Background Genetic stratification of Parkinson's disease (PD) patients facilitates gene‐tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants. Methods Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD‐linked genes, and (3) genome sequencing. Results Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers. Conclusions The ROPAD screening protocol is feasible for high‐throughput genetic characterization of PD participants and subsequent prioritization for gene‐focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Gaucher disease (GD) is a lysosomal storage disorder resulting from a biallelic mutation in the gene GBA1, leading to deficiencies in the enzyme β-glucocerebrosidase (Gcase). Inabilities of the Gcase to catabolize its substrate result in the accumulation of sphingolipids in macrophages, which impairs the cell functions and ultimately leads to multisystemic clinical manifestations. Important variability in symptoms and manifestations may lead to challenging diagnosis and patient care. Plasma glucosylsphingosine (lyso-Gb 1 ) is a biomarker frequently used for prognosis, monitoring, and patient follow-up. While lyso-Gb 1 appears to be a valid biomarker, few studies have investigated other matrices for potential GD biomarkers. The main objective of this study was to investigate the urine matrix as a potential source of new GD biomarkers by performing a metabolomic study using time-of-flight mass spectrometry. Our study highlighted a significant increase of eight urinary lyso-Gb 1 analogues. Moreover, a novel class of biomarkers, named polycyclic lyso-Gb 1 analogues, was identified. These four new molecules were more elevated than lyso-Gb 1 and related analogues in urine specimens of GD patients. Further investigations are warranted to validate the efficiency of these newly found biomarkers on a larger cohort of Gaucher patients and to compare them with plasma biomarkers currently quantified in clinical laboratories.
Aim: Gaucher disease (GD) is caused by a deficiency of the lysosomal enzyme acid β-glucocerebrosidase. Recent metabolomic studies highlighted several new metabolites increased in the plasma of GD patients. We aimed to develop and validate a UPLC–MS/MS method allowing a relative quantitation of lyso-Gb1 and lyso-Gb1 analogs -28, -12, -2, +14, +16 and +18 Da in addition to sphingosylphosphorylcholine, N-palmitoyl- O-phosphocholine to study potential correlations with clinical manifestations. Methodology & results: Following solid-phase extraction, plasma samples were evaporated and resuspended in 100 μl of resuspension solution. Three microliter is injected into the UPLC–MS/MS for analysis. Conclusion: All biomarkers studied were increased in GD patients. Significant correlations were observed between specific analogs and hematological, and visceral complications, as well as overall disease severity.
Gaucher disease is a rare inherited disorder caused by a deficiency of the lysosomal acid beta-glucocerebrosidase enzyme. Metabolomic studies by our group targeted several new potential urinary biomarkers. Apart from lyso-Gb1, these studies highlighted lyso-Gb1 analogs −28, −26, −12 (A/B), +2, +14, +16 (A/B), +30, and +32 Da, and polycyclic lyso-Gb1 analogs 362, 366, 390, and 394 Da. The main objective of the current study was to develop and validate a robust UPLC-MS/MS method to study the urine distribution of these biomarkers in patients. Method: Urine samples were purified using solid-phase extraction. A 12 min UPLC-MS/MS method was developed. Results: Validation assays revealed high precision and accuracy for creatinine and lyso-Gb1. Most lyso-Gb1 analogs had good recovery rates and high intra- and interday precision assays. Biomarker-estimated LOD and LOQ levels ranged from 56–109 pM to 186–354 pM, respectively. Comparison between GD patients and healthy controls showed significant differences in most biomarker levels. Typically, treated GD patients presented lower biomarker levels compared to untreated patients. Conclusions: These data suggest that the metabolites investigated might be interesting GD biomarkers. More studies with a larger cohort of patients will be needed to better understand the clinical significance of these GD biomarkers.
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