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

Nuria García Segarra, Ivan Gautschi, Laureane Mittaz-Crettol, Christine Kallay Zetchi, Lama Al-Qusairi, Miguel Xavier Van Bemmelen, Philippe Maeder, Luisa Bonafé, Laurent Schild, Eliane Roulet-Perez

Research output: Contribution to journalArticle

Abstract

Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel CaV2.1 (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 CaV2.1 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.

Original languageEnglish (US)
Pages (from-to)69-78
Number of pages10
JournalJournal of the Neurological Sciences
Volume342
Issue number1-2
DOIs
StatePublished - Jul 15 2014
Externally publishedYes

Keywords

  • Acetazolamide response
  • Congenital ataxia
  • Developmental delay
  • Gain of function
  • Novel CACNA1A mutation
  • Severe SHM1

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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  • Cite this

    García Segarra, N., Gautschi, I., Mittaz-Crettol, L., Kallay Zetchi, C., Al-Qusairi, L., Van Bemmelen, M. X., Maeder, P., Bonafé, L., Schild, L., & Roulet-Perez, E. (2014). Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A. Journal of the Neurological Sciences, 342(1-2), 69-78. https://doi.org/10.1016/j.jns.2014.04.027