Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant

John J. Millichap, Francesco Miceli, Michela De Maria, Cynthia Keator, Nishtha Joshi, Baouyen Tran, Maria Virginia Soldovieri, Paolo Ambrosino, Vandana Shashi, Mohamad A. Mikati, Edward C. Cooper*, Maurizio Taglialatela

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Variants in KCNQ2 encoding for Kv7.2 neuronal K+ channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2-related epilepsy: infantile spasms without prior neonatal seizures associated with a gain-of-function gene variant. With use of an international registry, we identified four unrelated patients with the same de novo heterozygous KCNQ2 c.593G>A, p.Arg198Gln (R198Q) variant. All were born at term and discharged home without seizures or concern of encephalopathy, but developed infantile spasms with hypsarrhythmia (or modified hypsarrhythmia) between the ages of 4 and 6 months. At last follow-up (ages 3–11 years), all patients were seizure-free and had severe developmental delay. In vitro experiments showed that Kv7.2 R198Q subunits shifted current activation gating to hyperpolarized potentials, indicative of gain-of-function; in neurons, Kv7.2 and Kv7.2 R198Q subunits similarly populated the axon initial segment, suggesting that gating changes rather than altered subcellular distribution contribute to disease molecular pathogenesis. We conclude that KCNQ2 R198Q is a model for a new subclass of KCNQ2 variants causing infantile spasms and encephalopathy, without preceding neonatal seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Original languageEnglish (US)
Pages (from-to)e10-e15
JournalEpilepsia
Volume58
Issue number1
DOIs
StatePublished - Jan 1 2017

Keywords

  • Epileptic encephalopathy
  • Gene variants
  • Genotype–phenotype
  • KCNQ2
  • Potassium channels
  • axon initial segment
  • retigabine

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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