Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia.

BACKGROUND

Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, localized at presynaptic terminals of brain and cerebellar neurons, result in clinically variable neurological disorders including hemiplegic migraine (HM) and episodic or progressive adult-onset ataxia (EA2, SCA6). Most recently, CACNA1A mutations have been identified in patients with nonprogressive congenital ataxia (NPCA).

METHODS

We performed targeted resequencing of known genes involved in cerebellar dysfunction, in 48 patients with congenital or early onset ataxia associated with cerebellar and/or vermis atrophy.

RESULTS

De novo missense mutations of CACNA1A were found in four patients (4/48, ∼8.3%). Three of them developed migraine before or after the onset of ataxia. Seizures were present in half of the cases.

CONCLUSION

Our results expand the clinical and mutational spectrum of CACNA1A-related phenotype in childhood and suggest that CACNA1A screening should be implemented in this subgroup of ataxias.