Medication Summary
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.
Metabolic analogue
Class Summary
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. [7, 8]
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.
Carglumic acid (Carbaglu)
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.
Metabolic agents
Class Summary
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.
Arginine (R-Gene 10)
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.
Sodium phenylacetate and sodium benzoate (Ammonul)
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.
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Compounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
