A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia

Neurology. 1999 Jul 13;53(1):38-43. doi: 10.1212/wnl.53.1.38.

Abstract

Objective: To search for mutations in the calcium channel gene CACNA1A and to study the genotype-phenotype correlation in a family with a severe familial hemiplegic migraine (FHM) phenotype and a slowly progressive cerebellar ataxia.

Background: CACNA1A gene mutations on chromosome 19 are involved in approximately 50% of FHM families. The association of FHM and cerebellar ataxia has been reported in a small number of FHM families, all linked to chromosome 19.

Methods: The proband, in addition to typical hemiplegic migraine attacks, experienced severe episodes during which hemiplegia was associated with acutely altered consciousness and fever lasting several days. She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and cerebellar atrophy evident on MRI. Linkage analysis was performed and the whole CACNA1A gene, 47 exon-intron boundaries, was analyzed by double gradient-denaturing gradient gel electrophoresis (DG-DGGE).

Results: Genetic studies suggested linkage to chromosome 19p13, and DG-DGGE analysis detected a heteroduplex fragment in exon 13 of the CACNA1A gene. By direct sequencing, a G-to-A substitution resulting in an arginine to glutamine change at codon 583 in the second putative voltage sensor domain of the channel alpha1A-subunit, was identified, possibly representing the disease-causing mutation. The proband and her affected sister were treated with acetazolamide, reporting freedom from new FHM attacks but no benefit in the progression of ataxia.

Conclusions: The combination of episodic dysfunction and permanent deficit could depend on the variety of functions of calcium channels and their distribution in the nervous system.

Publication types

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

MeSH terms

  • Acetazolamide / therapeutic use*
  • Adult
  • Aged
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Brain / pathology
  • Calcium Channels / chemistry
  • Calcium Channels / genetics*
  • Cerebellar Ataxia / drug therapy
  • Cerebellar Ataxia / genetics*
  • Cerebellar Ataxia / pathology
  • Convulsants / therapeutic use*
  • Exons
  • Female
  • Hemiplegia / drug therapy
  • Hemiplegia / genetics*
  • Hemiplegia / pathology
  • Humans
  • Introns
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Migraine Disorders / drug therapy
  • Migraine Disorders / genetics*
  • Migraine Disorders / pathology
  • Molecular Sequence Data
  • Pedigree
  • Point Mutation*
  • Rabbits
  • Sequence Alignment
  • Sequence Homology, Amino Acid

Substances

  • CACNA1A protein, human
  • Calcium Channels
  • Convulsants
  • Acetazolamide

Grants and funding