Treatment of Inborn Errors of Urea Synthesis: Activation of Alternative Pathways of Waste Nitrogen Synthesis and Excretion

Children with inborn errors of urea synthesis accumulate ammonium and other nitrogenous precursors of urea, leading to episodic coma and a high mortality rate. We used alternative pathways for the excretion of waste nitrogen as substitutes for the defective ureagenic pathways in 26 infants. These pathways involve synthesis and excretion of hippurate after sodium benzoate administration, and of citrulline and argininosuccinate after arginine supplementation. The children were treated for seven to 62 months; 22 survived. The mean plasma level of ammonium (±S.E.) was 36±2 μmol per liter, and that of benzoate was 1.5±1.0 mg per deciliter. Alternative pathways accounted for between 28 and 59 per cent of the total “effective” excretion of waste nitrogen. Nineteen infants had normal height, weight, and head circumference, and 13 had normal intellectual development. Activation of alternative pathways of waste nitrogen excretion can prolong survival and improve clinical outcome in children with inborn errors of urea synthesis. (N Engl J Med. 1982; 306:1387–92.) UNTREATED inborn errors of urea synthesis are fatal when the clinical presentation is that of neonatal hyperammonemic coma.¹ Therapy with peritoneal dialysis, essential amino acids, or their nitrogen-free analogues has increased survival.² However, all but one of these infants died before one year of age.³ The physiologic defect in these patients is an inability to synthesize and excrete waste nitrogen in the form of urea. This defect allows nitrogenous precursors of urea, glutamine, alanine, and ammonium to accumulate. We designed a study to test the hypothesis that other endogenous pathways for the synthesis and excretion of waste nitrogen might substitute.