BG was born at term after an uncomplicated pregnancy. Her birth weight was 2900g. She was the 2nd child to consanguineous parents. There had been meconium stained liquor at birth, but no other concerns. She was discharged home after 24 hours. However, she fed poorly and was referred to hospital the following day. Shortly after admission she was noted to have seizures and was given a loading dose of phenobarbitone.
Initial investigations were as follows; blood pH 7.52 pCO2 3.67 kPa, PO2 6.47 kPa, plasma bicarbonate 21.5 mmol/l, plasma lactate 3.2 mmol/l, Ca++ 1.0 mmol/l. Blood ammonia was 825 µmol/l. She was given a loading dose, followed by continuous infusions of sodium benzoate and arginine and electively intubated for transfer to the regional paediatric intensive care unit. Prior to transfer her ammonia had risen to 1046 µmol/l despite the treatment with scavengers. During transfer her ET tube became dislodged and was replaced. After 15 minutes she developed VT and later VF/PEA arrest (related to hypocalcaemia) and required defibrillation and adrenaline (down-time 14 min).
She developed persistent hypocalcaemia contributing to haemodynamic instability requiring multiple calcium boluses and a continuous calcium infusion. Arrangements were made to commence haemodiafiltration.
Prior to commencing filtration the blood ammonia was 3259 µmol/l even though the scavengers had been continued.
Commentary
Although blood ammonia in excess of 1000 µmol/l may be seen in propionic or methylmalonic acidaemia, this extremely high level is only likely in a urea cycle disorder or possibly transient hyperammonaemia of the newborn. The latter disorder primarily affects premature infants who, characteristically, develop respiratory distress in the first 24 hours after birth.
It is not possible on the basis of the history & blood ammonia result alone to determine the precise diagnosis.
Further investigations should include
- Plasma and urine amino acids
- Urine organic acids and orotic acid
- Bloodspot for acylcarnitines
The prognosis for the infant is extremely poor. This level of ammonia is incompatible with survival. The parents should be counselled accordingly. In this situation the parents agreed with the decision of medical staff not to continue therapy. The child was extubated and died in her parents' arms.
Although this infant could not be treated, at this stage further management of the family is needed. Apart from general counselling after the loss of a baby, they will need an explanation of the diagnosis and advice on future pregnancies, including what might be available in terms of further testing should they want to embark on future pregnancies. You might also want to ask for DNA samples from the parents to aid diagnosis.
Results from samples obtained before treatment was withdrawn were as follows--The urine organic acids showed a gross increase in hippurate, an increase in lactate. No orotic acid was seen.
Blood spot acyl carnitines showed a free carnitine of 40.8 µmol/L (reference range 20-40) with a normal acylcarnitine profile. Plasma amino acid profile showed a glutamine of 2800 µmol/L, alanine 600 µmol/L and citrulline 3 µmol/l.
The increase in hippurate is due to the sodium benzoate that conjugates with glycine to form hippurate. The high lactate is not significant from a metabolic diagnosis perspective as it just reflects the severe nature of the child’s illness with episodes of hypoxia and circulatory failure. The high lactate also explains the high alanine. While the exceptionally high glutamate with low citrulline suggests OTC deficiency, the absence of urinary orotic acid suggests that the defect is proximal to carbamoylphosphate. Thus the enzyme defect is either NAGS or CPS. Mutation analysis showed that she was homozygous for a mutation in the CPS1 gene thus giving the family an opportunity for prenatal testing.
CPS deficiency is more common than NAGS and more often associated with severe neonatal hyperammonaemia. Learning objectives:
- To know the causes of severe hyperammonaemia in the neonatal period.
- To be able to make an informed judgment as to when specific treatment should not be offered or withdrawn
- To consider the necessity of further post mortem testing.