Pathology

Neuroscience

Disease

Ataxia

Atrophy

Biology

Spinocerebellar ataxia

Cerebellum

Machado–Joseph disease

Cerebellar ataxia

Spinal cord

Medicine

Nature Reviews Disease Primers

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. The spinocerebellar ataxias (SCAs) are a group of autosomal dominant progressive disorders characterized by loss of balance and coordination and slurred speech. This Primer discusses the epidemiology of SCAs, the complex mechanisms underlying them and how they are diagnosed and managed in the clinic.