Urea Cycle Defects (NAGS, CPS1)

Clinical Features

Urea cycle defects are characterized by (1) hyperammonemia, (2) encephalopathy, and (3) respiratory alkalosis. Five clinical disorders have been described involving defective urea cycle enzymes: ornithine transcarbamolase deficiency (OMIM 311250), carbamoyl phosphate synthetase I deficiency (OMIM 237300), argininosuccinate synthetase deficiency (OMIM 215700), argininosuccinate lyase deficiency (OMIM 207900), and arginase deficiency (OMIM 207800). A sixth cause of hyperammonemia is N-acetlyglutamate synthase (NAGS) deficiency (OMIM 237310; (Bachmann et al., New Eng J Med. 1981; 304(9): 543).N-acetylglutamate is an essential activating cofactor for Carbamoyl Phosphate Synthetase I (CPS1) and, therefore, clinical signs of CPS1 and NAGS deficiencies are indistinguishable. Like CPS1 deficiency, two clinical presentations of NAGS deficiency are recognized: an acute neonatal hyperammonemia form and a delayed onset form (Haberle et al., Hum Mut. 2003; 21: 593-597). NAGS deficiency also presents with irritability and hyperammonemia leading to coma and death if untreated. Successful treatment with N-carbamylglutamate (NCG) has been reported (Bachmann et al., New Eng J Med. 1981; 304(9): 543).


Prompt recognition of a urea-cycle disorder and treatment with various drugs, along with dietary therapy, effectively lowers plasma ammonia levels and results in lower morbidity/mortality rates (Enns et al., The New England Journal of Medicine. 2007; 356: 2282-2292).

Drug Treatment

NAGS deficiency is the only urea cycle disorder in which urea cycle function may be restored through a pharmacological agent (Heibel et al., Human Genome Variation Society. 2011; hgvs.org). N-Carbamylglutamate therapy has shown to result in a significant increase in ammonia detoxification and could allow diagnosed patients to avoid further dialysis therapy (Gebhardt et al., Journal of Inherited Metabolic Disease. 2005; 241-244). This treatment, combined with ammonia scavengers like sodium phenylbutyrate and L-Citrulline/L-arginine free bases, promote optimal removal of ammonia and decrease risk of further complications (National Urea Cycle Disorders Foundation. 2013; nucdf.org). Mutations in the NAGS gene require rapid and vigorous treatment in order to normalize ammonia concentration as fast as possible to avoid high mortality and neurological complications, making an early, accurate diagnosis essential (Fillippi et al., Neonatology. 2010; 97: 286-290).

Dietary Therapy

Diet is one of the mainstays of the treatment of patients with urea cycle disorders. Protein intake should be properly adjusted and supplements should be distributed when necessary. All patients should also have an emergency regimen to prevent decompensation during periods of metabolic distress making awareness of the disorder key in avoiding morbidity/mortality (Leonard, J., The Journal of Pediatrics. 2001; 138(1): 540-545). Avoidance of high protein diets, Valproic acid and prolonged fasting allow a patient to maintain a higher quality of life and ensuring a better chance of survival (Lanpher et al., GeneReviews. 2003; ncbi.nlm.nih.gov/books/NBK1217).

For more information on NAGS and CPS1 testing, please see our full Test Description.


This article is a summary of information that has been reported in the biomedical research literature.It is not medical advice for patients. All disease treatments should be under the direction of a qualified healthcare provider.