Abstract

The overall goal of this application is to determine the short-term efficacy of N-carbamyl-L-glutamate (NCG) for the treatment of five inborn errors of metabolism that cause hyperammonemia and consequent brain damage: N-acetylglutamate synthase (NAGS) deficiency, carbamyl phosphate synthetase I (CPSI) deficiency, propionic acidemia (PA), methylmalonic acidemia (MMA), as well as hyperinsulinism and hyperammonemia syndrome (HHS).
Specific Aim 1 is to determine whether a three-day treatment with NCG improves or restores ureagenesis in patients with NAGS deficiency, CPSI deficiency, PA, MMA, and HHS as evidenced by 13C incorporation into urea, concentrations of plasma ammonia, urea, and amino acids as well as brain glutamine concentrations measured by magnetic resonance spectroscopy. The results in patients with each of the five inherited disorders will be compared to those obtained in healthy adult volunteers (normal controls). In addition, the results of patients with NAGS deficiency, who the investigators expect to respond best to NCG (positive controls), will be compared to the results from the other four disorders to gauge their degree of correction of ureagenesis in response to NCG.
Specific Aim 2 is to evaluate the safety of short-term (three-day) treatment with NCG in the healthy volunteers and patients. Clinical and laboratory safety parameters will be evaluated in all participants, including idiosyncratic symptoms and changes in blood counts as well as liver and kidney functions. The investigators'hypothesis is that NCG will ameliorate deficient ureagenesis in these congenital disorders. Thus, this application will provide important efficacy data for a novel treatment of several rare congenital disorders that are associated with hyperammonemia that often is refractory. Successful conclusion of the study may also afford a rationale for the investigation of other diseases and conditions that are complicated by hyperammonemia, including liver failure of diverse etiology and treatment with valproic acid.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD058567-02
Application #
7667880
Study Section
Special Emphasis Panel (ZHD1-MRG-C (07))
Program Officer
Oster-Granite, Mary Lou
Project Start
2008-08-05
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2009
Total Cost
$326,785
Indirect Cost

  Institution

Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010

  Publications

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

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