NAGS deficiency is a rare autosomal recessive inherited urea cycle disorder where a lack of a certain enzyme (N-acetyl glutamate synthetase) results in accumulation of ammonia in the blood as it can't be broken down and removed through the urine. Symptoms are visible within the first week of life and if not detected and diagnosed immediately consequences are fatal.

Causes

• The mutation is inherited as an autosomal recessive trait and the condition can occur in both sexes, presents at any age. As with many inherited metabolic diseases, the most likely time of presentation is in the newborn period.
• The NAGS gene locus is 17q21.31, spans 4.5 kb, and contains 6 introns and 7 exons. The 534 amino acid residues contained in the ribosomal protein are reduced to 486 by cleavage at the N -terminus upon import to the mitochondrion. A total of 21 mutations have been reported, 10 of which were associated with acute neonatal presentation.
•  Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle.

Symptoms

• High blood ammonia level
• Vomiting
•  Loss of appetite
•  Lethargy
•  Poor control of breathing rate
•  Poor body temperature regulation
•  Seizures
•  Unusual body movements
•  Lack of coordination due to ammonia toxicity
•  Confusion

Complications

• Brain damage if untreated
• Coma if untreated
• Life-threatening complications if untreated
• Developmental delay
•  Mental retardation

Treatment

Medical Care

Treatment of severe hyperammonemia is a true emergency.

• Immediate cessation of protein food and filling the energy gap with non-protein food is mandatory and the patient is given nothing enterally until the hyperammonemia is well controlled.
• Reduction of blood ammonia can usually be achieved with intravenous sodium benzoate and phenylacetate.
• Alternatively, hemodialysis is usually effective in bringing down the ammonia level, especially with the initial presentation.
• Exchange transfusion is ineffective and is not generally recommended.
• Intravenous fluids with glucose and sometimes arginine hydrochloride may be given
• Maintaining as high of an energy intake as possible is important.
• Specific therapy 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, a functional analogue of NAG.

• 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

• Specific therapy 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, a functional analogue of NAG.

Medication

Metabolic analogue

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, N -carbamoyl-L-glutamate is used as an analogue of N -acetyl-L-glutamate to activate CPS.

Carbamylglutamic acid (Carbaglu)

Also called N -carbamoyl-L-glutamate, carglumic acid, or carglutamic acid. Structural analogue of N -acetylglutamate, which enters cells and enables activation of CPS I in vitro.

The compound is also resistant to enzymatic degradation. Orphan drug available as a 200-mg dispersible tab. The tab is scored and can be split to provide accurate dose.