The overall objective of this project is to determine whether treatment of acute hyperammonemia with N-carbamyl-L-glutamate (NCG) in propionic acidemia (PA), methylmalonic acidemia (MMA), carbamyl phosphate synthetase 1 deficiency (CPSD) and ornithine transcarbamylase deficiency (OTCD) changes the clinical outcome of disease.
The specific aims are: 1. To determine whether NCG treatment of acute hyperammonemia in severe, neonatal-onset PA and MMA improves neurodevelopmental outcome, and whether it is safe. 2. To determine whether NCG treatment of acute hyperammonemia accelerates the resolution of hyperammonemia and clinical recovery in patients with severe PA and MMA and in those with partial CPSD and OTCD, and whether it is safe. 3. To determine whether, in metabolically stable patients, the effect of a 3-day NCG treatment on ureagenesis is predictive of the outcomes observed in Aims 1 and 2. This is a double blind, placebo controlled trial performed in seven children's hospitals across the country. The primary outcome measure for Aim 1 is neurocognitive development assessed using age-appropriate specific neurodevelopmental instruments. Primary outcomes of Aim 2 include the effect of NCG on the pace of resolution of hyperammonemia and its clinical symptoms and the length of hospitalization.
The Aim 3 outcome is an assessment of the correlation between the short-term effect of NCG on ureagenesis rate and the clinical response to NCG long term and in acute clinical settings as determined by Aims 1 and 2. Our hypothesis is that NCG will improve clinical outcome in these disorders. These studies are designed to provide scientific evidence for NCG efficacy and safety which can be used to expand the indication of this drug, leading to FDA approval.

Public Health Relevance

Elevated ammonia levels in the blood can cause severe brain damage, developmental disabilities and can be fatal. N-acetylglutamate (NAG) is a small molecule in the liver that is essential for the urea cycle, keeping blood ammonia levels below levels that are toxic to the brain. We now have strong preliminary evidence that N- carbamylglutamate (Carbaglu), a chemical that is very similar to NAG, but that, unlike NAG, is not broken down in the body, can mimic the effect of NAG to decrease ammonia levels in patients with a number of inherited metabolic diseases. This project will investigate whether Carbaglu can improve the clinical outcome and reduce or prevent brain damage from ammonia in patients with four different genetic diseases associated with high ammonia levels. If the results confirm our hypothesis, these patients can be treated with Carbaglu to keep their ammonia level at normal or close to normal levels, protecting them from brain damage.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GGG-N (02))
Program Officer
Oster-Granite, Mary Lou
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Research Institute
United States
Zip Code
Shi, Dashuang; Zhao, Gengxiang; Ah Mew, Nicholas et al. (2017) Precision medicine in rare disease: Mechanisms of disparate effects of N-carbamyl-l-glutamate on mutant CPS1 enzymes. Mol Genet Metab 120:198-206
Opladen, Thomas; Lindner, Martin; Das, Anibh M et al. (2016) In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis. Mol Genet Metab 117:19-26
Shinnar, Shlomo; Cnaan, Avital; Hu, Fengming et al. (2015) Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial. Neurology 85:1108-14
Ah Mew, Nicholas; McCarter, Robert; Daikhin, Yevgeny et al. (2014) Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1 deficiency with N-carbamyl-L-glutamate. J Pediatr 165:401-403.e3
Mew, Nicholas Ah; Yudkoff, Marc; Tuchman, Mendel (2014) Stable isotopes in the diagnosis and treatment of inherited hyperammonemia. J Pediatr Biochem 4:57-63
Dlugos, Dennis; Shinnar, Shlomo; Cnaan, Avital et al. (2013) Pretreatment EEG in childhood absence epilepsy: associations with attention and treatment outcome. Neurology 81:150-6
Cartagena, A; Prasad, A N; Rupar, C A et al. (2013) Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci 40:3-9
Heibel, Sandra K; Ah Mew, Nicholas; Caldovic, Ljubica et al. (2011) N-carbamylglutamate enhancement of ureagenesis leads to discovery of a novel deleterious mutation in a newly defined enhancer of the NAGS gene and to effective therapy. Hum Mutat 32:1153-60
Nissim, Itzhak; Horyn, Oksana; Nissim, Ilana et al. (2011) Down-regulation of hepatic urea synthesis by oxypurines: xanthine and uric acid inhibit N-acetylglutamate synthase. J Biol Chem 286:22055-68
Yudkoff, Marc; Ah Mew, Nicholas; Daikhin, Yevgeny et al. (2010) Measuring in vivo ureagenesis with stable isotopes. Mol Genet Metab 100 Suppl 1:S37-41

Showing the most recent 10 out of 13 publications