title: High Frequency of GBA Gene Mutations in Dementia With Lewy Bodies Among Ashkenazi Jews.
abstract: OBJECTIVE
  Mutations in the glucocerebrosidase (GBA) gene are a risk factor for the development of dementia with Lewy bodies (DLB). These mutations are common among Ashkenazi Jews (AJ) and appear to have an effect on the natural history of the disease.
  
  
  OBJECTIVE
  To evaluate the clinical and genetic characteristics of an AJ cohort of patients diagnosed with DLB, assess the association of phenotype of DLB with GBA mutations, and explore the effects of these mutations on the clinical course of the disease.
  
  
  METHODS
  Thirty-five consecutively recruited AJ patients with newly diagnosed clinically probable or possible DLB underwent genotyping for the 7 known AJ GBA mutations and the LRRK2 G2019S mutation. Two patients with the LRRK2 G2019S mutation were excluded from the final analysis. Data were collected from July 1, 2013, to July 31, 2015.
  
  
  METHODS
  Assessment of clinical markers included the following standardized scales: Autonomic Scale for Outcomes in Parkinson's Disease (SCOPA-AUT), REM (Rapid Eye Movement) Sleep Behavior Disorder Single-Question Screen, Geriatric Depression Scale, and Montreal Cognitive Assessment. Motor symptoms were assessed with the Unified Parkinson's Disease Rating Scale motor part III. A subset of 15 patients also underwent assessment with the Color Trail Making Test, FAS verbal fluency, Digit Span, Hooper Visual Organization Test, and Stroop test.
  
  
  RESULTS
  Among the 35 patients with DLB (23 men [66%] and 12 women [34%]; mean [SD], 69.6 [8.2] years), 11 (31%) were carriers of mutations in the GBA gene. Among the 33 patients undergoing further analysis, the GBA mutation carriers were younger at symptom onset (mean [SD] age, 65.7 [11.7] vs 72.1 [5.1] years; P = .03), had more frequent visual hallucinations that did not achieve significance (9 of 11 [82%] compared with 12 of 22 [55%]; P = .052), and had higher scores on the RBD questionnaire (mean [SD], 7.8 [2.2] vs 5.1 [3.3]; P = .03). After adjusting for age and duration of symptoms, testing revealed that GBA mutation carriers had poorer cognition as assessed by the Montreal Cognitive Assessment Battery (mean [SD] score, 18.75 [5.99] vs 23.23 [3.16]; P = .03), lower scores on tests of verbal fluency (adjusted z scores, 0.50 vs -2.02; P = .02), worse scores on tests of visuospatial function (adjusted t scores, 68.55 vs 79.57; P = .046), and higher mean (SD) scores on the Unified Parkinson's Disease Rating Scale motor part III (36.72 [10.62] vs 25.72 [10.32]; P = .03).
  
  
  CONCLUSIONS
  One in 3 AJ patients diagnosed with DLB were carriers of a GBA mutation, making it the most common genetic mutation identified in association with this disease and with any dementia disorder. Mutations in the GBA gene were associated with more severe motor and cognitive dysfunction, supporting a specific contribution of the GBA gene or lysosome function to this clinical syndrome.
authors.affiliation: Center for Neurodegeneration, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Tamara
authors.initials: T
authors.lastname: Shiner
authors.affiliation: Center for Neurodegeneration, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel2Sagol School for Neuroscience, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Mirelman
authors.affiliation: Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Mali
authors.initials: M
authors.lastname: Gana Weisz
authors.affiliation: Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Bar-Shira
authors.affiliation: Center for Neurodegeneration, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Elissa
authors.initials: E
authors.lastname: Ash
authors.affiliation: Center for Neurodegeneration, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Cialic
authors.affiliation: Center for Neurodegeneration, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Naomi
authors.initials: N
authors.lastname: Nevler
authors.affiliation: Center for Neurodegeneration, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Tanya
authors.initials: T
authors.lastname: Gurevich
authors.affiliation: Center for Neurodegeneration, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Bregman
authors.affiliation: Sagol School for Neuroscience, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel3Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Orr-Urtreger
authors.affiliation: Center for Neurodegeneration, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel2Sagol School for Neuroscience, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Giladi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005962:Glucosylceramidase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics*; D020961:Lewy Body Disease / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D005962:Glucosylceramidase