Tandem mass spectrometric determination of malonylcarnitine: diagnosis and neonatal screening of malonyl-CoA decarboxylase deficiency.

Abstract

Malonic aciduria (OMIM 248360) is a rarely diagnosed autosomal-recessive inborn error of metabolism caused by congenital deficiency of malonyl-CoA decarboxylase (MCD; EC 4.1.1.9). Hypoglycemia, seizures, developmental delay, and cardiomyopathy are among the most common symptoms, but both clinical signs and the time of presentation of patients with MCD deficiency can be variable. To date, only eight cases have been reported in the literature (1)(2)(3)(4)(5)(6)(7)(8), and recently molecular defects within the MCD gene (MLYCD) have been elucidated for the first time in some of these cases (8)(9)(10)(11). At least in part, clinical heterogeneity might be caused by the fact that MCD is expressed in different compartments of the cell and that MLYCD mutations with different effects on the subcellular localization of the MCD protein may thus affect different metabolic pathways (Wightman et al., submitted for publication). To date, only symptomatic patients with MCD deficiency have been detected, and many of them were already severely handicapped at the time of diagnosis because of residues of acute metabolic crises or from episodes of cardiac decompensation, which may develop as a consequence of secondary carnitine deficiency. Typically, the key to diagnosis is the excessive amount of malonic acid in the patient’s urine, which can be detected by gas chromatography–mass spectrometry. This then leads to a confirmatory test, such as the measurement of MCD activity in cell extracts, or to molecular genetic testing. Detection of the carnitine ester of malonic acid has been mentioned previously in single cases of malonic aciduria (4)(6)(7). In the study reported here, we systematically investigated the concentration of malonylcarnitine in the …