Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.
Genetics in Medicine. 2020-11-01; 22(11): 1851-1862
DOI: 10.1038/s41436-020-0899-x
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1. Genet Med. 2020 Nov;22(11):1851-1862. doi: 10.1038/s41436-020-0899-x. Epub 2020
Jul 27.
Clinical, neuropathological, and genetic characterization of STUB1 variants in
cerebellar ataxias: a frequent cause of predominant cognitive impairment.
Roux T(#)(1), Barbier M(#)(1), Papin M(#)(1)(2), Davoine CS(1)(2), Sayah S(1),
Coarelli G(1), Charles P(3), Marelli C(4), Parodi L(1), Tranchant C(5), Goizet
C(6), Klebe S(7), Lohmann E(8), Van Maldergem L(9), van Broeckhoven C(10),
Coutelier M(1)(2), Tesson C(1), Stevanin G(1)(2), Duyckaerts C(1), Brice A(1),
Durr A(11); SPATAX network.
Collaborators: Durr A, Stevanin G, Brice A, Darios F, Forlani S, Site PS, Banneau
G, Cazeneuve C, Charles P, Duyckaerts C, Fontaine B, Azulay JP, Boesfplug-Tanguy
O, Goizet C, Hannequin D, Hazan J, Burgo A, Verny C, Koenig M, Labauge P, Marelli
C, N’guyen K, Rodriguez D, Belarbi S, Hamri A, Tazir M, Boesch S, Pandolfo M,
Laura J, Guergueltcheva V, Tournev I, Pedraza Linarès OL, Nielsen JE, Svenstrup
K, Zaki M, Bauer P, Schöls L, Schüle R, Lossos A, Bassi MT, Basso M, Bertini E,
Brusco A, Casali C, Casari G, Criscuolo C, Filla A, Orsi L, Santorelli FM,
Valente EM, Vavla M, Vazza G, Megarbane A, Benomar A, Kremer B, Van Roon-Mom W,
Roxburgh R, Erichsen AK, Tallaksen C, Alonso I, Coutinho P, Loureiro JL,
Sequeiros J, Salih M, Kostic VS, Rouco Axpe I, Elsayed L, Paucar MA, Roumani S,
Bing-Wen S, Reid E, Suran N, Warner T, Wood N.
Author information:
(1)Sorbonne Université, Institut du Cerveau-Paris Brain Institute (ICM), AP-HP,
INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France.
(2)EPHE, PSL Research University, Neurogenetics Group, Paris, France.
(3)Genetic Department, University Hospital Pitié-Salpêtrière, AP-HP, Paris,
France.
(4)Expert center for Neurogenetic Diseases, Department of Neurology, CHU Gui de
Chauliac, MMDN, Univ Montpellier, INSERM, EPHE, Montpellier, France.
(5)Neurological Department University Hospital Strasbourg, Strasbourg, France.
(6)University Bordeaux, Laboratoire MRGM, INSERM U1211, Centre de Référence
Neurogénétique, Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
(7)University Hospital Essen, Department of Neurology, Essen, Germany.
(8)Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain
Research, University of Tübingen, Tübingen, Germany.
(9)Université de Franche-Comté, Centre de Génétique Humaine, Centre Hospitalier
Régional Universitaire, Besançon, France.
(10)Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology,
Laboratory of Neurogenetics, Institute Born-Bunge and Department of Biomedical
Sciences, University of Antwerp, Antwerp, Belgium.
(11)Sorbonne Université, Institut du Cerveau-Paris Brain Institute (ICM), AP-HP,
INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France.
.
(#)Contributed equally
Erratum in
Genet Med. 2020 Dec 22;:.
Comment in
Genet Med. 2021 Jun;23(6):1171-1172.
Genet Med. 2021 Jun;23(6):1173-1174.
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.
DOI: 10.1038/s41436-020-0899-x
PMID: 32713943 [Indexed for MEDLINE]