Untargeted Metabolomic Analysis Hits the Target (Editorial‪)‬

Propionic (PA) and methylmalonic (MMA) acidemias are inborn errors of the metabolism of several important amino acids, the side chain of the cholesterol molecule, and dietary odd chain-length fatty acids. PA results from a deficiency of mitochondrial propionyl-CoA carboxylase, an enzyme that requires biotin as a cofactor and converts propionyl-CoA to D-methylmalonyl-CoA. Classical MMA results from deficiency of methylmalonyl-CoA mutase, a cobalamin- (vitamin [B.sub.12]) dependent enzyme, which converts L-methylmalonyl-CoA to succinyl-CoA. The 2 enzymes are almost adjacent in this important metabolic pathway, and the 2 defects are very similar from the perspective of clinical presentation and metabolic biomarkers (1). For example, in expanded screening programs for metabolic diseases in newborns, observation of increased propionyl-carnitine (C3-carnitine) by tandem mass spectrometric analysis is predictive of the occurrence of both defects (2). Currently, the 2 defects are differentiated biochemically with targeted analysis by gas chromatography/mass spectrometry of characteristic urinary organic acid. Specifically, large amounts of MMA acid and several propionate metabolites are found in the urine from patients with MMA, whereas increased MMA acid has not been found in tests of urine, and more recently dried blood spots, from patients with PA (3). Although both of these disorders have been studied for more than 4 decades, several features and metabolic issues remain unresolved. Before the introduction of diagnostic methods to measure urinary organic acids, these disorders were defined as a syndrome called ketotic hyperglycinemia (4). The mechanism that leads to increased blood glycine has never been determined, and most patients remain hyperglycinemic throughout life. It is not known if hyperglycinemia contributes at all to the phenotype. It has been established, however, that several alternate pathways of propionyl-CoA metabolism that exist as minor pathways in healthy individuals are used extensively in patients with these diseases. The extent to which the use of these alternative pathways leads to the clinical phenotype has not been determined. One of these alternate pathways involves the condensation of propionyl-CoA with oxaloacetate to form methylcitrate. This pathway uses enzymes of the Krebs cycle (5). Whether this additional input into a vital metabolic pathway is beneficial or harmful is not known.