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Isabel Alonso, BSc; José Barros, MD; Assunção Tuna, MD; João Coelho, BSc; Jorge Sequeiros, MD, PhD; Isabel Silveira, PhD; Paula Coutinho, MD, PhD

Arch Neurol. 2003;60:610-614.

Background  Different mutations in the _1A-subunit of the brain P/Q-type calcium channel gene (CACNA1A) are responsible for familial hemiplegic migraine (FHM), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). Missense and splice site mutations have been found in FHM and episodic ataxia type 2, respectively, whereas a CAG repeat in the CACNA1A gene was found expanded in patients with SCA6.

Objective  To identify the disease causing mutation in a large family of patients with phenotypes of hemiplegic migraine with or without cerebellar signs or permanent cerebellar ataxia without migraine inherited in a dominant manner.

Patients and Methods  We examined 15 patients from a large family identified through a systematic survey of hereditary ataxias being conducted in Portugal. Linkage analysis was performed with CACNA1A gene markers, and mutation analysis was performed by single strand conformational polymorphism analysis and sequencing.

Results  Genetic linkage analysis with CACNA1A intragenic markers showed positive LOD scores. The maximal LOD score was obtained with the polymorphic CAG repeat (Z_max = 4.47, = 0). By single-strand conformational polymorphism analysis, a shift in exon 13 of the CACNA1A gene was detected in all patients. A G-to-A substitution was then identified, resulting in an arginine-to-glutamine change at codon 583 of this calcium channel _1A-subunit.

Conclusions  The disease-causing mutation in this family was identified, showing that a unique mutation in the CACNA1A gene causes several phenotypes, including those of SCA6 and FHM, thus suggesting that SCA6 and FHM are not only allelic diseases but are the same disorder with a large phenotypic variability.

From UnIGENe, IBMC, Porto (Ms Alonso, and Mr Coelho and Drs Sequeiros and Silveira); Laboratório de Genética Médica, ICBAS, Universidade do Porto (Ms Alonso and Drs Sequeiros and Silveira), and Serviço de Neurologia, HGSA (Drs Barros and Tuna), Porto; and Serviço de Neurologia, Hospital São Sebastião, Feira (Dr Coutinho), Portugal.

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