A 7-day-old male neonate, born to non-consanguineous parents in Delhi, presents with poor feeding, lethargy, and vomiting since day 5 of life. Antenatal and delivery history were unremarkable. On examination, the baby is hypotonic with a characteristic 'musty' or 'mousy' odour on the breath. Neonatal screening blood spot shows elevated phenylalanine (>20 mg/dL; normal <2 mg/dL) and normal tyrosine. Urine ferric chloride test is positive (green colour). What is the most likely diagnosis?

Explanation

## Diagnosis: Phenylketonuria (PKU) ### Clinical Presentation This neonate presents with the classic signs of untreated PKU: - **Onset:** Days 5–7 of life (after breast milk feeding establishes) - **Neurological signs:** Hypotonia, lethargy, poor feeding, vomiting - **Characteristic odour:** Musty or 'mousy' smell due to phenylacetic acid in sweat and urine - **Eczematous rash:** Often present (not mentioned but common) ### Biochemistry & Screening | Feature | PKU | MSUD | Homocystinuria | Tyrosinemia Type 1 | |---------|-----|------|-----------------|--------------------| | **Elevated amino acid** | Phenylalanine | Branched-chain (Leu, Ile, Val) | Homocysteine | Methionine, Tyrosine | | **Urine ferric chloride** | Green | Negative | Negative | Negative | | **Urine odour** | Musty/mousy | Maple syrup | Rotten cabbage | Rotten cabbage | | **Tyrosine level** | Normal or low | Normal | Normal | Elevated | | **Screening marker** | ↑ Phe, normal Tyr | ↑ Branched-chain AAs | ↑ Homocysteine, Met | ↑ Met, Tyr, α-fetoprotein | **Key Point:** The combination of **elevated phenylalanine with normal tyrosine** and **positive ferric chloride test** is pathognomonic for PKU. The musty odour is due to phenylacetic acid accumulation. ### Pathophysiology PKU results from deficiency of the enzyme **phenylalanine hydroxylase**, which normally converts phenylalanine to tyrosine. This leads to: 1. Accumulation of phenylalanine and its metabolites (phenylacetic acid, phenyllactic acid) 2. Competitive inhibition of neutral amino acid transporters in the blood–brain barrier 3. Reduced entry of other large neutral amino acids (tyrosine, tryptophan) into the brain 4. Deficient synthesis of neurotransmitters (dopamine, serotonin) and myelin proteins 5. Progressive neurological damage if untreated ### Management **High-Yield:** Early diagnosis via neonatal screening and **immediate initiation of a phenylalanine-restricted diet** (special formula with low Phe content) can prevent intellectual disability entirely. Screening is part of India's expanded newborn screening programme in many states. **Clinical Pearl:** If PKU is suspected, do NOT delay dietary intervention while awaiting confirmatory testing. Elevated Phe levels >10 mg/dL in the first week of life warrant urgent dietary restriction. ### Prognosis with Early Treatment - IQ remains normal (>85) if diet started before 2 weeks of age - IQ drops significantly if treatment delayed beyond 4 weeks - Untreated: severe intellectual disability (IQ <50), seizures, behavioural problems [cite:Park 26e Ch 9]