Urea cycle disorders and hyperammonaemia — formative SAQs

SAQ 1 (10 marks)

A term male infant is well at birth but at 48 hours of age becomes lethargic, feeds poorly, vomits, and is found hyperventilating with a respiratory rate of 80. Blood gas shows a respiratory alkalosis. Sepsis cultures are pending. A bedside clinician sends an ammonia, which returns at 620 micromoles per litre. [1] [4]

a) Explain why this picture of a well neonate deteriorating 24 to 72 hours into feeds with a respiratory alkalosis is a classic urea cycle disorder presentation, and list the four immediate resuscitation moves you make. (3 marks) [1] [4]

b) Describe the first-tier metabolic panel you order to localise the defect, and explain how plasma amino acids and urinary orotic acid distinguish ornithine transcarbamylase deficiency from carbamoyl phosphate synthetase 1 and NAGS deficiency. (3 marks) [1]

c) Outline the role of nitrogen scavengers, arginine, and extracorporeal removal in this child, including the ammonia thresholds that would prompt dialysis. (2 marks) [5]

d) Discuss the prognostic significance of the peak ammonia and time to treatment, and the implications for counselling this family. (2 marks) [6]

SAQ 2 (10 marks)

A four-year-old girl is referred for progressive spastic diplegia, intellectual disability and seizures, initially diagnosed as "cerebral palsy". A plasma amino acid profile returns with a markedly elevated arginine and a mildly elevated ammonia. [8] [1]

a) Name the diagnosis, explain why it is called the cerebral-palsy mimic, and contrast its ammonia profile with the classic neonatal urea cycle disorders. (3 marks) [8]

b) Outline the long-term management of this child, including dietary modification and pharmacological therapy, and how it may alter the neurological trajectory. (3 marks) [1]

c) Explain why intravenous arginine is essential in ASS1 and ASL deficiency but contraindicated as a supplement in arginase deficiency, relating the answer to the biochemistry of the cycle. (2 marks) [1]

d) Describe how you would distinguish a primary urea cycle disorder from an organic acidaemia causing secondary hyperammonaemia, naming the discriminating investigations. (2 marks) [1] [4]

Marking guide

SAQ 1. The neonate is well at birth because the maternal placenta clears ammonia, then deteriorates once protein-containing feeds generate a nitrogen load the blocked cycle cannot dispose of, typically at 24 to 72 hours. Hyperventilation and respiratory alkalosis arise from central ammonia-driven respiratory stimulation, a clue unusual in sepsis (usually metabolic acidosis). The four immediate moves are: stop protein, calorie-load (10% glucose + intralipid ± insulin to switch off catabolism), give nitrogen scavengers and arginine, and prepare for dialysis. The first-tier panel is ammonia, plasma amino acids, urinary orotic acid, blood gas, glucose, lactate, ketones, liver function and coagulation, and acylcarnitines. OTC deficiency shows low citrulline with high urinary orotic acid (carbamoyl phosphate shunted to pyrimidines), whereas CPS1 and NAGS deficiency show low citrulline with low or absent orotic acid. Nitrogen scavengers (sodium benzoate + sodium phenylbutyrate) provide alternative excretion pathways (hippurate, phenylacetylglutamine); arginine replenishes the cycle downstream. Dialysis is indicated when ammonia exceeds roughly 500 µmol/L in a neonate (or a lower threshold of 200–300 with encephalopathy or a rising trend) and must not await the diagnosis. Outcome tracks peak ammonia × duration — a 620 µmol/L peak carries a high risk of permanent cognitive impairment, and the family needs honest counselling plus carrier testing of the mother (X-linked if OTC). [1] [4] [5]

SAQ 2. The diagnosis is arginase deficiency (ARG1), the cerebral-palsy mimic: it presents not as acute neonatal hyperammonaemia but as a chronic progressive spastic diplegia with intellectual disability and seizures, and typically only mildly elevated ammonia. The hallmark is a markedly elevated plasma arginine. Management is a protein-restricted (low-arginine) diet with essential amino acid supplementation and nitrogen-scavenging therapy (sodium benzoate + phenylbutyrate), which can slow or halt the neurological progression if started early. Arginine is essential in ASS1 and ASL deficiency because it pushes metabolism toward citrulline/argininosuccinate excretion and replenishes the depleted pool, but in arginase deficiency the defect is arginine breakdown, so arginine is the accumulating toxin and must be restricted, not supplemented. A primary urea cycle disorder shows a normal anion gap with a respiratory alkalosis and an abnormal amino acid / orotic acid pattern, whereas an organic acidaemia shows a high anion-gap metabolic acidosis with ketosis, raised lactate, and abnormal acylcarnitines and urinary organic acids. [1] [8]