title: Axonal function in a family with episodic ataxia type 2 due to a novel mutation.
abstract: 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.
authors.affiliation: Prince of Wales Medical Research Institute, Barker Street, Randwick Sydney, NSW 2031, Australia.
authors.forename: Arun V
authors.initials: AV
authors.lastname: Krishnan
authors.forename: Hugh
authors.initials: H
authors.lastname: Bostock
authors.forename: Jerome
authors.initials: J
authors.lastname: Ip
authors.forename: Michael
authors.initials: M
authors.lastname: Hayes
authors.forename: Shaun
authors.initials: S
authors.lastname: Watson
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D015220:Calcium Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D004568:Electrodiagnosis / Q000379:methods; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008403:Mass Screening; D008475:Median Nerve / Q000378:metabolism / Q000503:physiopathology; D008564:Membrane Potentials / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009420:Nervous System / Q000378:metabolism / Q000503:physiopathology; D009431:Neural Conduction / Q000235:genetics; D010375:Pedigree; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; D005819:Genetic Markers; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type