Question

A 4-year-old boy of a first-degree consanguineous couple was noted by the parents to have darkening of the urine to an almost black color when it was left standing. He has a normal sibling, and there are no other medical problems. Growth and development to date are normal. Which of the following is most likely to be elevated in this patient?

• A. Methylmalonate
• B. Homogentisate
• C. Phenylpyruvate
• D. Alpha-ketoisovalerate

Hint:

Black urine on standing in a healthy child points to a tyrosine pathway defect.

Answer 1

The Correct Option is B

Step 1: The hallmark clue is urine that turns almost black on standing in an otherwise healthy, normally developing child of consanguineous parents. This is classic for alkaptonuria, an autosomal recessive condition.
Step 2: Alkaptonuria is caused by deficiency of homogentisate oxidase (homogentisate 1,2-dioxygenase) in tyrosine breakdown. Homogentisic acid accumulates and is excreted in urine, where it oxidizes and polymerizes to a black pigment on standing. So option (b), homogentisate, is elevated.
Step 3: Ruling out the rest by their clinical picture: methylmalonate rises in methylmalonyl-CoA mutase deficiency (acidosis, failure to thrive). Phenylpyruvate rises in PKU (phenylalanine hydroxylase deficiency) with intellectual disability if untreated. Alpha-ketoisovalerate rises in maple syrup urine disease (branched-chain alpha-keto acid dehydrogenase deficiency). All three would give a sick child, not the well child described here.
Ref: Lippincott's Illustrated Reviews Biochemistry, 5e, Amino Acid Degradation, p 276.