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From INSERM U25 (Drs. Denier, Ducros, Joutel, and Tournier–Lasserve), Faculté de Médecine Necker, Paris; the Services de Neurologie, Hôpital Lariboisière (Drs. Ducros, Vahedi, and Tournier–Lasserve), Paris; Hôpital de Vesoul (Drs. Thierry and Ritz); Centre Hospitalo-Universitaire de Nimes (Dr. Castelnovo); CHU Vaudois (Dr. Deonna), Lausanne; Hôpital d’Amiens (Dr. Gérard); CH d’Angoulême (Dr. Devoize); Hôpital Pellegrin (Dr. Gayou), Bordeaux; Hôpital de Carpentras (Dr. Perrouty); Hôpital d’Orléans (Dr. Soisson); Hôpital Bretonneau (Dr. Autret), Tours; Hôpital Civil de Strasbourg (Dr. Warter); Hôpital Neurologique (Dr. Vighetto), Lyon; Hôpital Erasmus (Dr. Van Bogaert), Université libre de Bruxelles; and Hôpital Tenon (Drs. Alamowitch and Roullet), Paris, France.
Address correspondence and reprint requests to Dr. E. Tournier–Lasserve, INSERM U25, Faculté de Médecine Necker, 156 rue de Vaugirard, 75730 Paris Cedex 15, France.
OBJECTIVE: To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum.
BACKGROUND: EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the 
1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified—in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype–phenotype correlations relied on the analysis of very few families.
METHODS: To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients.
RESULTS: Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range.
CONCLUSION: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).
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