Article Text

Identification of two novel mutations in the CACNA1A gene responsible for episodic ataxia type 2
  1. K A SCOGGAN*,
  2. T CHANDRA*,
  3. R NELSON,
  4. A F HAHN,
  5. D E BULMAN*
  1. *Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa Hospital - General Campus, Ottawa, Ontario, Canada K1H 8L6
  2. †Division of Neurology, Ottawa Hospital - General Campus, Ottawa, Ontario, Canada K1H 8L6
  3. ‡Department of Clinical Neurological Sciences, London Health Sciences Centre, London, Ontario, Canada N6A 5A5
  1. Dr Bulman, dbulman{at}

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Editor—Episodic ataxia type 2 (EA-2) (OMIM 108500) is an autosomal dominant neurological disorder. Affected subjects experience discrete episodes of cerebellar ataxia usually associated with migraine symptoms, interictal nystagmus, as well as residual mild and, in some cases, a progressive cerebellar incoordination. These attacks usually begin in childhood or adolescence, last a few hours, may be precipitated by stress, exercise, or fatigue, and respond to acetazolamide.1-3

As with other acetazolamide responsive diseases, EA-2 is a channelopathy.4 It was first linked to chromosome 19p133 5-7 and subsequently shown to be allelic to familial hemiplegic migraine (FHM) when mutations for both disorders were identified in the P/Q type calcium channel α1Asubunit gene, CACNA1A.8 Shortly thereafter, an intragenic expansion of a CAG repeat withinCACNA1A was shown to cause spinocerebellar ataxia type 6 (SCA6).9 To date, mutations causing EA-2 all appear to disrupt the translational reading frame of the α1A subunit gene,8 10-12 while those causing FHM all seem to be missense mutations.8 13-15 A single missense mutation, however, in theCACNA1A gene has also been shown to cause severe progressive cerebellar ataxia.16

The α1A subunit has been shown to be the pore forming unit of the P/Q type calcium channel17 18 which is involved in controlling neurotransmitter release19 and is expressed throughout the brain with abundant expression in the cerebellum.20-22 This high voltage activated calcium channel consists of five subunits, α1A, β4, α2, δ, and γ. The α1A subunit is subdivided into four homologous domains (DI-DIV) that each contain six putative transmembrane regions (S1-S6) (fig 1).19 The fourth transmembrane domain functions as the voltage sensor while the four loops between transmembrane domains S5-S6 compose the pore …

View Full Text