Objectives: In Spinocerebellar Ataxia type 17 (SCA17), penetrance is determined by repeat number of the CAG/CAA trinucleotide in the TATA-binding protein (TBP) gene. The intermediate range (41–48) exhibits only partial penetrance but may manifest a Huntington’s disease-like (HDL-4) syndrome with onset at age 50–60 years. We report a unique case of HDL-4 with childhood onset despite intermediate range repeats. Methods: This patient was evaluated at the University of Minnesota Movement Disorders Clinic. Standard Protocol Approvals, Registrations, and Patient Consents: Informed consent to disclose was obtained from the legal guardian of the subject of this report. Results: A 14-year-old male of Chinese descent presented with generalized dystonic and choreoathetoid movements since age 11 alongside motor delays, epilepsy, and speech, balance, and coordination dysfunction since infancy. Family history was limited given his adoptive status. Subsequent workup confirmed SCA17 with repeat numbers of 43 and 37 in the intermediate range. Discussion: This is the first case of intermediate range SCA17 of childhood-onset, emphasizing the evolving classification of intermediate vs. full penetrance while suggesting that the TBP repeat length may not be the sole determinant of disease onset and severity. It also highlights the importance of repeat expansion panels when investigating complex movement disorders.

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant disease caused by a polyglutamine-encoding CAG/CAA repeat expansion within the TATA box-binding protein (TBP) gene. It is characterized by a markedly heterogeneous phenomenology and complex genotype-phenotype relationships. We describe the clinical, neuropsychological, and neuroimaging findings of a 73-year-old patient who presented a 10-year history of generalized hyperkinetic movements and depressive symptoms. The patient's family history was unremarkable. Neurological examination revealed choreic movements affecting the upper and lower limbs, the face and the trunk with no additional neurological signs. Blood sample analysis, brain imaging, and neuropsychological evaluation revealed normal results. Genetic analysis identified, in the TBP gene, the 41-CAG pathological allele with reduced penetrance. The present case report provides further insight into the small-expanded allele SCA17-associated phenotype, supporting the recently updated genotype-phenotype assessment for SCA17.

The cooccurrence of intermediate (40-49 CAG/CAA) TBP repeat expansions with STUB1 variants questions the pathogenicity of monoallelic STUB1 variants in cerebellar ataxia. The objective of this study was to describe the phenotypic spectrum of heterozygous STUB1 variants with or without intermediate TBP repeat expansions. We determined the presence of TBP repeat expansions and STUB1 variants in six families with cerebellar ataxia. Cooccurrence of both genotypes in one family resulted in cerebellar ataxia, involving cognitive and extrapyramidal complications. Variable degrees of cerebellar ataxia and cognitive impairment were found in four families carrying a heterozygous STUB1 variant and normal TBP alleles. Finally, we report one patient with a mild late-onset cerebellar ataxia carrying an intermediate expanded TBP allele without the presence of a STUB1 variant. Heterozygous STUB1 variants are associated with a milder phenotype and reduced penetrance compared with the cosegregation with intermediate TBP alleles, which causes a fully penetrant complicated form of cerebellar ataxia. © 2025 International Parkinson and Movement Disorder Society.

Spinocerebellar ataxia type 17 (SCA17) is a hereditary neurodegenerative disorder characterized by progressive motor and cognitive decline, leading to severe disability and death. SCA17 is caused by a CAG repeat expansion mutation in the TBP gene, resulting in the production of an abnormally long polyglutamine tract, which classifies it as a polyglutamine disorder. At present, there is no effective treatment for SCA17, and existing therapies provide only symptomatic relief. While the exact pathogenic mechanisms of SCA17 remain unclear, the TBP mutation affects a well-characterized transcription factor, making it an ideal model for studying polyglutamine-related neurodegeneration. Here, we review the clinical features of SCA17 and explore proposed mechanisms of its pathogenesis.

Since 1991, several genetic disorders caused by unstable trinucleotide repeats (TNRs) have been identified, collectively referred to as triplet repeat diseases (TREDs). They share a common mutation mechanism: the expansion of repeats (dynamic mutations) due to the propensity of repeated sequences to form unusual DNA structures during replication. TREDs are characterized as neurodegenerative diseases or complex syndromes with significant neurological components. Spinocerebellar ataxia type 17 (SCA17) falls into the former category and is caused by the expansion of mixed CAA/CAG repeats in the TBP gene. To date, a five-unit organization of this region [(CAG)3 (CAA)3] [(CAG)n] [CAA CAG CAA] [(CAG)n] [CAA CAG], with expansion in the second [(CAG)n] unit being the most common, has been proposed. In this study, we propose an alternative organization scheme for the repeats. A search of the PubMed database was conducted to identify articles reporting both the number and composition of GAC/CAA repeats in TBP alleles. Nineteen reports were selected. The sequences of all identified CAG/CAA repeats in the TBP locus, including 67 cases (probands and b relatives), were analyzed in terms of their repetition structure and stability in inheritance, if possible. Based on the analysis of three units [(CAG)3 (CAA)2] [CAA (CAG)n CAA CAG] [CAA (CAG)n CAA CAG], the organization of repeats is proposed. Detailed analysis of the CAG/CAA repeat structure, not just the number of repeats, in TBP-expanded alleles should be performed, as it may have a prognostic value in the prediction of stability/instability during transmission and the possible anticipation of the disease.