title: Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease.
abstract: The glucocerebrosidase gene (GBA) is a known risk factor of Parkinson's disease (PD). We sequenced entire coding exons and exon/intron boundaries of GBA in 147 Japanese familial PD (FPD) patients from 144 families and 100 unrelated control subjects. Twenty-seven of 144 (18.8%) of index patients were heterozygous for known Gaucher disease mutations, suggesting that GBA heterozygous mutations are strongly associated with FPD (odds ratio = 22.9, 95% confidence interval = 3.1-171.2). The frequency was significantly higher in autosomal dominant PD (ADPD) compared with autosomal recessive PD. According to clinical assessments, PD patients with GBA mutations exhibited typical manifestations of PD or dementia with Lewy bodies (DLB), such as L-dopa responsive parkinsonism with psychiatric problems and/or cognitive decline. Interestingly, they also presented with reduced myocardial (123)I-metaiodobenzylguanidine uptake. Our findings suggest that heterozygous GBA mutations are strong risk factors in FPD, especially for autosomal dominant PD. Some patients with GBA heterozygous mutations develop clinical features of DLB. We speculate that GBA dysfunction may promote Lewy body formation, resulting in more severe PD or DLB phenotypes that are inherited in families.
authors.affiliation: Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo, Japan; Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yuanzhe
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sekine
authors.affiliation: Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo, Japan; Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Funayama
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Yoshino
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Nishioka
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan; Department of Neuroscience for Neurodegenerative Disorders, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomiyama
authors.affiliation: Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo, Japan; Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan; Department of Neuroscience for Neurodegenerative Disorders, Juntendo University School of Medicine, Tokyo, Japan. Electronic address: nhattori@juntendo.ac.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D005091:Exons / Q000235:genetics; D005260:Female; D005776:Gaucher Disease / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D005962:Glucosylceramidase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D005962:Glucosylceramidase
keywords: Dementia; GBA; Gaucher disease; Parkinson's disease/Parkinsonism