Approach to Inborn Errors of Metabolism
On this page
Direct answer
Inborn errors of metabolism are inherited enzyme or transport defects that usually present as acute illness, often in the newborn once feeds begin. Vomiting, lethargy, hypoglycaemia, metabolic acidosis and hyperammonaemia are the key clues. First-line tests are blood glucose, arterial blood gas, lactate, ammonia and ketones, and acute stabilisation begins before the specific diagnosis is made.
What you must remember
- Clinical clue: vomiting, poor feeding, lethargy and seizures that appear after protein or sugar intake, classically in the first days of life.
- Acidosis pattern: raised lactate suggests a mitochondrial or pyruvate metabolism disorder, while ketosis with acidosis points to an organic acidaemia.
- Hyperammonaemia: urea cycle defects and organic acidaemias both raise ammonia, so a raised level alone does not localise the defect.
- Hypoglycaemia: hypoglycaemia with low ketones suggests a fatty acid oxidation defect, while hepatomegaly with hypoglycaemia suggests a glycogen storage disorder.
- Odour: maple syrup odour in maple syrup urine disease and sweaty feet odour in isovaleric acidaemia are classic clues.
- Sample handling: ammonia samples must go on ice and be analysed quickly, because the value is unstable.
- Confirmatory tests: plasma amino acids, urine organic acids and an acylcarnitine profile by tandem mass spectrometry identify most conditions.
- Dietary management: protein restriction is temporary during decompensation, with calories maintained, and protein is reintroduced under specialist supervision.
A pathway from clue to treatment
A neonate who deteriorates after the first feeds, with vomiting and hypoglycaemia, should be assessed for an inborn error until proven otherwise. The steps below set out how the team moves from the clinical clue to definitive care.
- Recognise the pattern: look for vomiting, lethargy, seizures, unexplained acidosis or hyperammonaemia, dysmorphism and any characteristic odour.
- Stabilise first: correct hypoglycaemia and acidosis with intravenous dextrose and fluids, and treat sepsis in parallel.
- Send the first-line samples: draw blood glucose, blood gas with lactate, ammonia on ice, ketones and urine for reducing substances before definitive treatment changes the results.
- Start targeted detoxification: in hyperammonaemia, stop protein intake temporarily and give nitrogen scavenging drugs, with dialysis for severe or refractory cases.
- Confirm and specify: send plasma amino acids, urine organic acids and acylcarnitine profile, then reintroduce protein and plan long-term review with a metabolic specialist.
Documenting the feed history and the time of sampling helps the metabolic team interpret the results later. Early treatment matters because hyperammonaemia can progress quickly to brain injury, so the first hours carry most of the risk.
Frequently asked questions
Which first-line tests are sent in a suspected inborn error of metabolism?
Blood glucose, arterial blood gas with lactate, ammonia, ketones and urine for reducing substances are the first-line tests in suspected inborn errors of metabolism. Ammonia must be placed on ice and analysed quickly. Samples should be taken before major treatment changes the results.
Why is ammonia measured in suspected inborn errors of metabolism?
Raised ammonia suggests a urea cycle defect or an organic acidaemia, and it is dangerous because it causes cerebral oedema and encephalopathy. The level guides urgency and the need for dialysis in severe cases. A raised value does not identify the specific defect on its own.
Which metabolic disorder causes a maple syrup odour?
Maple syrup urine disease causes a maple syrup odour because branched-chain amino acids and their keto acids accumulate. It presents with encephalopathy and needs urgent management. Isovaleric acidaemia, by contrast, gives a sweaty feet odour.
What is the first step in managing acute hyperammonaemia?
The first step is to stop protein intake temporarily while maintaining adequate calories, usually with intravenous dextrose and lipid. Nitrogen scavenging drugs are then started, and dialysis is used for severe or refractory hyperammonaemia. The aim is to lower ammonia quickly before neurological damage occurs.
Why is a lactate test useful in suspected metabolic disease?
Raised lactate with acidosis suggests a mitochondrial disorder, a pyruvate dehydrogenase defect or a glycogen storage problem, as well as sepsis or hypoperfusion. Lactate is always interpreted with the anion gap and the clinical picture. It narrows the differential but does not confirm a specific diagnosis.