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

Objective: To search for mutations in the calcium channel gene CACNA1A and to study the genotype-phenotype correlation in a family with a severe famil ial hemiplegic migraine (FHM) phenotype and a slowly progressive cerebellar ataxia. Background: CACNA1A gene mutations on chromosome 19 are involved i n 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 c hromosome 19. Methods: The proband, in addition to typical hemiplegic migra ine attacks, experienced severe episodes during which hemiplegia was associ ated with acutely altered consciousness and fever lasting several days. She , as well as her affected sister, developed a permanent, late-onset cerebel lar ataxia and cerebellar atrophy evident on MRI. Linkage analysis was perf ormed and the whole CACNA1A gene, 47 exon-intron boundaries, was analyzed b y double gradient-denaturing gradient gel electrophoresis (DG-DGGE). Result s: Genetic studies suggested linkage to chromosome 19p13, and DG-DGGE analy sis detected a heteroduplex fragment in exon 13 of the CACNA1A gene. By dir ect 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 ch annel alpha(1A)-subunit, was identified, possibly representing the disease- causing mutation. The proband and her affected sister were treated with ace tazolamide, reporting freedom from new FHM attacks but no benefit in the pr ogression of ataxia. Conclusions: The combination of episodic dysfunction a nd permanent deficit could depend on the variety of functions of calcium ch annels and their distribution in the nervous system.