N-Carbamylglutamate Accelerates Ureagenesis in Patients with Hyperammonemia

N-Carbamylglutamate Accelerates Ureagenesis in Patients with Hyperammonemia N Ah Mew, E Daikhin, R McCarter, I Payan, I Nissim, M Yudkoff, M Tuchman Children's Research Institute, Children's National Medical Center, Washington, DC, Children's Hospital of Philadelphia, Philadelphia, PA The urea cycle is responsible for nitrogen regulation and balance in humans. Disruption of normal urea cycle function leads to hyperammonemia, neurological sequelae and can result in death. Current treatment for hyperammonemia is based on dietary protein restriction and ammonia-scavengers, but these interventions commonly fail to prevent hyperammonemia and avert brain damage. The carbamyl phosphate synthase I (CPSI) reaction, the first and rate-limiting step of the urea cycle, requires an allosteric activator, N-acetylglutamate (NAG). A shortage of NAG causes decreased flux through CPSI and is responsible for hyperammonemia in many conditions. Though orally administered NAG is hydrolyzed in vivo, N-carbamylglutamate (NCG) is a stable analog of NAG which is resistant to hydrolysis. Objectives: In this study, we investigate the use of N-carbamylglutamate (NCG), a new therapeutic agent for a subset of hyperammonemic conditions which are caused by a deficiency of NAG, including NAG synthase deficiency, propionic acidemia (PA) and methylmalonic acidemia (MMA) as well as in partial CPSI deficiency. Methods: Urea cycle function was assessed through stable isotope C studies before and after a 3-day trial of oral NCG in a total of 14 subjects with NAGS deficiency, partial CPSI deficiency, PA or MMA. Plasma urea, ammonia, and amino acids were also measured. Results: Oral NCG improves urea cycle function and decreases plasma ammonia levels in patients with NAGS deficiency, partial CPSI deficiency, PA and MMA. In 2 patients with NAGS deficiency, peak C-urea increased from 0.25 and 0.07 μmol/l to 2.3 and 2.0 μmol/l, respectively. In our largest cohort, 7 patients with PA, C-urea peak increased from 2.2 (95% CI: 1.5-3.1) to 3.8 μmol/l (95% CI: 2.9-5.0). Conclusions: NCG may be a useful adjunct in the treatment of acute hyperammonemia of various metabolic etiologies that are due to a lack of NAG. Also, NCG can restore ureagenesis in NAG synthase deficiency and is therefore curative for patients with this condition.