De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants

Am J Med Genet A. 2018 Aug;176(8):1748-1752. doi: 10.1002/ajmg.a.38840. Epub 2018 Jul 28.


Derangements in voltage-gated potassium channel function are responsible for a range of paroxysmal neurologic disorders. Pathogenic variants in the KCNA1 gene, which encodes the voltage-gated potassium channel Kv1.1, are responsible for Episodic Ataxia Type 1 (EA1). Patients with EA1 have an increased incidence of epilepsy, but KCNA1 variants have not been described in epileptic encephalopathy. Here, we describe four patients with infantile-onset epilepsy and cognitive impairment who harbor de novo KCNA1 variants located within the Kv-specific Pro-Val-Pro (PVP) motif which is essential for channel gating. The first two patients have KCNA1 variants resulting in (p.Pro405Ser) and (p.Pro405Leu), respectively, and a set of identical twins has a variant affecting a nearby residue (p.Pro403Ser). Notably, recurrent de novo variants in the paralogous PVP motif of KCNA2 have previously been shown to abolish channel function and also cause early-onset epileptic encephalopathy. Importantly, this report extends the range of phenotypes associated with KCNA1 variants to include epileptic encephalopathy when the PVP motif is involved.

Keywords: KCNA1, KCNA2; PVP motif; cognitive impairment; epilepsy; epileptic encephalopathy; infantile epilepsy; potassium channel mutation.

MeSH terms

  • Amino Acid Motifs / genetics
  • Ataxia / genetics
  • Child
  • Child, Preschool
  • Cognitive Dysfunction / genetics*
  • Cognitive Dysfunction / physiopathology
  • Epilepsy / genetics*
  • Epilepsy / physiopathology
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Infant, Newborn
  • Kv1.1 Potassium Channel / genetics*
  • Kv1.2 Potassium Channel / genetics*
  • Male
  • Mutation
  • Myokymia / genetics
  • Phenotype


  • KCNA1 protein, human
  • KCNA2 protein, human
  • Kv1.2 Potassium Channel
  • Kv1.1 Potassium Channel

Supplementary concepts

  • Episodic Ataxia, Type 1