Abstract
The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of autosomal dominantly inherited progressive disorders, the clinical hallmark of which is loss of balance and coordination accompanied by slurred speech; onset is most often in adult life. Genetically, SCAs are grouped as repeat expansion SCAs, such as SCA3/Machado–Joseph disease (MJD), and rare SCAs that are caused by non-repeat mutations, such as SCA5. Most SCA mutations cause prominent damage to cerebellar Purkinje neurons with consecutive cerebellar atrophy, although Purkinje neurons are only mildly affected in some SCAs. Furthermore, other parts of the nervous system, such as the spinal cord, basal ganglia and pontine nuclei in the brainstem, can be involved. As there is currently no treatment to slow or halt SCAs (many SCAs lead to premature death), the clinical care of patients with SCA focuses on managing the symptoms through physiotherapy, occupational therapy and speech therapy. Intense research has greatly expanded our understanding of the pathobiology of many SCAs, revealing that they occur via interrelated mechanisms (including proteotoxicity, RNA toxicity and ion channel dysfunction), and has led to the identification of new targets for treatment development. However, the development of effective therapies is hampered by the heterogeneity of the SCAs; specific therapeutic approaches may be required for each disease.
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Nature Reviews Disease Primers thanks L. Ranum, B. W. Soong, S. Tsuji, H. Zoghbi and the other anonymous reviewer(s), for their contribution to the peer review of this work.
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Introduction (T.K.); Epidemiology (C.M.); Mechanisms/pathophysiology (H.L.P.); Diagnosis, screening and prevention (T.K.); Management (C.M.); Quality of life (T.K.); Outlook (T.K. and H.L.P.); Overview of the Primer (T.K.)
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T.K. declares that he received honoraria for consulting services from Biohaven Pharmaceuticals. C.M. declares that she received an honorarium for educational service from Roche. H.L.P. has received research grants and contracts from Cydan, Inc. and Ionis Pharmaceuticals.
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Ataxia sections of the Neuromuscular Disease Center: https://neuromuscular.wustl.edu/ataxia/domatax.html
Guidelines of the UK patient organization (Ataxia UK): https://www.ataxia.org.uk/Handlers/Download.ashx?IDMF=261e0aa4-5ca0-4b90-9db0-1ecb6ef8738a
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Klockgether, T., Mariotti, C. & Paulson, H.L. Spinocerebellar ataxia. Nat Rev Dis Primers 5, 24 (2019). https://doi.org/10.1038/s41572-019-0074-3
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DOI: https://doi.org/10.1038/s41572-019-0074-3
