The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by limb and gait ataxia. More than 25 different types of SCA have been described, although the causative genes have not yet been identified for all types. SCA type 17 (SCA17), which accounts for approximately 0.5% to 1% of autosomal dominant SCA cases, is characterized by a variable combination of cerebellar ataxia, psychiatric symptoms (such as changes in personality, mood disorders, depression, hallucinations, and psychosis), and cognitive impairment (including dementia). In addition, movement disorders are prominent among those with SCA17 and can included dystonia (involuntary movements and prolonged muscle contractions), chorea (involuntary, irregular muscle contractions), choreoathetosis (chorea associated with twisting and writhing movements), and rigidity. Importantly, some individuals with SCA17 exhibit symptoms that are clinically indistinguishable from those seen in Huntington disease,
Parkinson disease, or Alzheimer disease. Additional features that may be seen in SCA17 patients include dysarthria (slow, distorted speech), dysphagia (difficulty swallowing), seizures, hyperreflexia, hypertonia, and urinary incontinence. SCA17 is caused by expansion of CAG/CAA sequence in the TATA-binding protein gene (TBP) located on chromosome 6 at band q27. In most individuals, this polyglutamine-encoding sequence includes 2 variable CAG tracts [(CAG)n] and interrupting CAA trinucleotides: (CAG)3 (CAA)3 (CAG)n CAA CAG CAA (CAG)n CAA CAG. Because of the CAA interruptions, the CAG/CAA expansion is typically stable when passed from parent to child, and genetic anticipation (an earlier age at onset and increased disease severity with successive generations) is not seen. Occasionally, the CAG/CAA repeat tract in affected individuals
lacks the CAA CAG CAA sequence between the 2 variable segments; in these cases, the repeat exhibits intergenerational instability and genetic anticipation can be seen.