URINARY 3-HYDROXYDICARBOXYLIC ACIDS IN PATHOPHYSIOLOGY OF METABOLIC DISORDERS WITH DICARBOXYLIC ACIDURIA

Dicarboxylic aciduria occurs during increased mobilization or inhibited β-oxidation of fatty acids. In these conditions, a number of 3-hydroxydicarboxylic acids are excreted in the urine. These 3-hydroxydicarboxylic acids include 3-hydroxyadipic (3OHDC6), 3-hydroxyoctanedioic (3OHDC8), 3-hydroxydecanedioic (3OHDC10), 3-hydroxydodecanedioic (3OHDC12), and a number of unsaturated homologues. The metabolic origin of these 3-hydroxydicarboxylic acids is from the ω-oxidation of 3-hydroxy fatty acids. Subsequent β-oxidation of the dicarboxylates yields lower-chain 3-hydroxydicarboxylic acids. A new defect in fatty acid oxidation characterized by increased urinary ratios of 3OHDC6, 3OHDC12, and unsaturated 3OHDC14s relative to 3OHDC10 is described. This pattern is consistent with a defect inllong-chain 3-hydroxyacyl-CoA dehydrogenase (LHAD), which was confirmed by enzyme assay in fibroblasts. In contrast, patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency had lower ratios of 3OHDC6 and 3OHDC8 to 3OHDC10, consistent with a decreased activity of MCAD. Nonketotic dicarboxylic aciduria, other than MCAD and LHAD deficiencies, is shown to have a normal 3-hydroxydicarboxylic acid profile when compared with fasting normal controls. Since increased excretion of 3-hydroxydicarboxylic acids was observed in all patients with dicarboxylic aciduria, an increased excretion of these compounds is not an adequate criterion to suspect a defect in 3-hydroxyacyl-CoA dehydrogenases. The analysis of the metabolite ratios (3OHDC6 and 3OHDC12 relative to 3OHDC10) is a more useful indicator for defects in LHAD. © 1991.