Management of Inherited Disorders of Ureagenesis

The conversion of ammonia to urea is known to require the function of at least nine proteins. Five of these are urea cycle enzymes (carbamyl phosphate synthetase I, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, and arginase). A sixth enzyme (N-acetylglutamate synthase) catalyzes the formation of N-acetylglutamate, a cofactor for carbamyl phosphate synthetase I. The remaining three proteins are amino acid transporters for ornithine, aspartate/glutamate, and dibasic amino acids, respectively. An inherited deficiency in any of these proteins causes a block in the urea cycle and resultant hyperammonemia. Although the severity of these disorders varies, symptoms, diagnostic testing, and treatments are similar. Common symptoms include episodes of vomiting, lethargy, and coma associated with hyperammonemia. Diagnosis is based on a combination of measurement of plasma ammonia, plasma and urinary amino acids, urinary orotic acid, enzyme analysis, and molecular testing. Therapy involves a nitrogen-restricted diet, supplementation of essential amino acids and l-citrulline/l-arginine (except for hyperargininemia [l-citrulline is not approved by the United States Food and Drug Administration]), alternative pathway therapy with phenylbutyrate (or phenylacetate and benzoate), and, for the most severe cases, liver transplantation.