N-Acetylglutamate Synthetase Deficiency Medication
- Author: Karl S Roth, MD; Chief Editor: Luis O Rohena, MD more...
The specific treatment of N -acetylglutamate synthetase (NAGS) deficiency following diagnosis depends on dietary protein restriction and provision of arginine to enhance availability of ornithine and administration of carbamylglutamate (which is not widely available), a functional analogue of NAG. Some patients have done well using this regimen.
Intravenous sodium benzoate and phenylacetate can usually reduce blood ammonia levels. The addition of intravenous fluids with glucose and sometimes arginine hydrochloride (HCl) may also be indicated.
In the absence of any ability to fix nitrogen generated from endogenous catabolism of protein, the urea cycle is of no use whatsoever to the homeostasis of nitrogen metabolism. In order to stimulate urea cycle action, investigators have used N -carbamoyl-L-glutamate as an analogue of N -acetyl-L-glutamate to activate CPS.[4, 5]
Safety and efficacy of carglumic acid was studied in 23 patients with NAGS who received the treatment for times ranging from 6 months to 21 years. In these patients, carglumic acid reduced blood ammonia levels within 24 h and normalized ammonia levels within 3 days. Majority of those in the study appeared to maintain normal plasma ammonia levels with long-term treatment.
Also called N -carbamoyl-L-glutamate, carbamylglutamic acid, or carglutamic acid. Structural analogue of N -acetylglutamate, which enters cells and enables activation of CPS I (first enzyme in urea cycle) in vivo. Decreases hyperammonemia by converting ammonia into urea. More resistant to enzymatic degradation by hydrolysis compared with N -acetylglutamate. Indicated for NAGS deficiency, a rare genetic disorder that results in hyperammonemia.
Available as a 200-mg dispersible tab. Tab is scored and can be split to provide accurate dose.
These agents assist in the excretion of nitrogen and serve as an alternative to urea to reduce waste nitrogen levels. Administer only in a large medical facility with close laboratory monitoring available.
Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate. Provides 1 mol of urea plus 1 mol ornithine per mol arginine when cleaved by arginase. Pituitary stimulant for the release of human growth hormone (HGH). Often induces pronounced HGH levels in patients with intact pituitary function.
Benzoate combines with glycine to form hippurate, which is excreted in urine. 1 mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mol is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for CPS, ornithine transcarbamylase (OTC), argininosuccinate synthetase, or argininosuccinate lyase (ASL) deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.
Tuchman M, Lee B, Lichter-Konecki U, et al. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008 Aug. 94(4):397-402. [Medline]. [Full Text].
Cartagena A, Prasad AN, Rupar CA, Strong M, Tuchman M, Ah Mew N, et al. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci. 2013 Jan. 40(1):3-9. [Medline]. [Full Text].
Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007 Aug. 28(8):754-9. [Medline].
Gessler P, Buchal P, Schwenk HU, Wermuth B. Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency. Eur J Pediatr. 2010 Feb. 169(2):197-9. [Medline].
Tuchman M, Caldovic L, Daikhin Y, et al. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. Pediatr Res. 2008 Aug. 64(2):213-7. [Medline]. [Full Text].
Bachmann C, Colombo JP, Jaggi K. N-acetylglutamate synthetase (NAGS) deficiency: diagnosis, clinical observations and treatment. Adv Exp Med Biol. 1982. 153:39-45. [Medline].
Caldovic L, Ah Mew N, Shi D, et al. N-acetyglutamate synthase: structure, function and defects. Mol Genet Metab. Feb/2010. 100(Supplement 1):S13-S19.
Caldovic L, Morizono H, Panglao MG, et al. Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles. Hum Mutat. 2005 Mar. 25(3):293-8. [Medline].
Caldovic L, Morizono H, Panglao MG, et al. Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet. 2003 Apr. 112(4):364-8. [Medline].
Elpeleg O, Shaag A, Ben-Shalom E, Schmid T, Bachmann C. N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy. Ann Neurol. 2002 Dec. 52(6):845-9. [Medline].
Elpeleg ON, Colombo JP, Amir N, et al. Late-onset form of partial N-acetylglutamate synthetase deficiency. Eur J Pediatr. 1990 Jun. 149(9):634-6. [Medline].
Guffon N, Schiff M, Cheillan D, et al. Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test. J Pediatr. 2005 Aug. 147(2):260-2. [Medline].
Guffon N, Vianey-Saban C, Bourgeois J, et al. A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J Inherit Metab Dis. 1995. 18(1):61-5. [Medline].
Haberle J, Koch HG. Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn. 2004 May. 24(5):378-83. [Medline].
Plecko B, Erwa W, Wermuth B. Partial N-acetylglutamate synthetase deficiency in a 13-year-old girl: diagnosis and response to treatment with N-carbamylglutamate. Eur J Pediatr. 1998 Dec. 157(12):996-8. [Medline].
[No authors listed]. Carglumic acid: new preparation. An advance in rare urea cycle disorders. Prescrire Int. 2004 Feb. 13(69):3-4. [Medline].