Age-specific Risk of Parkinson’s Disease and Parkinsonian Syndrome in Patients with Type 1 Gaucher Disease: Real-world Evidence from the International Collaborative Gaucher Group Gaucher Registry
Roy Alcalay1, Pramod Mistry2, Alessio Di Fonzo3, Julie Batista4, Pablo Bianculli5, Jenny Carwile4, Gabriela Perichon4, Manisha Balwani6
1Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA, 2Yale Lysosomal Disease Center and Gaucher Disease Treatment Center, Yale School of Medicine, New Haven, CT, USA, 3Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy, 4Sanofi, Cambridge, MA, USA, 5Sanofi, Buenos Aires, Argentina, 6Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Objective:
To estimate the risk of Parkinson’s disease (PD) using Kaplan-Meier survival curves, and to estimate relative hazards of PD using Cox proportional hazards models adjusted for age (as time scale), sex, glucocerebrosidase (GBA1) genotype category (mild versus severe mutations), and disease severity (history of bone crisis).
Background:
GBA1 gene mutations are the most common risk factor for PD; however, there is insufficient data on the age-specific risk for PD among biallelic GBA1 mutations carriers with type 1 Gaucher disease (GD1). These data are essential for counseling and identification of risk modifiers.
Design/Methods:
Participants were GD1 patients enrolled in the International Collaborative Gaucher Group Gaucher Registry as of August 4, 2023. We collected data on occurrence of clinical diagnosis of PD and motor (e.g., rest tremor, falls) and non-motor (cognitive impairment, REM sleep behavior disorder, loss of sense of smell, autonomic dysfunction) signs often present in parkinsonian syndrome. To not miss patients not yet formally diagnosed with PD, dementia with Lewy bodies (DLB), or prodromal PD/DLB, we defined possible parkinsonian syndrome based on self-reported signs and symptoms (data not shown).
Results:
Overall, 39 of 1,452 patients were diagnosed with PD. Sex (p=0.93) and disease severity (p=0.82) were not associated with risk of PD. Overall, age-specific risk for PD was 3.3% at age 60 and 11.8% at age 80 years. Among patients with genotype data (N=1,376), N370S homozygotes had a lower risk for PD than patients with 1 or 0 N370S variants (at age 60 years, 1.9%, 3.4%, 9.1% respectively; at age 80 years, 11.5%, 10.8%, and 23.3%).
Conclusions:
We provide age-specific risk for PD in the largest GD1 cohort studied to date. Risk was highest for patients with severe GBA1 mutations. While risk is higher than the general population, we estimated that most GD1 patients will not develop PD by age 80.