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We recently identified a form of SCA transmitted with a digenic pattern of inheritance caused by the concomitant presence of an intermediate\u2010length expansion in TATA\u2010box binding protein gene (<jats:italic>TBP<\/jats:italic><jats:sub>40\u201346<\/jats:sub>) and a heterozygous pathogenic variant in the Stip1\u2010homologous and U\u2010Box containing protein 1 gene (<jats:italic>STUB1<\/jats:italic>). This SCA<jats:sup><jats:italic>TBP\/STUB1<\/jats:italic><\/jats:sup> represents the first example of a cerebellar disorder in which digenic inheritance has been identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>We studied a large cohort of patients with SCA<jats:sup><jats:italic>TBP\/STUB1<\/jats:italic><\/jats:sup> with the aim of describing specific clinical and neuroimaging features of this distinctive genotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this observational study, we recruited 65 affected and unaffected family members from 21 SCA<jats:sup><jats:italic>TBP\/STUB1<\/jats:italic><\/jats:sup> families and from eight families with monogenic SCA17. Their characteristics and phenotypes were compared with those of 33 age\u2010matched controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SCA<jats:sup><jats:italic>TBP\/STUB1<\/jats:italic><\/jats:sup> patients had multi\u2010domain 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<jats:sup><jats:italic>TBP\/STUB1<\/jats:italic><\/jats:sup> compared with SCA17 patients (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.03; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.008). Basal ganglia volumes were reduced in both patient groups, as compared with controls, whereas brainstem volumes were significantly reduced in SCA<jats:sup><jats:italic>TBP\/STUB1<\/jats:italic><\/jats:sup>, but not in SCA17 patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The identification of the complex SCA<jats:sup><jats:italic>TBP\/STUB1<\/jats:italic><\/jats:sup> phenotype may impact on diagnosis and genetic counseling in the families with both hereditary and sporadic ataxia. The independent segregation of <jats:italic>TBP<\/jats:italic> and <jats:italic>STUB1<\/jats:italic> alleles needs to be considered for recurrence risk and predictive genetic tests. \u00a9 2023 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.29352","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T07:43:52Z","timestamp":1676619832000},"page":"665-675","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Complex Ataxia\u2010Dementia Phenotype in Patients with Digenic <i>TBP\/STUB1<\/i> Spinocerebellar Ataxia"],"prefix":"10.1002","volume":"38","author":[{"given":"Lorenzo","family":"Nanetti","sequence":"first","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan  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