Omar Shalaby

 Introduction: Mutations in the GBA gene are implicated in lysosomal storage diseases such as Gaucher disease but may also be important in the pathogenesis of Parkinson’s disease. Loss of function mutations in the GBA gene, which codes for glucocerebrosidase, have been shown to increase the risk of Parkinson’s disease across a wide spectrum, from 1.4 to 10x increase in risk. These loss of function mutations lead to the accumulation of glucosylsphingosine and glucosylceramide. Increased levels of these two lipids have been shown to promote α-synuclein aggregates in the brain.⁷ This risk increase is most associated with the SNCA, LRRK2, and GBA genes.⁵ Aside from increasing risk of disease, mutations in these genes may also – Other loss of function mutations, in genes such as CTSD, SLC17A5, SNCA, LRRK2 and ASAH1, have also been considered potential candidates for Parkinson’s disease risk modulators.¹ Certain populations may have a higher incidence of Parkinson’s disease due to an increased prevalence of GBA gene mutations.⁴

Methods: Many articles and primary sources were reviewed to investigate the role of GBA gene loss of function mutations in the progression of Parkinson’s disease. In one such experiment that was performed, the association between lysosomal storage disorder variants was robust to the exclusion of GBA.¹ The two main GBA mutations associated with Parkinson’s disease are N370S and L444P, and the two main polymorphic variants are E326K and T369M.³ Patients with mutations and polymorphic mutations were compared to patients without mutations and it was discovered that those with mutations experienced affective disorders such as depression and anxiety were more expressed in the mutant GBA=PD group (p=0.001).³ Cognitive impairment measured with MMSE was more marked in single mutant GBA-PD patients (p=0.022). Differences in motor and non-motor clinical symptoms between pGBA-PD and mGBA-PD groups were not found.³

Results: GBA gene mutations are associated with a 6-10 fold risk increase for Parkinson’s disease, and patients with polymorphic variants were associated with a two-fold risk increase.³ Non-motor symptoms assessed with the PD-NMS were more expressed in the polymorphic GBA-PD patients (p=0.007) and in the total group with GBA=PD (0.014) compared to sPD.³ Analysis of Parkinson’s disease genetic risk score increases showed that increased genetic risk score not only increases the risk for Parkinson’s disease, but can also decrease age of onset of Parkinsonian symptoms.⁵

Conclusion: This study, as well as many others, confirms the linkage between GBA gene mutations, such as N370S and L444P, and earlier onset and worse symptoms of Parkinson’s disease. Other studies demonstrate a linkage between Type 1 Gaucher’s disease and Parkinson’s disease.⁸ Polymorphic mutations, such as E326K and T369M, can lead to worse outcomes than those with monomorphic mutations.³

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