A 3-day-old male neonate born to non-consanguineous parents presents with poor feeding, lethargy, and a musty or mousy odour on examination. Routine newborn screening reveals elevated plasma phenylalanine (>20 mg/dL) and normal tyrosine levels. Urine phenylketones are positive. The infant has no hepatomegaly or jaundice. What is the most likely enzymatic defect?

Explanation

## Clinical Presentation Analysis This neonate exhibits the classic presentation of **phenylketonuria (PKU)**, an autosomal recessive disorder of phenylalanine metabolism. ### Key Diagnostic Features **High-Yield:** The triad of elevated plasma phenylalanine, normal tyrosine, and positive urine phenylketones is pathognomonic for phenylalanine hydroxylase deficiency. | Feature | PKU (Phe Hydroxylase ↓) | Tyrosine Aminotransferase ↓ | Homogentisate Oxidase ↓ | |---------|--------------------------|------------------------------|-------------------------| | Plasma Phe | ↑↑ (>20 mg/dL) | Normal | Normal | | Plasma Tyr | Normal or ↓ | ↑↑ | Normal | | Urine Phe metabolites | Phenylketones, phenylacetate | Absent | Homogentisic acid | | Musty odour | Yes (phenylacetate) | No | No (dark urine) | | Age of presentation | 3–7 days | 1–3 months | Adulthood (ochronosis) | ### Biochemical Mechanism **Key Point:** Phenylalanine hydroxylase catalyzes the conversion of phenylalanine → tyrosine using tetrahydrofolate (BH₄) as a cofactor. When this enzyme is deficient: 1. Phenylalanine accumulates in plasma and urine 2. Alternative transamination pathways activate: Phe → phenylpyruvate → phenyllactate and phenylacetate 3. Phenylacetate produces the characteristic musty/mousy odour 4. Tyrosine becomes conditionally essential (cannot be synthesized from Phe) 5. Elevated Phe and metabolites cross the blood–brain barrier, causing intellectual disability if untreated **Clinical Pearl:** The musty odour is due to phenylacetate in sweat and urine—a key clinical clue that distinguishes PKU from other aminoacidopathies. ### Why Early Detection Matters **High-Yield:** Newborn screening for PKU is mandatory in India and globally. Early dietary restriction of phenylalanine (Phe-restricted formula) begun within the first 2 weeks of life prevents intellectual disability. The critical window is the first 3 months of life, when brain development is most vulnerable. [cite:Robbins 10e Ch 5]