Lipidomic Profiling of Red Blood Cells in the Mitochondrial Fatty Acid β-oxidation Disorder MCADD Reveals Phospholipid and Sphingolipid Dysregulation

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is characterized by the accumulation of medium-chain acylcarnitines. Despite the therapeutic approach, changes in lipid homeostasis have been reported in MCADD plasma samples. Compared to plasma lipidomics, red blood cell (RBC) profiling provides a more stable biomarker that is less influenced by dietary changes and reflects long-term metabolic alterations. In this study, we assessed the plasticity of the lipidomic profile of RBC from children with MCADD and controls using C18 liquid chromatography-mass spectrometry. The results revealed significant alterations in 240 lipid species in MCADD, highlighting an upregulation of sphingolipids (sphingomyelins and ceramides) and lysophospholipid species (lysophosphatidylcholines and lysophosphatidylethanolamines) alongside a downregulation of polyunsaturated and ether-linked phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs). Also, altered PC/PE and (PC + SM)/(PE + PS) ratios could be associated with alterations in RBC membranes properties, e.g., fluidity and asymmetry. The observed changes in the lipidome suggest compromised antioxidant defenses, enhanced oxidative stress, and an inflammatory state, with potential systemic implications in MCADD lipid metabolism and long-term complications in older age. This study underscores the utility of RBC lipidomics as a robust tool for understanding the pathophysiology of MCADD. It may prove to be a useful tool for monitoring disease progression in the near future.