Clinical and molecular characterization of large cohort of patients with novel and recurrent CACNA1A gene mutations

The CACNA1A gene encodes for the Cav2.1 subunit of P/Q voltage gated calcium channel. It is expressed in Purkinje, granule cells and in the neuromuscular junction. Loss or gain of function mutations are responsible for Episodic Ataxia 2 (EA2) and Familial Hemiplegic Migraine 1 (FHM1) respectively, while small expansion of a CAG repeat are causing Spinocerebellar Ataxia 6 (SCA6). Screening for mutations in EA2 patients is very inefficient (detection rate 20-30%) and time consuming (50 exons and no recurring mutations or preferential sites). Aims: a) detecting novel or recurrent mutations in a series of patients with EA2 phenotype and a few patients with uncommon phenotypes congruent with the clinical spectrum observed in CACNA1A mutated subjects; b) comparing the clinical features of EA2 patients carrying mutation vs EA2 patients with no detected mutation; c) contributing to the delineation of clinical and molecular criteria for differential diagnosis of EA2 and for a more efficient and focused genetic screening. Results: a) 16 mutations (13 newly identified and 3 previously reported among 45 index cases were detected; b) a lower age of onset and a higher frequency of the ataxic episodes emerged comparing the clinical characteristics in mutated and non mutated EA2 patients, while duration of attacks and frequency of different symptoms did not differ between the two groups; c) a review of mutation so far reported suggests a few criteria for a more efficient molecular diagnosis Grant National Ataxia Foundation to LV