PR001649 (Project)

Description:Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited mitochondrial metabolic disease of fatty acid ß-oxidation, especially in newborns. MCADD is clinically diagnosed using Newborn Bloodspot Screening (NBS) and genetic testing. Still, these methods have limitations, such as false negatives or positives in NBS and variants of uncertain significance in genetic testing. Thus, complementary diagnostic approaches for MCADD are needed. Recently, untargeted metabolomics has been proposed as a diagnostic approach for inherited metabolic diseases (IMDs) due to its ability to detect a wide range of metabolic alterations. We performed untargeted metabolic profiling of dried blood spots (DBS) from MCADD newborns (n=14) and healthy controls (n=14) to discover potential metabolic biomarkers/pathways associated with MCADD. Extracted metabolites from DBS samples were analyzed using UPLC-QToF-MS for untargeted metabolomics analyses. Multivariate and univariate analyses were used to analyze the metabolomics data, and pathway and biomarker analyses were also performed on the significantly endogenous identified metabolites. MCADD newborns had 1034 significantly dysregulated metabolites compared to healthy newborns (Moderated t-test, no correction, p-value = 0.05, FC 1.5). 23 endogenous metabolites were upregulated, while 84 endogenous metabolites were downregulated. Pathway analyses showed phenylalanine, tyrosine, and tryptophan biosynthesis as the most affected pathway. Potential metabolic biomarkers for MCADD were PGP (a21:0/PG/F1alpha) and glutathione with an area under the curve (AUC) of 0.949 and 0.898, respectively. PGP (a21:0/PG/F1alpha) was the only oxidized lipid in the top-15 biomarker list with the highest p-value and FC. Also, glutathione was chosen to indicate oxidative stress events that could happen during fatty acid oxidation defects. Our findings suggest that MCADD newborns may have oxidative stress events as signs of the disease. However, further validations of these biomarkers are needed in future studies to ensure their accuracy and reliability as complementary markers with established MCADD markers for clinical diagnosis.