Complex Ataxia-Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia

Background and objectives: Spinocerebellar ataxias (SCAs) are autosomal dominant disorders with extensive clinical and genetic heterogeneity. We recently identified a form of SCA transmitted with a digenic pattern of inheritance caused by the concomitant presence of an intermediate-length expansion in TATA-box binding protein gene (TBP_40-46 ) and a heterozygous pathogenic variant in the Stip1-homologous and U-Box containing protein 1 gene (STUB1). This SCA^TBP/STUB1 represents the first example of a cerebellar disorder in which digenic inheritance has been identified.

Objectives: We studied a large cohort of patients with SCA^TBP/STUB1 with the aim of describing specific clinical and neuroimaging features of this distinctive genotype.

Methods: In this observational study, we recruited 65 affected and unaffected family members from 21 SCA^TBP/STUB1 families and from eight families with monogenic SCA17. Their characteristics and phenotypes were compared with those of 33 age-matched controls.

Results: SCA^TBP/STUB1 patients had multi-domain dementia with a more severe impairment in respect to patient carrying only fully expanded SCA17 alleles. Cerebellar volume and thickness of cerebellar cortex were reduced in SCA^TBP/STUB1 compared with SCA17 patients (P = 0.03; P = 0.008). Basal ganglia volumes were reduced in both patient groups, as compared with controls, whereas brainstem volumes were significantly reduced in SCA^TBP/STUB1 , but not in SCA17 patients.

Conclusions: The identification of the complex SCA^TBP/STUB1 phenotype may impact on diagnosis and genetic counseling in the families with both hereditary and sporadic ataxia. The independent segregation of TBP and STUB1 alleles needs to be considered for recurrence risk and predictive genetic tests. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.