Leiden University Scholarly Publications

Heijer, J.M. den; Cullen, V.C.; Pereira, D.R.; Yavuz, Y.; Kam, M.L. de; Grievink, H.W.; ... ; Groeneveld, G.J. 2023

A biomarker study in patients with GBA1-parkinson's disease and healthy controls

Article / Letter to editor

open access

BackgroundMolecules related to glucocerebrosidase (GCase) are potential biomarkers for development of compounds targeting GBA1-associated Parkinson's disease (GBA-PD).ObjectivesAssessing... Show moreBackgroundMolecules related to glucocerebrosidase (GCase) are potential biomarkers for development of compounds targeting GBA1-associated Parkinson's disease (GBA-PD).ObjectivesAssessing variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA-PD, idiopathic PD (iPD), and healthy volunteers (HVs).MethodsData from five studies were combined. Variability was assessed of glucosylceramide (various isoforms), lactosylceramide (various isoforms), glucosylsphingosine, galactosylsphingosine, GCase activity (using fluorescent 4-methylumbeliferryl-β-glucoside), and GCase protein (using enzyme-linked immunosorbent assay) in plasma, PBMCs, and CSF if available, in GBA-PD, iPD, and HVs. GSLs in leukocyte subtypes were compared in HVs. Principal component analysis was used to explore global patterns in GSLs, clinical characteristics (Movement Disorder Society – Unified Parkinson's Disease Rating Scale Part 3 [MDS-UPDRS-3], Mini-Mental State Examination [MMSE], GBA1 mutation type), and participant status (GBA-PD, iPD, HVs).ResultsWithin-subject between-day variability ranged from 5.8% to 44.5% and was generally lower in plasma than in PBMCs. Extracellular glucosylceramide levels (plasma) were slightly higher in GBA-PD compared with both iPD and HVs, while intracellular levels were comparable. GSLs in the different matrices (plasma, PBMCs, CSF) did not correlate. Both lactosylceramide and glucosylsphingosine were more abundant in granulocytes compared with monocytes and lymphocytes. Absolute levels of GSL isoforms differed greatly. GBA1 mutation types could not be differentiated based on GSL data.ConclusionsGlucosylceramide can stably be measured over days in both plasma and PBMCs and may be used as a biomarker in clinical trials targeting GBA-PD. Glucosylsphingosine and lactosylceramide are stable in plasma but are strongly affected by leukocyte subtypes in PBMCs. GBA-PD could be differentiated from iPD and HVs, primarily based on glucosylceramide levels in plasma. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less

Heijer, J.M. den; Cullen, V.C.; Quadri, M.; Schmitz, A.; Hilt, D.C.; Lansbury, P.; ... ; Groeneveld, G.J. 2020

A large-scale full GBA1 gene screening in Parkinson's disease in the Netherlands

Article / Letter to editor

open access

Background The most common genetic risk factor for Parkinson's disease known is a damaging variant in theGBA1gene. The entireGBA1gene has rarely been studied in a large cohort from a single... Show moreBackground The most common genetic risk factor for Parkinson's disease known is a damaging variant in theGBA1gene. The entireGBA1gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entireGBA1gene in Parkinson's disease from a single large population. Methods TheGBA1gene was assessed in 3402 Dutch Parkinson's disease patients using next-generation sequencing. Frequencies were compared with Dutch controls (n = 655). Family history of Parkinson's disease was compared in carriers and noncarriers. Results Fifteen percent of patients had aGBA1nonsynonymous variant (including missense, frameshift, and recombinant alleles), compared with 6.4% of controls (OR, 2.6;P < 0.001). Eighteen novel variants were detected. Variants previously associated with Gaucher's disease were identified in 5.0% of patients compared with 1.5% of controls (OR, 3.4;P < 0.001). The rarely reported complex allele p.D140H + p.E326K appears to likely be a Dutch founder variant, found in 2.4% of patients and 0.9% of controls (OR, 2.7;P= 0.012). The number of first-degree relatives (excluding children) with Parkinson's disease was higher in p.D140H + p.E326K carriers (5.6%, 21 of 376) compared with p.E326K carriers (2.9%, 29 of 1014); OR, 2.0;P= 0.022, suggestive of a dose effect for differentGBA1variants. Conclusions Dutch Parkinson's disease patients display one of the largest frequencies ofGBA1variants reported so far, consisting in large part of the mild p.E326K variant and the more severe Dutch p.D140H + p.E326K founder allele. (c) 2020 International Parkinson and Movement Disorder Society Show less