Background At least 28 loci have been linked to autosomal dominant spinocerebellar ataxia (ADCA). Causative genes have been cloned for 10 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 and 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, the authors screened 148 index patients of predominantly German (n=69) and French (n=79) descent 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 customised multiplex ligation probe amplification (MLPA) assay.
Results In two of 148 ADCA families—one German and one French—the authors 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, the 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.
- Gait disorders/ataxias
- spinocerebellar ataxias
- prevalence studies
- cerebellar ataxia
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PB, GS & CB contributed equally to this work.
Funding This work was funded by INSERM, the European Union (to the EUROSCA consortium) and the Programme Hospitalier de Recherche Clinique (to AD), research grants from the German Research Council (BMBF) to GeNeMove (01GM0603) and EU for EUROSCA (LSHM-CT-2004-503304). PB received research grants from the German Research Council (BMBF) to GeNeMove (01GM0603), EUROSPA (01GM0807) and RISCA (09GM0820) as well as from the EU for EUROSCA (LSHM-CT-2004-503304), MarkMD (FP7-People PIAP-2008-230596) and TECHGENE (FP7-Health 2007-B 223143). He further received funding from the HSP-Selbsthilfegruppe Deutschland eV. LS served as an editorial board member of Movement Disorders and was a member of the scientific advisory board for Takeda Pharma. As a participant of the MICONOS trial. LS received research grants from the Deutsche Forschungsgemeinschaft (SCHO754/3-1 and SCHO754/4-1), grants from the German Research Council (BMBF) to Leukonet (01GM0644) and GeNeMove (01GM0603), funding from the EU for EUROSCA (LSHM-CT-2004-503304) and E-RARE grants to EUROSPA (01GM0807) RISCA (01GM0820) and mitoNET (01GM0864) as well as a grant from the Volkswagen Foundation (I/80711). He further received funding from the HSP-Selbsthilfegruppe Deutschland eV. AB, AD and GS received research grants from of EU for Eurosca (LSHM-CT-2004-503304), E-RARE grant to EUROSPA (ANR-07-E-RARE-005-01/R07202DS) as well as a grant from the Agence Nationale pour la Recherche (ANR-07-NEURO-041-01/R07047DS). The work of CB has been supported by the Stiftung für Pathobiochemie und Molekulare Diagnostik.
Competing interests PB received honoraria from Roche Diagnostics. LS received fees from Santhera Pharmaceuticals.
Patient consent Obtained.
Ethics approval Ethics approval was provided by the local ethic committees in Tübingen (GER), Paris (FR) and Bonn (GER).
Provenance and peer review Not commissioned; externally peer reviewed.