A 6-month-old girl born to consanguineous parents presents with poor feeding, developmental delay, and a distinctive musty or 'mousy' odor to her urine and sweat. Newborn screening was not performed. On examination, she has fair skin, light-colored hair, and eczematous rash. Serum phenylalanine level is 1,200 μmol/L (normal <120 μmol/L). What is the most likely diagnosis?

Explanation

## Diagnosis: Phenylketonuria (PKU) **Key Point:** Phenylketonuria is an autosomal recessive disorder of phenylalanine metabolism caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), leading to accumulation of phenylalanine and its metabolites. ### Pathophysiology 1. **Enzyme defect:** Phenylalanine hydroxylase converts phenylalanine → tyrosine 2. **Result of deficiency:** Phenylalanine accumulates; tyrosine becomes essential 3. **Metabolic consequence:** Excess phenylalanine is transaminated to phenylpyruvate and phenyllactate 4. **Neurological damage:** Phenylalanine inhibits neutral amino acid transport across blood–brain barrier; excess phenylpyruvate is neurotoxic ### Clinical Features | Feature | Timing | Manifestation | | --- | --- | --- | | **Musty/mousy odor** | Early infancy | Phenylacetate in urine and sweat | | **Poor feeding** | 1–3 months | Vomiting, anorexia | | **Developmental delay** | 3–6 months | Untreated cases; progressive | | **Seizures** | 6–12 months | Generalized tonic–clonic | | **Hypopigmentation** | Early | Fair skin, light hair (phenylalanine competes with tyrosine for melanin synthesis) | | **Eczema** | Early | Atopic dermatitis-like rash | | **Intellectual disability** | Progressive | Severe if untreated; preventable with early dietary intervention | | **Behavioral abnormalities** | Later | Hyperactivity, aggression (untreated) | **High-Yield:** The **musty/mousy odor** is the clinical hallmark — caused by phenylacetate in urine and sweat. This is virtually pathognomonic when combined with elevated serum phenylalanine. ### Laboratory Findings - **Serum phenylalanine:** >1,200 μmol/L (normal <120 μmol/L); markedly elevated - **Serum tyrosine:** Low (becomes essential amino acid) - **Urine:** Phenylpyruvate, phenyllactate, phenylacetate (positive ferric chloride test — green color) - **Newborn screening:** Elevated phenylalanine on dried blood spot ### Management 1. **Dietary restriction:** Low-phenylalanine diet (special formula, restricted protein) 2. **Monitoring:** Serial phenylalanine levels; target 2–10 mg/dL (120–600 μmol/L) 3. **Tyrosine supplementation:** As it becomes essential 4. **Maternal PKU:** Pregnant women with PKU require strict dietary control to prevent fetal damage (maternal PKU syndrome) **Clinical Pearl:** Early diagnosis via newborn screening and prompt dietary intervention can completely prevent intellectual disability. This case likely represents delayed diagnosis (no newborn screening performed), explaining the developmental delay and clinical signs already present at 6 months. **Mnemonic: PKU = Phenylalanine ↑, Hydroxylase ↓, Urine mousy** — autosomal recessive, preventable with early diet.