A 3-day-old male neonate born to non-consanguineous parents presents with poor feeding, lethargy, and a characteristic musty or mousy odour in the urine. Physical examination reveals developmental delay and eczematous skin lesions. Newborn screening confirms elevated plasma phenylalanine (>20 mg/dL; normal <2 mg/dL) and elevated urinary phenylketones. The infant's mother reports no prenatal complications. What is the most likely diagnosis?

Explanation

## Diagnosis: Classical Phenylketonuria (PKU) ### Clinical Presentation Matching **Key Point:** The constellation of elevated plasma phenylalanine, urinary phenylketones, musty odour, and early-onset developmental delay in a neonate is pathognomonic for classical PKU. ### Pathophysiology Classical PKU results from deficiency of the hepatic enzyme **phenylalanine hydroxylase (PAH)**, which catalyzes the conversion of phenylalanine to tyrosine. This autosomal recessive disorder leads to: 1. Accumulation of phenylalanine in blood and urine 2. Shunting of phenylalanine into alternative metabolic pathways: - Transamination → phenylpyruvate (phenylketone) - Reduction → phenyllactate - Decarboxylation → phenylethylamine 3. The phenylketones and phenylethylamine produce the characteristic **musty/mousy odour** 4. Excess phenylalanine and its metabolites inhibit: - Tyrosine synthesis (tyrosine becomes conditionally essential) - Serotonin and dopamine synthesis → neurological damage - Melanin synthesis → fair skin and light hair ### Biochemical Findings | Parameter | Classical PKU | Normal | |-----------|---------------|--------| | Plasma phenylalanine | >20 mg/dL (>1200 µmol/L) | <2 mg/dL (<120 µmol/L) | | Urinary phenylketones | Positive (FeCl₃ green colour) | Negative | | Plasma tyrosine | Low (tyrosine deficiency) | Normal | | Urine phenylpyruvate | Elevated | Absent | **High-Yield:** The **FeCl₃ test** (ferric chloride test) on urine produces a characteristic **green colour** in PKU due to reaction with phenylpyruvate — this was historically the screening test before tandem mass spectrometry. ### Clinical Features in Untreated PKU - **Neurological:** Developmental delay, seizures, tremor, behavioural problems, intellectual disability - **Dermatological:** Eczema, fair skin (hypopigmentation due to melanin synthesis inhibition) - **Metabolic odour:** Musty/mousy/mousy smell from phenylethylamine - **Growth:** Failure to thrive if untreated ### Management **Clinical Pearl:** Early diagnosis via newborn screening (Guthrie test or tandem MS) and **immediate initiation of phenylalanine-restricted diet** (low-Phe formula, special medical foods) prevents all neurological sequelae. Dietary management must begin within the first 2 weeks of life to prevent irreversible brain damage. ### Why This Case is PKU and Not Other Disorders - **Elevated phenylalanine** is the hallmark — tyrosinemia type I presents with elevated tyrosine and methionine, not phenylalanine - **Urinary phenylketones** are specific to PKU (phenylpyruvate accumulation) - **Early presentation (3 days)** and **musty odour** are classic PKU features - **Normal liver function** (implied) — tyrosinemia type I presents with acute liver failure **Mnemonic: PAH-deficiency = Phenylalanine Accumulation Hyperplasia** — remember that the enzyme defect is PAH (phenylalanine hydroxylase), leading to phenylalanine accumulation and the characteristic phenylketones. [cite:Robbins 10e Ch 5]