Abstract
Very long-chain acylcarnitine dehydrogenase deficiency (VLCADD) is a rare inherited metabolic disorder associated with fatty acid β-oxidation and characterized by genetic mutations in the ACADVL gene and accumulations of acylcarnitines. VLCADD, developed in neonates or later adults, can be diagnosed using newborn bloodspot screening (NBS) or genetic sequencing. These techniques have limitations, such as a high false discovery rate and variants of uncertain significance (VUS). As a result, an extra diagnostic tool is needed to deliver improved performance and health outcomes. As VLCADD is linked with metabolic disturbance, we postulated that newborn patients with VLCADD could display a distinct metabolomics pattern compared to healthy newborns and other disorders. Herein, we applied an untargeted metabolomics approach using liquid chromatography-high resolution mass spectrometry (LC-HRMS) to measure the global metabolites in dried blood spot (DBS) cards collected from VLCADD newborns (n = 15) and healthy controls (n = 15). Two hundred and six significantly dysregulated endogenous metabolites were identified in VLCADD, in contrast to healthy newborns. Fifty-eight and one hundred and eight up- and down-regulated endogenous metabolites were involved in several pathways such as tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, amino sugar and nucleotide sugar metabolism, pyrimidine metabolism and pantothenate, and CoA biosynthesis. Furthermore, biomarker analyses identified 3,4-Dihydroxytetradecanoylcarnitine (AUC = 1), PIP (20:1)/PGF1alpha) (AUC = 0.982), and PIP2 (16:0/22:3) (AUC = 0.978) as potential metabolic biomarkers for VLCADD diagnosis. Our findings showed that compared to healthy newborns, VLCAADD newborns exhibit a distinctive metabolic profile, and identified potential biomarkers that can be used for early diagnosis, which improves the identification of the affected patients earlier. This allows for the timely administration of proper treatments, leading to improved health. However, further studies with large independent cohorts of VLCADD patients with different ages and phenotypes need to be studied to validate our potential diagnostic biomarkers and their specificity and accuracy during early life.