Category: Parkinson's Disease: Genetics
Objective: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and beta-glucocerebrosidase activity in patients with Parkinson’s disease (PD) in cross-sectional and longitudinal case-control studies.
Background: Genotype-phenotype correlations have linked specific types of GBA mutations to the severity of clinical traits such as susceptibility, progression, and prognosis of Parkinson’s disease (PD). However, the precise mechanism linking the types of GBA mutations to phenotypic variation is unknown.
Method: 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson Disease Biomarkers Program (PDBP) were analyzed, including 47 PD patients carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (IQR, 1–2 years).
Results: Beta-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative Enzymatic Quantitative Trait Locus (xQTL) analysis revealed a negative linear association between residual b-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean b-glucocerebrosidase activity by 0.85 mmol/l/h (95% CI, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in b-glucocerebrosidase activity during a median two-years of follow-up (p = 0.02).
Conclusion: Residual activity of the beta-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. Beta-Glucocerebrosidase activity is a quantitative endophenotype that can be non-invasively monitored and therapeutically targeted.
To cite this abstract in AMA style:
Y.E Huh, M.S Chiang, J. Locascio, Z. Liao, G. Liu, K. Choudhury, Y. Kuras, I. Tuncali, A. Videnovic, A. Hunt, M. Schwarzschild, A. Hung, T. Herrington, M. Hayes, B. Hyman, A.M Wills, S. Gomperts, J. Growdon, S. Sardi, C. Scherzer. Beta-Glucocerebrosidase Activity in GBA-linked Parkinson’s Disease: The Type of Mutation Matters [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/beta-glucocerebrosidase-activity-in-gba-linked-parkinsons-disease-the-type-of-mutation-matters/. Accessed June 15, 2025.« Back to MDS Virtual Congress 2020
MDS Abstracts - https://www.mdsabstracts.org/abstract/beta-glucocerebrosidase-activity-in-gba-linked-parkinsons-disease-the-type-of-mutation-matters/