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

Research output: Contribution to journalJournal articlepeer-review

  • Thomas Roux
  • Mathieu Barbier
  • Mélanie Papin
  • Claire Sophie Davoine
  • Sabrina Sayah
  • Giulia Coarelli
  • Perrine Charles
  • Cecilia Marelli
  • Livia Parodi
  • Christine Tranchant
  • Cyril Goizet
  • Stephan Klebe
  • Ebba Lohmann
  • Lionel Van Maldergen
  • Christine van Broeckhoven
  • Marie Coutelier
  • Christelle Tesson
  • Giovanni Stevanin
  • Charles Duyckaerts
  • Alexis Brice
  • Alexandra Durr
  • Alexandra Durr
  • Giovanni Stevanin
  • Alexis Brice
  • Frédéric Darios
  • Sylvie Forlani
  • Pitié Salpêtrière Site
  • Guillaume Banneau
  • Cécile Cazeneuve
  • Perrine Charles
  • Charles Duyckaerts
  • Bertrand Fontaine
  • Jean Philippe Azulay
  • Odile Boesfplug-Tanguy
  • Cyril Goizet
  • Didier Hannequin
  • Jamilé Hazan
  • Andrea Burgo
  • Christophe Verny
  • Michel Koenig
  • Pierre Labauge
  • Cecilia Marelli
  • Karine N’guyen
  • Rodriguez, Diana Jimenez Thomas
  • Soraya Belarbi
  • Abdelmadjid Hamri
  • Meriem Tazir
  • Sylvia Boesch
  • Nielsen, Jørgen Erik
  • Kirsten Svenstrup
  • SPATAX network

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.

Original languageEnglish
JournalGenetics in Medicine
Volume22
Issue number11
Pages (from-to)1851-1862
Number of pages12
ISSN1098-3600
DOIs
Publication statusPublished - 1 Nov 2020

Bibliographical note

Publisher Copyright:
© 2020, American College of Medical Genetics and Genomics.

    Research areas

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

ID: 269672242