Ornithine Transcarbamylase Deficiency

Ornithine transcarbamylase (OTC) deficiency is the commonest urea cycle disorder (about 1 in 56,500 births) and the only one with X-linked inheritance (OTC, Xp11.4). Hemizygous males have severe neonatal onset disease if there is complete enzyme deficiency, or later onset with partial deficiency.

Heterozygous females are variably affected (from asymptomatic to severe hyperammonaemic crises, depending on skewed X-inactivation in the liver); about 15 to 20% of female carriers have symptoms. About 80% of mothers of isolated cases are carriers; de novo variants and germline mosaicism occur.

OTC converts carbamoyl phosphate and ornithine to citrulline in hepatocyte mitochondria, so blockade leads to carbamoyl phosphate diversion into orotic acid pathways and hyperammonaemia.

• Males, neonatal onset: normal at birth then feeding refusal, vomiting, hypothermia, tachypnoea and respiratory alkalosis, lethargy, seizures and coma within 24 to 72 hours; cerebral oedema, with high mortality and severe neurological impairment in survivors
• Late onset males and symptomatic females: episodic vomiting, headaches, behavioural change, hyperactivity, ataxia, confusion, protein aversion, psychiatric symptoms, and stroke like episodes, often triggered by infection, fasting, surgery, trauma, valproate, high protein meal, postpartum state, or corticosteroids; liver injury; developmental delay and intellectual disability
• Postpartum hyperammonaemic encephalopathy in carrier women (days to weeks after delivery)

1. Plasma ammonia (very high; often above 500 to 1,000 micromol/L in neonatal disease) and amino acids (high glutamine and alanine; low or absent citrulline and arginine).
2. Urinary orotic acid markedly elevated (after allopurinol challenge in females, orotic acid and orotidine rise) which differentiates from CPS1 and NAGS deficiency.
3. OTC gene sequencing with deletion analysis (detects 80 to 90% of mutations); mRNA studies and liver enzyme assay if no variant found.
4. Carrier testing in female relatives: genetic testing is the standard (the allopurinol challenge test and protein load are no longer preferred).
5. Neuroimaging and EEG during acute episodes.

Acute hyperammonaemia follows the urea cycle disorder emergency protocol:

• stop protein and give high energy intravenous glucose with insulin
• sodium benzoate and sodium phenylacetate (Ammonul) 250 mg/kg IV loading over 90 to 120 minutes then 250 mg/kg/day continuous infusion (5.5 g/m2 in children over 20 kg)
• arginine hydrochloride 200 mg/kg IV (OTC) or citrulline
• haemodialysis or CRRT for ammonia above 400 micromol/L, rising despite treatment, or with severe encephalopathy
• manage cerebral oedema
• avoid hypotonic fluids, valproate and corticosteroids
• restart protein within 24 to 48 hours at 0.5 g/kg/day increasing

Chronic therapy:

• Low protein diet (0.7 to 1.2 g/kg/day, with essential amino acid supplementation) to maintain normal growth
• Sodium phenylbutyrate 450 to 600 mg/kg/day (patients under 20 kg) or 9.9 to 13 g/m2/day (above 20 kg) in 3 to 6 divided doses, or glycerol phenylbutyrate
• L-citrulline 100 to 200 mg/kg/day (in OTC deficiency; arginine 100 to 200 mg/kg/day is an alternative)
• Monitor ammonia, glutamine (target below 1000 micromol/L), and amino acids
• Liver transplantation in early childhood for severe disease, with an excellent outcome (survival above 90%); hepatocyte transplantation and gene therapy are being investigated

Women carriers: careful pregnancy and delivery planning, with increased risk around delivery (give high energy intravenous glucose, monitor ammonia, avoid catabolism); symptomatic carriers treated as males.

Emergency plan: a written protocol, with sick day management, and early hospital review for infection or vomiting.

Genetic counselling: X-linked; 50% risk of transmission for carrier mothers; prenatal and preimplantation testing.