<b><i>LRRK2, GBA </i></b>and<b><i> SMPD1 </i></b>Founder Mutations and Parkinson's Disease in Ashkenazi Jews

Abstract

Background/Aim: Parkinson's disease (PD) is associated with mutations in LRRK2, GBA, and SMPD1 genes. We describe the clinical characteristics of PD patients related to their carrier status of the Ashkenazi founder mutations in the aforementioned genes. Methods: Ashkenazi PD patients (n = 270) were recruited following informed consent, and tested for the founder Ashkenazi mutations in the above genes. Clinical characteristics were compared between carriers and noncarriers. Homozygotes for mutations in GBA or LRRK2, and those who carried mutations in two causative genes were excluded from the analysis. Results: Five (1.85%), 54 (20%), and 22 (8.1%) PD patients carried mutations in SMPD1, GBA or LRRK2, respectively. By post hoc Bonferroni analysis, GBA carriers were singled at a significantly earlier age at diagnosis compared to noncarriers (58.06 ± 10.84 and 62.65 ± 10.86 years, respectively; p = 0.036), and due to bilateral manifestation at diagnosis compared to all other PD groups (n = 8, 15.7% compared to n = 2, 1.1%, respectively; p < 0.001). Other clinical manifestations were comparable between groups. Conclusion: Although only GBA mutation carriers, compared to noncarriers, reached statistical significance regarding age at diagnosis, it appears that LRRK2 and SMPD1 mutation carriers may reach significance with larger group numbers.

An Exploratory Study Using Electronic Medical Records to Assess the Feasibility of Establishing Cohorts of Patients with Genetic Causes of Parkinson’s Disease

“…In this study, the percentage of participants who reported a family history of PD and the percentage of LRRK2 and GBA mutations among the AJ PD population was lower than anticipated. Specifically, the observed frequency of LRRK2 and GBA mutations among overall PD cases of AJ ancestry was approximately 7% and 11%, respectively (Table 2), compared to previous publications showing approximately 10-20% for LRRK2 (p.(Gly2019Ser)) and 12-20% for aggregate GBA mutations [4,5,[9][10][11][12][13][14][15]. It is unclear why the observed frequencies of the mutations in this study were lower than expected based on prior estimates.…”

High Glucosylceramides and Low Anandamide Contribute to Sensory Loss and Pain in Parkinson's Disease

“…Importantly, low GBA1 activity has been observed in PD patients carrying or not carrying GBA1 mutations, 75 suggesting that a loss of GBA1 activity is highly prevalent in PD and possibly contributes to the development or progression to PD‐associated sensory neuropathy 74 . Indeed, we found similarly elevated levels of glucosylceramides in both our patient populations, although known GBA1 mutations are frequent in Jews 76,77 but rare in German PD patients. Accumulation of glucosylceramides in lysosomes may result in defects of lysosomal trafficking 78,79 membrane leaks and possibly expelling of GlcCer‐laden lysosomes, which would explain high extracellular levels in plasma.…”

The Complicated Relationship between Gaucher Disease and Parkinsonism: Insights from a Rare Disease

“…Genetic studies of patients with PD indicate that mutations in sphingomyelin phosphodiesterase 1 which cause Niemann-Pick disease may be more frequent than in controls, although larger studies are still required. (Dagan et al, 2016; Mao et al, 2017). A recent study in the Twitcher mouse model of Krabbe disease demonstrated α-syn aggregation in the brain and possible dysfunction in synaptic function, which was believed to be associated with the altered lipid profile (Marshall & Bongarzone, 2016).…”