Urea Cycle Disorder

Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification. Combined incidence is about 1 in 35,000. Hyperammonaemia is neurotoxic (glutamine accumulates in astrocytes, causing cerebral oedema and raised intracranial pressure).

Each UCD is due to deficiency of one of the six enzymes or two transporters in the cycle:

• carbamoyl phosphate synthetase I (CPS1)
• ornithine transcarbamylase (OTC; X-linked)
• argininosuccinate synthetase (ASS1; citrullinaemia type I)
• argininosuccinate lyase (ASL; argininosuccinic aciduria)
• arginase 1 (ARG1; argininaemia)
• N-acetylglutamate synthase (NAGS)
• the transporters ORNT1 (HHH syndrome) and citrin

• Neonatal onset (complete defects, within 24 to 72 hours): poor feeding, vomiting, lethargy, hypothermia, tachypnoea (respiratory alkalosis), seizures, cerebral oedema, coma, and death without treatment
• Late onset (partial defects): episodic encephalopathy triggered by catabolic stress (infection, fasting, surgery, postpartum state, high protein intake, valproate, corticosteroids, chemotherapy): vomiting, headaches, confusion, ataxia, psychiatric symptoms, and coma
• Chronic: failure to thrive, protein aversion, developmental delay, learning disability, seizures, liver dysfunction, and hepatomegaly
• ASL: brittle hair (trichorrhexis nodosa), hepatomegaly, and hypertension; arginase deficiency: progressive spastic diplegia, and hyperargininaemia
• Intellectual disability and cerebral palsy features may result despite treatment

1. Plasma ammonia (above 150 micromol/L in neonates with symptoms and above 100 micromol/L in others; collect without delay, on ice) with normal anion gap and respiratory alkalosis; urgent in any unexplained encephalopathy.
2. Plasma amino acids (high glutamine and alanine, low or absent citrulline in CPS1, OTC and NAGS deficiencies; high citrulline in citrullinaemia; argininosuccinic acid and citrulline in ASL; high arginine in arginase deficiency).
3. Urine orotic acid (elevated in OTC deficiency and others; low in CPS1 and NAGS).
4. Blood gas, glucose, lactate, liver function, coagulation, ketones, urine organic acids, acylcarnitines to exclude organic acidaemias.
5. Genetic testing and enzyme analysis (liver biopsy for CPS1 and OTC when needed), and newborn screening for citrullinaemia, argininosuccinic aciduria and argininaemia.
6. Neuroimaging for cerebral oedema.

• Acute hyperammonaemia (a medical emergency).
  1. Stop protein intake; provide high caloric intake (dextrose 10 to 12.5% IV at 8 to 10 mg/kg/min, with insulin if needed, and lipid emulsion 1 to 3 g/kg/day).
  2. Nitrogen scavengers, via a central line:
     • Sodium benzoate 250 mg/kg IV loading dose over 90 to 120 minutes, then 250 mg/kg/day.
     • Sodium phenylacetate 250 mg/kg (combined as Ammonul 2.5 mL/kg) over 90 to 120 minutes, then continuous infusion.
     • Arginine hydrochloride 200 to 600 mg/kg IV (not in arginase deficiency; 200 mg/kg in CPS1 and OTC, 600 mg/kg in citrullinaemia and ASL deficiency).
  3. Renal replacement: haemodialysis (the most effective way to lower ammonia) for ammonia above 400 to 500 micromol/L, or ammonia not falling rapidly, or severe encephalopathy.
  4. Carglumic acid 100 to 250 mg/kg/day orally or by nasogastric tube in NAGS deficiency and for acute hyperammonaemia of unknown cause.
  5. Supportive care: treat cerebral oedema, seizures, infection; avoid valproate; consider a protein reintroduction after 24 to 48 hours (0.5 to 1.5 g/kg/day).
• Long term.
  • Low protein diet (protein restriction at about 0.7 to 1.2 g/kg/day, with essential amino acid supplements) and adequate calories.
  • Oral sodium phenylbutyrate 450 to 600 mg/kg/day (under 20 kg) or 9.9 to 13 g/m2/day (above 20 kg) divided in 3 to 6 doses with meals, or glycerol phenylbutyrate 4.5 to 11.2 mL/m2/day.
  • L-arginine or L-citrulline supplementation (citrulline 100 to 200 mg/kg/day in OTC and CPS1 deficiency; arginine 400 to 700 mg/kg/day in ASL and ASS).
  • Monitoring of plasma ammonia, glutamine, amino acids, and growth.
  • Liver transplantation (preferably by 3 to 12 months) is recommended for severe neonatal onset disease.
  • Provide an emergency protocol letter for sick day management, with early admission for fever or vomiting.
• Genetic counselling: autosomal recessive (25%), X-linked for OTC; prenatal diagnosis.