ornithine carbamoyltransferase deficiency

Ornithine carbamoyltransferase deficiency (OTCD) is a metabolic condition that disrupts the urea cycle, the body’s main pathway for removing excess ammonia. Variants in the OTC gene reduce or eliminate the ornithine transcarbamylase enzyme, leading to toxic ammonia buildup that primarily affects the brain and liver. Because the gene is located on the X chromosome, severe, newborn-onset illness is seen almost exclusively in boys, while girls and some boys may present later in childhood or adulthood with milder episodes. The disorder is considered uncommon, affecting roughly one to nine individuals per 100,000 people. Episodes of hyperammonemia can be life-threatening, but early recognition and specialized care have improved outcomes for many families.

Hyperammonemia is the hallmark feature of OTCD and can appear within the first few days of life in the classic, severe form. Newborns may suddenly develop poor feeding, vomiting, lethargy, rapid breathing, or even coma. In later-onset forms, individuals of any age can experience intermittent episodes triggered by high protein intake, illness, certain medications, or prolonged fasting. Neurological complications are common during crises because ammonia directly injures the brain; affected people may have headaches, irritability, confusion, seizures, or strokes, and some develop long-term cognitive or developmental challenges after severe episodes. Laboratory studies during attacks often show elevated liver enzymes, low citrulline, orotic acid in the urine, and high levels of glutamine and uracil in the blood. Less frequent findings include prolonged bleeding times or abdominal pain. Not all individuals experience all features, and severity varies considerably, even among members of the same family.

OTCD results from pathogenic variants in the OTC gene. The gene provides instructions for making the ornithine transcarbamylase enzyme, which joins ammonia-derived carbamoyl phosphate to ornithine inside liver cells. When the enzyme is deficient, ammonia accumulates to toxic levels. The condition follows an X-linked inheritance pattern. Males who inherit the altered gene typically develop symptoms because they have only one X chromosome. Females have two X chromosomes; if one carries the variant, the other may partially compensate, so their symptoms range from absent to severe depending on X-inactivation. Each son of a carrier woman has a 50 percent chance of being affected, and each daughter has a 50 percent chance of being a carrier who may or may not develop symptoms. Affected males will pass the variant to all of their daughters and none of their sons. Because presentation can be unpredictable, genetic counseling and carrier testing for at-risk relatives are strongly recommended.

Currently, management focuses on supportive and preventive strategies tailored to each individual, and care is typically coordinated by a multidisciplinary metabolic team. During acute hyperammonemic crises, rapid hospital treatment aims to lower ammonia through intravenous medications that provide alternative nitrogen excretion pathways, glucose to reduce catabolism, and in severe cases dialysis. Between episodes, long-term management includes a protein-restricted diet designed by metabolic nutrition specialists, essential amino-acid or nitrogen-scavenger supplementation as prescribed, and close monitoring of growth, liver function, and ammonia levels. Regular surveillance helps detect rising ammonia early, allowing prompt intervention before neurological damage occurs. Liver transplantation is considered for some individuals with recurrent, difficult-to-control episodes, though suitability depends on multiple factors that must be discussed with specialists. Because no therapies are specifically approved for OTCD, families are encouraged to work closely with metabolic physicians, dietitians, and genetic counselors to develop individualized plans and to update these plans as new evidence emerges.

Outcomes depend on the age of onset, the promptness of treatment during hyperammonemic episodes, and long-term adherence to dietary and medical therapies. Some individuals with partial enzyme activity can lead relatively typical lives with careful monitoring, while others with neonatal-onset disease may have recurrent crises and long-term neurological challenges. Severity and symptoms vary widely between individuals. Early recognition of high ammonia and immediate medical intervention are key factors in preserving cognitive function. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with metabolic specialists and genetic counselors, both for ongoing management and for guidance about future family planning.

OTCD remains an active research area, with several clinical trials currently investigating novel ammonia-lowering drugs, gene-based therapies, and optimized nutritional approaches. Individuals interested in research opportunities can search ClinicalTrials.gov or discuss eligibility with their healthcare team.