On the basis of the neuropathological identity of SCA 6 with CCA, and of the effect of gabapentin and pregabalin on recombinant VDCCs the authors put forward the hypothesis that these drugs might prove beneficial in SCA 6, as the ataxia would be expected to improve.
Mutations at the mouse orthologue of the CACNA1A gene cause a group of recessive neurological disorders, including the tottering, leaner, and rocker phenotypes with ataxia and absence epilepsy, and the rolling Nagoya phenotype with ataxia without seizures.
Autosomal dominant mutations in the CACNA1A gene, which encodes voltage-gated P/Q-type calcium channel subunit α(1) (the principal pore-forming subunit of the P/Q channel) are associated with episodic and progressive forms of cerebellar ataxia, familial hemiplegic migraine, vertigo and epilepsy.
Here, we explored the effects of G protein-dependent modulation on mutations W1684R and V1696I which cause FHM-1 with and without cerebellar ataxia, respectively.
In over 50% of cases the causative gene is CACNA1A (FHM1), which in some cases produces a phenotype with cerebellar signs, including ataxia and nystagmus.
DNA sequencing and gene expression data demonstrate that Cacnl1a4 mutations are the primary cause of seizures and ataxia in tottering and leaner mutant mice, and suggest that tottering locus mutations and human diseases, episodic ataxia 2 and familial hemiplegic migraine, represent mutations in mouse and human versions of the same channel-encoding gene.
Given the dependence of γ-aminobutyric acid type A (GABAA) receptor subunit functioning on localized calcium currents, and the functional link between GABAergic inhibition and ataxia, we hypothesized that cerebellar GABAA receptor expression is differentially affected in Cacna1a mutants and contributes to the ataxic phenotype.
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.
In addition, the authors identified the first pathogenic duplication in CACNA1A in an index case with isolated episodic diplopia without ataxia and in a first degree relative with episodic ataxia.
CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6).
Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function.
Familial hemiplegic migraine type 1 (FHM-1) is an autosomal dominant form of migraine with aura characterized by recurrent migraine, hemiparesis and ataxia.