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

T. Roux, M. Barbier, M. Papin, C.-S. Davoine, S. Sayah, G. Coarelli, P. Charles, C. Marelli, L. Parodi, C. Tranchant, C. Goizet, S. Klebe, E. Lohmann, L. Van Maldergen, C. van Broeckhoven, M. Coutelier, C. Tesson, G. Stevanin, C. Duyckaerts, A. BriceA. Durr, F. Darios, S. Forlani, P.-S. Site, G. Banneau, C. Cazeneuve, B. Fontaine, J.-P. Azulay, O. Boesfplug-Tanguy, D. Hannequin, J. Hazan, A. Burgo, C. Verny, M. Koenig, P. Labauge, K. N’guyen, D. Rodriguez, S. Belarbi, A. Hamri, M. Tazir, S. Boesch, M. Pandolfo, J. Laura, V. Guergueltcheva, I. Tournev, O.L. Pedraza Linarès, J.E. Nielsen, K. Svenstrup, M. Zaki, P. Bauer, L. Schöls, R. Schüle, A. Lossos, M.-T. Bassi, M. Basso, E. Bertini, A. Brusco, C. Casali, G. Casari, C. Criscuolo, A. Filla, L. Orsi, F.M. Santorelli, E.M. Valente, M. Vavla, G. Vazza, A. Megarbane, A. Benomar, B. Kremer, W. Van Roon-Mom, R. Roxburgh, A.K. Erichsen, C. Tallaksen, I. Alonso, P. Coutinho, J.L. Loureiro, J. Sequeiros, M. Salih, V.S. Kostic, I. Rouco Axpe, L. Elsayed, M.A. Paucar, S. Roumani, S. Bing-Wen, E. Reid, N. Suran, T. Warner, N. Wood, SPATAX network

Research output: Contribution to journalArticlepeer-review


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. © 2020, American College of Medical Genetics and Genomics.
Original languageEnglish
Pages (from-to)1851-1862
Number of pages12
JournalGen. Med.
Issue number11
Publication statusPublished - 2020


  • cognitive impairment
  • SCA48
  • SCAR16
  • spinocerebellar ataxia
  • STUB1
  • adult
  • aged
  • Article
  • cell loss
  • cerebellar ataxia
  • cerebellum vermis
  • clinical article
  • clinical feature
  • cognitive defect
  • disease severity
  • female
  • frontotemporal dementia
  • gene
  • genetic association
  • genetic variability
  • hemisphere
  • heterozygosity
  • hippocampus
  • human
  • Huntington chorea
  • male
  • middle aged
  • neuropathology
  • onset age
  • phenotype
  • pons
  • Purkinje cell
  • risk factor
  • STUB1 gene


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