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Semin Neurol 2011; 31(5): 461-469
DOI: 10.1055/s-0031-1299785
© Thieme Medical Publishers

Genetics of the Dominant Ataxias

Dineke S. Verbeek1 , Bart P.C. van de Warrenburg2
  • 1Department of Medical Genetics, University Medical Centre Groningen, Groningen
  • 2Departments of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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Publication History

Publication Date:
21 January 2012 (online)

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ABSTRACT

The relevant clinical, genetic, and cell biologic aspects of the dominantly inherited spinocerebellar ataxias (SCAs) are reviewed in this article. SCAs are diseases of the entire nervous system; in addition to cerebellar ataxia, the central (but not obligate) disease feature, many noncerebellar complications can be present as well. There are over 35 genetic subtypes: although those caused by expanded CAG repeats are still the more common ones, the majority of the recent SCAs have been caused by more conventional mutations. Genotype–phenotype correlations do exist and are most clear for the repeat expansion, where repeat length partially explains age at onset, disease severity and progression, and the core clinical phenotype. Some common themes within the disease mechanisms seem to emerge, including misfolding and aggregation, impairment of the protein quality control system, abnormal protein interactions, disruption of gene transcription, RNA toxicity, and changes in glutamate and calcium signaling. Yet despite this exciting progress in the molecular genetic background and suggested corresponding pathways, there is still no drug available that is specifically designed for or targeted at the mechanisms at play.

KEYWORDS

Ataxia - cerebellum - polyglutamine - genotype–phenotype correlations

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Bart P.C. van de Warrenburg

Department of Neurology, Radboud University Nijmegen Medical Centre

Nijmegen, The Netherlands

Email: b.vandewarrenburg@neuro.umcn.nl