Variants associated with Gaucher disease in multiple system atrophy

Jun Mitsui (1) , Takashi Matsukawa (1) , Hidenao Sasaki (1) , Ichiro Yabe (1) , Masaaki Matsushima (1) , Alexandra Dürr (2) , Alexis Brice (2) , Hiroshi Takashima (3) , Akio Kikuchi (1) , Masashi Aoki (1) , Hiroyuki Ishiura (1) , Tsutomu Yasuda (1) , Hidetoshi Date (1) , Budrul Ahsan (1) , Atsushi Iwata (1) , Jun Goto (1) , Yaeko Ichikawa (1) , Yasuo Nakahara (1) , Yoshio Momose (1) , Yuji Takahashi (1) , Kenju Hara (1) , Akiyoshi Kakita (4) , Mitsunori Yamada (4, 5) , Hitoshi Takahashi (4) , Osamu Onodera (1) , Masatoyo Nishizawa (1) , Hirohisa Watanabe (1) , Mizuki Ito (1) , Gen Sobue (1) , Kinya Ishikawa (6) , Hidehiro Mizusawa (6) , Kazuaki Kanai (1) , Takamichi Hattori (1) , Satoshi Kuwabara (1) , Kimihito Arai (7) , Shigeru Koyano (8) , Yoshiyuki Kuroiwa (1) , Kazuko Hasegawa (9) , Tatsuhiko Yuasa (10) , Kenichi Yasui (7) , Kenji Nakashima (7) , Hijiri Ito (1) , Yuishin Izumi (11) , Ryuji Kaji (11) , Takeo Kato (12) , Susumu Kusunoki (1) , Yasushi Osaki (13) , Masahiro Horiuchi (14) , Tomoyoshi Kondo (1) , Shigeo Murayama (15) , Nobutaka Hattori (1) , Mitsutoshi Yamamoto (1) , Miho Murata (16) , Wataru Satake (17) , Tatsushi Toda (17) , Alessandro Filla (18) , Thomas Klockgether (19) , Ullrich Wüllner (19) , Garth Nicholson (20) , Sid Gilman (21) , Caroline M Tanner (22) , Walter A Kukull (23) , Mathew B Stern (24) , Virginia M-y Lee (25) , John Q. Trojanowski (25) , Eliezer Masliah (26) , Phillip A Low (21) , Paola Sandroni (21) , Laurie J Ozelius (27) , Tatiana Foroud (28) , Shoji Tsuji (1)

1 Department of neurology
2 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
3 Department of neurology and geriatrics
4 Department of pathology
5 department of clinical research
6 Department of Neurology and Neurological Science
7 Division of neurology
8 Department of clinical neurology and stroke medicine
9 Division of neurology
10 Department of neurology
11 Department of clinical neuroscience
12 Departments of neurology, hematology, metabolism, endocrinology and diabetology
13 Department of geriatrics, cardiology and neurology
14 Division of neurology
15 Department of neuropathology and the Brain bank for aging research
16 Department of neurology
17 Division of neurology/molecular brain science
18 Department of Neurological Sciences
19 Department of neurology
20 Concord Hospital
21 Department of neurology
22 Parkinson's disease research education and clinical center
23 Department of epidemiology
24 Parkinson's disease and movement disorders center
25 Institute of aging, Udall Parkinson's research center
26 Department of neurosciences
27 Departments of genetics and genomic sciences and neurology
28 Department of Medical and Molecular Genetics

Objective : Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case–control series. Methods : We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. Results : In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel–Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14–5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15–5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10−3). Interpretation : The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Domaines: Neurosciences; Médecine humaine et pathologie; Génétique humaine

Jun Mitsui, Takashi Matsukawa, Hidenao Sasaki, Ichiro Yabe, Masaaki Matsushima, et al.. Variants associated with Gaucher disease in multiple system atrophy. Annals of Clinical and Translational Neurology, 2015, 2 (4), pp.417-426 ⟨10.1002/acn3.185⟩. ⟨hal-01122349⟩