Inborn errors of metabolism (IEMs) are inherited defects in an enzyme or transporter. A substance before the block accumulates to toxic levels, or a product after the block becomes deficient. Most are autosomal recessive: when both parents are carriers, each pregnancy has a 25% chance of an affected child, 50% carrier, 25% unaffected.

Infants usually look normal at birth because the placenta cleared toxins in utero. Symptoms appear after feeding begins (protein or lactose load) or during catabolic stress (fasting, infection). Many conditions are detected by newborn screening before symptoms start, and early treatment prevents intellectual disability or death.

Key disorders

Congenital hypothyroidism and CAH are endocrine rather than metabolic disorders but are screened and managed in the same newborn program.

Red flags suggesting an IEM in a newborn: a previously well infant who, after starting feeds, develops poor feeding, vomiting, lethargy, hypotonia, seizures, or coma; unusual odor; unexplained hypoglycemia, metabolic acidosis, or hyperammonemia; hepatomegaly or jaundice; family history of sibling deaths. These signs mimic sepsis — both must be considered together.

Newborn screening principles

• A few drops of heel blood on a filter-paper card; tested by tandem mass spectrometry and other methods for many conditions.
• Collected after 24 hours of age (typically 24–48 hours) so that protein feeding has had time to raise phenylalanine and similar markers. A sample taken before 24 hours risks false negatives and must be repeated. Ideally collect before a blood transfusion.
• Screening is not diagnosis: a positive screen requires prompt confirmatory testing (e.g., quantitative plasma phenylalanine for PKU, GALT enzyme activity, thyroid function tests, serum 17-hydroxyprogesterone). A negative screen does not exclude a disorder if the infant has symptoms.
• Preterm, sick, or transfused infants often need repeat screening (false positives for CAH and hypothyroidism are common in preterm infants).

Tests during a metabolic crisis: glucose, blood gas, electrolytes and anion gap, ammonia, lactate, urine ketones and reducing substances, plasma amino acids, urine organic acids, acylcarnitine profile. Ammonia samples must be free-flowing, placed on ice, and analyzed immediately — delays falsely raise the value.

General emergency approach (acute decompensation)

1. ABCs; treat hypoglycemia and shock
2. Stop protein (and galactose/lactose) intake temporarily
3. Prevent catabolism: high-calorie IV dextrose (with insulin if hyperglycemic) and lipids as ordered
4. Remove toxins: nitrogen scavengers or hemodialysis for severe hyperammonemia or MSUD crisis
5. Reintroduce protein carefully under metabolic specialist guidance (prolonged protein restriction causes catabolism)

PKU

• Lifelong phenylalanine-restricted diet, not phenylalanine-free — phenylalanine is an essential amino acid needed for growth. Infants receive a phenylalanine-free medical formula plus a measured amount of breast milk or standard formula to supply the phenylalanine they need.
• Avoid high-protein foods (meat, fish, eggs, dairy, legumes, nuts, regular bread and pasta) and aspartame (metabolized to phenylalanine). Fruits, most vegetables, fats, and special low-protein foods are used in measured or allowed amounts.
• Target blood phenylalanine 120–360 µmol/L (2–6 mg/dL) for life; frequent monitoring (weekly in infancy).
• Sapropterin (tetrahydrobiopterin) lowers phenylalanine in responsive patients: headache, rhinorrhea, GI upset, hypersensitivity; can cause low phenylalanine — monitor levels. Pegvaliase (adults) carries a risk of anaphylaxis — patients carry auto-injectable epinephrine.
• Maternal PKU: high maternal phenylalanine damages the fetus (microcephaly, intellectual disability, congenital heart disease, growth restriction). Women with PKU must achieve target levels before conception and throughout pregnancy. Every child of a mother with PKU is at least a carrier; if the father is also a carrier, each child has a 50% chance of PKU. These infants undergo routine newborn screening.

Galactosemia

• Remove lactose/galactose immediately when suspected — soy-based or other lactose-free formula; breastfeeding is contraindicated in classic galactosemia.
• Lifelong avoidance of milk and dairy; read labels (lactose is used as a filler in some medicines).
• Despite treatment, risks remain for speech and learning difficulties and primary ovarian insufficiency in females.

MSUD: branched-chain amino acid-free formula with measured natural protein; sick-day emergency plan; liver transplantation in some.

Urea cycle disorders: low-protein diet; essential amino acid supplements; arginine or citrulline; nitrogen scavengers (IV sodium phenylacetate/sodium benzoate in crisis, oral sodium or glycerol phenylbutyrate long-term). Safety: IV scavengers require a central line (extravasation causes tissue injury), cause nausea and vomiting, and carry a large sodium load and hypokalemia; oral phenylbutyrate may cause body odor and menstrual irregularities.

GSD type I: frequent daytime feeds, overnight continuous feeds or uncooked cornstarch; limit fructose and galactose; never fast.

Congenital hypothyroidism

• Levothyroxine started as soon as possible (within the first 2 weeks), commonly 10–15 mcg/kg/day (verify against a pediatric reference). Crush the tablet and mix with a small amount of water, breast milk, or formula given by spoon or syringe — not in a full bottle.
• Separate from soy formula, iron, and calcium (they reduce absorption). Monitor TSH and free T4 frequently. Overtreatment: tachycardia, irritability, poor sleep, advanced bone age. Most children need lifelong therapy.

CAH

• Hydrocortisone (replaces cortisol and suppresses androgen excess) — stress dosing (higher doses) during fever, vomiting, or surgery; emergency IM hydrocortisone if vomiting or collapse. Overtreatment causes growth suppression and Cushingoid features; undertreatment causes crisis and virilization.
• Fludrocortisone (mineralocorticoid) plus sodium chloride supplements in infancy for salt wasting — monitor BP (hypertension) and potassium.
• Females with ambiguous genitalia: defer sex assignment until evaluation (karyotype, hormones) by a multidisciplinary team.

Listed in priority order.

1. Recognize the critically ill infant — lethargy, apnea, seizures, shock; support airway and circulation; check glucose immediately
2. Stop feeds as ordered during suspected crisis; start IV dextrose promptly
3. Collect specimens correctly — ammonia on ice immediately; critical samples during the acute episode before treatment changes results
4. Seizure precautions and neurologic monitoring (level of consciousness, fontanel)
5. Newborn screening — collect at the correct age, fill the card circles completely with a single drop per circle, dry flat away from heat; document; ensure follow-up of positive or unsatisfactory results
6. Diet management — exact formula preparation; measured intake; growth monitoring
7. CAH — monitor electrolytes, glucose, BP; strict intake and output
8. Family support — genetic counseling (25% recurrence risk), emotional support for lifelong management

• PKU: the diet is for life; read labels for aspartame ("contains phenylalanine"); check medicines and chewable products; keep scheduled blood tests; illness can raise phenylalanine — follow the sick-day plan; school staff should know the diet to support the child socially, not to isolate them
• Galactosemia: no breast milk or regular formula; lifelong dairy avoidance; eye and developmental follow-up
• Urea cycle disorders, MSUD, GSD: never let the child fast; have an emergency letter for the emergency department; seek care early for vomiting or lethargy
• Hypothyroidism: give levothyroxine daily; do not stop; if a dose is missed, give it as soon as remembered
• CAH: stress-dose hydrocortisone for fever or illness, keep an emergency hydrocortisone injection kit, wear medical identification
• Future pregnancies: genetic counseling and prenatal or early newborn testing

• Most IEMs are autosomal recessive — 25% recurrence risk per pregnancy
• Newborn screening: heel blood after 24 hours; if collected earlier, repeat; positive screen requires confirmation
• PKU = phenylalanine hydroxylase deficiency; musty odor, fair skin, intellectual disability if untreated
• PKU diet: restrict, do not eliminate phenylalanine; avoid aspartame; target 2–6 mg/dL (120–360 µmol/L) for life
• Maternal PKU: control phenylalanine before conception
• Galactosemia: jaundice, vomiting, E. coli sepsis, cataracts; no breast milk — use soy/lactose-free formula
• MSUD: maple syrup odor, branched-chain amino acids
• Urea cycle disorder: hyperammonemia with respiratory alkalosis; stop protein, give glucose, scavengers, dialysis
• Congenital hypothyroidism: levothyroxine within 2 weeks; do not mix with soy, iron, or calcium
• CAH: females ambiguous genitalia; males salt-wasting crisis at 1–3 weeks — hydrocortisone and fludrocortisone