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

Explanation

## Most Common Cause of Neonatal Hyperphenylalanemia **Key Point:** Phenylketonuria (PKU) is the most common cause of elevated plasma phenylalanine in neonates, with an incidence of approximately 1 in 10,000–15,000 live births globally (higher in certain populations). ### Pathophysiology of Classical PKU Classical PKU results from deficiency of the enzyme **phenylalanine hydroxylase (PAH)**, which catalyzes the conversion of phenylalanine to tyrosine. This is the rate-limiting step in phenylalanine catabolism. $$\text{Phenylalanine} \xrightarrow{\text{PAH}} \text{Tyrosine} \xrightarrow{\text{Tyrosine hydroxylase}} \text{L-DOPA}$$ Without functional PAH: - Phenylalanine accumulates in plasma and tissues - Phenylalanine is shunted into alternative pathways, producing phenylpyruvate, phenyllactate, and phenylacetate - These metabolites are excreted in urine, causing the characteristic **musty or 'mousy' odour** ### Clinical Presentation **High-Yield:** The classic triad of untreated PKU includes: 1. **Intellectual disability** (if untreated; preventable with early diagnosis) 2. **Eczema and hypopigmentation** (due to competitive inhibition of tyrosine uptake by excess phenylalanine, reducing melanin synthesis) 3. **Mousy/musty odour** of urine and sweat (phenylacetate) **Clinical Pearl:** Modern neonatal screening programs detect PKU within 24–48 hours of birth via tandem mass spectrometry or fluorometric assays, allowing early dietary intervention before neurological damage occurs. Dietary restriction of phenylalanine (special medical foods) begun in the first weeks of life prevents intellectual disability. ### Why PKU Is Most Common Comparison of hyperphenylalanemia causes: | Disorder | Enzyme Defect | Incidence | Plasma Phe Level | Other Features | | --- | --- | --- | --- | --- | | **Classical PKU** | Phenylalanine hydroxylase | 1:10,000–15,000 | >1200 µmol/L | Mousy odour, eczema, hypopigmentation | | Tyrosinemia type I | Fumarylacetoacetase | 1:100,000 | Normal/low Phe | Hepatic failure, renal tubular dysfunction, neurological crises | | MSUD | Branched-chain α-ketoacid DH | 1:185,000 | Normal Phe | Maple syrup odour, encephalopathy, elevated BCAAs | | Homocystinuria | Cystathionine β-synthase | 1:344,000 | Normal Phe | Lens dislocation, thrombosis, marfanoid features | **Mnemonic: PKU is the MOST common amino acid disorder — MOST = Mousy odour, Obvious hyperphenylalanemia, Screening detects early, Treatable with diet** ### Neonatal Screening **Key Point:** All developed countries screen for PKU as part of routine newborn screening. Early detection and dietary management (phenylalanine-restricted formula) begun before 2 weeks of age prevents intellectual disability and allows normal neurodevelopment.