Objective: To compare progression of motor- and non-motor symptoms in people with Parkinson’s disease (PD) with Gaucher-related gene glucocerebrosidase (GBA1) variants compared to people with PD with Parkinson’s-private GBA1 variants (variants not observed in Gaucher’s disease but contributing to a higher risk for PD).

Background: In some GBA1 variants, Gaucher’s disease, a recessive lysosomal storage disorder, is involved in PD pathogenesis. An association of those Gaucher-related GBA1 variants with progression of non-motor symptoms in PD has been reported but the role of Parkinson’s-private GBA1 variants is less clear. Analysis of longitudinal changes in motor- and non-motor symptoms in carriers of Gaucher-related compared to Parkinson’s-private GBA1 variants could elucidate their pathogenic relevance.

Method: We included longitudinal data of 733 people with typical PD. We included 29 carriers of Gaucher-related GBA1 variants (22 and 7 carriers of severe or mild variants, respectively) and 47 carriers of Parkinson’s-private GBA1 variants (PD-risk). A two-level mixed models analysis examined the interaction effect of the categorical variable “carriers of one of the three GBA1 variants” (PD-risk, mild or severe) compared to non-carriers with time since diagnosis on motor- and non-motor symptoms. To facilitate interpretation, scores were inverted to higher values indicate worse outcomes.

Results: Although the findings were not significant after Bonferroni-adjustment (p-value ≤ 0.05/(15 outcomes*3 variants)), compared to non-carriers, carrying PD-risk or severe variants was associated with faster cognitive decline. Carrying Parkinson’s-private PD-risk variants was associated with a more rapid worsening of apathy, quality of sleep, tremor and MDS-UPDRS I compared to non-carriers, while we did not observe this tendency in people with Gaucher-related mild or severe variants. Finally, we observed overall slower progression of carriers of mild variants as compared to carriers of PD-risk or severe variants in non-motor symptoms (except RBD and depression).

Conclusion: The study highlights the association of the Parkinson’s-private variants with disease progression. We cannot confirm general hypotheses of non-motor symptoms progressing faster in Gaucher-related GBA1 variants. Moreover, as progression of mild and severe variants appear to differ, we recommend separate investigation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-gaucher-related-and-parkinsons-private-gba1-variants-with-progression-of-pd-a-longitudinal-mixed-model-analysis/