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

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 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 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 Kostic; Idoia Rouco Axpe; Liena Elsayed; Martin Arce Paucar; Samir Roumani; Soong Bing-Wen; Evan Reid; Nethisinghe Suran; Thomas Warner; Nicholas Wood

doi:10.1038/s41436-020-0899-x

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

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

Thomas Roux, Mathieu Barbier, Mélanie Papin, Claire-Sophie Davoine, Sabrina Sayah, Giulia Coarelli, Perrine Charles, Cecilia Marelli, Livia Parodi, Christine Tranchant, …

Genetics in Medicine, Vol.22(11), pp.1851-1862

11/2020

DOI: https://doi.org/10.1038/s41436-020-0899-x

PMID: 32713943

Résumé

SCA48

SCAR16

STUB1

cognitive impairment

spinocerebellar ataxia

ATP-Dependent Proteases

ATPases Associated with Diverse Cellular Activities

Ataxia

Cerebellar Ataxia

Cognitive Dysfunction

Female

Humans

Male

Spinocerebellar Ataxias

Ubiquitin-Protein Ligases

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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Titre: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment
Créateurs - sans rôle: Thomas Roux - Assistance Publique – Hôpitaux de Paris
Mathieu Barbier - Sorbonne Université
Mélanie Papin - Assistance Publique – Hôpitaux de Paris
Claire-Sophie Davoine - Sorbonne Université
Sabrina Sayah - Assistance Publique – Hôpitaux de Paris
Giulia Coarelli - Inserm
Perrine Charles - Pitié-Salpêtrière Hospital
Cecilia Marelli - Hôpital Gui de Chauliac
Livia Parodi - Sorbonne Université
Christine Tranchant - Université de Strasbourg
Cyril Goizet - Centre Hospitalier Universitaire de Bordeaux
Stephan Klebe - Essen University Hospital
Ebba Lohmann - University of Tübingen
Lionel van Maldergem - Centre Hospitalier Universitaire de Besançon
Christine van Broeckhoven - University of Antwerp
Marie Coutelier - Sorbonne Université
Christelle Tesson - Inserm
Giovanni Stevanin - Institut du Cerveau
Charles Duyckaerts - Inserm
Alexis Brice - Institut du Cerveau
Alexandra Durr - Pitié-Salpêtrière Hospital
Frédéric Darios - Inserm
Sylvie Forlani - Sorbonne Université
Pitié-Salpêtrière Site - Immunologie et Neurogénétique Expérimentales et Moléculaires
Guillaume Banneau - Sorbonne Université
Cécile Cazeneuve - Immunologie et Neurogénétique Expérimentales et Moléculaires
Bertrand Fontaine - Sorbonne Université
Jean-Philippe Azulay
Odile Boesfplug-Tanguy - Université Clermont Auvergne
Didier Hannequin - Inserm
Jamilé Hazan - Sorbonne Université
Andrea Burgo - Hôpital Charles-Nicolle
Christophe Verny - Clinique Charcot
Michel Koenig - Centre Hospitalier Régional Universitaire [Montpellier]
Pierre Labauge - Clinique Charcot
Karine N’guyen - Hôpital d'Enfants
Diana Rodriguez - Université de Montpellier
Soraya Belarbi - Hôpital d'Enfants
Abdelmadjid Hamri - Centre Hospitalo-Universitaire Dr Benbadis Constantine
Meriem Tazir - Hôpital Mustapha Pacha
Sylvia Boesch - Centre Hospitalo-Universitaire Dr Benbadis Constantine
Massimo Pandolfo - Hôpital Mustapha Pacha
Jardim Laura - Innsbruck Medical University
Velina Guergueltcheva - Erasmus Hospital
Ivalo Tournev - Universidade Federal do Rio Grande do Sul
Olga Lucia Pedraza Linarès
Jørgen Nielsen - Alexandrovska Hospital
Kirsten Svenstrup - University of Copenhagen
Maha Zaki - National Research Centre
Peter Bauer - University of Tübingen
Lüdger Schöls - National Research Centre
Rebecca Schüle - University of Tübingen
Alexander Lossos - Hadassah Medical Center
Maria-Teresa Bassi - Hertie Institute for Clinical Brain Research
Manuela Basso - University of Trento
Enrico Bertini - Bambino Gesù Children's Hospital
Alfredo Brusco - University of Turin
Carlo Casali - Sapienza University of Rome
Giorgio Casari - Vita-Salute San Raffaele University
Chiara Criscuolo - University of Naples Federico II
Alessandro Filla - University of Naples Federico II
Laura Orsi - University of Turin
Filippo Santorelli - University of Naples Federico II
Enza Maria Valente - Istituto di Genetica Molecolare
Marinela Vavla - IRCCS Eugenio Medea
Giovanni Vazza - University of Padua
André Megarbane - Saint Joseph University
Ali Benomar - University of Padua
Berry Kremer - Radboud University Nijmegen
Willeke van Roon-Mom - Leiden University Medical Center
Richard Roxburgh - Radboud University Nijmegen
Anne Kjersti Erichsen - Leiden University Medical Center
Chantal Tallaksen - Oslo University Hospital
Isabel Alonso - Oslo University Hospital
Paula Coutinho - Hospital de São Sebastião
José Léal Loureiro - Hospital de São Sebastião
Jorge Sequeiros - Hospital de São Sebastião
Mustapha Salih - King Khalid University Hospital
Vladimir Kostic - Universidade do Porto
Idoia Rouco Axpe
Liena Elsayed
Martin Arce Paucar - Karolinska University Hospital
Samir Roumani - Damascus Hospital
Soong Bing-Wen - National Yang Ming Chiao Tung University
Evan Reid - Damascus Hospital
Nethisinghe Suran
Thomas Warner - The Royal Free Hospital
Nicholas Wood - University College London
Détails de publication: Genetics in Medicine, Vol.22(11), pp.1851-1862
Identifiants: 99152299409311
Unité académique: Mécanismes Moléculaires dans les Démences Neurodégénératives - MMDN
Langue: English
Type de ressource: Journal article
Champs locaux: hal-03369330