Β-Glucocerebrosidase activity in GBA-linked Parkinson disease: The type of mutation matters. (11th August 2020)

• Record Type: Journal Article
• 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.
• Is Part Of: Neurology. Volume 95:Number 6(2020)
• Publication Date: 2020-08-11
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000009989
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : Objective: To test the relationship between clinically relevant types of GBA 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. Methods: 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 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 (interquartile range, 1–2 years). Results: β-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 β-glucocerebrosidase activity and mutation type with p < 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 ( p = 0.02). Conclusions: Residual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.