title: Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course.
abstract: Mutations in the glucocerebrosidase gene are associated with Parkinson's disease and Lewy body dementia. However, whether these alterations have any effect on the clinical course of Parkinson's disease is not clear. The glucocerebrosidase coding region was fully sequenced in 225 Parkinson's disease patients, 17 pathologically confirmed Lewy body dementia patients, and 186 controls from Spain. Twenty-two Parkinson's disease patients (9.8%) and 2 Lewy body dementia patients (11.8%) carried mutations in the glucocerebrosidase gene, compared with only 1 control (0.5%); P = .016 and P = .021 for Parkinson's disease and Lewy body dementia, respectively. The N370S and the L444P mutations represented 50% of the alterations. Two novel variants, L144V and S488T, and 7 previously described alterations were also found. Alterations in glucocerebrosidase were associated with a significant risk of dementia during the clinical course of Parkinson's disease (age at onset, years of evolution, and sex-adjusted odds ratio, 5.8; P = .001). Mutation carriers did not show worse motor symptoms, had good response to L-dopa, and tended to present the intermediate parkinsonian phenotype. Our findings suggest that mutations in the glucocerebrosidase gene not only increase the risk of both Parkinson's disease and Lewy body dementia but also strongly influence the course of Parkinson's disease with respect to the appearance of dementia.
authors.affiliation: Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Setó-Salvia
authors.forename: Javier
authors.initials: J
authors.lastname: Pagonabarraga
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Berta
authors.initials: B
authors.lastname: Pascual-Sedano
authors.forename: Oriol
authors.initials: O
authors.lastname: Dols-Icardo
authors.forename: Arianna
authors.initials: A
authors.lastname: Tucci
authors.forename: Coro
authors.initials: C
authors.lastname: Paisán-Ruiz
authors.forename: Antonia
authors.initials: A
authors.lastname: Campolongo
authors.forename: Sofía
authors.initials: S
authors.lastname: Antón-Aguirre
authors.forename: Inés
authors.initials: I
authors.lastname: Martín
authors.forename: Laia
authors.initials: L
authors.lastname: Muñoz
authors.forename: Enric
authors.initials: E
authors.lastname: Bufill
authors.forename: Lluïsa
authors.initials: L
authors.lastname: Vilageliu
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.forename: Mónica
authors.initials: M
authors.lastname: Cozar
authors.forename: Rafael
authors.initials: R
authors.lastname: Blesa
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Jaime
authors.initials: J
authors.lastname: Kulisevsky
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D020961:Lewy Body Disease / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D020734:Parkinsonian Disorders / Q000150:complications / Q000235:genetics*; D012307:Risk Factors
chemical_list: D005962:Glucosylceramidase