Scripties UMCG - Rijksuniversiteit Groningen
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Enzymatic activity of GCase in GBA mutations and the associated phenotype in patients with Parkinson’s Disease

(2019) Gulik, M. van der (Maureen)

Parkinson’s Disease (PD) is a neurodegenerative disease with a heterogeneous clinical picture. The aggregated form of α-Synuclein (aSyn) plays a major role in its pathophysiology. The protein aSyn is normally degraded in the lysosome, therefore, lysosomal dysfunction is a proposed contributing mechanism for excess levels of the protein and aggregation. One of the reasons for this hypothesis is the association of PD with mutations in the GBA-1 (GBA) gene, which encodes for the lysosomal enzyme glucocerebrosidase (GCase). Heterozygous carriers of these mutations have an increased risk of developing PD. Carriers also develop a slightly different clinical picture than non-carriers. Furthermore, GCase activity in carriers is generally decreased, but the precise association between this activity and phenotype in PD is still quite unclear. Knowledge on the presence of an association or non-association is important for the development of personalized therapy aimed at slowing the progression of PD, by targeting GCase. In this retrospective cohort study, enzymatic activity of GCase, extracted from literature, was linked to PD clinical markers from medical records. A cohort of 3638 Dutch PD patients was genotyped in a previous study from which 96 GBA mutation carriers became available for further analysis. These patients were divided into groups based on the residual GCase activity that corresponded to their GBA mutation. Clinical phenotype in these patients was then classified in several ways, through (1) Levodopa equivalent daily dose (LEDD), (2) clinical subtype, (3) symptomatology and (4) treatment response. Differences were observed between groups but could not be statistically verified, probably due to insufficient power in this sample size. The current cohort will therefore be expanded to all GBA+ PD patients of the original cohort in the near future, which was not possible at this moment because of logistic reasons. Even though no significant results could be presented, some findings are still of interest when keeping cohort expansion in mind. One of the findings was that patients with the lowest activity of GCase had the worst prognostic markers in almost all of the variables. They presented with the highest LEDD score in all measurements, the most unfavorable clinical subtype and the largest proportion of all treatment response indicators and symptoms except for orthostatic hypotension.

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