Ornithine transcarbamylase (OTC) deficiency is a metabolic disorder caused by issues in the urea cycle, a process crucial for removing ammonia from the body.
The symptoms of OTC deficiency result from high levels of ammonia in the blood, known as hyperammonemia. While ammonia is a normal part of breaking down protein, having too much of it is harmful, especially to the liver and nervous system. The condition varies, affecting individuals from birth to adulthood with different levels of severity based on the OTC enzyme deficiency. As an X-linked disorder, OTC deficiency mostly affects males, although some females may also show signs. There are two forms of the disorder:
Neonatal Onset Form: This severe form of OTC deficiency, caused by little or no enzyme activity, shows up at or shortly after birth. Symptoms include poor feeding, lethargy, low muscle tone, seizures, breathing difficulties, and possibly a hyperammonemic coma. Repeated periods of high ammonia levels lead to ongoing damage to the liver and brain.
Later Onset Form: Partial OTC deficiency results in symptoms appearing later in life, from infancy to adulthood. Individuals with this form may experience recurrent vomiting, a history of protein intolerance, a Reye-like syndrome (involving brain and liver swelling), developmental delays, intellectual disability, and/or seizures.
The treatment of OTC deficiency focuses on managing metabolic crises by reducing ammonia levels. Liver transplantation is often necessary for those with the neonatal onset form and might be considered in some cases of partial OTC deficiency. Seizures are treated with medications, and developmental delays and intellectual disabilities are managed with supportive therapies. To avoid manifestations of OTC deficiency, affected individuals are prescribed intravenous medications, specialized formulas, and a restricted diet with lower protein intake.
OTC deficiency is caused by pathogenic (disease-causing) variants in the OTC gene on the X chromosome and exhibits X-linked recessive inheritance. This means that one pathogenic variant is enough to cause the disease in both males (who have one X chromosome and one Y chromosome) and females (who have two X chromosomes) may experience symptoms depending on how many copies of the X chromosome that has the pathogenic variant are turned on in the cells.
Most carrier females (those with one altered copy of the OTC gene and one normal copy) usually show no signs of OTC deficiency. However, around 15-20% may have a partial enzyme deficiency and could develop symptoms. It’s essential to note that all carrier females, even those without prior signs, are more likely to experience symptoms of OTC deficiency during and after pregnancy.