Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and evidence of further heterogeneity.

Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped an FHM gene on the short arm of chromosome 19. Mutations in this gene, recently shown to be the alpha1 subunit of a P/Q-type voltage-dependent calcium channel, CACNL1A4, are involved in approximately 50% of unselected FHM families and in all families where migraine attacks are associated with permanent cerebellar ataxia. As a first step toward the identification of other FHM genes, we conducted a genetic linkage analysis in one large French pedigree and showed significant linkage to two microsatellite markers D1S2635 (Zmax: 3.33 at theta = 0.05) and D1S2705 (Zmax: 3.64 at theta = 0.05), establishing the existence of a second locus for FHM (FHM2) on chromosome 1q21-q23. Analysis of six additional FHM families favored linkage to this locus in two of them; linkage was excluded in the last four families, indicating further heterogeneity. Chromosome 1-linked families differ from the ones linked to chromosome 19, because penetrance in those families is much lower, and in some of their members, epileptic seizures occur during severe migraine attacks.