Which enzyme deficiency is the most common cause of urea cycle disorder presenting with hyperammonemia in neonates and infants?

Explanation

## Epidemiology of Urea Cycle Defects **Key Point:** Ornithine transcarbamylase (OTC) deficiency accounts for approximately 50–60% of all urea cycle disorders, making it the most common enzymatic defect in this group. ### Why OTC Deficiency is Most Common 1. **X-linked inheritance pattern** — affects both hemizygous males and heterozygous females (who may show variable expression due to X-inactivation) 2. **High mutation rate** — the OTC gene is relatively large and prone to de novo mutations 3. **Clinical presentation** — typically manifests in the neonatal period (first 24–72 hours of life) with poor feeding, lethargy, vomiting, and seizures ### Comparison of Urea Cycle Defects | Enzyme Defect | Inheritance | Frequency | Age of Onset | Key Feature | | --- | --- | --- | --- | --- | | OTC deficiency | X-linked | 50–60% | Neonatal/infantile | Most common; males severely affected | | CPS I deficiency | Autosomal recessive | 5–10% | Neonatal | Severe; accumulation of ammonia | | Argininosuccinate synthetase | Autosomal recessive | 5–10% | Neonatal/infantile | Citrulline accumulation | | Argininosuccinate lyase | Autosomal recessive | 5–10% | Neonatal/infantile | Argininosuccinate in urine | **High-Yield:** OTC deficiency is X-linked; hemizygous males present severely in the neonatal period, while heterozygous females may present later or remain asymptomatic depending on X-inactivation patterns. **Clinical Pearl:** The hallmark biochemical finding in OTC deficiency is elevated ammonia with normal or low citrulline (because the first committed step of the cycle is blocked). In contrast, CPS I deficiency also shows elevated ammonia but low citrulline, whereas argininosuccinate synthetase deficiency shows elevated citrulline. ### Pathophysiology OTC catalyzes the condensation of carbamoyl phosphate and ornithine to form citrulline — the second step of the urea cycle. When this enzyme is deficient: - Ammonia accumulates (cannot be incorporated into the cycle) - Carbamoyl phosphate is shunted to the pyrimidine synthesis pathway - Hyperammonemia leads to cerebral edema, seizures, and neurological damage if untreated [cite:Lehninger Principles of Biochemistry Ch 23]