A 3-year-old boy presents with hyperammonemia, developmental delay, and seizures. Plasma amino acid analysis shows elevated glutamine and alanine. Urine orotic acid is markedly elevated. Which enzyme deficiency is the most common cause of neonatal-onset urea cycle disorder?

Explanation

## Most Common Urea Cycle Disorder **Key Point:** Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, accounting for approximately 50–60% of all cases. ### Why OTC Deficiency? 1. **X-linked inheritance** — OTC gene is located on the X chromosome, making hemizygous males severely affected and heterozygous females variably affected 2. **Enzyme function** — OTC catalyzes the second step of the urea cycle (condensation of carbamoyl phosphate + ornithine → citrulline) 3. **Biochemical hallmark** — Accumulation of carbamoyl phosphate drives pyrimidine synthesis, leading to **markedly elevated urinary orotic acid** (pathognomonic finding) 4. **Clinical presentation** — Neonatal or early infantile hyperammonemia with poor feeding, lethargy, seizures, and developmental delay ### Urea Cycle Enzyme Defects — Comparative Table | Enzyme Defect | Inheritance | Frequency | Urinary Orotic Acid | Key Finding | | --- | --- | --- | --- | --- | | **OTC deficiency** | X-linked | **50–60%** | **Markedly ↑↑** | Most common; carbamoyl phosphate accumulation | | CPS I deficiency | Autosomal recessive | ~10% | Normal | Defect in ammonia fixation | | Argininosuccinate synthetase | Autosomal recessive | ~10% | Normal | Citrulline accumulation | | Argininosuccinate lyase | Autosomal recessive | ~6% | Normal | Argininosuccinate accumulation | | Arginase deficiency | Autosomal recessive | ~4% | Normal | Arginine accumulation; spasticity | **High-Yield:** The **elevated urinary orotic acid** in this case is the diagnostic clue pointing to OTC deficiency — this occurs because carbamoyl phosphate, which cannot be used in the urea cycle, is shunted into the pyrimidine synthesis pathway. **Clinical Pearl:** OTC deficiency shows **X-linked dominant inheritance with male lethality** — affected hemizygous males often die in the neonatal period; heterozygous females present with variable severity depending on X-inactivation patterns. **Mnemonic:** **OCAT** — OTC is the most Common Amino acid (urea) cycle defect. [cite:Lehninger Principles of Biochemistry 8e Ch 27]