Which enzyme deficiency in the urea cycle results in the accumulation of carbamoyl phosphate and orotic acid, leading to orotic aciduria?

Explanation

## Enzyme Deficiency and Metabolic Consequence **Key Point:** Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, accounting for ~50% of all cases. When OTC is deficient, carbamoyl phosphate cannot be converted to citrulline, causing carbamoyl phosphate to accumulate and be shunted into the pyrimidine synthesis pathway, producing excess orotic acid. ### Biochemical Mechanism The urea cycle step catalyzed by OTC: $$\text{Carbamoyl phosphate} + \text{Ornithine} \xrightarrow{OTC} \text{Citrulline} + \text{Pi}$$ When OTC is absent: - Carbamoyl phosphate accumulates (cannot form citrulline) - Excess carbamoyl phosphate enters pyrimidine synthesis via the pathway: carbamoyl phosphate → carbamoyl aspartate → ... → orotic acid - Orotic acid is excreted in large amounts in urine (orotic aciduria) - Ammonia accumulates (hyperammonemia) because the urea cycle cannot function ### Clinical Features of OTC Deficiency | Feature | Details | | --- | --- | | **Inheritance** | X-linked (hemizygous males more severely affected) | | **Presentation** | Neonatal hyperammonemia, encephalopathy, seizures | | **Lab findings** | ↑ Ammonia, ↑ Orotic acid in urine, ↓ Citrulline | | **Management** | Protein restriction, arginine supplementation, sodium benzoate | **High-Yield:** Orotic aciduria is pathognomonic for OTC deficiency among urea cycle disorders. The combination of hyperammonemia + orotic aciduria is diagnostic. **Clinical Pearl:** OTC deficiency can present in neonates (within 24–72 hours of life) with poor feeding, vomiting, lethargy, and seizures. Heterozygous females may have variable presentations depending on X-inactivation patterns.