🧠 Phenylketonuria (PKU) for USMLE Step 1: Pathophysiology, Presentation, and Treatment

PKU is a classic metabolic disorder tested on Step 1 because it touches on:

• Amino acid metabolism

• Enzyme deficiencies

• Newborn screening

• Genetic inheritance

• Neurologic + dermatologic symptoms

🧬 Pathophysiology

Step	Normal Process	PKU Defect
1	Phenylalanine → Tyrosine	Deficiency of Phenylalanine Hydroxylase (PAH)
2	Tyrosine used to make dopamine, melanin, T₃/T₄	↓ Dopamine, ↓ Melanin
3	Normal metabolism of phenylalanine	Phenylalanine → phenylketones (toxic)

🧪 Genetics

• Autosomal recessive

• Gene: PAH (phenylalanine hydroxylase)

• Some cases are due to BH₄ (tetrahydrobiopterin) deficiency → cofactor for PAH

🧠 Mnemonic:
"Pee-K-U = PAH Enzyme Error"

🩺 Symptoms of PKU

System	Presentation
CNS	Intellectual disability, seizures, microcephaly
Skin	Fair skin, blue eyes (hypopigmentation)
Smell	Musty or mousy odor
Development	Delayed milestones, hyperreflexia

🧠 Symptoms appear after birth unless detected early by screening!

🧪 Newborn Screening

• PKU is part of mandatory newborn screening in the US

• Normal at birth, but symptoms begin within first few months

• Detects elevated phenylalanine levels

🍽️ Management

Strategy	Goal
Low-phenylalanine diet	Avoid toxic buildup
Tyrosine supplementation	Becomes essential amino acid
BH₄ supplementation	For cofactor deficiency (sapropterin)
Frequent screening	Monitor phenylalanine levels

🧠 Mnemonics for Step 1

“PKU = PAH Knocked Out”

→ Phenylalanine Hydroxylase deficiency

“Musty baby, pale skin, poor brain = PKU”

⚠️ Step 1 Question Clues

A 2-month-old infant has fair skin, microcephaly, developmental delay, and a musty body odor. What is the likely diagnosis?

✅ Answer: Phenylketonuria (PKU)

🧬 Confirm with elevated phenylalanine levels and genetic testing for PAH mutation

🎯 Call-To-Action

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