A New Case Series Suggests That SCA48 (ATX/STUB1) Is Primarily a Monogenic Disorder

Abstract

AbstractBackgroundMonoallelic, pathogenic STUB1 variants cause autosomal dominant cerebellar ataxia (ATX‐STUB1/SCA48). Recently, a genetic interaction between STUB1 variants and intermediate or high‐normal CAG/CAA repeats in TBP was suggested, indicating digenic inheritance or a disease‐modifying role for TBP expansions.ObjectiveTo determine the presence and impact of intermediate or high‐normal TBP expansions in ataxic patients with heterozygous STUB1 variants.MethodsWe describe 21 patients with ataxia carrying a heterozygous STUB1 variant and determined TBP repeat length.ResultsA total of 15 of 21 patients (71%) carried a normal TBP<40 allele, 4 (19%) carried an intermediate TBP41–42 allele, and two carried a high‐normal TBP40 allele (9.5%). Five of six carriers (83%) of both STUB1 variants and TBP40–42 alleles showed marked cognitive impairment.ConclusionsSCA48 is predominantly a monogenic disorder, because most patients carried an isolated, heterozygous STUB1 variant and presented with the typical combined phenotype of ataxia and cognitive dysfunction. Still, co‐occurrence of TBP41–42 or high‐normal TBP40 alleles was relatively frequent and associated with marked cognitive defects (28.5%), suggesting a modifying effect on clinical expression in some cases. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.