Background Familial hemiplegic migraine, an autosomal dominantdisorder characterized by attacks of transient hemiparesis followedby a migraine headache, is divided into pure familial hemiplegicmigraine (affecting 80 percent of families) and familial hemiplegicmigraine with permanent cerebellar signs (affecting 20 percentof families). Mutations in CACNA1A, which encodes a neuronalcalcium channel, are present in 50 percent of families withhemiplegic migraine, including all those with cerebellar signs.We studied the various clinical manifestations associated withmutations in CACNA1A in 28 families with hemiplegic migrainewith and without cerebellar signs.
Methods CACNA1A was analyzed and nine mutations were detectedin 15 of 16 probands of families affected by hemiplegic migraineand cerebellar signs, in 2 of 3 subjects with sporadic hemiplegicmigraine and cerebellar signs, and in 4 of 12 probands of familiesaffected by pure hemiplegic migraine. Genotyping of probandsand relatives identified a total of 117 subjects with mutationswhose clinical manifestations were assessed in detail.
Results Eighty-nine percent of the subjects with mutations hadattacks of hemiplegic migraine. One third had severe attackswith coma, prolonged hemiplegia, or both, with full recovery.All nine mutations, including five newly identified ones, weremissense mutations. Six mutations were associated with hemiplegicmigraine and cerebellar signs, and 83 percent of the subjectswith these six mutations had nystagmus, ataxia, or both. Threemutations were associated with pure hemiplegic migraine.
Conclusions Hemiplegic migraine in subjects with mutations inCACNA1A has a broad clinical spectrum. This clinical variabilityis partially associated with the various types of mutations.
Source Information
From INSERM E99-21, Faculté de Médecine Lariboisière, Paris (A.D., C.D., A.J., M.C., C.L., E.T.-L.); the Département de Neurologie (A.D., K.V., M.-G.B.) and Laboratoire de Génétique (A.J., M.C., E.T.-L.), Hôpital Lariboisière, Paris; the Département de Neurologie, Centre Hospitalier Universitaire, Rennes, France (F.D.); and the Laboratoire de Biophysique, Hôpital Fernand Widal, Paris (E.V.).
Address reprint requests to Dr. Ducros at the Department of Neurology, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris CEDEX 10, France, or at anne.ducros{at}lrb.ap-hop-paris.fr.
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