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Ann Clin Transl Neurol. 2015 Apr;2(4):417-26. doi: 10.1002/acn3.185. Epub 2015 Feb 28.

Variants associated with Gaucher disease in multiple system atrophy.

Author information

1
Department of Neurology, Graduate School of Medicine, University of Tokyo Tokyo, Japan.
2
Department of Neurology, Hokkaido University Graduate School of Medicine Sapporo, Japan.
3
AP-HP, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Inserm, U 1127, Cnrs, UMR 7225, 3- Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM F-75013, Paris, France.
4
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Kagoshima, Japan.
5
Department of Neurology, Tohoku University School of Medicine Sendai, Japan.
6
Department of Neurology, Brain Research Institute, Niigata University Niigata, Japan.
7
Department of Pathology, Brain Research Institute, Niigata University Niigata, Japan.
8
Department of Pathology, Brain Research Institute, Niigata University Niigata, Japan ; Department of Clinical Research, Saigata Medical Center, National Hospital Organization Niigata, Japan.
9
Department of Neurology, Nagoya University Graduate School of Medicine Nagoya, Japan.
10
Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University Tokyo, Japan.
11
Department of Neurology, Chiba University School of Medicine Chiba, Japan.
12
Division of Neurology, National Hospital Organization, Chiba East Hospital Chiba, Japan.
13
Department of Clinical Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University Yokohama, Japan.
14
Department of Neurology, Teikyo University School of Medicine University Hospital Mizonokuchi, Kawasaki, Japan.
15
Division of Neurology, National Hospital Organization, Sagamihara National Hospital Sagamihara, Japan.
16
Department of Neurology, Kamagaya-Chiba Medical Center for Intractable Neurological Disease, Kamagaya General Hospital Chiba, Japan.
17
Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University Yonago, Japan.
18
Department of Neurology, Mifukai Vihara Hananosato Hospital Hiroshima, Japan.
19
Department of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima Graduate School Tokushima, Japan.
20
Departments of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Faculty of Medicine, Yamagata University Yamagata, Japan.
21
Department of Neurology, Kinki University School of Medicine Osaka, Japan.
22
Department of Geriatrics, Cardiology and Neurology, Kochi Medical School Nankoku, Japan.
23
Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine Kawasaki, Japan.
24
Department of Neurology, Wakayama Medical University Wakayama, Japan.
25
Department of Neuropathology and the Brain Bank for Aging Research, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology Tokyo, Japan.
26
Department of Neurology, Juntendo University School of Medicine Tokyo, Japan.
27
Department of Neurology, Kagawa Prefectural Central Hospital Takamatsu, Japan.
28
Department of Neurology, National Center Hospital of Neurology and Psychiatry Tokyo, Japan.
29
Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine Kobe, Japan.
30
Department of Neurological Sciences, University Federico II Naples, Italy.
31
Department of Neurology, University of Bonn and German Center for Neurodegenerative Diseases (DZNE) Bonn, Germany.
32
Concord Hospital, University of Sydney at the Australian and New Zealand Army Corps (ANZAC) Research Institute Sydney, Australia.
33
Department of Neurology, University of Michigan Ann Arbor, Michigan.
34
Parkinson's Disease Research Education and Clinical Center, San Francisco Veteran's Affairs Medical Center San Francisco, California.
35
Department of Epidemiology, University of Washington School of Public Health Seattle, Washington.
36
Parkinson's Disease and Movement Disorders Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania.
37
Institute on Aging, Udall Parkinson's Research Center, Center for Neurodegenerative Disease Research and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania.
38
Department of Neurosciences, University of California San Diego San Diego, California.
39
Department of Neurology, Mayo Clinic Rochester, Minnesota.
40
Departments of Genetics and Genomic Sciences and Neurology, Icahn School of Medicine at Mount Sinai New York, New York.
41
Department of Medical and Molecular Genetics, Indiana University School of Medicine Indianapolis, Indiana.

Abstract

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.

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