Normal neurological development during infancy despite massive hyperammonemia in early treated NAGS deficiency

Our patient, a baby girl, is the first child of unrelated, healthy parents. In pregnancy the mother was treated with clomipramine, lithium, and quetiapine due to bipolar disease. She was born 2 days before estimated day of delivery, 64 h after rupture of membranes. A vacuum extraction was performed because of suspected intrauterine hypoxia. She had Apgar scores of 6, 7, and 8 after 1, 5, and 10 min, respectively, and a birth weight of 3,380 g.

Shortly after birth she was admitted to the neonatal intensive care unit because of mild respiratory distress and was treated with nasal continuous positive airway pressure (CPAP) and antibiotics, and recovered in a few hours. She was fed formula by bottle.

Apart from a blood glucose of 1.1 mmol/l (normal ≥2.2 mmol/l) 6 h after birth, blood count, electrolytes, ionized calcium, and capillary acid base were normal. CRP was a maximum of 20 mg/l (normal <5 mg/l). Blood cultures remained negative.

She was discharged to the maternity unit at 48 h postnatal age but readmitted 10 h later with mild respiratory distress and general increased muscular tone. Blood pressure was 112/78 mmHg, capillary pCO₂ 5.0 kPa with a pH of 7.44. Neonatal abstinence syndrome due to maternal quetiapine use was suspected, and treatment was started with phenobarbital. Formula was given by nasogastric tube.

From 88 h of age she had apneic episodes, and after failure of nasal CPAP she was intubated at 100 h of postnatal age because of respiratory failure, after analgesia with fentanyl 3 μg/kg. At 115 h of age she did not respond to pain or suction, and had no spontaneous ventilation. Therefore, a work-up for neonatal coma was immediately started. Ultrasound of brain was normal, CRP was negative, but arterial ammonia was highly elevated (2,235 μmol/l, normal <100 μmol/l). Buffer base was 2.1 mmol/l (normal −3.0 to +3.0), alanine aminotransferase 21 U/l (normal 7–40), quetiapine was undetectable, lithium 0.3 mmol/l (therapeutic range for adults 0.5–1 mmol/l).

With ammonia levels above 400–500 μmol/l, invasive extracorporeal detoxification is recommended (Häberle et al. 2012). Since the prognosis in the presence of severe hyperammonemia was considered grim, it was decided, after discussion with the parents, to limit treatment to a trial of sodium benzoate, sodium phenylacetate, l-arginine, and NCG.

On start of this emergency treatment for hyperammonemia (at 120 h of age), ammonia was further increased to 2,455 μmol/l, but 3 h later already declined to 1,746 μmol/l, and 16 h after treatment was started ammonia was in the normal range (36 μmol/l).

With normalized ammonia the patient became awake again but was extremely irritable. She also had abdominal distension and bloody diarrhea, and on day 7 required laparotomy for a partial gangrenous large bowel resection and enterostomy.

Plasma for analysis of amino acids was taken approximately 30 min after start of loading dose of sodium benzoate, sodium phenylacetate, and l-arginine, which was likely the cause for the elevation of arginine (938 μmol/l, normal 17–120), while glutamine was only slightly elevated to 872 μmol/l (normal 400–850), and citrulline was unmeasurably low. In urine, excretion of orotic acid was normal. Analysis of urine and plasma did not show evidence of an organic aciduria or a fatty acid oxidation defect. Biochemical results therefore suggested a urea cycle defect, either of N-acetyl glutamate synthase (NAGS) or of carbamoyl phosphate synthetase 1 (CPS1).

Given the fast response to the above treatment NAGS deficiency was suspected. This was later confirmed by DNA-analysis, which identified a known homozygous nonsense mutation in exon 4 of the NAGS gene, c.971G>A (p.Trp324*) (University Children’s Hospital, Zürich, Switzerland) (Sancho-Vaello et al. 2016). The parents were confirmed to be heterozygous for the same mutation.

After gradual decrease of the above medical treatment, the patient was discharged at 5 weeks of age. By that time she was feeding well, on treatment with NCG 40 mg/kg/day, without any dietary restriction or other medication. She smiled at 7 weeks. At 7 months she develops normally. Her enterostomy has been closed without any complications. Plasma ammonia levels on follow-up remained normal.