In families with hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) discovered a C-to-T transition in nucleotide 2272 of CACNL1A4, resulting in a thr666-to-met (T666M) amino acid substitution.
Friend et al. (1999) found this recurrent mutation in exon 16 in an Australian patient with familial hemiplegic migraine.
Ducros et al. (1999) screened 16 families and 3 nonfamilial cases with hemiplegic migraine associated with progressive cerebellar ataxia (see 141500). They found the T666M mutation in 9 families and 1 nonfamilial case. The T666M mutation was absent in 12 probands belonging to pure HPM families whose disease appeared to be linked to CACNA1A.
Terwindt et al. (2002) studied 27 patients with sporadic hemiplegic migraine and found the T666M mutation in a 78-year-old woman who had characteristic attacks starting at age 14 as well as interictal nystagmus, dysarthria, limb and gait ataxia, and cerebellar atrophy.
Kors et al. (2003) reported the clinical symptoms of 5 families with hemiplegic migraine and the T666M mutation. Three of the families displayed cerebellar ataxia, 3 had loss of consciousness or coma associated with episodes, 1 had attacks with confusion but without hemiparesis, and 1 had progressive cognitive dysfunction. The authors emphasized the inter- and intrafamilial clinical heterogeneity.
Barrett et al. (2005) found that CACNA1A channels with the T666M mutation were expressed and trafficked normally to the cell surface in transfected HEK293 cells. However, T666M mutant channels exhibited defective voltage-dependent gating to support calcium influx.
