Serum Metabolic and Lipidomic Changes in Marfan Syndrome Patients

Background/Objectives: Marfan syndrome (MFS) is a hereditary connective tissue disorder caused by mutations in the fibrillin-1 gene, affecting both extracellular matrix integrity and metabolic regulation. Recent studies have linked MFS to altered phospholipid metabolism. Diagnosis remains challenging due to broad clinical variability and phenotypic overlap with similar conditions, underscoring the need for improved diagnostic approaches, particularly in children and sporadic cases without family history. Methods: In total, 79 serum samples (49 MFS; 30 control) were subjected to untargeted lipidomic and metabolomic analysis to gain a closer insight into the downstream metabolic processes of the pathophysiology of MFS. Measurements were conducted on an ultra-high-performance liquid chromatography (UHPLC) system coupled to an orbital-trapping mass spectrometer. Data were subjected to statistical analysis and corresponding metabolic pathway analysis. Results: LC-MS analysis revealed 1076 annotated analytes across lipid and low-molecular-weight metabolite classes. Statistical comparison between MFS patients and controls indicated six analytes that were significantly altered after FDR correction: two putative sterols (ST 28:1;O, ST 27:1;O), one phosphatidylcholine (PC 26:0;O2), one diacylglycerol (DG 36:4), 25-hydroxycholecalciferol, and pseudouridine. Lipid species were predominantly downregulated, whereas pseudouridine and 25-hydroxycholecalciferol were upregulated. Subgroup analyses based on BMI, age, and symptom severity revealed additional altered analytes, predominantly downregulated lipids. Pathway analyses indicated disrupted phospholipid metabolism, particularly affecting PC, LPC, and DAG pathways. Conclusions: This study identified metabolic alterations in MFS patients associated with cholesterol homeostasis, TGF-β signalling, and phospholipid metabolism. The analytes of interest provide insights into MFS pathophysiology and represent candidate biomarkers that warrant further validation in independent patient cohorts.