Sayarifard F¹, Hadipour F², Hadipour Z², Häberle J³, Shafeghati Y², Sagheb S⁴, Sarkhail P^2,

Background: N-acetyl-glutamate synthase (NAGS) deficiency is a rare cause of severe neonatal hyperammonemia. Case report: An 8-day old boy, who was born of non-consanguineous Iranian parents by cesarean section, was admitted to the neonatal intensive care unit due to poor feeding, unconsciousness, and seizures. High Ammonia (920 µmol/L, ref. < 100), high plasma glutamine (1628.6 µmol/L, ref. 410-960) and alanine (1151.5 µmol/L, ref. 200-600), low plasma citrulline (6.6 µmol/L, ref. 8-47) and arginine (26.7 µmol/L, ref. 20-160), without orotic aciduria (orotic acid in urine below detection limit) was revealed in metabolic work-up. Based on these results carbamoyl-phosphate synthetase 1 (CPS1) or NAGS deficiency were suspected. The infant was treated by peritoneal dialysis, intravenous sodium benzoate, L-arginine, and oral sodium phenylbutyrate and ammonia declined to 390 µmol/Lafter 10 days. Results: The genetic analysis in the patient and parents confirmed the NAGS deficiency with a novel heterozygous maternal missense mutation in exon 5 c.1172T>G (p.Leu391Arg) and the known change in exon 6c.1450T>C (p.Trp484Arg) on the paternal allele. Carglumic acid (Carbaglu®, Orphan Europe Recordati, Paris, France) was started and ammonia declined to normal (55 µmol/l) after 24 hours, for the first time ever in the patient. Based on the severe neurological impairment due to the initial hyperammonemic crisis and difficulties to access to the drug in Iran, a decision was made with the parents to stop treatment with carglumic acid (while sodium benzoate and sodium phenylbutyrate were continued) and the patient died five days later due to hyperammonemic decompensation. Conclusion: NAGS deficiency, although rare, seems to be panethnic. Thus, in case of hyperammonemia without orotic aciduria but with low plasma citrulline, NAGS deficiency should be considered and a trial with carglumic acid started as early as possible. Our case demonstrates that the prognosis of neonatal onset NAGS deficiency largely depends on early recognition and start of therapy.

Urea cycle disorder, NAGS deficiency, N-carbamylglutamate, hyperammonemia