Objective: To compare the phenotype of patients with Parkinson’s disease (PD) who carry dual mutation in both LRRK2 and GBA genes with patients with PD who carry a single mutation.

Background: Differences in PD symptoms have been described between carriers of mutations in the GBA or LRRK2 genes. A small percentage of patients with genetic PD harbor mutations of both genes (<10%). However, the phenotypic presentation of these patients has not been well described.

Method: Patients with PD of Ashkenazi decent were genotyped for the G2019S-LRRK2 mutation and 8 common mutations in the GBA gene (N370S, R496H and E326K considered mild mutations and L444P, 84GG, IVS2+1G->A, V394L, 370Rec considered severe GBA mutations). Subjects were classified into 4 groups: PD-mGBA, PD-sGBA, PD-LRRK2 and PD-LRRK2+GBA for those carrying both mutations. Clinical symptoms were evaluated using performance based measures such as the UPSIT, MoCA and the sub-section of the MDS-UPDRS. Autonomic symptoms were evaluated using the SCOPA-AUT questionnaire. Differences in phenotype between the groups were explored using ANOVA models with genotype as the categorical variable. Analysis was adjusted for age, gender and age at onset (AAO) and controlled for FDR at 0.05 using the Benjamini-Hochberg method.

Results: 152 patients were tested positive for the LRRK2 mutation (age: 67.17±10.02, 50% male, AAO:58.59±10.99), 165 were mGBA (age: 66.66±9.84, 62% male, AAO:59.77±10.68), 48 were sGBA (age: 64.45±10.33, 56% male, AAO:57.66±10.62), and 23 patients had both LRRK2 and GBA mutations (age: 67.04±10.41, 34% male, AAO:58.01±8.84). Differences between groups were found in all measures except the UPDRS part IV. sGBA mutation carriers exhibited more severe motor, cognitive, autonomic and olfactory dysfunction as compared to the three other groups (<0.008). mGBA carriers showed significantly worse symptoms on all parts of the UPDRS compared to LRRK2 and LRRK2+GBA carriers, but were similar to the LRRK2+GBA group in their cognitive function. No differences were found between PD-LRRK2 and PD- LRRK2+GBA.

Conclusion: Patients with LRRK2 and GBA mutations were more symptomatically similar to LRRK2 carriers than to GBA, suggesting the dominant effect of LRRK2 over GBA in phenotypic presentation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-patients-with-both-gba-and-lrrk2-mutations-are-phenotypically-similar-to-lrrk2-a-possible-protective-effect/