A 3-day-old male neonate born to consanguineous parents presents with poor feeding, lethargy, and a distinctive musty or mousy odour on the breath and urine. Newborn screening shows elevated plasma phenylalanine (>20 mg/dL; normal <2 mg/dL) and elevated urinary phenylketones. Physical examination reveals fair skin and blonde hair. What is the most likely diagnosis?

## Clinical Presentation and Diagnosis **Key Point:** Classical PKU is an autosomal recessive disorder caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. ### Pathophysiology 1. **Enzyme defect**: Phenylalanine hydroxylase (PAH) deficiency 2. **Substrate accumulation**: Plasma phenylalanine rises dramatically (>20 mg/dL) 3. **Alternative metabolism**: Excess phenylalanine is transaminated to phenylpyruvate and phenyllactate, which are excreted in urine (phenylketones) 4. **Neurotoxicity**: Elevated phenylalanine and its metabolites inhibit: - Tyrosine uptake into the brain - Myelin formation - Dopamine and serotonin synthesis ### Clinical Features of Classical PKU | Feature | Mechanism | |---------|----------| | **Musty/mousy odour** | Phenylacetate in sweat and urine | | **Fair skin, blonde hair** | Phenylalanine inhibits tyrosinase (melanin synthesis) | | **Intellectual disability** (if untreated) | Neurotoxic effects of elevated Phe and phenylpyruvate | | **Seizures** | Brain damage from metabolite accumulation | | **Eczema, hypopigmentation** | Tyrosine deficiency (essential in PKU) | | **Hyperactivity, behavioural problems** | Dopamine/serotonin depletion | ### Diagnostic Confirmation - **Elevated plasma phenylalanine** (>20 mg/dL in classical PKU; 4–20 mg/dL in mild/moderate forms) - **Positive urinary phenylketones** (ferric chloride test turns green) - **Normal plasma tyrosine** (or low, due to competitive inhibition of uptake) - **Elevated urinary phenylpyruvate and phenyllactate** - **Genetic testing**: PAH gene mutations confirm diagnosis **High-Yield:** Newborn screening detects PKU within 24–48 hours of life, allowing early dietary intervention (phenylalanine-restricted diet) to prevent neurological damage. Early treatment is the key to normal development. ### Management 1. **Phenylalanine-restricted diet** (special medical foods, low-protein diet) 2. **Lifelong dietary management** (especially critical during brain development, ages 0–8 years) 3. **Regular monitoring** of plasma phenylalanine levels (target: 2–6 mg/dL) 4. **Maternal PKU management** during pregnancy (strict diet to prevent fetal damage) **Clinical Pearl:** Even mild elevations of maternal phenylalanine during pregnancy cause fetal damage (maternal PKU syndrome: microcephaly, congenital heart disease, intellectual disability) despite the fetus having normal PAH. This is why women with PKU must maintain strict dietary control during childbearing years.