Association of GBA Genotype With Motor and Functional Decline in Patients With Newly Diagnosed Parkinson Disease.

Abstract

To establish the significance of glucocerebrosidase gene (<i>GBA</i>) carrier status on motor impairment in a large cohort of patients with incident Parkinson disease (PD). Three European population-based studies followed 528 patients with PD from diagnosis. A total of 440 with genomic DNA from baseline were assessed for <i>GBA</i> variants. We evaluated motor and functional impairment annually using the Unified Parkinson's Disease Rating Scale (UPDRS) motor and activities of daily living (ADL) sections. Differential effects of classes of <i>GBA</i> variants on disease progression were evaluated using mixed random and fixed effects models. A total of 387 patients with idiopathic disease (age at baseline 70.3 ± 9.5 years; 60.2% male) and 53 <i>GBA</i> carriers (age at baseline 66.8 ± 10.1 years; 64.2% male) were included. The motor profile of the groups was clinically indistinguishable at diagnosis. <i>GBA</i> carriers showed faster annual increase in UPDRS scores measuring ADL (1.5 point per year, 95% confidence interval [CI] 1.1-2.0) and motor symptoms (2.2 points per year, 95% CI 1.3-3.1) compared to noncarriers (ADL, 1.0 point per year, 95% CI 0.9-1.1, <i>p</i> = 0.003; motor, 1.3 point per year, 95% CI 1.1-1.6, <i>p</i> = 0.007). Simulations of clinical trial designs showed that recruiting only <i>GBA</i> carriers can reduce trial size by up to 65% compared to a trial recruiting all patients with PD. <i>GBA</i> variants are linked to a more aggressive motor disease course over 7 years from diagnosis in patients with PD. A better understanding of PD progression in genetic subpopulations may improve disease management and has direct implications for improving the design of clinical trials.