Objective: To measure plasma glucosylsphingosine levels in heterozygous carriers with and without Parkinson’s disease (PD) of three variants in GBA1: 1. E326K (risk factor for PD that does not cause Gaucher’s disease), 2. N370S (mild GBA1 mutation), and 3. L444P (severe GBA1 mutation) [1].

Background: Heterozygous mutations in the GBA1 gene encoding glucocerebrosidase are a risk factor for PD. Plasma glucosylsphingosine levels (a glucocerebrosidase substrate) have previously been shown to be higher in GBA1 N370S mutation carriers and may be a clinically meaningful biomarker for glucocerebrosidase enzymatic function [2].

Method: Glucosylsphingosine, glucosylceramide, as well as three other lipids were quantified in plasma from E326K (n = 22), N370S (n = 29) and L444P (n = 15) heterozygotes with or without PD, healthy controls (n = 45), and idiopathic PD (n = 26) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted quantification. Plasma specimens were spiked with stable isotopically labeled lipid standards prior to methanol/chloroform extraction. Separation was achieved by hydrophilic interaction liquid chromatography using a Waters Acquity UPLC, and targeted quantification performed by multiple reaction monitoring using a SciEx QTRAP 5500 mass spectrometer.

Results: Plasma glucosylsphingosine concentration was significantly higher in L444P (0.634 ng/ml; p = 0.002), N370S (0.590 ng/ml; p = 0.002) and E326K (0.591 ng/ml; p = 0.007) heterozygotes compared to noncarriers (0.456 ng/ml), independent of disease status. While nominally glucosylsphingosine levels were higher in L444P carriers than in E326K or N370S carriers, results were not statistically significant. PD status was not associated with glucosylsphingosine levels in either group.

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Conclusion: Elevated plasma glucosylsphingosine is observed in heterozygous carriers of GBA1 variants with different pathogenicity (risk variant, mild and severe mutations), confirming the reduced glucocerebrosidase enzymatic activity previously observed in E326K carriers [3]. Larger studies may be required to test if concentrations are different among carriers of different GBA1 mutations.

References: 1. Huh YE, Chiang MSR, Locascio JJ, Liao Z, Liu G, Choudhury K, Kuras YI, Tuncali I, Videnovic A, Hunt AL, Schwarzschild MA, Hung AY, Herrington TM, Hayes MT, Hyman BT, Wills AM, Gomperts SN, Growdon JH, Sardi SP, Scherzer CR. β-Glucocerebrosidase activity in GBA-linked Parkinson disease: The type of mutation matters. Neurology. 2020 Aug 11;95(6):e685-e696. doi: 10.1212/WNL.0000000000009989. Epub 2020 Jun 15. PMID: 32540937; PMCID: PMC7455354.

2. Surface M, Balwani M, Waters C, Haimovich A, Gan-Or Z, Marder KS, Hsieh T, Song L, Padmanabhan S, Hsieh F, Merchant KM, Alcalay RN. Plasma Glucosylsphingosine in GBA1 Mutation Carriers with and without Parkinson’s Disease. Mov Disord. 2022 Feb;37(2):416-421. doi: 10.1002/mds.28846. Epub 2021 Nov 6. PMID: 34741486; PMCID: PMC8840974.

3. Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B, Kuo SH, Mazzoni P, Pauciulo MW, Nichols WC, Gan-Or Z, Rouleau GA, Chung WK, Wolf P, Oliva P, Keutzer J, Marder K, Zhang X. Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain. 2015 Sep;138(Pt 9):2648-58. doi: 10.1093/brain/awv179. Epub 2015 Jun 27. PMID: 26117366; PMCID: PMC4564023.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/plasma-glucosylsphingosine-in-gba1-e326k-n370s-and-l444p-mutation-carriers-with-and-without-parkinsons-disease/