOIs
Publication statusPublished - Jul 1 2018

Keywords

  • movement disorder
  • myoclonus
  • Nav1.6
  • sodium channel

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Wagnon, J. L., Mencacci, N. E., Barker, B. S., Wengert, E. R., Bhatia, K. P., Balint, B., Carecchio, M., Wood, N. W., Patel, M. K., & Meisler, M. H. (2018). Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Human Mutation, 39(7), 965-969. https://doi.org/10.1002/humu.23547