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

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.

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Fig. 1: Variants of STUB1 detected in 30 families.
Fig. 2: Cerebral magnetic resonance image (MRI) of two patients of family AAD-541 with the STUB1 p.Y49C variant.
Fig. 3: Neuropathology of SAL-345–015 who carried the STUB1 p.A46P variant.

Data availability

Anonymized data from this study will be shared by request from any qualified investigator.

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Acknowledgements

We are very grateful to the patients and their families for participating. Many thanks to Ludivine Chamard, Pierre Clavelou, Nathalie Daluzeau, Didier Deffond, Bernard Floccard, Pascal Labouret, Isabelle Le Ber, Roberto Marconi, Pascal Menage, Michel Obadia, Elisabeth Ollagnon Roman, Anne-Marie Ouvrard-Hernandez, Michel Rendu, Vincent de la Sayette, Xavier Soulages, Philippe Svrin, Maya Tchikvildazé, Jacques Touchon, Urielle Ullmann, Fausto Viader, Francois Viallet, and Marc Wagner, who referred cases. Many thanks to the Pitié-Salpêtrière Brain and DNA and cell banks. Members of the SPATAX network are listed in Supplementary data. Funding provided by Grand Prix Lamonica de Neurologie (Académie des Sciences).

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Correspondence to Alexandra Durr MD, PhD.

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Roux, T., Barbier, M., Papin, M. et al. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment. Genet Med (2020). https://doi.org/10.1038/s41436-020-0899-x

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Keywords

  • STUB1
  • spinocerebellar ataxia
  • cognitive impairment
  • SCA48
  • SCAR16