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. 2020 Nov;22(11):1851-1862.
doi: 10.1038/s41436-020-0899-x. Epub 2020 Jul 27.

Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Thomas Roux #  1 , Mathieu Barbier #  1 , Mélanie Papin #  1   2 , Claire-Sophie Davoine  1   2 , Sabrina Sayah  1 , Giulia Coarelli  1 , Perrine Charles  3 , Cecilia Marelli  4 , Livia Parodi  1 , Christine Tranchant  5 , Cyril Goizet  6 , Stephan Klebe  7 , Ebba Lohmann  8 , Lionel Van Maldergem  9 , Christine van Broeckhoven  10 , Marie Coutelier  1   2 , Christelle Tesson  1 , Giovanni Stevanin  1   2 , Charles Duyckaerts  1 , Alexis Brice  1 , Alexandra Durr  11 ; SPATAX network
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Free article

Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Thomas Roux et al. Genet Med. 2020 Nov.
Free article

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Abstract

Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48).

Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance.

Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects.

Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

Keywords: SCA48; SCAR16; STUB1; cognitive impairment; spinocerebellar ataxia.

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