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

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

Authors :
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 Maldergem
Christine van Broeckhoven
Marie Coutelier
Christelle Tesson
Giovanni Stevanin
Charles Duyckaerts
Alexis Brice
Alexandra Durr
Frédéric Darios
Sylvie Forlani
Pitié-Salpêtrière Site
Guillaume Banneau
Cécile Cazeneuve
Bertrand Fontaine
Jean-Philippe Azulay
Odile Boesfplug-Tanguy
Didier Hannequin
Jamilé Hazan
Andrea Burgo
Christophe Verny
Michel Koenig
Pierre Labauge
Karine N’guyen
Diana Rodriguez
Soraya Belarbi
Abdelmadjid Hamri
Meriem Tazir
Sylvia Boesch
Massimo Pandolfo
Jardim Laura
Velina Guergueltcheva
Ivalo Tournev
Olga Lucia Pedraza Linarès
Jørgen E. Nielsen
Kirsten Svenstrup
Maha Zaki
Peter Bauer
Lüdger Schöls
Rebecca Schüle
Alexander Lossos
Maria-Teresa Bassi
Manuela Basso
Enrico Bertini
Alfredo Brusco
Carlo Casali
Giorgio Casari
Chiara Criscuolo
Alessandro Filla
Laura Orsi
Filippo M. Santorelli
Enza Maria Valente
Marinela Vavla
Giovanni Vazza
André Megarbane
Ali Benomar
Berry Kremer
Willeke Van Roon-Mom
Richard Roxburgh
Anne Kjersti Erichsen
Chantal Tallaksen
Isabel Alonso
Paula Coutinho
José Léal Loureiro
Jorge Sequeiros
Mustapha Salih
Vladimir S. Kostic
Idoia Rouco Axpe
Liena Elsayed
Martin Arce Paucar
Samir Roumani
Soong Bing-Wen
Evan Reid
Nethisinghe Suran
Thomas Warner
Nicholas Wood
Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM)
Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
École pratique des hautes études (EPHE)
Université Paris sciences et lettres (PSL)
Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
CHU Pitié-Salpêtrière [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Département de neurologie [Montpellier]
Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM)
Mécanismes moléculaires dans les démences neurodégénératives (MMDN)
Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE)
Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
CHU Strasbourg
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM)
Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
CHU Bordeaux [Bordeaux]
Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)
University of Tübingen
Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)
University of Antwerp (UA)
Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
SPATAX Network
Roux, T.
Barbier, M.
Papin, M.
Davoine, C. -S.
Sayah, S.
Coarelli, G.
Charles, P.
Marelli, C.
Parodi, L.
Tranchant, C.
Goizet, C.
Klebe, S.
Lohmann, E.
Van Maldergen, L.
van Broeckhoven, C.
Coutelier, M.
Tesson, C.
Stevanin, G.
Duyckaerts, C.
Brice, A.
Durr, A.
Darios, F.
Forlani, S.
Site, P. -S.
Banneau, G.
Cazeneuve, C.
Fontaine, B.
Azulay, J. -P.
Boesfplug-Tanguy, O.
Hannequin, D.
Hazan, J.
Burgo, A.
Verny, C.
Koenig, M.
Labauge, P.
N'Guyen, K.
Rodriguez, D.
Belarbi, S.
Hamri, A.
Tazir, M.
Boesch, S.
Pandolfo, M.
Laura, J.
Guergueltcheva, V.
Tournev, I.
Pedraza Linares, O. L.
Nielsen, J. E.
Svenstrup, K.
Zaki, M.
Bauer, P.
Schols, L.
Schule, R.
Lossos, A.
Bassi, M. -T.
Basso, M.
Bertini, E.
Brusco, A.
Casali, C.
Casari, G.
Criscuolo, C.
Filla, A.
Orsi, L.
Santorelli, F. M.
Valente, E. M.
Vavla, M.
Vazza, G.
Megarbane, A.
Benomar, A.
Kremer, B.
Van Roon-Mom, W.
Roxburgh, R.
Erichsen, A. K.
Tallaksen, C.
Alonso, I.
Coutinho, P.
Loureiro, J. L.
Sequeiros, J.
Salih, M.
Kostic, V. S.
Rouco Axpe, I.
Elsayed, L.
Paucar, M. A.
Roumani, S.
Bing-Wen, S.
Reid, E.
Suran, N.
Warner, T.
Wood, N.
Source :
Genetics in Medicine, Genetics in Medicine, Nature Publishing Group, 2020, 22 (11), pp.1851-1862. ⟨10.1038/s41436-020-0899-x⟩, Genetics in medicine
Publication Year :
2020
Publisher :
HAL CCSD, 2020.

Abstract

International audience; 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.

Details

Language :
English
ISSN :
10983600
Database :
OpenAIRE
Journal :
Genetics in Medicine, Genetics in Medicine, Nature Publishing Group, 2020, 22 (11), pp.1851-1862. ⟨10.1038/s41436-020-0899-x⟩, Genetics in medicine
Accession number :
edsair.doi.dedup.....10c4642c4e5d177527da8016ea948e04
Full Text :
https://doi.org/10.1038/s41436-020-0899-x⟩