A 3-day-old neonate born to non-consanguineous parents presents with poor feeding, vomiting, and a characteristic 'musty' or 'mousy' odor in urine and sweat. Plasma phenylalanine is markedly elevated at 1200 µmol/L (normal <120 µmol/L). What is the most common cause of this presentation?

## Diagnosis: Classic Phenylketonuria (PKU) **Key Point:** Phenylalanine hydroxylase (PAH) deficiency accounts for ~98% of all PKU cases and is the most common inborn error of phenylalanine metabolism. ### Enzyme Defect Phenylalanine hydroxylase catalyzes the irreversible hydroxylation of phenylalanine to tyrosine: $$\text{L-Phenylalanine} + \text{BH}_4 + \text{O}_2 \xrightarrow{\text{PAH}} \text{L-Tyrosine} + \text{dihydrofolate}$$ Deficiency leads to: 1. **Accumulation of phenylalanine** → plasma levels >1200 µmol/L 2. **Shunting to alternative pathways** → phenylpyruvate, phenyllactate, phenylacetate 3. **Characteristic 'mousy' odor** from phenylacetate in urine and sweat ### Clinical Features - Intellectual disability (if untreated) - Fair skin and light hair (reduced melanin synthesis due to tyrosine deficiency) - Eczema, seizures, behavioral problems - **Neonatal screening detects before symptoms** (elevated plasma Phe >360 µmol/L at 24–48 h) ### Inheritance - Autosomal recessive - >1000 mutations in the *PAH* gene described - Incidence: ~1 in 10,000–15,000 in most populations **High-Yield:** Classic PKU is the **most common** form; variant forms (BH₄-deficient PKU, transient hyperphenylalaninemia) are rare and usually detected on newborn screening. **Clinical Pearl:** Early dietary restriction of phenylalanine (Phe-restricted formula) initiated within the first 1–2 weeks of life prevents intellectual disability; outcome depends on early detection and compliance with diet.