Objective: To investigate the association of GBA variants with pre-diagnostic features of Parkinson’s disease (PD) within the PREDICT-PD cohort.

Background: Subtle motor and non-motor symptoms can occur before PD is diagnosed according to clinical criteria. GBA mutations are the most common known genetic risk factor for PD and non-manifesting GBA carriers have increased levels of depression, RBD, hyposmia and cognitive dysfunction than non-GBA-carriers (Beavan 2015). The PREDICT-PD study aims to define a group at higher risk of PD using an algorithm compromised of risk factors and early non-motor identified through systematic review. Subjects aged between 60-80 years at baseline have been tested annually since 2011, predominantly via the internet using questionnaires, and objective smell (UPSIT) and alternative tapping (BRAIN-tap) tests (Noyce 2013).

Methods: Sanger sequencing of exons 8-11 of the GBA gene was undertaken in DNA obtained from saliva. Samples were also screened for the G2019S LRRK2 mutation. Baseline data were compared between carriers of GBA mutations and age- and gender-matched non-carriers (1:3 ratio cases to controls). Fisher’s exact test was used to compare proportions between groups.

Results: GBA variants were found in 45 participants (23 E326K, 12 T369M, 8 N370S, 1 R463C, 1 Rec/Ncil) and these were matched with 135 non-GBA, non-LRRK2 controls. Average age of cases and controls was 67.6 years and females comprised 53.3% of each group (males 46.7%). There were no significant differences between carriers and non-carriers in terms of subjective non-motor and motor features, or environmental risk factors for PD. Neither were there differences in the proportion of those meeting the cut-offs for RBD as assessed using the RBD screening questionnaire (RBDSQ) or alternate finger taps. Hyposmia was found in a significantly higher proportion of GBA carriers (23.5%) than in non-carriers (8.5%; p=0.018).

Conclusions: These data support previous reports of hyposmia occurring in GBA variant carriers that do not have overt motor features of PD. That similar differences were not observed for other pre-diagnostic features may be explained by the high proportion of milder variants included, the subjective nature of reporting features or that controls from the cohort may be more likely to have pre-diagnostic features than the general population.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-association-of-gba-variants-with-pre-diagnostic-features-of-pd-in-the-predict-pd-cohort-a-nested-case-control-study/