Inborn Errors of Metabolism: Recognition & Acute Management
Spot the crisis that mimics sepsis, then stop catabolism fast
When to suspect an inborn error
The classic story. Many "intoxication" disorders — urea cycle defects, organic acidemias, maple syrup urine disease (MSUD), galactosemia — largely spare the fetus because the placenta clears toxic metabolites. The newborn is well at birth, then after hours to days of milk feeding develops poor feeding, vomiting, lethargy, tachypnea, seizures, and coma. The picture looks like sepsis, but cultures are negative. Untreated, cerebral edema and death follow.
Other clues. An unusual odor, recurrent decompensation with intercurrent illness or fasting, unexplained hypoglycemia or metabolic acidosis, consanguinity, and a sibling who died unexpectedly. Characteristic odors include burnt sugar or maple syrup (MSUD), musty (PKU), sweaty feet (isovaleric acidemia), and boiled cabbage (tyrosinemia type 1).
Every encephalopathic neonate needs a plasma ammonia level alongside the sepsis workup.
First-line laboratory evaluation
The panel. Glucose, ammonia, blood gas with anion gap, lactate, urine ketones, plasma amino acids, urine organic acids, and an acylcarnitine profile, plus liver tests and a CBC. Draw these during the acute episode, before dextrose if that causes no delay, because values may normalize once the child is treated; freeze extra plasma and urine for later testing.
Ammonia handling. Use a free-flowing sample placed on ice and analyzed promptly; hemolysis, a squeezed heel stick, or delay falsely raises the value.
| Disorder | Ammonia | Blood gas and ketones | Glucose | Confirm with |
|---|---|---|---|---|
| Urea cycle defect | Very high | Respiratory alkalosis; no ketoacidosis | Normal | Plasma amino acids, urine orotic acid |
| Organic acidemia | Moderately high | Anion-gap acidosis, ketosis, ↑lactate | Low or high | Urine organic acids, acylcarnitines (↑C3) |
| MSUD | Normal or mildly high | Ketosis; acidosis usually mild | Usually normal | Plasma amino acids (↑leucine, alloisoleucine) |
| MCAD deficiency | Mildly high | Inappropriately low ketones | Low | Acylcarnitines (↑C8) |
Disorders of protein metabolism
Urea cycle defects. Ammonia is very high, often hundreds to more than 1,000 μmol/L, and stimulates the brainstem to cause primary respiratory alkalosis; glucose is normal and there is no ketoacidosis. Plasma amino acids localize the block: citrulline is low in proximal defects and very high in citrullinemia. Hyperammonemia causes cerebral edema.
OTC deficiency. Ornithine transcarbamylase deficiency is the most common urea cycle defect and the only X-linked one. Affected boys crash as neonates; carrier girls may present later with protein-triggered vomiting, confusion, or coma, sometimes after valproate. Carbamoyl phosphate backs up into pyrimidine synthesis, so urinary orotic acid is high, whereas CPS1 deficiency causes the same low citrulline without orotic aciduria.
Organic acidemias. Propionic and methylmalonic acidemia cause anion-gap metabolic acidosis with ketosis (ketonuria is a red flag in a neonate), raised lactate, secondary hyperammonemia from inhibition of the urea cycle, neutropenia or pancytopenia, and low or high glucose. Urine organic acids and an acylcarnitine profile (↑propionylcarnitine, C3) are diagnostic. Some methylmalonic acidemia responds to vitamin B12.
Maple syrup urine disease. Deficiency of the thiamine-dependent branched-chain α-ketoacid dehydrogenase raises leucine, isoleucine, and valine; alloisoleucine is diagnostic, and leucine is the neurotoxin. Within the first week come poor feeding, alternating hypertonia and hypotonia, fencing or bicycling movements, cerebral edema, and coma, with a burnt-sugar odor of urine and cerumen.
MCAD deficiency, galactosemia, and PKU
MCAD deficiency. The most common fatty acid oxidation disorder (autosomal recessive) is silent until fasting or illness, usually between 3 and 24 months. Then come vomiting, lethargy, seizures, hepatomegaly, and hypoketotic hypoglycemia, sometimes sudden death. Low glucose with inappropriately low ketones means a fatty acid oxidation defect or hyperinsulinism. Newborn screening and acylcarnitines show elevated octanoylcarnitine (C8). Treat with IV 10% dextrose; lipids are useless when fatty acids cannot be oxidized.
Galactosemia. Classic galactosemia (galactose-1-phosphate uridyltransferase, GALT, deficiency) appears after breast milk or formula starts: vomiting, poor feeding, jaundice, hepatomegaly progressing to liver failure, hypoglycemia, renal tubular dysfunction, cataracts, and E. coli sepsis. Urine contains non-glucose reducing substances. Stop all lactose, including breast and donor milk, and switch to soy formula. Premature ovarian insufficiency and speech and learning problems are common despite good dietary control. Galactokinase deficiency causes cataracts alone; aldolase B deficiency (hereditary fructose intolerance) appears only after fructose or sucrose exposure.
Phenylketonuria. Phenylalanine hydroxylase deficiency (autosomal recessive) is silent at birth and found by newborn screening. Untreated, it causes intellectual disability, seizures, eczema, fair skin and hair, and a musty odor. Treatment is a lifelong phenylalanine-restricted diet with phenylalanine-free medical formula; tyrosine becomes essential, and sapropterin (BH4) helps responsive patients. High maternal phenylalanine is teratogenic (microcephaly, intellectual disability, congenital heart disease, growth restriction), so control must be tight before conception.
Acute management
- Stop proteinfor no more than 24–48 hours, then reintroduce to avoid catabolism
- Reverse catabolismIV 10% dextrose at about 1.5× maintenance (glucose about 8–10 mg/kg/min), insulin if hyperglycemia develops, IV lipids once a fatty acid oxidation defect is excluded
- Correct acidosis and give cofactorsbicarbonate as needed; L-carnitine; hydroxocobalamin, biotin, thiamine
- Remove ammoniaIV sodium benzoate/phenylacetate plus IV arginine; carglumic acid when indicated
- Hemodialysisfor very high, rising, or scavenger-refractory hyperammonemia
Scavengers. Sodium benzoate conjugates glycine to form hippurate, and sodium phenylacetate conjugates glutamine to form phenylacetylglutamine; both are excreted in urine, bypassing the urea cycle. Arginine becomes essential in urea cycle defects (except arginase deficiency) and keeps the cycle turning. Carglumic acid, an N-acetylglutamate analog, activates CPS1 in NAGS deficiency and organic acidemias.
Dialysis. Hemodialysis or continuous kidney replacement therapy clears ammonia fastest; peritoneal dialysis and exchange transfusion are far less effective. The duration of hyperammonemic coma predicts neurologic outcome, so dialysis should not wait for scavengers to fail slowly.
Carnitine and cofactors. L-carnitine binds toxic acyl groups in organic acidemias and replaces secondary carnitine deficiency. Treat presumed sepsis in parallel and avoid prolonged fasting and dehydration.
Valproate can precipitate fatal hyperammonemia in urea cycle disorders, classically unmasking OTC deficiency in carrier females.
Long-term care and prevention
Children need disorder-specific diets (protein or amino acid restriction with medical formulas, lactose elimination for galactosemia, frequent feeds and fasting limits for MCAD) and written emergency letters that direct early IV dextrose during illness. Newborn screening by tandem mass spectrometry detects PKU, MSUD, MCAD deficiency, and many organic acidemias, and galactosemia is screened separately. A normal screen does not exclude disease: OTC deficiency is not reliably detected, and results may return after the infant is already sick.