Ornithine transcarbamylase deficiency

Ornithine transcarbamylase (OTC) deficiency is the most common inherited disorder of the urea cycle, caused by pathogenic variants in the OTC gene located on the X chromosome. The OTC enzyme is critical for the second step of the urea cycle, which takes place in the liver and is responsible for converting ammonia—a toxic byproduct of protein metabolism—into urea for excretion by the kidneys. When this enzyme is deficient or absent, ammonia accumulates in the blood (hyperammonemia), leading to potentially life-threatening neurological damage. The condition is also known as OTC deficiency or ornithine carbamoyltransferase deficiency. The clinical presentation is highly variable. Severely affected males (hemizygous) typically present in the neonatal period with catastrophic hyperammonemia characterized by poor feeding, vomiting, lethargy, hypothermia, hyperventilation, and rapid progression to seizures, coma, and death if untreated. Later-onset forms can present in infancy, childhood, or even adulthood, often triggered by illness, surgery, fasting, or high-protein intake, with symptoms including recurrent vomiting, confusion, behavioral changes, headaches, and episodic encephalopathy. Heterozygous females can range from completely asymptomatic to severely affected, depending on the pattern of X-inactivation in their liver cells. Chronic complications include intellectual disability, developmental delay, and liver dysfunction. Management involves a combination of dietary protein restriction, nitrogen-scavenging medications (sodium benzoate, sodium phenylbutyrate, or glycerol phenylbutyrate) to provide alternative pathways for nitrogen excretion, and essential amino acid supplementation including citrulline or arginine. Acute hyperammonemic crises require emergency treatment with intravenous nitrogen scavengers and, in severe cases, hemodialysis. Liver transplantation is considered curative and is recommended for patients with severe neonatal-onset disease or recurrent metabolic crises refractory to medical management. Gene therapy approaches are under active investigation as potential future treatments.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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