SCN8A Epilepsy, Developmental Encephalopathy, and Related Disorders

Dinesh Talwar, Michael F. Hammer

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations

Abstract

Understanding the precise genetic -basis of disease is one of the critical developments in medicine in the twenty-first century. Genetic testing has revolutionized the diagnosis and treatment of neurological diseases in children. Whole-genome and whole-exome sequencing have particularly been useful in understanding the genetic basis of childhood epileptic encephalopathies characterized by early-onset seizures with significant developmental impairment and regression. In this review we describe the identification of a new epileptic encephalopathy caused by a de novo mutation in the SCN8A gene, which encodes for NaV1.6, a vital sodium channel in the central nervous system. SCN8A variants in patients with epilepsy result primarily in gain-of-function in Nav1.6 and hyperexcitability of neurons in the central nervous system. Following the original discovery in 2012 of a de novo mutation in a child with developmental and epileptic encephalopathy (DEE), more than 400 individuals with SCN8A-related disorders have been identified. Clinical manifestations range from movement disorders or intellectual disability only to severe DEE, which includes epileptic encephalopathy with intractable multivariate seizure types, developmental impairment and regression, intellectual disability, and other neurological manifestations. Gain-of-function of the Nav1.6 channel predicts effectiveness of sodium channel-blocking agents in the treatment of seizures, which has been corroborated by clinical experience. Nevertheless, treatment options remain limited and adverse effects are common. However, with the availability of a growing database of genetic and clinical data along with transfected cell lines and mouse models, more efficacious, targeted, and selective treatments may soon be feasible.

Original languageEnglish (US)
Pages (from-to)76-83
Number of pages8
JournalPediatric Neurology
Volume122
DOIs
StatePublished - Sep 2021

Keywords

  • Epileptic encephalopathy
  • Gain-of-function variants
  • Loss-of-function variants
  • Na1.6 channel
  • SCN8A encephalopathy

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neurology
  • Developmental Neuroscience
  • Clinical Neurology

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