High Frequency of GBA Gene Mutations in Dementia With Lewy Bodies Among Ashkenazi Jews

Abstract

IMPORTANCE 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. OBJECTIVES 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. DESIGN, SETTING, AND PARTICIPANTS 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. MAIN OUTCOMES AND MEASURES 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

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

“…These demographic and clinical characteristics in our german DLB cohort are in line with findings from two small DLB cohorts of Ashkenazi Jews ancestry and Spanish origin, in which GBA1 promoted a younger onset and higher prevalence of RBD …”

“…9 These demographic and clinical characteristics in our german DLB cohort are in line with findings from two small DLB cohorts of Ashkenazi Jews ancestry and Spanish origin, in which GBA1 promoted a younger onset and higher prevalence of RBD. 10,11 To what extent CSF profiles of respective proteins might reflect the underlying pathology in the brain is unclear. Following the mechanistic link between GBA1 mutations and alpha-synuclein, which highlights alphasynuclein accumulation attributed to functional loss of the encoded lysosomal enzyme GCase, it is tempting to speculate that the reduced CSF levels of total alphasynuclein observed in our DLB patients with severe GBA1 mutations might reflect alpha-synuclein accumulation in the brain.…”

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

“…The association of GBA1 with a higher prevalence of RBD was also shown for DLB patients. 6,10,11 This is of interest as RBD is specifically associated with alphasynucleinopathies and the GBA1 mutation carriers of the RBD cohort had a 3.2-fold higher phenoconversion rate from RBD to parkinsonism and/or dementia than non-GBA1 carriers. 12 Moreover, a recent review reported RBD to be positively associated with a more severe "malignant" phenotype, including cognitive impairment in PD and DLB.…”

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

“…GBA1 heterozygotes have an earlier age at onset compared with noncarriers of 3‐6 years for PD and 5‐7 years for DLB, respectively. Mean age at onset in heterozygous PD carriers is about 50‐55 years .…”

“…In a DLB cohort, GBA1 carriers were at increased risk of visual hallucinations compared with DLB noncarriers. 65 Concerning other neuropsychiatric symptoms, GBA1-associated PD patients have a 2.2-fold increased risk of developing trait anxiety and depression compared with noncarriers, 10,49,66,83,88 as well as increased prevalence of apathy. 58,66 Autonomic dysfunction.…”