OTC (ornithine transcarbamylase) catalyzes the second step of the urea cycle, catalyzing the condensation of carbamoyl phosphate with L-ornithine to form L-citrulline 1. This enzymatic reaction is essential for ammonia detoxification, converting toxic ammonia to urea for excretion and maintaining ammonium homeostasis 1. OTC deficiency, caused by mutations in the X-linked OTC gene, is the most common inherited urea cycle disorder 2. Pathogenic OTC variants result in impaired ureagenesis and hyperammonemia, which can present as acute neonatal-onset disease within the first week of life or later-onset disease in either sex 3. Neonatal presentation typically involves rapid development of severe hyperammonemia progressing to cerebral edema, coma, and death without rapid intervention 3. Over 341 distinct mutations have been identified throughout the OTC gene, with most being family-specific 2. High-throughput functional assays can distinguish benign from pathogenic variants and differentiate neonatal-onset from late-onset disease phenotypes 3. Recent evidence demonstrates that OTC deficiency also leads to liver inflammation and fibrosis in heterozygous females 4. AAV gene therapy can correct metabolic abnormalities and prevent liver fibrosis development in affected individuals 4.