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CACNA1A Mutation in a EA-2 Patient Responsive to Acetazolamide and Valproic Acid

Published online by Cambridge University Press:  02 December 2014


Kylie A. Scoggan
Affiliation:
Ottawa Health Research Institute, Ottawa, ON, Canada Nutrition Research Division, Health Canada, Ottawa, ON, Canada
Joseph H. Friedman
Affiliation:
Division of Neurology, Brown University, Ottawa, ON, Canada NeuroHealth Parkinson's Disease and Movement Disorders Center 227, Warwich, RI, USA
Dennis E. Bulman
Affiliation:
Ottawa Health Research Institute, Ottawa, ON, Canada Division of Neurology, University of Ottawa, Ottawa, ON, Canada

Abstract:

Background:

Episodic ataxia type-2 (EA-2) is an autosomal dominant neurological disorder that has been shown to result from mutations in the CACNA1A gene encoding the P/Q-type calcium channel. Affected individuals experience episodes of cerebellar ataxia usually associated with migraine symptoms, interictal nystagmus, mild residual and in some cases a progressive cerebellar incoordination and respond to acetazolamide treatment. We identified a patient with a positive family history for episodic ataxia, who was originally diagnosed with epilepsy and treated with valproic acid. Subsequent examination revealed that the symptoms were consistent with a diagnosis of EA-2. The patient responded positively to a combination of acetazolamide and valproic acid. Molecular genetic analysis of the CACNA1A gene was performed in order to confirm a diagnosis of EA-2.

Methods:

The CACNA1A gene was evaluated for mutations using single strand conformational polymorphism analysis and direct DNA sequencing. Allele specific oligo hybridization was used to confirm that the mutation was segregating with only affected family members and was not present in the control group.

Results:

In this study we identified a new missense mutation in exon 12 of the CACNA1A gene from a patient with EA-2 whose symptoms could be controlled with a combination of acetazolamide and valproic acid. This G to A transition changes a highly conserved glutamic acid residue to a lysine residue in domain II S2 of the P/Q-type calcium channel α1A subunit.

Conclusions:

The use of valproic acid in treating patients with EA-2 is not well documented. Here we describe a patient with a novel mutation in the CACNA1A gene who responded positively to a combination of acetazolamide and valproic acid.


Résumé

RÉSUMÉ Contexte:

L'ataxie épisodique de type 2 (AE-2) est une maladie neurologique de transmission autosomique dominante qui est due à des mutations du gène CACNA1A codant le canal calcique de type P/Q. Les individus atteints présentent des épisodes d'ataxie cérébelleuse habituellement associés à des symptômes migraineux, un nystagmus intercritique, une légère incoordination cérébelleuse résiduelle qui est progressive chez certains patients et répond au traitement par l'acétazolamide. Nous avons identifié un patient ayant une histoire familiale d'ataxie épisodique, chez qui un diagnostic d'épilepsie avait été posé et qui avait été traité par l'acide valproïque. Un nouvel examen du patient a permis de déterminer que ses symptômes étaient suggestifs d'une AE-2. Le patient a bien répondu à une association médicamenteuse, soit l'acétazolamide administré avec l'acide valproïque. L'analyse du gène CACNA1A a été effectuée pour confirmer le diagnostic d'AE-2.

Méthodes:

Des mutations du gène CACNA1A ont été recherchées par la technique de détection des polymorphismes de conformation monocaténaires (single-strand conformation polymorphism - SSCP) et par séquençage direct de l'ADN. L'hybridation d'un oligo allèle spécifique a confirmé que la mutation ségrégait seulement chez les membres atteints de la famille et n'était pas présente chez le groupe témoin.

Résultats:

Nous avons identifié une nouvelle mutation faux-sens dans l'exon 12 du gène CACNA1A de ce patient atteint d'AE-2 dont les symptômes étaient contrôlés par une association médicamenteuse, soit l'acétazolamide et l'acide valproïque. La substitution d'un A à un G change un acide glutamique hautement conservé en une lysine dans le domaine II S2 de la sous-unité α1A du canal calcique de type P/Q.

Conclusions:

Il existe peu de données sur l'utilisation de l'acide valproïque pour traiter les patients atteints d'AE-2. Nous décrivons un patient porteur d'une nouvelle mutation du gène CACNA1A qui a bien répondu à une association médicamenteuse, l'acétazolamide et l'acide valproïque.


Type
Original Article
Copyright
Copyright © The Canadian Journal of Neurological 2006

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