2.1. Initial investigations

A female infant was born at 40 weeks gestation by normal vaginal delivery with a birth weight of 3.9kg. There were no neonatal problems and she was discharged home with her mother at 24 hours. She was initially breast fed but after 6 weeks she was changed to a standard milk formula feed. From that time she started having episodes of vomiting and her weight gain was poor. Cow's milk protein intolerance was suspected and she was changed to a soya milk preparation but without improvement. At 4 months she was admitted to hospital with a 4 day history of becoming increasingly lethargic. On examination she is sleepy but rousable. She is visually alert but not smiling. Her liver is palpable at 4 cm below the right costal margin. Her pulse is 100/min, respiratory rate 30/min and capillary refill time (CRT) 2 seconds. Her weight is 5.8 kg.

Initial investigations are as follows:

She is commenced on IV antibiotics and fluids. After 6 hours there is no improvement. Further samples are taken:

Blood lactate 2.8 mM

Blood ammonia 340 μM

A level of 340 μmol/l is well above normal for a 4 month old infant. Although blood ammonia can be increased in severe illness such as sepsis a level in excess of 150 to 180 μmol/l is likely to reflect a defect in ammonia removal. As the ammonia is high repeat the level (remember the problems that might occur with ammonia level measurement both in the lab and during blood sampling and transport) and immediately start specific treatment. The earlier that treatment is started the more likely a good outcome will be achieved. Then you can begin to investigate as to the exact cause of the hyperammonaemia.

In order to consider the appropriate treatment you need to have knowledge of the outcome for infants and children with hyperammonaemia and what factors can affect this outcome. To find out you might like to conduct a Pub Med search using the terms 'urea [ti] cycle [ti] outcome [ti]'. To help you, four references are listed in the reference section at the end of the course—Ref 18-21

COMMENTARY

The literature points out that the long term outcome for severe hyperammonaemia is poor. However, aggressive and appropriate treatment may ameliorate this, particularly if started sufficiently early. In this child the ammonia is below 350 μmol/l and the presentation is outside the newborn period so that the outcome may be good. Repeat the measurement of blood ammonia but this should not delay the start of specific and immediate treatment. At this stage the actual cause of the hyperammonaemia is of less importance than immediate treatment, particularly since the results of other investigations will take hours or days to become available. However since it is important for you to have a good understanding of the inborn errors that can cause hyperammonaemia we will consider these now before returning to immediate management.

A thorough patient history is very often a good way to narrow down the possible diagnosis.

The mother tells you that she and her partner are not consanguineous. She has a healthy daughter aged 4 years. However her first 2 children, both boys, died in the newborn period. The first boy was born prematurely at 30 weeks gestation and was said to have succumbed to necrotising enterocolitis. The second child died at 2 weeks of age from a cerebral haemorrhage.

Significant hyperammonaemia in infants is most commonly caused by inherited metabolic disorders but not just enzyme deficiencies of the urea cycle.

The diagnosis of a primary urea cycle enzyme deficiency can often be ascertained from a few biochemical investigations:

Urine orotic acid
Plasma amino acids or urine amino acids

Other metabolic investigations including urine organic acid and blood acylcarnitine analysis are necessary to exclude secondary causes such as an organic acidaemia or a disorder of fat oxidation.

In our patient, urine organic acids and blood acylcarnitines showed no evidence of either an organic acidemia or a fat oxidation disorder. Orotic acid was increased in urine and plasma citrulline was low, suggesting a diagnosis of OCT deficiency. The diagnosis can usually be confirmed by mutation analysis, avoiding the need for a liver biopsy.