High Frequency of <i>GBA</i> Gene Mutations in Dementia With Lewy Bodies Among Ashkenazi Jews
Authors: Tamara Shiner, Anat Mirelman, Mali Gana Weisz, Anat Bar-Shira, Elissa Ash, Ron Cialic, Naomi Nevler, Tanya Gurevich, Noa Bregman, Avi Orr-Urtreger, Nir Giladi
Journal: JAMA Neurology (2016)

<h3>Importance</h3> Mutations in the glucocerebrosidase (<i>GBA</i>) 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. <h3>Objectives</h3> To evaluate the clinical and genetic characteristics of an AJ cohort of patients diagnosed with DLB, assess the association of phenotype of DLB with<i>GBA</i>mutations, and explore the effects of these mutations on the clinical course of the disease. <h3>Design, Setting, and Participants</h3> Thirty-five consecutively recruited AJ patients with newly diagnosed clinically probable or possible DLB underwent genotyping for the 7 known AJ<i>GBA</i>mutations and the<i>LRRK2</i>G2019S mutation. Two patients with the<i>LRRK2</i>G2019S mutation were excluded from the final analysis. Data were collected from July 1, 2013, to July 31, 2015. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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<i>GBA</i>gene. Among the 33 patients undergoing further analysis, the<i>GBA</i>mutation carriers were younger at symptom onset (mean [SD] age, 65.7 [11.7] vs 72.1 [5.1] years;<i>P</i> = .03), had more frequent visual hallucinations that did not achieve significance (9 of 11 [82%] compared with 12 of 22 [55%];<i>P</i> = .052), and had higher scores on the RBD questionnaire (mean [SD], 7.8 [2.2] vs 5.1 [3.3];<i>P</i> = .03). After adjusting for age and duration of symptoms, testing revealed that<i>GBA</i>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];<i>P</i> = .03), lower scores on tests of verbal fluency (adjusted<i>z</i>scores, 0.50 vs −2.02;<i>P</i> = .02), worse scores on tests of visuospatial function (adjusted<i>t</i>scores, 68.55 vs 79.57;<i>P</i> = .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];<i>P</i> = .03). <h3>Conclusions and Relevance</h3> One in 3 AJ patients diagnosed with DLB were carriers of a<i>GBA</i>mutation, making it the most common genetic mutation identified in association with this disease and with any dementia disorder. Mutations in the<i>GBA</i>gene were associated with more severe motor and cognitive dysfunction, supporting a specific contribution of the<i>GBA</i>gene or lysosome function to this clinical syndrome.