Which enzyme is deficient in phenylketonuria (PKU)?

Explanation

## Phenylketonuria (PKU) — Enzyme Defect **Key Point:** PKU is caused by deficiency of **phenylalanine hydroxylase**, the enzyme that catalyzes the conversion of phenylalanine to tyrosine. ### Biochemical Mechanism Phenylalanine hydroxylase is a hepatic enzyme that requires the cofactor **tetrahydrofolate (BH₄)**. When deficient: - Phenylalanine accumulates in blood and urine (hyperphenylalaninemia) - Tyrosine becomes conditionally essential (cannot be synthesized from phenylalanine) - Alternative metabolic pathways are activated, producing phenylpyruvate, phenyllactate, and phenylacetate (causing the characteristic "mousy" or "musty" odor in urine) ### Clinical Consequences - **Intellectual disability** (if untreated) due to accumulation of phenylalanine and its metabolites, which are neurotoxic - **Hypopigmentation** (fair skin, blonde hair, blue eyes) because tyrosine is a precursor of melanin - **Eczema and seizures** in untreated cases **High-Yield:** PKU is screened universally in newborns via **Guthrie test** (elevated blood phenylalanine >20 mg/dL). Early dietary restriction of phenylalanine prevents neurological damage. ### Differential Diagnosis of Amino Acidurias | Condition | Enzyme Defect | Primary Accumulation | Key Feature | |-----------|---------------|----------------------|-------------| | **PKU** | Phenylalanine hydroxylase | Phenylalanine | Hyperphenylalaninemia; mousy odor | | **Alkaptonuria** | Homogentisate 1,2-dioxygenase | Homogentisic acid | Dark urine on standing; ochronosis | | **Maple Syrup Urine Disease** | Branched-chain α-ketoacid dehydrogenase | Leucine, isoleucine, valine | Sweet-smelling urine; neurological crisis | | **Tyrosinemia** | Fumarylacetoacetate hydrolase (Type I) | Tyrosine metabolites | Liver failure; renal tubular dysfunction | **Clinical Pearl:** Maternal PKU (untreated) causes **fetal PKU syndrome** — intrauterine exposure to high phenylalanine causes microcephaly, cardiac defects, and intellectual disability even if the fetus is heterozygous.