Objective: To investigate whether glucocerebrosidase (GBA) L444P and leucine-rich repeat kinase 2 (LRRK2) G2385R and R1628P mutations are associated with different symptoms and manifesting patterns in the pre-diagnostic stage of PD.

Background: Previous studies suggested that GBA L444P mutation was associated with postural instability and gait disorders, motor complications, cognitive decline and constipation in manifesting PD; whereas the motor and nonmotor symptoms of PD patients with LRRK2 G2385R or R1628P mutations were similar to that of idiopathic PD. The features and manifesting patterns in the pre-diagnostic stage of PD patients with or without these mutations have not been examined.

Methods: PD patients were recruited from the PD cohort of the Chinese National Consortium on Neurodegenerative Diseases established by the Chinese Parkinson Study Group [1]. The occurrence and onset time of pre-diagnostic symptoms and history of environmental exposures were collected and compared between groups. Individual likelihood ratios (LR) before diagnosis were calculated according the MDS research criteria for prodromal PD [2], which were modified based on the evidence from Chinese population and were compared as indicators for PD manifestation.

Results: 1796 PD patients entered the study, including 226 patients with LRRK2 G2385R (9.89%) or R1628P (2.84%) mutation, 44 patients with GBA L444P (2.45%) mutation and 1526 patients (87.28%) without mutations. GBA-subjects had nearly 4 times higher LR at -3 years before diagnosis (P = 0.006), and more than 2 times higher LR at -2 years (P = 0.024; Table 1) than idiopathic subjects. The increase patterns of LR differed between groups: LR of LRRK2-subjects increased from 19.73 at -3 years to 80.95 at diagnosis and the value almost doubled within the last year; whereas GBA-subjects had high LR of 80.82 at -3 years which increased steadily to 137.43 at diagnosis (Table 1). Micrographia and “mask face” were the only symptoms that differed in cumulative percentage between groups before diagnosis and no significant difference in environmental exposure was found.

Conclusions: The PD manifestation of GBA L444P mutation carriers is early and gradual in the pre-diagnostic stage; while the manifestation of LRRK2 G2385R or R1628P mutation carriers tends to be radical within the last year before diagnosis, possibly representing the breakdown of compensation.

References: [1] Wang C, Cai Y, Zheng Z, et al. Penetrance of LRRK2 G2385R and R1628P is modified by common PD-associated genetic variants. Parkinsonism Relat Disord 2012;18(8):958-963.

[2] Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson’s disease. Mov Disord 2015;30(12):1600-1611.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gene-associated-differences-in-pre-diagnostic-symptoms-of-parkinsons-disease-a-retrospective-study/