FMGE 2025 — Biochemistry

Question 21: A 2-month-old infant presents with poor feeding, vomiting, and lethargy. Laboratory studies show hyperammonemia and elevated levels of orotic acid in the urine. Which of the following is the most likely enzyme deficiency?

• A. Orotidine 5′-phosphate decarboxylase deficiency
• B. Carbamoyl phosphate synthetase I deficiency
• C. Argininosuccinate lyase deficiency
• D. Ornithine transcarbamylase (OTC) deficiency (Correct Answer)

Explanation: ***Ornithine transcarbamylase (OTC) deficiency*** - **Most common X-linked urea cycle disorder** presenting in infancy with hyperammonemia - **Classic triad:** Hyperammonemia + elevated urinary orotic acid + low blood urea nitrogen - **Biochemical mechanism:** OTC converts carbamoyl phosphate + ornithine → citrulline. When deficient, carbamoyl phosphate accumulates and spills into the pyrimidine synthesis pathway, producing excess orotic acid - Clinical features: poor feeding, vomiting, lethargy, seizures, developmental delay *Carbamoyl phosphate synthetase I (CPS I) deficiency* - Also causes hyperammonemia but **NO orotic aciduria** (defect occurs before OTC step) - Carbamoyl phosphate is not formed, so cannot enter pyrimidine pathway - Cannot be distinguished clinically from OTC deficiency without measuring orotic acid *Argininosuccinate lyase deficiency* - Causes hyperammonemia with elevated **argininosuccinate** in blood/urine - Does not cause orotic aciduria (defect is downstream of OTC) - May present with trichorrhexis nodosa (brittle hair) *Orotidine 5′-phosphate decarboxylase deficiency* - Causes hereditary **orotic aciduria** but **NO hyperammonemia** (not a urea cycle disorder) - Defect in de novo pyrimidine synthesis pathway - Presents with megaloblastic anemia, growth retardation, responds to uridine supplementation