Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A

J Neurol Sci. 2014 Jul 15;342(1-2):69-78. doi: 10.1016/j.jns.2014.04.027. Epub 2014 Apr 27.


Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel Ca(V)2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3 bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant Ca(V)2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset.

Keywords: Acetazolamide response; Congenital ataxia; Developmental delay; Gain of function; Novel CACNA1A mutation; Severe SHM1.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetazolamide / therapeutic use
  • Adolescent
  • Animals
  • Ataxia / complications*
  • Ataxia / drug therapy
  • Ataxia / genetics*
  • Brain Edema / complications*
  • Brain Edema / drug therapy
  • Brain Edema / genetics*
  • Calcium Channels / genetics*
  • Calcium Channels / physiology
  • Cerebellar Ataxia / complications*
  • Cerebellar Ataxia / drug therapy
  • Cerebellar Ataxia / genetics*
  • Child
  • Child, Preschool
  • Female
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Membrane Potentials
  • Migraine Disorders / complications*
  • Migraine Disorders / drug therapy
  • Migraine Disorders / genetics*
  • Mutation, Missense / genetics
  • Neuroimaging
  • Oocytes
  • Xenopus laevis


  • CACNA1A protein, human
  • Calcium Channels
  • Acetazolamide

Supplementary concepts

  • Hemiplegic migraine, familial type 1