While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. Eleven centers from sites around the world performing genotyping. Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. Frequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.

Carriers of mutations in the glucocerebrosidase gene (GBA) are at increased risk of developing Parkinson’s disease. The frequency of GBA mutations in unselected Parkinson’s disease populations has not been established. Furthermore, no previous studies have investigated the influence of GBA mutations on the natural history of Parkinson’s disease using prospective follow-up. We studied DNA from 262 cases who had been recruited at diagnosis into one of two independent community-based incidence studies of Parkinson's disease. In 121 cases, longitudinal data regarding progression of motor disability and cognitive function were derived from follow-up assessments conducted every 18 months for a median of 71 months. Sequencing of the GBA was performed after two-stage polymerase chain reaction amplification. The carrier frequency of genetic variants in GBA was determined. Baseline demographic and clinical variables were compared between cases who were either GBA mutation carriers, polymorphism carriers or wild-type homozygotes. Cox regression analysis was used to model progression to major motor (Hoehn and Yahr stage 3), and cognitive (dementia) end-points in cases followed longitudinally. We show that in a representative, unselected UK Parkinson’s disease population, GBA mutations are present at a frequency of 3.5%. This is higher than the prevalence of other genetic mutations currently associated with Parkinson’s disease and indicates that GBA mutations make an important contribution to Parkinson’s disease encountered in the community setting. Baseline clinical characteristics did not differ significantly between cases with and without GBA sequence variants. However, the hazard ratio for progression both to dementia (5.7, P = 0.003) and Hoehn and Yahr stage 3 (4.2, P = 0.003) were significantly greater in GBA mutation carriers. We also show that carriers of polymorphisms in GBA which are not generally considered to increase Parkinson’s disease risk are at significantly increased risk of progression to Hoehn and Yahr stage 3 (3.2, P = 0.004). Our results indicate that genetic variation in GBA has an important impact on the natural history of Parkinson’s disease. To our knowledge, this is the first time a genetic locus has been shown to influence motor progression in Parkinson’s disease. If confirmed in further studies, this may indicate that GBA mutation status could be used as a prognostic marker in Parkinson’s disease. Elucidation of the molecular mechanisms that underlie this effect will further our understanding of the pathogenesis of the disease and may in turn suggest novel therapeutic strategies.

Background: Heterozygous loss‐of‐function mutations in the acid beta‐glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher's disease (GD), are the strongest known risk factor for Parkinson's disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early‐onset PD.Methods: One hundred and eighty‐five PD patients (with an onset age of ≤50) and 283 age‐matched controls were screened for GBA1 mutations by Sanger sequencing.Results: We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late‐onset patient cohorts. Furthermore, our results reveal that the most prevalent PD‐associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD.Conclusions: Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease. © 2012 Movement Disorder Society

Type I Gaucher disease (GD), the most common lysosomal storage disorder, is caused by recessive glucocerebrosidase mutations.1 Both patients with Type I GD and heterozygous glucocerebrosidase mutation carriers have increased Parkinson's disease (PD) risk.1 Non-motor symptoms (NMS) are more frequent in PD with heterozygous glucocerebrosidase mutations (PD-GBA).2 We used the non-motor symptoms scale (NMSS) and Parkinson's disease questionairre (PDQ-39) to quantify NMS in PD-GBA.3 The age related PD risk in heterozygous glucocerebrosidase carriers has been reported in familial PD.4 Here, we calculate PD risk in obligate carrier relatives (parents) of Type I GD patients. ### Patients and methods PD-GBA patients were identified by Sanger sequencing of the glucocerebrosidase gene in 220 sporadic PD (PD-S) patients. The G2019S mutation in LRRK2 had previously been excluded. A control group of glucocerebrosidase mutation negative PD-S were selected from the same cohort. Each participant had the following administered: 40 item smell identification test (SIT), Montreal Cognitive assessment (MoCA), Parts I–IV of Unified Parkinson's Disease Rating Scale (UPDRS), NMSS, PDQ-39 and Rapid Eye Movement (REM) Sleep Behaviour Disorder Questionnaire (RBDQ). Statistical analysis was performed using SPSS (version 17). The proportion of participants with a MoCA score 6/10 (signifying possible REM sleep behaviour disorder) was compared using the χ2 test.3 In parallel, family history data were obtained from 83 Type I GD patients, detailing age of onset of PD in their parents …

The objective of this study was to assess a cohort of Gaucher disease patients and their heterozygous carrier relatives for potential clinical signs of early neurodegeneration. Gaucher disease patients (n = 30), heterozygous glucocerebrosidase mutation carriers (n = 30), and mutation‐negative controls matched by age, sex, and ethnicity (n = 30) were recruited. Assessment was done for olfactory function (University of Pennsylvania Smell Identification Test), cognitive function (Mini‐Mental State Examination, Montreal Cognitive Assessment), rapid eye movement sleep disorder, autonomic symptoms, and parkinsonian motor signs (Unified Parkinson's Disease Rating Scale part III, Purdue pegboard). Olfactory function scores were significantly lower in Gaucher disease patients (P = .010) and heterozygous carriers (P < .001) than in controls. Cognitive assessment scores were significantly lower in Gaucher disease patients (P = .002) and carriers (P = .002) than in controls. Unified Parkinson's Disease Rating Scale motor subscale scores were significantly higher in Gaucher disease patients (P < .001) and heterozygotes (P = .0010) than in controls. There was no difference in scores for symptoms of rapid eye movement sleep disorder or autonomic dysfunction. Impairment of olfaction, cognition, and parkinsonian motor signs occurs more frequently in Gaucher disease patients and carriers than in controls, which may indicate the early stages of neurodegeneration. © 2012 The Authors. International Parkinson and Movement Disorder Society published by Wiley Periodicals, Inc.