A 3-week-old male infant born to non-consanguineous parents in Delhi presents with poor feeding, irritability, and a musty or "mousy" odour noticed by the parents. Routine newborn screening was not performed. Physical examination reveals fair skin and blonde hair. Developmental milestones are normal so far. 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 This infant exhibits the classic triad of untreated PKU: 1. **Musty/mousy odour** — due to phenylacetic acid and phenylacetyl-CoA in urine and sweat 2. **Fair skin and blonde hair** — hypopigmentation from competitive inhibition of tyrosine uptake by excess phenylalanine (tyrosine is a precursor for melanin) 3. **Early neurological signs** — irritability and poor feeding are early manifestations; if untreated, leads to severe intellectual disability by 6–12 months ### Biochemistry **Key Point:** PKU results from deficiency of the enzyme **phenylalanine hydroxylase**, which catalyzes the conversion of phenylalanine → tyrosine. $$\text{Phenylalanine} \xrightarrow{\text{phenylalanine hydroxylase}} \text{Tyrosine}$$ When this enzyme is deficient or absent: - Phenylalanine accumulates in blood and is shunted to alternative pathways - Produces phenylketones (phenylacetate, phenylpyruvate) → excreted in urine - Excess phenylalanine competitively inhibits neutral amino acid transporters (LAT1, LAT2) at the blood–brain barrier, reducing tyrosine and other large neutral amino acids in the CNS - This leads to deficiency of dopamine and norepinephrine synthesis → neurological damage ### Laboratory Findings - **Serum phenylalanine >1200 µmol/L** (this patient: 1240 µmol/L) — diagnostic - **Positive urine phenylketones** — ferric chloride test turns green; Guthrie test (newborn screening) is gold standard - Normal or low serum tyrosine (due to competitive inhibition) ### Pathophysiology of Hypopigmentation **Clinical Pearl:** The fair skin and blonde hair are NOT due to albinism but to **reduced melanin synthesis**. Tyrosine is the substrate for melanin production via the pathway: Tyrosine → L-DOPA → dopaquinone → melanin. When phenylalanine competitively inhibits tyrosine uptake, melanin synthesis is impaired. ### Management - **Dietary restriction of phenylalanine** — initiated before 2 weeks of age to prevent neurological damage - **Phenylalanine-restricted formula** (e.g., Lofenalac) with supplemental tyrosine - **Lifelong dietary management** — especially critical during childhood and adolescence - **Maternal PKU** — women with PKU who become pregnant require strict phenylalanine control to prevent fetal damage (maternal PKU syndrome: microcephaly, cardiac defects, intellectual disability in offspring) ### High-Yield Mnemonic **"PHEN-KEY"** for PKU features: - **P**henylalanine ↑↑ - **H**ypopigmentation (fair skin, blonde hair) - **E**arly neurological signs (irritability, seizures if untreated) - **N**ewborn screening (Guthrie test) - **K**etones in urine (phenylketones) - **E**nzyme defect: phenylalanine hydroxylase - **Y**ellow/musty odour