Which enzyme deficiency is the most common cause of hyperammonemia due to urea cycle disorder?

Explanation

## Epidemiology of Urea Cycle Disorders **High-Yield:** OTC deficiency accounts for approximately 50–60% of all urea cycle disorders, making it the most common cause of hyperammonemia among these genetic conditions. ### Why OTC Deficiency is Most Common **Key Point:** OTC is the second enzyme in the urea cycle and catalyzes the condensation of carbamoyl phosphate and ornithine to form citrulline. Its deficiency leads to: - Accumulation of carbamoyl phosphate (shunted to pyrimidine synthesis) - Severe hyperammonemia - X-linked inheritance pattern (hemizygous males severely affected; heterozygous females variable) ### Comparative Frequency of Urea Cycle Defects | Enzyme Deficiency | Frequency (%) | Inheritance | Severity | |---|---|---|---| | OTC deficiency | 50–60 | X-linked | Severe in males | | CPS I deficiency | 5–10 | Autosomal recessive | Severe | | Argininosuccinate lyase | 15–20 | Autosomal recessive | Moderate to severe | | Arginitase | <5 | Autosomal recessive | Mild to moderate | | Argininosuccinate synthetase | 10–15 | Autosomal recessive | Severe | **Clinical Pearl:** OTC deficiency in heterozygous females can present with hyperammonemia triggered by protein loading, infection, or pregnancy due to X-inactivation patterns. **Mnemonic:** **CAAO** — Carbamoyl phosphate synthetase, Argininosuccinate synthetase, Argininosuccinate lyase, Ornithine transcarbamylase. OTC is the second step and the most commonly deficient. ### Clinical Presentation of OTC Deficiency - Neonatal hyperammonemic encephalopathy (males) - Lethargy, poor feeding, seizures, coma - Elevated ammonia (often >200 μmol/L) - Low citrulline and arginine - Elevated carbamoyl phosphate → increased orotic acid in urine (crystalline orotic acid) **Warning:** Do not confuse OTC deficiency with CPS I deficiency — both present with severe hyperammonemia, but OTC causes elevated urinary orotic acid, whereas CPS I causes low orotic acid.