Objective: To explore the association between GCase activity, PD phenotype and probability for prodromal PD among PD and non-manifesting carriers (NMC) of mutations in the GBA and LRRK2 genes.

Background: Mutations in the GBA gene, which encodes the lysosomal enzyme Glucocerebrosidase (GCase), are risk factors for Parkinson’s disease (PD).

Method: PD and NMC were genotyped for the G2019S-LRRK2 and the following GBA mutations; N370S and R496H, considered mild mutations (mGBA), L444P, 84GG, IVS2+1G>A, V394L, 370Rec considered severe GBA mutations (sGBA) and E326K and T369M, considered risk variants (vGBA). Performance-based measures enabling the calculation of the MDS prodromal probability score, together with complete blood counts and GCase activity were collected.

Results: A total of 119 PD patients (59 GBA-PD (47 mGBA, 10 sGBA, 2 vGBA), 30 LRRK2-PD and 30 iPD) and 175 non-manifesting subjects (87 GBA-NMC (55 mGBA, 26 sGBA and 6 vGBA), 43 LRRK2-NMC, 13 GBA–LRRK2-NMC and 32 NMNC) participated in this study. GCase activity was lower among GBA-PD 3.02±1.39 µmol/L/h, GBA-NMC 3.08±0.89 µmol/L/h and GBA–LRRK2-NMC 3.10±0.79 µmol/L/h compared to the other groups of participants, with no phenotypical correlation. No significant difference in GCase activity was detected between mGBA-PD and sGBA-PD (3.09±0.84 µmol/L/h vs 3.10± 0.72 µmol/L/h; p=0.913). A stepwise increase in GCase activity was detected between sGBA-NMC, mGBA-NMC and vGBA-NMC (2.76±0.16 39 µmol/L/h vs 3.18±0.12 39 µmol/L/h and 3.80±0.3639 µmol/L/h; p=0.020).

Conclusion: The lower GCase activity detected among GBA carriers cannot solely explain the clinical phenotype or risk for prodromal PD in this cohort.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/glucocerebrosidase-activity-does-not-predict-parkinsons-disease-risk-or-severity/