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. / Roux, Thomas; Barbier, Mathieu; Papin, Mélanie; Davoine, Claire Sophie; Sayah, Sabrina; Coarelli, Giulia; Charles, Perrine; Marelli, Cecilia; Parodi, Livia; Tranchant, Christine; Goizet, Cyril; Klebe, Stephan; Lohmann, Ebba; Van Maldergen, Lionel; van Broeckhoven, Christine; Coutelier, Marie; Tesson, Christelle; Stevanin, Giovanni; Duyckaerts, Charles; Brice, Alexis; Durr, Alexandra; Durr, Alexandra; Stevanin, Giovanni; Brice, Alexis; Darios, Frédéric; Forlani, Sylvie; Site, Pitié Salpêtrière; Banneau, Guillaume; Cazeneuve, Cécile; Charles, Perrine; Duyckaerts, Charles; Fontaine, Bertrand; Azulay, Jean Philippe; Boesfplug-Tanguy, Odile; Goizet, Cyril; Hannequin, Didier; Hazan, Jamilé; Burgo, Andrea; Verny, Christophe; Koenig, Michel; Labauge, Pierre; Marelli, Cecilia; N’guyen, Karine; Rodriguez, Diana; Belarbi, Soraya; Hamri, Abdelmadjid; Tazir, Meriem; Boesch, Sylvia; Nielsen, Jørgen E.; Svenstrup, Kirsten; SPATAX network.
In: Genetics in Medicine, Vol. 22, No. 11, 01.11.2020, p. 1851-1862.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias
T2 - a frequent cause of predominant cognitive impairment
AU - Roux, Thomas
AU - Barbier, Mathieu
AU - Papin, Mélanie
AU - Davoine, Claire Sophie
AU - Sayah, Sabrina
AU - Coarelli, Giulia
AU - Charles, Perrine
AU - Marelli, Cecilia
AU - Parodi, Livia
AU - Tranchant, Christine
AU - Goizet, Cyril
AU - Klebe, Stephan
AU - Lohmann, Ebba
AU - Van Maldergen, Lionel
AU - van Broeckhoven, Christine
AU - Coutelier, Marie
AU - Tesson, Christelle
AU - Stevanin, Giovanni
AU - Duyckaerts, Charles
AU - Brice, Alexis
AU - Durr, Alexandra
AU - Durr, Alexandra
AU - Stevanin, Giovanni
AU - Brice, Alexis
AU - Darios, Frédéric
AU - Forlani, Sylvie
AU - Site, Pitié Salpêtrière
AU - Banneau, Guillaume
AU - Cazeneuve, Cécile
AU - Charles, Perrine
AU - Duyckaerts, Charles
AU - Fontaine, Bertrand
AU - Azulay, Jean Philippe
AU - Boesfplug-Tanguy, Odile
AU - Goizet, Cyril
AU - Hannequin, Didier
AU - Hazan, Jamilé
AU - Burgo, Andrea
AU - Verny, Christophe
AU - Koenig, Michel
AU - Labauge, Pierre
AU - Marelli, Cecilia
AU - N’guyen, Karine
AU - Rodriguez, Diana
AU - Belarbi, Soraya
AU - Hamri, Abdelmadjid
AU - Tazir, Meriem
AU - Boesch, Sylvia
AU - Nielsen, Jørgen E.
AU - Svenstrup, Kirsten
AU - SPATAX network
N1 - Publisher Copyright: © 2020, American College of Medical Genetics and Genomics.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - cognitive impairment
KW - SCA48
KW - SCAR16
KW - spinocerebellar ataxia
KW - STUB1
U2 - 10.1038/s41436-020-0899-x
DO - 10.1038/s41436-020-0899-x
M3 - Journal article
C2 - 32713943
AN - SCOPUS:85088563670
VL - 22
SP - 1851
EP - 1862
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
IS - 11
ER -
ID: 269672242