Genetic studies on Finnish families with familial hemiplegic migraine. M. Kaunisto1,2, M. Kallela1, P. Marttila3, M. Färkkilä1, H. Havanka4, E. Hämäläinen2, I. Hovatta5, A. Orpana2, L. Peltonen3, A. Palotie3, M. Wessman1,2. 1) Departments of Biosciences and Neurology, University of Helsinki, Helsinki, Finland; 2) Laboratory of Helsinki University Central Hospital, Helsinki, Finland; 3) Departments of Pathology and Human Genetics, UCLA, LA, USA; 4) Länsi-Pohja Central Hospital, Kemi, Finland; 5) Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland.
Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with aura. Patients with FHM have migraine attacks which are associated with hemiparesis or hemiplegia. In addition, some patients have progressive cerebellar ataxia. The gene for approximately a half of the reported FHM-families has been localized to chromosome 19p13. This gene, CACNA1A, encodes the a1A subunit of a P/Q-type voltage-gated calcium channel. 5 different missense mutations in CACNA1A (in FHM) have been published so far. FHM has shown to be a genetically heterogeneous disease after 2 groups found linkage to chromosome 1q.
We studied 9 families (71 members) fulfilling the IHS diagnosis criteria for FHM. These families originate from a database of 255 Finnish migraine families. Altogether 25 subjects were classified as affected: they fulfilled the IHS criteria for migraine with aura and had some degree of hemiparesis with their attacks. We analyzed the families for linkage to 3 chromosomal areas (19p13, 1q21-23 and 1q31) previously linked to FHM. 3 of the 9 families gave suggestive evidence for linkage to 19p13 showing positive lod scores with several markers. The total maximum LOD score was 3.3. For these families haplotypes segregating with the disease were determined. This data gave evidence against a major founder effect. Evidence for linkage to chromosome 1q was not obtained. We are currently screening these families for mutations in CACNA1A gene. So far no mutations have been found in 15/47 exons. These 15 exons include all previously published FHM mutation sites. However, we observed 4 previously described polymorphisms. Our data indicates that the Finnish FHM-mutations at least in these families are different from the previously published ones.