ornithine transcarbamylase deficiency

What is Ornithine Transcarbamylase Deficiency?

Ornithine transcarbamylase (OTC) deficiency is a metabolic disorder that results from problems in the urea cycle, a metabolic pathway necessary for the removal of ammonia from the body. The symptoms of OTC deficiency, which is the most common urea cycle disorder, result from elevated levels of ammonia in the blood (hyperammonemia). While ammonia is a normal byproduct of protein breakdown, it is toxic if there is too much in the body. An excess of ammonia is particularly damaging to the liver and nervous system. However, the condition is quite variable, with affected individuals presenting from birth to adulthood and with differing levels of disease severity, based on the degree of OTC enzyme deficiency. As this is an X-linked disorder (the gene that causes the condition is located on the X chromosome), OTC deficiency most often affects males, although some females may show signs of the condition.

Neonatal Onset Form

This severe form of OTC deficiency, which results from absent or near-absent enzyme activity, first presents at or shortly after birth. Symptoms may include poor feeding, lethargy, low muscle tone, seizures, breathing difficulties, and potentially a hyperammonemic coma. Recurrent hyperammonemic crises (periods of high ammonia levels) lead to continued liver and brain damage and resulting complications.

Later Onset Form

Partial OTC deficiency results in a later onset of symptoms (anywhere from infancy to adulthood). Individuals with this form may present with recurrent vomiting, a history of protein intolerance or avoidance, a Reye-like syndrome (with brain and liver swelling), developmental delays, intellectual disability, and/or seizures.

Carrier Females

While most carrier females (females that have one altered copy of the OTC gene and one copy that functions normally) show no signs of OTC deficiency, it is estimated that at least 15-20% will have a partial enzyme deficiency and may develop symptoms of the condition. It is important to know, however, that all carrier females (even those who have previously shown no signs of the condition) are more prone to experience symptoms of OTC deficiency during and just after pregnancy.

How common is Ornithine Transcarbamylase Deficiency?

It is not yet known precisely how common OTC deficiency is worldwide. While some sources estimate that OTC deficiency may occur in as many as 1 in 14,000 individuals, others estimate that it may affect approximately 1 in 50,000 to 1 in 80,000 individuals.

How is Ornithine Transcarbamylase Deficiency treated?

The treatment of OTC deficiency is focused on managing metabolic crises by reducing ammonia levels. If an infant presents with suddenly high ammonia levels, dialysis is performed, intravenous medications are given, and dietary restrictions are utilized to clear the body of problematic proteins. Liver transplantation is almost always necessary in those with the neonatal onset form, and may be considered in some cases of partial OTC deficiency. Seizures are treated with medications, while 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 less protein intake. People with OTC deficiency should also avoid exposure to valproic acid (Depakote, an anti-seizure medication), prolonged fasting or starvation, intravenous steroids, and high levels of protein or amino acids, which may trigger a metabolic crisis.

What is the prognosis for a person with Ornithine Transcarbamylase Deficiency?

The overall outcome for an individual with this condition depends on the severity of the enzyme deficiency and the extent of damage that occurs during hyperammonemic episodes. If an individual remains asymptomatic or mildly symptomatic, their prognosis may be good. However, if there is significant brain and liver damage as a result of metabolic crises, neuropsychological, gastrointestinal, and/or liver complications may occur. Adequate management of the condition during and between crises may improve prognosis, although hyperammonemic crises may lead to coma and even death, if untreated.