Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation

Background: Familial hermplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. Missense mutations in the chromosome 19 CACNA1A calcium channel gene have been found in approximately half of the families. The T666M mutation, replacing a threonine by, a methionine at residue number 666, is the most frequent mutation, reported in 14 independent FHM families; other mutations have so far been described in only I or 2 families each. The clinical features of T666M families have been reported, but the course is unknown. Objective: To present a detailed description of the clinical features of new FHM families in which We identified the T666M mutation in our CACNA1A screening program. Methods: As part of our ongoing genetic screening, mutation analysis of the CACNA1A gene was performed by single-strand conformational polymorphism analysis in 33 probands of families with FHM. Results: We identified the T666M mutation in 5 unrelated FHM families. In 3 of the families, patients displayed cerebellar ataxia. In I family, some affected members with the mutation had attacks with confusion but without hemiparesis. In I family, patients had progressive cognitive dysfunction. Conclusions: The T666M mutation is the most frequent CACNA1A mutation in FHM; it was found in 5 of 33 FHM families at our laboratory, and in 19 of 39 families with a known mutation reported in the literature (including the present study). Screening for the T666M mutation should therefore be the first step when screening families with FHM. There is a remarkable clinical heterogeneity among families with the T666M mutation.