Axonal function in a family with episodic ataxia type 2 due to a novel mutation

Episodic ataxia type 2(EA-2) is a rare, autosomal dominant disorder characterised by recurrent episodes of ataxia and dysarthria,due to mutations in the CACNA1A gene on chromosome 19 encoding voltage-dependent Ca2+ channels. The aim of the present study was to explore whether axonal membrane properties, assessed using nerve excitability techniques, were abnormal in patients with EA-2 . Nerve excitability techniques were applied to the median nerve of three individuals from three generations of a single family, all of whom had typical features of EA-2. This family was found to have a novel mutation at codon 1451 of the Ca2+ channel alpha 1A subunit. Nerve excitability testing demonstrated significant abnormalities,with all patients outside the normal 95 % confidence limits in having a high rheobase and reduced early hyperpolarizing threshold electrotonus. On average there were also significant reductions in refractoriness,late sub excitability and early depolarizing threshold electrotonus. Mathematical modelling indicated that a similar pattern of abnormalities may result from a reduced voltage dependence of slow K+ channels (KCNQ channels). There are significant and distinctive changes in peripheral nerve excitability in EA-2 patients,which are presumably induced indirectly. These findings raise the possibility that excitability testing may prove a convenient screening test for patients with this suspected channelopathy.