A physician-validated, board-style question from the Active Transport QBank. Try it, then check the reasoning for every option.
A 3-day-old boy is brought to the emergency department because of a 4-hour history of somnolence, poor feeding, and one episode of vomiting. He is exclusively breastfed. His serum glucose concentration is 88 mg/dL and his serum ammonia concentration is 850 μmol/L (N<90). Urinalysis shows an increased orotic acid to creatinine ratio. Urinary ketones are absent. This patient is most likely deficient in an enzyme that catalyzes which of the following reactions?
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A
Ornithine and carbamoyl phosphate to citrullineCorrect. OTC catalyzes ornithine + carbamoyl phosphate to citrulline; deficiency causes hyperammonemia plus excess orotic acid (from carbamoyl phosphate shunted to pyrimidine synthesis) without ketosis.
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B
Orotic acid to uridine monophosphateIncorrect. Conversion of orotic acid to UMP is catalyzed by UMP synthase (orotic aciduria type I) — this presents with megaloblastic anemia and growth failure, not hyperammonemia.
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C
Pyruvate to acetyl-coenzyme AIncorrect. Pyruvate dehydrogenase deficiency causes lactic acidosis and neurologic disease, not hyperammonemia with orotic aciduria.
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D
Glutamate and acetyl-coenzyme A to N-acetylglutamateIncorrect. N-acetylglutamate synthase (NAGS) deficiency also causes hyperammonemia but without elevated orotic acid (because carbamoyl phosphate cannot accumulate — it isn't being made).
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E
Argininosuccinate to arginine and fumarateIncorrect. Argininosuccinate lyase deficiency also causes hyperammonemia but elevates argininosuccinate (not orotic acid) in urine, distinguishing it from the OTC deficiency pattern seen in this patient.
↑ Tap an answer to reveal the reasoning
Answer: A. This neonate with hyperammonemia (850 vs normal <90), absent ketones, and elevated urinary orotic acid has ornithine transcarbamylase (OTC) deficiency — the most common urea cycle disorder. OTC catalyzes the second step of the urea cycle: condensation of ornithine and carbamoyl phosphate to form citrulline within mitochondria. When OTC is deficient, carbamoyl phosphate accumulates and spills into the cytosol, where it enters pyrimidine synthesis and produces excess orotic acid (excreted in urine). Ammonia accumulates because the urea cycle cannot dispose of nitrogen.
The absence of ketones argues against organic acidemias (propionic, methylmalonic) which cause ketotic hyperammonemia. OTC deficiency is X-linked recessive, distinguishing it from other (autosomal recessive) urea cycle defects and explaining its predominance in male neonates. Symptoms emerge as the infant ingests protein (breast milk), accumulates ammonia, and develops lethargy, vomiting, and seizures.
Management: stop protein, give IV dextrose, ammonia scavengers (sodium phenylacetate/benzoate), and arginine/citrulline supplementation; hemodialysis for severe hyperammonemia.
**Why each option:**
**A.** Correct. OTC catalyzes ornithine + carbamoyl phosphate to citrulline; deficiency causes hyperammonemia plus excess orotic acid (from carbamoyl phosphate shunted to pyrimidine synthesis) without ketosis.
**B.** Conversion of orotic acid to UMP is catalyzed by UMP synthase (orotic aciduria type I) — this presents with megaloblastic anemia and growth failure, not hyperammonemia.
**C.** Pyruvate dehydrogenase deficiency causes lactic acidosis and neurologic disease, not hyperammonemia with orotic aciduria.
**D.** N-acetylglutamate synthase (NAGS) deficiency also causes hyperammonemia but without elevated orotic acid (because carbamoyl phosphate cannot accumulate — it isn't being made).