VARIABLE CLINICAL EXPRESSION OF MUTATIONS IN THE P Q-TYPE CALCIUM-CHANNEL GENE IN FAMILIAL HEMIPLEGIC MIGRAINE/

Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with aura, with half of the families being assigned to chrom osome 19p13. We identified missense mutations in a brain-specific calc ium channel alpha(1A)-subunit (CACNA1A) gene on 19p13 segregating with FHM and truncating mutations in families with episodic ataxia type 2 (EA-2). Expansions of an intragenic CAG repeat have been shown in auto somal dominant cerebellar ataxia (SCA6). Hence, FHM, EA-2, and SCA6 ar e allelic ion channel disorders. We analyzed the phenotype-genotype re lation in three unrelated FHM families with the calcium channel alpha( 1A)-subunit gene mutations I1811L (two families) and V714A (one family ). We found mutations in all but three patients with FHM (i.e., three phenocopies). In addition, the I1811L mutation occurred in two patient s with ''nonhemiplegic'' migraine and in one subject without migraine. Cerebellar ataxia was found in both families with the I1811L mutation but not in the family with the V714A mutation. We failed to find expa nsions of the intragenic CAG repeat in FHM patients with cerebellar at axia. We conclude that the I1811L mutation causes both FHM and cerebel lar ataxia independent of the number of CAG repeats. The I1811L mutati on may also occur in ''normal'' migraine patients, supporting the hypo thesis that FHM is part of the migraine spectrum.