A 3-day-old neonate born to non-consanguineous parents in Delhi presents with poor feeding, lethargy, and a characteristic musty or mousy odour on the nappy. Serum phenylalanine is markedly elevated at 1200 µmol/L (normal <120 µmol/L). Which enzyme deficiency is the most common cause of this clinical presentation?

## Phenylketonuria (PKU) — Enzyme Deficiency **Key Point:** Phenylalanine hydroxylase (PAH) deficiency is the most common cause of elevated serum phenylalanine and the most frequent autosomal recessive amino aciduria in most populations, including India. ### Pathophysiology Phenylalanine hydroxylase catalyzes the conversion of phenylalanine → tyrosine. When deficient: 1. Phenylalanine accumulates in blood and urine (hyperphenylalaninemia) 2. Alternative pathways activate: phenylalanine → phenylpyruvate (via transamination) → phenyllactate and phenylacetate 3. These metabolites produce the characteristic **musty/mousy odour** (phenylacetate) 4. Excess phenylalanine crosses the blood–brain barrier, inhibiting tyrosine and tryptophan uptake → reduced neurotransmitter synthesis (dopamine, serotonin, norepinephrine) ### Clinical Features of Classic PKU | Feature | Timing | Mechanism | |---------|--------|----------| | Musty/mousy odour | Days 3–5 | Phenylacetate in sweat/urine | | Poor feeding, lethargy | Days 3–7 | Elevated Phe, ↓ neurotransmitters | | Intellectual disability (if untreated) | Weeks–months | Myelin damage, neurotransmitter deficiency | | Eczema, fair skin, light hair | Months | ↓ Melanin (tyrosine-dependent) | | Seizures | Months | Neuronal dysfunction | **High-Yield:** PKU is detected on **newborn screening** (Guthrie test or tandem MS) in most developed countries. Early dietary restriction of phenylalanine (phenylalanine-restricted formula) prevents neurological damage. ### Epidemiology - **Incidence:** ~1 in 10,000–15,000 live births globally - **Most common** cause of elevated plasma phenylalanine and preventable intellectual disability - Autosomal recessive inheritance; >1000 mutations in PAH gene identified **Clinical Pearl:** The musty odour is pathognomonic for PKU and results from phenylacetate accumulation — this is the clinical clue that distinguishes PKU from other hyperaminoacidemias in the newborn period.