A 3-day-old male neonate born to non-consanguineous parents presents with poor feeding, lethargy, and a musty or 'mousy' odour on his clothes and nappy. Newborn screening shows elevated plasma phenylalanine (>20 mg/dL; normal <2 mg/dL) and elevated urinary phenylketones. Serum tyrosine is normal. The infant's parents are phenotypically normal. What is the most likely enzymatic defect?

Explanation

## Diagnosis: Phenylketonuria (PKU) — Classic Form ### Clinical Presentation The vignette describes the cardinal features of **classical phenylketonuria (PKU)**: - Neonatal onset (3 days old) - Poor feeding and lethargy (neurological effects of phenylalanine toxicity) - **Musty/mousy odour** (pathognomonic — due to phenylacetate and phenylacetyl-CoA in sweat and urine) - Elevated plasma phenylalanine with normal tyrosine - Elevated urinary phenylketones (phenylpyruvate, phenyllactate, phenylacetate) - Autosomal recessive inheritance (normal parents, affected neonate) ### Biochemistry of Phenylalanine Metabolism **Key Point:** Phenylalanine hydroxylase catalyzes the first and rate-limiting step: phenylalanine → tyrosine. This enzyme requires **tetrahydrofolate (BH₄)** as a cofactor. When phenylalanine hydroxylase is deficient: 1. Phenylalanine accumulates in blood and urine 2. Excess phenylalanine is shunted to alternative pathways: - Transamination → phenylpyruvate (detected in urine) - Reduction → phenyllactate - Oxidative decarboxylation → phenylacetyl-CoA → phenylacetate (musty odour) 3. Tyrosine becomes **conditionally essential** (cannot be synthesized from phenylalanine) ### Pathophysiology of Neurological Damage **High-Yield:** Elevated phenylalanine causes: - Competitive inhibition of neutral amino acid transporters (LAT) at the blood–brain barrier → reduced entry of other large neutral amino acids (tyrosine, tryptophan, BCAA) - Decreased synthesis of dopamine, noradrenaline, and serotonin - Accumulation of phenylacetyl-CoA inhibits myelination - Results in **intellectual disability, seizures, light skin/hair pigmentation** (tyrosine deficiency), and eczema if untreated ### Why Phenylalanine Hydroxylase Deficiency? **Clinical Pearl:** The pattern of **elevated phenylalanine + normal tyrosine** is pathognomonic for phenylalanine hydroxylase deficiency. In other defects in the pathway (e.g., homogentisate oxidase deficiency in alkaptonuria), tyrosine is elevated or the clinical presentation differs. ### Management - **Newborn screening** (mandatory in India and most countries) — detected on day 3–5 - **Early dietary intervention:** Phenylalanine-restricted formula + tyrosine supplementation - **Outcome:** If treated before 2 weeks of age, intellectual disability is prevented - **Monitoring:** Regular plasma phenylalanine levels (target 2–10 mg/dL during childhood) ### Mnemonic: PKU Features **MOUSY ODOUR** = Musty Odour, Urine Screening positive, Serum elevated, Yellowing skin (hypopigmentation), Odour in sweat [cite:Harper Illustrated Biochemistry 31e Ch 32; Robbins 10e Ch 5]