A 4-month-old boy is brought in for failure to meet milestones. He is not tracking, not smiling, and had two brief jerking episodes last week. On exam he has dry, scaly patches on the cheeks and trunk. His hair is fine and pale blond; both parents have dark brown hair and brown eyes. Mom mentions a strange smell to his urine that reminds her of old mouse cages. The pediatrician asks whether he received his newborn screen at the rural birthing center: mom is not sure.
Classic Phenylketonuria (PAH deficiency)
The clue: mouse-urine odor + blond child of dark-haired parents + missed newborn screen + early seizures. That smell is phenylacetate, a side-pathway dump product the body makes when phenylalanine has nowhere else to go.
The chain: PAH is broken → phenylalanine piles up → tyrosine drops out → no melanin (pale hair, fair skin) → phenylalanine spills into ketone side pathways (the smell) → high phenylalanine in the brain blocks neurotransmitter synthesis (seizures, delay).
The move: tandem mass spec on dried blood spot, then a phenylalanine-restricted diet for life, plus tyrosine supplementation. Caught at 24 to 48 hours, the brain is saved. Caught at 4 months, damage is already locked in.
Stem Clues
What the question stem is screaming at you
Four signature phrases. If you spot any of them, this is PKU until proven otherwise. Tap a card to see why each one works.
🦤
Musty / Mousy Odor
Urine smells like a basement, old mouse cage, or stale gym socks.
Phenylalanine cannot become tyrosine, so it spills into side pathways producing phenylpyruvate (the actual ketone that names the disease) and phenylacetate (a carboxylic acid responsible for the mousy odor). The disease is named for phenylpyruvate in urine (phenyl + keto + uria).
🎀
Fair Skin, Blond Hair, Blue Eyes
A pale child born to dark-haired, dark-skinned parents.
Tyrosine is the precursor to melanin. No PAH means almost no tyrosine. No tyrosine, no melanin. The child looks like an outlier in family photos because the pigment factory is shut down at the loading dock.
🪥
Missed Newborn Screen
Home birth, rural delivery, or "screening unclear" in the chart.
PKU babies look normal at birth. Symptoms unfold over weeks as phenylalanine accumulates. The heel-stick at 24 to 48 hours is the only window where treatment fully prevents intellectual disability. Miss it and the brain damage is silent and irreversible.
🧠
Seizures + Developmental Delay
An infant who stopped meeting milestones and started having jerks.
High phenylalanine competes with the other large neutral amino acids at the blood-brain barrier and blocks the synthesis of dopamine and serotonin. The brain runs on monoamines. Starve those signals and you get a baby who cannot learn and starts seizing.
The Pathway, Three Ways
One enzyme. Three different blackouts.
Tap a mode and watch what survives. Healthy = everything lights up. Classic PKU = PAH alone is broken. Malignant PKU = the BH4 cofactor is broken, which knocks out PAH, TH, and TPH together. Notice what dies in each mode.
Healthy state
PAH converts phenylalanine to tyrosine using BH4 as a cofactor. Tyrosine fans out into melanin (pigment), the catecholamines (DOPA → dopamine → NE → epinephrine), and supports the brain. BH4 also serves tryptophan hydroxylase, so serotonin is intact.
The Cofactor That Runs Three Reactions
BH4: the master key for monoamines
BH4 (tetrahydrobiopterin) is not glamorous like an enzyme, but it is the cofactor for three hydroxylase reactions that build the brain. Lose BH4 and you lose all three at once. That is malignant PKU.
PAH
Phe → Tyr
Makes tyrosine: the upstream piece for melanin and every catecholamine.
Lose this → pale skin, no dopamine precursor, phenylalanine builds up.
Tyrosine Hydroxylase
Tyr → L-DOPA
Rate-limiting step for the catecholamines: dopamine, norepinephrine, epinephrine.
Lose this → no dopamine, severe parkinsonism in an infant.
Tryptophan Hydroxylase
Trp → 5-HTP
Rate-limiting step for serotonin synthesis.
Lose this → no serotonin, mood and sleep collapse, intractable seizures.
The trap on the exam: a kid is on a strict phenylalanine-restricted diet but is still deteriorating neurologically. Classic PKU should improve on diet. If diet does not rescue the brain, you are dealing with malignant PKU (DHPR deficiency or other BH4-cycle defects). Diet only fixes the phenylalanine load, not the missing dopamine and serotonin. Treat with sapropterin (synthetic BH4) plus L-DOPA and 5-HTP supplementation. DHPR is the recycling enzyme that regenerates BH4 after PAH uses it; without DHPR, BH4 runs out for all three hydroxylases.
Screening
The heel stick that saves the brain
PKU was the original reason newborn screening exists. Every state in the US requires it. Miss the window and the damage is silent and permanent.
The Test
Newborn Screen for PKU
Heel stick at 24 to 48 hours. Blood drops are spotted on filter paper (Guthrie card) and sent to the state lab.Dried blood spots on a Guthrie card. Tandem mass spectrometry reads phenylalanine concentration directly.
When
24 to 48 hours after the first protein feeding. Earlier than 24 hours misses cases because phenylalanine has not built up yet.
How
Heel stick into filter paper card (the Guthrie card). Original Guthrie test used bacterial inhibition. Modern labs use tandem mass spec, which screens dozens of disorders from the same spots in one run.
Cutoff
Phenylalanine above ~120 micromoles per liter (~2 mg per deciliter) flags for confirmation. Normal newborn level is ~50.
Confirm
Quantitative plasma amino acids. Add a BH4 loading test or pterin profile to separate classic PKU (PAH only) from malignant PKU (BH4 cycle).
Window
Start the diet by day 7 to 10 of life to fully prevent intellectual disability. Every week of delay buys irreversible brain damage.
Treatment
The diet is the medicine
PKU is not cured. It is managed for life. The food list looks restrictive because it is.
Lifelong Diet
Phenylalanine-Restricted Diet
Avoid
High-protein foods: meat, fish, eggs, dairy, nuts, legumes, regular bread, beer. Anything that translates to Phe in the body.
No Aspartame
Diet sodas and sugar-free gum are off limits. Aspartame breaks down to phenylalanine in the gut. Every can of diet soda is a microdose of poison. Cans are required to carry a warning label specifically for PKU patients.
Formula
Medical food (Lofenalac and equivalents) provides the essential amino acids minus phenylalanine, plus all the vitamins and minerals. This is the bulk calorie source.
Tyrosine
In PKU, tyrosine becomes essential. The body usually makes it from Phe, but PAH is broken. Daily tyrosine supplementation is required to keep melanin, dopamine, and thyroid hormone synthesis going.
Sapropterin
Synthetic BH4. Helps the subset of patients with residual PAH activity (BH4-responsive). Mandatory for malignant PKU (BH4-cycle defect).
For Life
Old teaching was "diet until age 6." New consensus is diet for life. Even adults show executive function dips when phenylalanine climbs.
Pregnancy
Maternal PKU: the second danger
A woman with PKU who has been off the diet for years can carry a totally normal-genome baby and still cause teratogenic damage. Her high phenylalanine crosses the placenta and poisons a fetus that does not even have the disease.
Risk
Microcephaly, intellectual disability, congenital heart defects, intrauterine growth restriction. The fetus has functional PAH but is swimming in toxic maternal phenylalanine.
Plan
Strict phenylalanine restriction before conception (target Phe under 360 micromoles per liter) and throughout pregnancy. Counsel every PKU woman of childbearing age at every visit.
Board trap: the question shows a woman who "had PKU as a child" and stopped the diet in college. She gets pregnant and her baby is born with microcephaly and a VSD. The answer is maternal PKU, not a separate genetic defect in the baby. The disease in the baby came from her bloodstream, not his genes.
Test It
Five vignettes. No second-guessing.
Medically reviewed by Kaitlyn Cocuzzo, MD and Fatima Ali, DO · Last updated July 5, 2026 at 8:33 PM ET
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