Spinocerebellar ataxia type 11 (SCA11) is an uncommon cause of dominant ataxia among French and German kindreds
Résumé
Background: At least 28 loci have been linked to autosomal dominant spinocerebellar ataxia (ADCA). Causative genes have been cloned for ten nucleotide repeat expansions (SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and 31) and six genes with classical mutations (SCA5, 13, 14, 15/16, 27, adn 28). Recently, a large British pedigree linked to SCA11 has been reported to carry a mutation in the TTBK2-gene. In order to assess the prevalence and phenotypic spectrum of SCA11, we screened 148 index patients of predominantly German (n=69) and French (n=79) descents with ADCA tested negative for a panel of SCA mutations (SCA1, 2, 3, 6, 7, and 17), for mutations in TTBK2. Methods: In the German ADCA cohort the complete coding sequence of the TTBK2-gene was PCR-amplified and screened for mutations by high-resolution-melting (HRM) analysis. In the French cohort, exons known to carry mutations were directly sequenced. For both cohorts, the gene-dosage alterations were assessed using a customized multiplex ligation probe amplification (MLPA) assay. Results: In two of 148 ADCA families – one German and one French - we identified a potentially disease-causing SCA11 mutation. Interestingly, both carried an identical two basepair deletion (c.1306_1307delGA, p.D435fs448X in exon 12) leading to a premature stop codon. Gene dosage alterations were not detected in the TTBK2-gene. Clinically, our SCA11 patients had phenotypic characteristics as described before presenting with slowly progressive almost pure cerebellar ataxia with normal life expectancy. Conclusion: SCA11 presented as ADCA III according to Harding's classification and is a rare cause of spinocerebellar ataxia in Caucasians accounting for less than 1% of dominant ataxias in central Europe.
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