Argininosuccinic Aciduria

Argininosuccinic aciduria is an autosomal recessive urea cycle disorder caused by deficiency of argininosuccinate lyase. It causes hyperammonaemia and, unlike most other urea cycle disorders, a chronic multisystem phenotype that is not explained by ammonia alone.

Incidence is about 1 in 70 000 to 220 000 live births. Presentation is either neonatal, with hyperammonaemic coma in the first week, or later in infancy or childhood.

Chronic complications include hepatomegaly with fibrosis, brittle hair (trichorrhexis nodosa), learning difficulty, epilepsy, hypertension and behavioural problems.

Pathophysiology.

Failure to cleave argininosuccinate causes accumulation of argininosuccinic acid and citrulline and a deficiency of arginine. Ammonia accumulates because arginine and urea production fall.

Arginine is the substrate of nitric oxide synthase. Lyase deficiency also reduces nitric oxide signalling, which is proposed to explain hypertension and neurocognitive deficits that occur despite normal ammonia.

• Neonatal onset after 24 to 72 hours of feeding: poor feeding, vomiting, hypothermia, tachypnoea with respiratory alkalosis, lethargy, seizures and coma.
• Later onset: episodic vomiting, ataxia, behaviour change and encephalopathy with illness or high protein intake.
• Chronic disease: hepatomegaly, raised transaminases, hepatic fibrosis, brittle sparse hair, developmental delay, epilepsy and hypertension.

Red flags.

• Ammonia over 150 micromol/L with encephalopathy.
• Respiratory alkalosis with lethargy in a feeding neonate.
• Signs of cerebral oedema.

• Ammonia on ice sent urgently (before treatment), blood gas, glucose, lactate, liver function and electrolytes.
• Plasma amino acids: argininosuccinic acid present, citrulline moderately raised, arginine low, glutamine raised. Urine argininosuccinic acid, with raised orotic acid.
• Molecular testing of ASL. Hair microscopy shows trichorrhexis nodosa.
• Blood pressure, liver ultrasound and neurodevelopmental assessment in chronic disease.

Differential diagnosis. Citrullinaemia type 1 (very high citrulline and no argininosuccinic acid), 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.
• 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 or haemofiltration for ammonia over 400 micromol/L, poor response or encephalopathy.
• Manage cerebral oedema with head elevation, careful fluid and sodium management and osmotherapy, and avoid hypotonic fluids.

Long term.

• Natural protein restriction with an essential amino acid supplement to meet growth needs.
• Oral arginine 100 to 300 mg/kg/day in divided doses.
• Sodium phenylbutyrate when ammonia stays raised: 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, maximum 20 g daily.
• Liver transplant is considered for recurrent severe hyperammonaemia. It does not reliably correct neurocognitive outcome.

Monitoring. Ammonia in illness, plasma amino acids, liver function, blood pressure, growth and development.

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.