CAG repeat expansion in the TATA box-binding protein gene causes autosomaldominant cerebellar ataxia

At least 13 loci responsible for autosomal dominant cerebellar ataxia (ADCA ) have been identified. Spinocerebellar ataxia 1, 2, 3, 6 and 7 are caused by translated CAG repeat expansions. However, in France, >30% of ADCAs are not explained by the known genes. Recently, analysis of the TATA box-bindin g protein (TBP) gene, one of the transcription factors known to contain a C AG/CAA repeat, in patients with progressive cerebellar ataxia revealed one sporadic case with 63 repeats. We examined this gene in 162 index cases wit h ADCA. An expanded repeat with 46 repeat units was detected in a single in dex case from Belgium. In this family, two affected members and six unaffec ted, but at-risk, individuals carried expanded alleles. Interestingly, the expanded repeat was stable during transmission. The main clinical features in six patients were cerebellar ataxia, dementia and behavioural disturbanc es with onset in their fourth to sixth decade. The main neuropathological f inding was severe neuronal loss and gliosis in the Purkinje cell layer. Imm unohistochemical analysis showed neuronal intranuclear inclusions containin g expanded polyglutamine, indicating that this disease shares several featu res with other polyglutamine diseases. This study demonstrates that CAG/CAA repeat expansion in the TBP gene causes ADCA with dementia and/or psychiat ric manifestations.