Genetic heterogeneity in Italian families with familial hemiplegic migraine

Objective: To verify linkage to chromosome 19p13, to detect mutations in th e CACNAlA gene, and to correlate genetic results to their clinical phenotyp es in Italian families with familial hemiplegic migraine (FHM). Background: FHM is an autosomal dominant disease, classified as a subtype of migraine with aura. Only a proportion of FHM patients have been associated with chro mosome 19p13. Among these, four missense mutations within the CACNAlA gene in five unrelated families have been described. Methods: A linkage study wa s performed in 19 patients affected by FHM. from five families by studying microsatellite markers associated with the 19p13 region. All familial and s even additional sporadic patients with FHM were analyzed to search for muta tions within the CACNAlA gene by applying the double gradient-denaturant gr adient electrophoresis technique. Results: Lod score values did not establi sh significantly linkage to chromosome 19. However, seven new genetic varia nts were detected: six were new polymorphisms. The seventh was a missense m utation present in family 1, and it was associated with a hemiplegic migrai ne phenotype without unconsciousness and cerebellar ataxia. Because this mi ssense mutation is absent in the general population and cosegregates with t he disease, it may be a pathologic mutation. Conclusions: Genetic heterogen eity of FHM has been shown in familial and sporadic FHM patients of Italian origin. The new missense mutation-G4644T-is associated with milder clinica l features compared with typical FHM.