Citrullinaemia

Citrullinaemia is a group of urea cycle disorders. Type 1 is caused by deficiency of argininosuccinate synthetase and is the classic form. Type 2 (citrin deficiency) is a different disease caused by a defect in a mitochondrial aspartate glutamate carrier, with intrahepatic cholestasis in infancy and neuropsychiatric disease in adults.

Type 1 has an incidence of about 1 in 57 000 to 250 000 live births. Type 2 is more frequent in East Asian populations.

Type 1 presents as an acute neonatal (severe) form, a late onset (mild) form, or an asymptomatic form found by newborn screening.

Pathophysiology.

Deficiency of argininosuccinate synthetase blocks the combination of citrulline with aspartate to form argininosuccinate. Citrulline and ammonia accumulate and arginine becomes an essential amino acid.

Hyperammonaemia and raised glutamine cause astrocyte swelling, cerebral oedema and raised intracranial pressure.

• Neonatal onset after 24 to 48 hours of protein feeding: poor feeding, vomiting, lethargy, hypothermia, tachypnoea with respiratory alkalosis, seizures and coma.
• Late onset: episodic vomiting, ataxia, behaviour change, headache and encephalopathy with illness, fasting or high protein intake.
• Type 2 (citrin deficiency): neonatal cholestasis, fatty liver, growth failure, and adult onset citrullinaemia with neuropsychiatric features and a preference for protein rich and fatty foods.

Red flags.

• Hypothermia, tachypnoea and encephalopathy in a neonate with poor feeding.
• Ammonia over 150 micromol/L in a neonate or over 100 micromol/L in a child with encephalopathy.
• Cerebral oedema signs.

• Ammonia on ice sent urgently (before treatment), blood gas, glucose, lactate, liver function and electrolytes.
• Plasma amino acids: very high citrulline (over 1000 micromol/L in type 1) with low arginine and raised glutamine. Urine orotic acid is normal or low in type 1.
• Molecular testing of ASS1 (type 1) and SLC25A13 (type 2).
• Newborn screening by citrulline.

Differential diagnosis. Argininosuccinic aciduria (citrulline raised with argininosuccinate), other urea cycle disorders, organic acidaemias, fatty acid oxidation defects, transient hyperammonaemia of the newborn, liver failure and sepsis.

Acute hyperammonaemia.

• Stop protein for 24 to 48 hours and give IV glucose 10% with electrolytes at 8 to 10 mg/kg/min to suppress catabolism, with lipid if needed.
• Ammonia over 150 micromol/L: arginine hydrochloride 600 mg/kg IV over 90 to 120 minutes, then 600 mg/kg/day by infusion. Sodium benzoate 250 mg/kg and sodium phenylbutyrate 250 mg/kg IV in glucose 10% over 90 to 120 minutes, then 250 mg/kg of each over 24 hours. Maximum 12 g daily for each. Avoid sodium benzoate with severe unconjugated hyperbilirubinaemia.
• Haemodialysis (preferably continuous haemofiltration or haemodialysis) for ammonia over 400 micromol/L, or poor response, or encephalopathy.
• Manage cerebral oedema with head elevation, careful fluid and sodium management and osmotherapy, with avoidance of hypotonic fluids.

Long term.

• Natural protein restriction with essential amino acid supplement to meet growth needs.
• Oral arginine 100 to 300 mg/kg/day in divided doses, and sodium phenylbutyrate 450 to 600 mg/kg/day in divided doses for children under 20 kg, or 9.9 to 13 g/m2/day for those over 20 kg, with a maximum of 20 g daily.
• Liver transplant for severe or recurrent hyperammonaemia.
• Citrin deficiency: lactose free and medium chain triglyceride supplemented feeds for infant cholestasis, then a high protein, high fat, low carbohydrate diet in later life.

Monitoring. Ammonia in illness, plasma amino acids (citrulline, arginine, glutamine), growth, development and liver function.

Referral and escalation. Refer to a metabolic centre at once. Provide an emergency regimen letter and early admission for febrile illness, vomiting or refusal of feeds.

Special groups. Pregnancy in affected women needs metabolic care and avoidance of hyperammonaemia during delivery and postpartum.