A 3-week-old male infant born to non-consanguineous parents presents with poor feeding, irritability, and a musty or "mousy" odour on the nappy. Newborn screening was not performed. Physical examination reveals fair skin and light-coloured hair. Serum phenylalanine is 1240 µmol/L (normal <120 µmol/L). Urine ferric chloride test shows a green colour. What is the most likely diagnosis?

Explanation

## Diagnosis: Phenylketonuria (PKU) ### Clinical Presentation This infant presents with the classic triad of untreated PKU: 1. **Musty/mousy odour** — due to phenylacetic acid and phenylpyruvic acid in urine and sweat 2. **Fair skin and light hair** — hypopigmentation from competitive inhibition of tyrosine uptake by excess phenylalanine (tyrosine is a precursor of melanin) 3. **Neurological symptoms** — irritability and poor feeding are early signs; untreated PKU leads to intellectual disability, seizures, and behavioural problems ### Laboratory Findings **Key Point:** Markedly elevated serum phenylalanine (>1200 µmol/L) is pathognomonic for PKU. The ferric chloride test produces a **green colour** with phenylpyruvic acid (a ketone metabolite of phenylalanine), which is diagnostic. ### Biochemical Mechanism PKU results from deficiency of the enzyme **phenylalanine hydroxylase**, which normally converts phenylalanine → tyrosine. This leads to: - Accumulation of phenylalanine and its transamination product phenylpyruvate - Phenylpyruvate is reduced to phenyllactate and oxidised to phenylacetate - These metabolites cause the characteristic musty odour - Excess phenylalanine competitively inhibits neutral amino acid transporters (LAT) at the blood–brain barrier, reducing tyrosine and other large neutral amino acids in the CNS - Tyrosine depletion → reduced dopamine, noradrenaline, and melanin synthesis ### Diagnostic Criteria | Feature | PKU | Alkaptonuria | MSUD | Homocystinuria | | --- | --- | --- | --- | --- | | **Elevated amino acid** | Phenylalanine | None (normal) | Branched-chain AAs | Homocysteine | | **Urine odour** | Musty/mousy | Dark/black (oxidation) | Maple syrup | None | | **Ferric chloride test** | Green | Negative | Negative | Negative | | **Age of onset** | 2–4 weeks | Adulthood (ochronosis) | 1–2 weeks (MSUD) | Variable | | **Skin/hair** | Fair, hypopigmented | Normal | Normal | Ectopia lentis, marfanoid | **High-Yield:** PKU is the most common cause of preventable intellectual disability in developed countries. Early diagnosis (via newborn screening) and dietary restriction of phenylalanine prevents neurological damage. ### Management 1. **Dietary restriction** — phenylalanine-restricted formula (e.g., Lofenalac) from diagnosis 2. **Monitoring** — serum phenylalanine levels maintained at 2–10 mg/dL (120–600 µmol/L) 3. **Supplementation** — tyrosine (becomes conditionally essential) and other large neutral amino acids 4. **Prognosis** — with early treatment, normal development is achievable **Clinical Pearl:** The "mousy" odour is often the first clinical clue in unscreened infants and should immediately raise suspicion for PKU, even before biochemical confirmation.