Age-Specific Parkinson Disease Risk in Gaucher Disease Type 1

BACKGROUND AND OBJECTIVES: genotype. METHODS: Participants were patients with GD1 in the International Collaborative Gaucher Group Gaucher Registry, a global GD database, as of February 2024. We longitudinally collected data on clinical diagnosis of PD and dementia with Lewy bodies (DLB) and report of motor (rest tremor, falls) and nonmotor (cognitive impairment, REM sleep behavior disorder, loss of sense of smell, autonomic dysfunction) signs/symptoms. In addition to a conservative physician-based PD and DLB diagnosis, we created a liberal definition of possible parkinsonian syndrome (pPS; ≥2 signs/symptoms, PD, or DLB) to test whether previous low penetrance estimates stem from underdiagnosis. Patients were classified as pPS at earliest of the following dates: PD diagnosis, DLB diagnosis, or report of second sign/symptom. We separately estimated age-specific prevalence of PD and pPS using Kaplan-Meier survival curves. RESULTS: variants had a qualitatively lower prevalence of PD and pPS vs patients with one mild variant. DISCUSSION: In this large cohort of 1,618 patients, approximately one-in-nine patients with GD1 were diagnosed with PD and more than one-in-five patients were diagnosed with PD/DLB or experienced movement disorder symptoms by 80 years. Most patients were from North America and Europe; generalizability to other regions is unknown. Our finding that most patients remain free of PD despite very low residual enzyme activity informs the hypothesis that acid ß-glucosidase levels directly predict risk of PD.