C6-C10-Dicarboxylic aciduria: Biochemical considerations in relation to diagnosis of β-oxidation defects

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Abstract
By means of gas chromatographic methods substantial amounts of the C6-C10-dicarboxylic acids, i.e., adipic, suberic and sebacic acids, were found in the urine of children with unexplained attacks of lethargy and hypotonia, presumably related to episodes of fever and/or insufficient food intake. The course was once fatal and is often characterized by severe hypoglycemia without ketonuria. Systematic gas chromatographic/mass spectrometric determinations of seleted organic acid metabolites in the urine, together with enzymatic measurements in fibroblasts and clinical data from 4 patients of this category, show that the biochemical basis of this syndrome can be inborn errors of the .beta.-oxidation of fatty acids, localized to the medium-chain acyl-CoA dehydrogenation system. The biosyntheis of adipic, suberic and sebacic acids was studied using ketotic rats as the model, since ketosis in rats and humans is accompanied by excessive urinary excretion of adipic and suberic acids. A probable pathway for the production of the 3 dicarboxylic acids was an initial .omega.-oxidation of the medium-chain C10-C14-monocarboxylic acids followed by .beta.-oxidation of the resulting medium-chain dicarboxylic acids. The source of the .omega.-oxidizable monocarboxylic acids in ketosis most probably is the fat deposits, and the patients with .beta.-oxidation defects may supplement this source with .beta.-oxidation intermediate medium-chain monocarboxylic acids, accumulated as a result of the defect. The ratio between the excreted amounts of adipic acid and sebacic acid in the urine from the patients with .beta.-oxidation defects is < 50. This is in contrast to the ratio in urine from ketotic patients, where it is > 100. Adipic acid/sebacic acid ratio measured by means of a gas chromatographic analysis is therfore suggested as a tool in the diagnosis of dicarboxylic acidurias. Based on the clinical picture and the pattern of a series of organic acids in the urinary metabolic profile the four patients can be divided in 2 types of dicarboxylic aciduria. The 2 types have different therapeutic implications.