Identification of 19 New Metabolites Induced by Abnormal Amino Acid Conjugation in Isovaleric Acidemia

Isovaleric acidemia (IVA) is an autosomal recessive genetic disorder of the enzyme isovaleryl-CoA dehydrogenase, which is involved in leucine metabolism (1). Clinical symptoms include poor feeding, tachypnea, vomiting (2), listlessness, lethargy, coma (2)(3), and dehydration (4). Individuals homozygous for this defect are characterized primarily by the excretion of isovalerylglycine (2). The metabolic profile may be further complicated by intermediate metabolites such as 3- and 4-hydroxyisovaleric acid (5), methylsuccinic acid (6), methylfumaric acid (7), isovalerylglucuronide (8), isovalerylglutamic acid (9), N -isovalerylalanine and N -isovalerylsarcosine (10), isovalerylcarnitine (11), 3-hydroxyisoheptanioc acid (12), and alloisoleucine (4). Diagnosis of IVA is based on clinical symptoms and the presence of isovalerylglycine and 3-hydroxyisovaleric acid (13), with some of the above-mentioned metabolites also occurring to a greater or lesser extent (4). Despite the large number of already identified excreted metabolites, their occurrence still does not entirely explain all of the clinical symptoms experienced by these patients. The statement made in 1982 by Duran et al. (14) that “[t]he continuing search for ‘new’ metabolites may eventually lead to a better understanding of the relationship between the clinical conditions and their biochemical abnormalities” is the motivation for our search for previously unidentified metabolites in IVA. In this study, we analyzed the urine of IVA patients for the presence of induced amino acid metabolites not previously identified in IVA.Most of the amino acid conjugates occurring in the …