nags

N-acetylglutamate synthase (NAGS) is an enzyme that catalyzes the synthesis of N-acetylglutamate (NAG) from acetyl-CoA and L-glutamate. NAG is an essential allosteric activator of carbamoyl phosphate synthetase I (CPS1), the first enzyme of the urea cycle, which converts ammonia to urea in the liver. In humans, NAGS is encoded by the NAGS gene.

NAGS deficiency is a rare autosomal recessive urea cycle disorder caused by mutations in the NAGS gene that reduce production of NAG. Without adequate NAG, CPS1 activity is insufficient, leading to impaired ammonia detoxification and hyperammonemia. Clinical presentation ranges from onset in the neonatal period with severe hyperammonemia to later childhood or adult-onset with vomiting, lethargy, and neurocognitive impairment.

Diagnosis is based on elevated blood ammonia with low or normal plasma urea cycle intermediates such as citrulline and orotic acid, along with confirmation by genetic testing of NAGS mutations or measurement of reduced NAG production. Diagnosis may be supported by therapeutic responsiveness to N-carbamylglutamate (carbaglumate), an oral analog of NAG that activates CPS1.

Treatment focuses on controlling hyperammonemia and maintaining nitrogen balance. Acute management uses ammonia scavengers and sometimes dialysis. Long-term therapy may include carbaglumate to bypass the enzymatic defect, a supervised low-protein diet, and monitoring of growth and neurodevelopment. The prognosis improves with early detection and treatment.

See also: N-acetylglutamate synthetase, urea cycle disorders, CPS1 deficiency.