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. 2024 Sep;39(9):1636-1640.
doi: 10.1002/mds.29912. Epub 2024 Jul 7.

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

Teije H van Prooije  1 , Maartje Pennings  2 , Lucille Dorresteijn  3 , Thatjana Gardeitchik  2 , Vincent J J Odekerken  4 , Mayke Oosterloo  5 , Annie Pedersen  6   7 , Corien C Verschuuren-Bemelmans  8 , Alexander Vrancken  9 , Erik-Jan Kamsteeg  2 , Bart P C van de Warrenburg  1
Affiliations

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

Teije H van Prooije et al. Mov Disord. 2024 Sep.

Abstract

Background: Monoallelic, 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.

Objective: To determine the presence and impact of intermediate or high-normal TBP expansions in ataxic patients with heterozygous STUB1 variants.

Methods: We describe 21 patients with ataxia carrying a heterozygous STUB1 variant and determined TBP repeat length.

Results: A total of 15 of 21 patients (71%) carried a normal TBP <40 allele, 4 (19%) carried an intermediate TBP 41-42 allele, and two carried a high-normal TBP 40 allele (9.5%). Five of six carriers (83%) of both STUB1 variants and TBP 40-42 alleles showed marked cognitive impairment.

Conclusions: SCA48 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 TBP 41-42 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.

Keywords: ataxia; genetics.

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References

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