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Deficiency of propionyl-CoA carboxylase causes propionic acidemia and deficiencies of methylmalonyl-CoA mutase or its cofactor adenosylcobalamin cause methylmalonic acidemia. These inherited disorders lead to pathological accumulation of propionyl-CoA which is converted in Krebs cycle to methylcitrate (MCA) in a reaction catalyzed by citrate synthase. In healthy individuals where no propionyl-CoA accumulation occurs, this enzyme drives the condensation of acetyl-CoA with oxaloacetate to produce citric acid (CA), a normal Krebs cycle intermediate. The competitive synthesis of CA and MCA through the same enzymatic mechanism implies that increase in MCA production is accompanied by decrease in CA levels. In this study, we assessed MCA concentration and the ratio of MCA/CA as plausible markers for propionic and methylmalonic acidemias. We measured MCA and CA in dried blood spots using liquid chromatography tandem mass spectrometry. The reference ranges of MCA, CA and MCA/CA in 123 healthy individuals were ≤0.63 µmol/L, 36.6–126.4 µmol/L and 0.0019–0.0074, respectively. In patients with propionic and methylmalnic acidemias (n = 7), MCA concentration ranged between 1.0–12.0 µmol/L whereas MCA/CA was between 0.012–0.279. This is the first report to describe the potential role of MCA and MCA/CA in dried blood spots as diagnostic and monitoring biomarkers for inherited disorders of propionyl-CoA metabolism.

Assessment of methylcitrate and methylcitrate to citrate ratio in dried blood spots as biomarkers for inborn errors of propionate metabolism