Age-Specific Parkinson Disease Risk in Gaucher Disease Type 1: Data From the ICGG Gaucher Registry.

BACKGROUND AND

objectivesGlucocerebrosidase (

methodsParticipants 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.

resultsAmong 1,618 patients with GD1 (median age at last follow-up 47.8 years; 53% female), 51 were diagnosed with PD and 86 as pPS. The age-specific prevalence (95% CI) of PD and pPS was 4.0% (2.7-5.7) and 6.0% (4.5-7.9) at 60 years and 12.2% (8.6-17.0) and 22.9% (17.1-30.1) at 80 years, respectively. Patients with 2 mild pathogenic 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.