Genetics at different levels in machado-joseph disease (MJD/SCA3): Cause, modifiers and therapy

Hereditary ataxias constitute a clinically and genetically heterogeneous group of rare neurological disorders that cannot be distinguished solely by clinical criteria, thus demanding a subtype confirmation by molecular diagnosis. Enclosed in this group are spinocerebellar ataxias (SCAs), which are autosomal dominant disorders. In several SCAs, the causative genes display age-dependent patterns of penetrance, implying that the a posteriori risk of being a carrier diminishes with aging of at-risk individuals that remain asymptomatic. Machado-Joseph disease (MJD), also known as SCA3, corresponds to the most frequent form of SCA. Similarly to other SCAs, named "polyglutamine" ataxias (e.g., SCA1, SCA2, SCA6, SCA7, SCA17 and DRPLA), MJD is caused by an expansion of a CAG repeat motif in the coding region of its causative gene. In this particular case, more than 52 CAG repeats in exon 10 of the ATXN3 gene (14q32.1) are necessary for disease expression. Despite the inverse correlation between the size of the CAG tract and the age at onset, the causative mutation only partially (50-75%) explains the observed variation in phenotype. Therefore, precise predictions of the age at onset are currently impossible. Results from recent research studies are pointing to the involvement of other factors, namely additional genetic variability related to the causative gene itself (e.g., generated by alternative splicing) and/or modifier genes. The knowledge of such factors may not only enable improvements of phenotype predictions, but may also raise hypotheses of new targets for gene therapy. The present chapter will focus on MJD, using it as a paradigm to demonstrate multiple roles and usefulness of genetics for a vaster group of neurodegenerative disorders. © 2012 by Nova Science Publishers, Inc. All rights reserved.