Methods Eight patients from a multigenerational FHM type 1 family harbouring a T666M mutation in the CACNA1A gene were referred to our ataxia outpatient clinic.
Method The clinical manifestations of a Chinese FHM family were recorded and all coding exons and flanking intronic regions of the CACNA1A, ATP1A2, and SCN1A genes were tested for mutations.
Mutations in three different genes, two ion-channel genes and one encoding an ATP exchanger, CACNA1A, ATP1A2 and SCN1A are all responsible for the FHM phenotype, thus indicating a genetic heterogeneity for this disorder.
A Single Amino Acid Deletion (ΔF1502) in the S6 Segment of CaV2.1 Domain III Associated with Congenital Ataxia Increases Channel Activity and Promotes Ca2+ Influx.
We now report on a mutation identified in the first intracellular loop of CACNA1A (alpha(1A(A454T))) that does not cause FHM but is associated with the absence of sensorimotor symptoms in a migraine with aura pedigree.
Familial hemiplegic migraine (FHM) is a genetically heterogeneous disorder in which three genes, CACNA1A, ATP1A2, and SCN1A, are currently known to be involved.
In this issue of the JCI, Eikermann-Haerter et al. show that transgenic mice with FHM-associated mutations in Cacna1a have increased susceptibility to CSD compared with wild-type animals, likely due to augmentation of excitatory neurotransmission (see the related article beginning on page 99).
We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation.
However, a review of the genetic studies suggests that the FHM genes are not involved in the typical migraines and that FHM should be considered as a syndromic migraine rather than a subtype of MA.
Because FHM gene mutations were also found in family members with "nonhemiplegic" typical migraine with and without aura, our findings reinforce the hypothesis that FHM, SHM, and "normal" migraine are part of a disease spectrum with shared pathogenetic mechanisms.