Prof. Thomas Klockgether | Clinical and biological characteristics of ataxia disorders

In Clinical Neurology, ataxia denotes a syndrome of motor incoordination that typically results from dysfunction of the cerebellum and its afferent and efferent connections. Ataxia is also used to denote a group of neurodegenerative diseases of the cerebellum and its connections that are clinically characterized by progressive motor incoordination. Many of the ataxias have genetic causes, but there are also sporadic degenerative ataxias and ataxias which are due to acquired non-genetic causes. Overall, there is an enormous degree of heterogeneity among the ataxias with an estimated number of more than 150 different, molecularly defined diseases. Our research is focusing on the common, autosomal dominantly inherited spinocerebellar ataxias (SCA) which are caused by translated CAG repeat expansion mutations that code for an elongated polyglutamine tract within the respective proteins. To define the phenotype and natural history of these disorders we recruited a cohort of more than 500 patients and followed them over more than 8 years. Multivariate models allowed to explain up to 60% of the variability of the ataxia severity at baseline. Modelling of disease progression revealed genotype-specific patterns and identified biological factors that determine the rate of progression. MRI studies showed progressive grey and white matter tissue loss in cerebellum, brainstem and basal ganglia. Studies of a cohort of more than 300 apparently healthy SCA mutation carriers showed that first signs of impaired coordination and tissue loss of the brainstem or cerebellum occur more than 10 years before the clinical onset of ataxia. These observation led to a refined disease model of ataxia disorders that considers ataxia as a late disease stage which is preceded by extended asymptomatic and preclinical disease stages that offer a time window for early therapeutic intervention. Although CAG repeat expansion mutations are now known for more than two decades the mechanism how these mutations cause neurodegeneration remain far from clear. There is one component which is due to the toxic properties of proteins or protein fragments that contain elongated polyglutamine tracts. However, there are additional components that depend on the protein context of the polyglutamine tract and are disease specific. Currently, there is no treatment for SCA. Experimental work in cells and animals aims to reduce levels of mutant proteins using RNA interference (RNAi)and antisense oligonucleotides (AONs). An alternative approach is protein modification through AON-mediated exon skipping. As there are many obstacles to translate these approaches into clinical application there is renewed interest in finding drugs that interfere with cerebellar neuronal activity and thereby symptomatically improve ataxia.