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Christian Denier, MD; Anne Ducros, MD, PhD; Alexandra Durr, MD, PhD; Bruno Eymard, MD; Bénédicte Chassande, MD; Elisabeth Tournier-Lasserve, MD

Arch Neurol. 2001;58:292-295.

Objectives  To characterize the nature of CACNA1A mutation in a previously unreported family with episodic ataxia type 2 (EA2) and to better delineate EA2 clinical features.

Background  Episodic ataxia type 2 is an autosomal dominant disorder characterized by the recurrence of acetazolamide-responsive spells of cerebellar ataxia, usually starting during childhood or adolescence. The mutated gene, CACNA1A, is located on chromosome 19 and encodes the 1A subunit voltage-dependent calcium channel. So far, most CACNA1A mutations detected in patients with EA2 have led to a truncated CACNA1A protein, whereas missense mutations cause familial hemiplegic migraine.

Methods  All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis.

Results  A CACNA1A missense mutation, Glu 1757 Lys, was identified. It was absent in 200 control chromosomes. It is predicted to result in an amino acid substitution at a highly phylogenetically conserved position, within a domain that plays a major role in the function of the channel.

Conclusions  The Glu 1757 Lys missense mutation is likely to be pathogenic, causing episodic ataxia within a family whose phenotype is indistinguishable from EA2 except for a slightly later age of onset. These data strongly suggest that additional work is needed to fully establish genotype/phenotype correlations for CACNA1A mutations.

Institut National de la Santé et de la Réchérche Médicale (INSERM) EPI 99-21, Faculté de Médecine Lariboisière (Drs Denier, Ducros and Tournier-Lasserve), INSERM U289 (Dr Durr), Service de Neurologie du Pr J-Y, Delattre, Hôpital de la Salpêtrière, (Drs Eymard and Chassande), and Laboratoire de Cytogénétique, Hôpital Lariboisière (Dr Tournier-Lasserve), Paris, France.

Corresponding author: Elisabeth Tournier-Lasserve, MD, Inserm EPI 99-21, Faculté de Médecine Lariboisière, 10, Avenue de Verdun, 75010 Paris, France (e-mail: elisabeth.tournier{at}lrb.ap-hop-paris.fr).

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