As the name implies, the odor of urine in maple syrup urine disease (branched-chain ketonuria, or MSUD) suggests maple syrup, or burnt sugar. The biochemical defect in MSUD involves theα-ketoacid decarboxylase complex(reaction 2, Figure 1). Plasma and urinary levels of leucine, isoleucine, valine, and their cognate α-keto acids and α-hydroxy acids (reduced α-keto acids) are elevated, but the urinary keto acids derive principally from leucine. Signs and symptoms of MSUD often include ketoacidosis, neurologic derangements, mental retardation, and a maple syrup odor of urine. The mechanism of toxicity is unknown. Early diagnosis by enzymatic analysis is essential to avoid brain damage and early mortality by replacing dietary protein by an amino acid mixture that lacks leucine, isoleucine, and valine.
Fig1. The first three reactions in the catabolism of leucine, valine, and isoleucine. Note the analogy of reactions 2 and 3 to reactions of the catabolism of fatty acids. The analogy to fatty acid catabolism continues, as shown in subsequent figures.
The molecular genetics of MSUD are heterogeneous. MSUD can result from mutations in the genes that encode E1α, E1β, E2, and E3. Based on the locus affected, genetic subtypes of MSUD are recognized. Type IA MSUD arises from mutations in theE1αgene, type IB in the E1βgene, type II in theE2gene, and type III in the E3 gene (Table 1). In intermittent branched chain ketonuria, the α-ketoacid decarboxylase retains some activity, and symptoms occur later in life. In isovaleric acidemia, ingestion of protein-rich foods elevates isovalerate, the deacylation product of isovaleryl-CoA. The impaired enzyme in iso valeric acidemia is isovaleryl-CoA dehydrogenase, EC 1.3.8.4 (reaction 3, Figure 1). Vomiting, acidosis, and coma follow ingestion of excess protein. Accumulated isovaleryl-CoA is hydrolyzed to isovalerate and excreted.
Table 2 summarizes the metabolic disorders associated with the catabolism of amino acids, and lists the impaired enzyme, its IUB enzyme catalog (EC) number, a cross-reference to a specific figure, and numbered reaction in this text, and a numerical link to the Online Mendelian Inheritance in Man (OMIM) database.
Table1. Maple Syrup Urine Disease Can Reflect Impaired Function of Various Components of the α-Ketoacid Decarboxylase Complex
Table2. Metabolic Diseases of Amino Acid Metabolism
