AUTHOR=Chen Chen , Lou Min-Min , Sun Yi-Min , Luo Fang , Liu Feng-Tao , Luo Su-Shan , Wang Wen-Yuan , Wang Jian 

TITLE=Serum metabolomic characterization of PLA2G6-associated dystonia–parkinsonism: A case-control biomarker study

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 16 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.879548

DOI=10.3389/fnins.2022.879548

ISSN=1662-453X

ABSTRACT=Introduction: Phospholipase A2 Group VI (PLA2G6), encoding calcium-independent phospholipase A2, has been isolated as the gene responsible for an autosomal recessive form of early-onset Parkinson's disease (namely, PARK14). Compared to idiopathic Parkinson's disease (iPD), PARK14 has several atypical clinical features. PARK14 has an earlier age at onset and is more likely to develop levodopa-induced dyskinesia. In iPD, serum metabolomics have observed alterations in several metabolic pathways that are related to disease status and clinical manifestations. The aim of this study is to describe the serum metabolomics features for PARK14 patients. 
Design: This case-control biomarker study tested nine patients diagnosed as PARK14. Eight age and sex-matched healthy subjects were recruited as controls. To evaluate the influence of single heterozygous mutation, we enrolled eight healthy one-degree family members of the PARK14 patients, two patients diagnosed with early-onset Parkinson's disease (EOPD) who had only single heterozygous PLA2G6 mutation and one EOPD patient without any known pathogenic mutation. 
Methods: The diagnosis of PARK14 was made according to the diagnostic criteria for Parkinson's disease and confirmed by genetic testing. To study the serum metabolomics features, we analyzed participants’ serum using UHPLC-QTOF/MS analysis, a well-established technology. 
Results: We quantified 50 compounds of metabolites from the serum of all the study subjects. Metabolites alterations in serum had good predictive accuracy for PARK14 diagnose (AUC 0.903) and advanced stage in PARK14 (AUC 0.944). Of the 24 metabolites that changed significantly in patients’ serum, eight related to lipid metabolism. Oleic acid and Xanthine were associated with MMSE scores. Xanthine, L-Histidine and Phenol correlated with UPDRS-III scores. Oleic-acid and 1-Oleoyl-L-alpha-lysophosphatidic acid could also predict the subclass of more advanced stage in PLA2G6 Group in ROC models.  
Conclusion: The significantly altered metabolites can be used to differentiate PLA2G6 pathogenic mutations and predict disease severity. Patients with PLA2G6 mutations had elevated lipid compounds with C18:1 and C16:0 group. The alteration of lipid metabolism might be the key intermediate process in PLA2G6-related disease that need further investigation.