Objective: To explore the influence of carrying mutations in both the GBA and LRRK2 genes (dual mutation carriers) on risk for future development of Parkinson’s disease (PD) based on the Movement Disorders Society probability score for prodromal PD.

Background: Dual mutation carriers with PD have been described as having a milder phenotype compared with GBA mutation carriers. However, the clinical phenotype of non-manifesting carriers (NMC) of dual mutations has not been reported to date.

Method: NMC were genotyped for the G2019S-LRRK2 mutation and nine mutations in the GBA gene (L444P, 84GG, IVS2+1G->A, V394L, N370S, R496H, E326K and T369M). Subjects were classified into four groups: non-manifesting non-carriers (NMNC), LRRK2-NMC, GBA-NMC, and LRRK2+GBA-NMC. Clinical data enabling the construction of the updated MDS probability score for prodromal PD was collected.

Results: 220 NMNC, 75 LRRK2-NMC, 124 GBA-NMC and 18 LRRK2+GBA-NMC participated in this study. Participants were well matched regarding age and sex as well as other clinical measures. GBA-NMC had a significantly higher probability scores (27.29±31.61) compared with NMNC (13.43±24.32), while LRRK2-NMC (22.62±33.52) and LRRK2–GBA-NMC (16.61±24.06) did not differ in probability scores compared with NMNC (p=0.01).

Conclusion: LRRK2+GBA-NMC did not have a higher probability score for prodromal PD compared with NMC of mutations in a single gene. This finding suggests that carrying dual mutation does not negatively affect risk for future PD among “at risk” healthy NMC just as it does not affect the clinical phenotype of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-phenotype-of-non-manifesting-carriers-of-mutations-in-the-gba-and-lrrk2-genes/