The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.

Background: Familial hemiplegic migraine, an autosomal dominant disorder ch aracterized by attacks of transient hemiparesis followed by a migraine head ache, is divided into pure familial hemiplegic migraine (affecting 80 perce nt of families) and familial hemiplegic migraine with permanent cerebellar signs (affecting 20 percent of families). Mutations in CACNA1A, which encod es a neuronal calcium channel, are present in 50 percent of families with h emiplegic migraine, including all those with cerebellar signs. We studied t he various clinical manifestations associated with mutations in CACNA1A in 28 families with hemiplegic migraine with and without cerebellar signs. Methods: CACNA1A was analyzed and nine mutations were detected in 15 of 16 probands of families affected by hemiplegic migraine and cerebellar signs, in 2 of 3 subjects with sporadic hemiplegic migraine and cerebellar signs, and in 4 of 12 probands of families affected by pure hemiplegic migraine. G enotyping of probands and relatives identified a total of 117 subjects with mutations whose clinical manifestations were assessed in detail. Results: Eighty-nine percent of the subjects with mutations had attacks of hemiplegic migraine. One third had severe attacks with coma, prolonged hemi plegia, or both, with full recovery. All nine mutations, including five new ly identified ones, were missense mutations. Six mutations were associated with hemiplegic migraine and cerebellar signs, and 83 percent of the subjec ts with these six mutations had nystagmus, ataxia, or both. Three mutations were associated with pure hemiplegic migraine. Conclusions: Hemiplegic migraine in subjects with mutations in CACNA1A has a broad clinical spectrum. This clinical variability is partially associate d with the various types of mutations. (N Engl J Med 2001;345:17-24.) Copyr ight (C) 2001 Massachusetts Medical Society.