A 5-day-old male neonate born to a healthy mother presents with lethargy, poor feeding, and a single seizure. Serum ammonia is 180 µmol/L (normal <50), blood urea nitrogen is 8 mg/dL (low), and urine orotic acid is markedly elevated. The enzyme marked **B** in the urea cycle diagram is deficient. Which of the following best explains the elevated urinary orotic acid in this patient?

Explanation

## Why "Carbamoyl phosphate accumulates and shunts into pyrimidine synthesis, increasing orotic acid production" is right Ornithine transcarbamoylase (OTC) catalyzes the second step of the urea cycle, condensing carbamoyl phosphate with ornithine to form citrulline. When OTC is deficient, carbamoyl phosphate cannot be utilized in the urea cycle and accumulates. This excess carbamoyl phosphate is diverted into the pyrimidine synthesis pathway, where it is converted to orotate (orotic acid), which is then excreted in large quantities in the urine. This is a pathognomonic finding in OTC deficiency and distinguishes it from other urea cycle disorders. (Harper 32e Ch 28; Robbins 10e Ch 6) ## Why each distractor is wrong - **Argininosuccinate lyase deficiency causes backup of argininosuccinate into pyrimidine pathways**: Argininosuccinate lyase deficiency (step 4 of the urea cycle) causes argininosuccinate to accumulate and be excreted in urine, not orotic acid. This is a different urea cycle disorder with a different biochemical signature. - **Arginase deficiency prevents arginine catabolism, leading to orotic acid accumulation**: Arginase deficiency (the final step of the urea cycle) causes arginine accumulation and hyperargininemia, not orotic acid elevation. Orotic acid is not produced in this disorder. - **Carbamoyl phosphate synthetase I hyperactivity drives excessive pyrimidine synthesis**: CPS-I deficiency (not hyperactivity) is a separate urea cycle disorder. Hyperactivity of CPS-I would not explain the clinical presentation; moreover, OTC deficiency—not CPS-I dysfunction—is the cause of this patient's symptoms. **High-Yield:** OTC deficiency = X-linked, most common urea cycle disorder, presents in male neonates with hyperammonemia + elevated urinary orotic acid (carbamoyl phosphate shunt into pyrimidine synthesis). [cite: Harper 32e Ch 28; Robbins 10e Ch 6]