Phenylketonuria
USMLE Step 1Difficulty: easyLast updated:
A 10-month-old boy who was born at home and did not undergo newborn screening is evaluated for developmental delay. He cannot sit without support. His parents note a 'mousy' odor to his urine and sweat. His skin and hair are noticeably lighter than those of his siblings, and he has an eczema-like rash. Plasma amino acid analysis shows a markedly elevated phenylalanine level and a low tyrosine level.
Deficiency of which of the following enzymes is the most likely cause?
Answer and explanation
Correct answer: B. Phenylalanine hydroxylase
Untreated phenylketonuria (PKU) presents with intellectual disability, a mousy body odor from phenylacetic acid, lighter skin, hair, and eye color than unaffected family members, and sometimes an eczema-like rash. The source states that diagnosis is made by detecting high phenylalanine with normal or low tyrosine. It also states that nearly all cases (98–99%) result from phenylalanine hydroxylase deficiency, the enzyme that converts phenylalanine to tyrosine with tetrahydrobiopterin (BH4) as a cofactor. Less commonly, phenylalanine accumulates because BH4 is not synthesized or regenerated. Hypopigmentation reflects reduced tyrosine availability for melanin synthesis. Newborn screening and early dietary phenylalanine restriction prevent the intellectual disability.
Each option explained
- A. Homogentisate oxidaseIncorrect. Homogentisate oxidase deficiency causes alkaptonuria (dark urine, ochronosis), not hyperphenylalaninemia.
- B. Phenylalanine hydroxylaseCorrect. Phenylalanine hydroxylase deficiency causes 98–99% of PKU, producing high phenylalanine and low tyrosine.
- C. Branched-chain alpha-ketoacid dehydrogenaseIncorrect. Branched-chain alpha-ketoacid dehydrogenase deficiency causes maple syrup urine disease (sweet odor, elevated leucine, isoleucine, valine).
- D. Cystathionine beta-synthaseIncorrect. Cystathionine beta-synthase deficiency causes homocystinuria (lens dislocation, thrombosis, marfanoid habitus).
- E. Fumarylacetoacetate hydrolaseIncorrect. Fumarylacetoacetate hydrolase deficiency causes tyrosinemia type I (liver failure, renal tubular dysfunction).
Key point
PKU: high phenylalanine with low tyrosine, mousy odor, and hypopigmentation; 98–99% of cases are due to phenylalanine hydroxylase deficiency.
From the source
“Although nearly all cases (98 to 99%) of PKU result from phenylalanine hydroxylase deficiency”