Produção Nacional
Revisado por pares
Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment
2020; Elsevier BV; Volume: 22; Issue: 11 Linguagem: Inglês
10.1038/s41436-020-0899-x
ISSN1530-0366
AutoresThomas Roux, Mathieu Barbier, Mélanie Papin, Claire-Sophie Davoine, Sabrina Sayah, Giulia Coarelli, Perrine Charles, Cécilia Marelli, Livia Parodi, Christine Tranchant, Cyril Goizet, Stephan Klebe, Ebba Lohmann, Lionel Van Maldergem, Christine Van Broeckhoven, Marie Coutelier, Christelle Tesson, Giovanni Stévanin, Charles Duyckaerts, Alexis Brice, Alexandra Dürr, Alexandra Durr, Giovanni Stévanin, 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, Jamïlé Hazan, Andrea Burgo, Christophe Verny, M. Kœnig, Pierre Labauge, Cécilia Marelli, Karine N’guyen, Diana Rodriguez, Soraya Belarbi, Abdelmadjid Hamri, Mériem Tazir, Sylvia Boesch, Massimo Pandolfo, Jardim Laura, Velina Guergueltcheva, Ivalo Tournev, Olga Lucia Pedraza Linarès, Jørgen E. Nielsen, Kirsten Svenstrup, Maha S. 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 Mégarbané, Ali Benomar, Berry Kremer, Willeke M. C. van Roon‐Mom, Richard Roxburgh, Anne Kjersti Erichsen, Chantal Tallaksen, Isabel Alonso, Paula Coutinho, José Léal Loureiro, Jorge Sequeiros, Mustapha Salih, Vladimir Kostić, Idoia Rouco Axpe, Liena E. O. Elsayed, Martin Paucar, Samir Roumani, Soong Bing-Wen, Evan Reid, Suran Nethisinghe, Thomas T. Warner, Nicholas Wood,
Tópico(s)Neurological diseases and metabolism
ResumoPathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48).We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance.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.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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