A neonate presents with hyperammonemia, seizures, and respiratory alkalosis. Plasma citrulline is markedly elevated. Urine orotic acid is elevated. Which urea cycle enzyme deficiency does this pattern indicate?

• A Carbamoyl phosphate synthetase I (CPS-I) deficiency
• B Ornithine transcarbamylase (OTC) deficiency
• C Argininosuccinate synthetase (ASS) deficiency (citrullinemia type I) ✓
• D Arginase deficiency

Explanation

Biochemical profiling of urea cycle defects: elevated citrulline indicates a block DOWNSTREAM of citrulline production (i.e., after OTC step, which produces citrulline). Argininosuccinate synthetase (ASS1) condenses citrulline + aspartate → argininosuccinate. ASS deficiency (citrullinemia type I) causes marked citrulline accumulation (plasma citrulline >1000 µmol/L), hyperammonemia, and elevated orotic acid (due to carbamoyl phosphate overflow into pyrimidine pathway). OTC deficiency (option B) has low/absent citrulline with elevated orotic acid. CPS-I deficiency (option A) has undetectable citrulline with LOW orotic acid (as carbamoyl phosphate does not even form). Arginase deficiency causes elevated arginine.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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