Objective: To evaluate the symptoms of Parkinson’s disease (PD) and time to diagnosis in single and dual carriers of LRRK2 G2019S and GBA N370S.

Background: Variants in the LRRK2 and GBA genes are the most common cause of monogenic PD. Little is known about the phenotype of dual carriers but data from small clinical cohorts suggest that the combination of both variants may be less severe.

Method: This longitudinal cohort study combined prospective data from the 23andMe Research Cohort and Fox Insight Study that included 7,879 LRRK2 G2019S carriers, 33,852 GBA N370S carriers, 216 LRRK2 G2019S/GBA N370S dual carriers, and 6.8 million non-carriers with and without PD. Symptoms were collected on surveys across 3, 6, or 12 month intervals. Disease-free survival was estimated using accelerated failure time modeling. Differences between groups were assessed using linear and logistic regression. All analyses were adjusted for sex and education. Non-carriers with PD and non-carriers served as the reference group in regressions and survival analyses, respectively.

Results: GBA carriers reported an earlier age of PD diagnosis (Mean=59.3 years, SEM=±.5) than LRRK2 (61.5 ± .47, p=.01) and non-carriers (61.5 ± .07, p<.001). The average age of PD diagnosis for dual carriers was 60.1 years (SEM=1.8). The predicted cumulative incidence of PD by the age of 70 was 2% in non-carriers, 4% in GBA carriers, 19% in LRRK2 carriers, and 34% in LRRK2/GBA dual carriers. Relative to non-carriers with PD, GBA-PD cases reported higher rates of REM behavior disorder (RBD, 34% vs. 26%, p<.001) and hyposmia (54% vs. 45%, p=.02), but a similar prevalence of hallucinations (both 15%). Relative to non-carriers with PD, LRRK2-PD cases were less likely to report non-motor symptoms (RBD 14% vs. 26%, p<.001; hyposmia 31% vs. 45%, p<.001), hallucinations (7% vs. 15%, p=.01), and bradykinesia (76% vs. 82%, p=.03). Symptoms in dual carriers were more variable and trended towards the less severe LRRK2 phenotype.

Conclusion: Dual LRRK2/GBA carriers were at higher risk of PD than LRRK2 or GBA carriers. Consistent with the literature, GBA N370S carriers reported the earliest age of PD diagnosis with a higher burden of non-motor symptoms consistent with a pattern of widespread neuronal degeneration extending to the olfactory bulb, pons, and cortex. LRRK2 G2019S carriers reported a less severe non-motor PD phenotype consistent with a more restricted pattern of neurodegeneration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-and-gba-founder-mutations-and-their-interactions-in-parkinsons-disease/