Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University.
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.
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.
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.
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).
Familial hemiplegic migraine type 1 (FHM-1) is an autosomal dominant form of migraine with aura characterized by recurrent migraine, hemiparesis and ataxia.
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.
Besides the classical phenotype, mutations on CACNA1A gene are associated with a broader spectrum of clinical features including cerebellar ataxia, making FHM1 a complex channelopathy.
In the ataxia group, we found (CAG)n above the range of the asymptomatic blood donors in SCA3 (21.74%) followed by SCA2 (5.22%), SCA7 (2.61%), SCA6 (0.87%), and no cases of SCA1.
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.