About NAGS deficiency

In the United States, the incidence of urea cycle disorders (UCDs) is estimated to be 1 in every 35,000 births, or about 113 new patients per year across all age groups.1 NAGS deficiency, the rarest of the UCDs, is an autosomal recessive disorder.2

NAGS deficiency is the only inherited urea cycle disorder that can be specifically and effectively treated by a drug.2

Review guidelines for diagnostic testing

NAGS deficiency pathophysiology

The urea cycle

The urea cycle is the process by which the waste nitrogen (ammonium) that is produced by the catabolism of proteins is excreted as urea via the kidneys. Urea is produced primarily in the liver, which acts as the main ammonia detoxification center.3,4

The biochemical urea cycle pathway involves 5 catalytic enzmes and a cofactor producing enzyme: N-acetylglutamate synthase (NAGS), as well as 2 transporters: ornithase translocase and citrin.5

Enzymes of the urea cycle:

NAGS: N-acetylglutamate synthase (produces co-factor NAG)
CPS1: carbamoyl phosphate synthetase 1
OTC: ornithine transcarbamylase
ASS: argininosuccinate synthetase
ASL: argininosuccinate lyase
ARG1: arginase

Disruption due to NAGS deficiency

The urea cycle involves many sequential steps:

  • The process begins with NAGS, which catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme A.2,6
  • NAG then activates CPS1, the first and rate-limiting enzyme of the urea cycle.2,6
  • In the absence of NAG, there is no activation of CPS1 to trigger the urea cycle; thus, a deficiency of NAGS may result in hyperammonemia.2

See how CARBAGLU® (carglumic acid) activates the CPS1 enzyme, starting the first step of the urea cycle in patients with NAGSD.


  1. Summar ML, Koelker A, Freedenberg D, Le Mons C, Haberle J, Lee H-S, Kirmse B, European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD), Urea Cycle Disorders Consortium (UCDC). The incidence of urea cycle disorders. Mol Genet Metab. 2013;110:179-180.
  2. Ah Mew N, Caldovic L. N-acetylglutamate synthase deficiency: an insight into the genetics, epidemiology, pathophysiology, and treatment. Appl Clin Gen. 2011;4:127-135.
  3. Cartagena A, Prasad AN, Rupar CA, Strong M, Tuchman M, Ah Mew N, Prasad C. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci. 2013;40:3-9.
  4. Summar ML, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr. 2001;138(1 Suppl):S6-S10.
  5. Ah Mew N, Lanpher BC, Gropman A, Chapman KA, Simpson KL, Urea Cycle Disorders Consortium, Summar ML. Urea cycle disorders overview. In Pagon RA, Adam MP, Ardinger HH et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2017. http://www.ncbi.nlm.nih.gov/books/NBK1217. Revised June 22, 2017. Accessed December 4, 2017.
  6. Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007;28:754-759.