β-Glucocerebrosidase activity in GBA -linked Parkinson disease: The type of mutation matters

• Published in: Neurology Vol. 95; no. 6; p. e685
• Main Authors: Huh, Young Eun, Chiang, Ming Sum Ruby, Locascio, Joseph J, Liao, Zhixiang, Liu, Ganqiang, Choudhury, Karbi, Kuras, Yuliya I, Tuncali, Idil, Videnovic, Aleksandar, Hunt, Ann L, Schwarzschild, Michael A, Hung, Albert Y, Herrington, Todd M, Hayes, Michael T, Hyman, Bradley T, Wills, Anne-Marie, Gomperts, Stephen N, Growdon, John H, Sardi, Sergio Pablo, Scherzer, Clemens R
• Format: Journal Article
• Language: English
• Published: United States 11.08.2020
• Subjects: Aged; Aged, 80 and over; Cognition Disorders - etiology; Cross-Sectional Studies; Female; Follow-Up Studies; Genetic Association Studies; Glucosylceramidase - blood; Glucosylceramidase - genetics; Humans; Male; Middle Aged; Mutation; Neurologic Examination; Parkinson Disease - enzymology; Parkinson Disease - genetics; Parkinson Disease - physiopathology; Parkinson Disease - psychology; Quantitative Trait Loci; Severity of Illness Index
• ISSN: 1526-632X
• DOI: 10.1212/WNL.0000000000009989

To test the relationship between clinically relevant types of mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies. A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying variants ( -PD), 247 without a 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 (interquartile range, 1-2 years). β-Glucocerebrosidase activity was low in blood of patients with -PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS ( < 0.001) and PDBP ( < 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 β-glucocerebrosidase activity and mutation type with < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median 2 years of follow-up ( = 0.02). Residual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.