A 3-week-old male neonate born to non-consanguineous parents presents with poor feeding, irritability, and a musty or 'mousy' odour on his nappies. Routine newborn screening was not performed. On examination, he is hypotonic with exaggerated deep tendon reflexes. Serum phenylalanine is 1240 µmol/L (normal <120 µmol/L), and urine phenylketones are positive. What is the most likely diagnosis?

Explanation

## Diagnosis: Phenylketonuria (PKU) ### Clinical Presentation The vignette describes a classic presentation of **untreated PKU** in an early neonatal period: - **Musty/mousy odour** — pathognomonic for phenylacetic acid and phenylacetyl-CoA in urine and sweat - **Poor feeding and irritability** — early neurological signs from hyperphenylalaninaemia - **Hypotonia progressing to hypertonia with hyperreflexia** — reflects evolving cerebral damage - **Positive urine phenylketones** — diagnostic for PKU ### Biochemistry of PKU **Key Point:** PKU results from deficiency of the enzyme **phenylalanine hydroxylase (PAH)**, which catalyzes the conversion of phenylalanine → tyrosine. ``` Phenylalanine ──(PAH deficiency)──> Accumulates in serum & urine ↓ Phenylpyruvate (transaminated) ↓ Phenylacetate & Phenylacetyl-CoA ↓ Musty odour in urine/sweat ``` ### Diagnostic Criteria | Feature | PKU | Alkaptonuria | MSUD | |---------|-----|--------------|------| | **Enzyme defect** | Phenylalanine hydroxylase | Homogentisate 1,2-dioxygenase | Branched-chain α-ketoacid dehydrogenase | | **Elevated amino acid** | Phenylalanine | Homogentisic acid | Leucine, isoleucine, valine | | **Urine odour** | Musty/mousy | Dark/alkapton (oxidizes black) | Maple syrup | | **Age of onset** | 1–4 weeks | Childhood (dark urine) | 4–7 days (severe form) | | **Neurological signs** | Seizures, developmental delay if untreated | None | Lethargy, seizures, cerebral edema | | **Positive ferric chloride test** | Yes (green) | Yes (dark brown) | Yes (grey-green) | **High-Yield:** Serum phenylalanine >1200 µmol/L is diagnostic for PKU. Normal is <120 µmol/L. ### Inheritance & Screening **Key Point:** PKU is **autosomal recessive**. Early detection via newborn screening (Guthrie test or tandem MS) within 48–72 hours of birth allows initiation of a **phenylalanine-restricted diet** before neurological damage occurs. **Clinical Pearl:** If detected and treated early (diet started before 4 weeks), intellectual disability is prevented. Untreated PKU leads to severe intellectual disability, seizures, eczema, light skin, and blonde hair (due to tyrosine deficiency affecting melanin synthesis). ### Why This Case Is PKU - Serum phenylalanine **1240 µmol/L** (>1200 = PKU) - **Musty odour** (pathognomonic) - **Positive urine phenylketones** - **Early neonatal presentation** (3 weeks) - **Neurological signs** (hypotonia, hyperreflexia)