Ornithine transcarbamylase deficiency is an inherited disorder that causes ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Ornithine transcarbamylase deficiency can become evident at any age. The most severe form occurs in the first few days of life. This neonatal-onset form of the disorder usually affects males; it is very rare in females. An infant with the neonatal-onset form of ornithine transcarbamylase deficiency may be lacking in energy (lethargic) or unwilling to eat, and have a poorly-controlled breathing rate or body temperature. Infants with this disorder may be described as "floppy" and can experience seizures or coma. Complications from ornithine transcarbamylase deficiency may include developmental delay and intellectual disability. Progressive liver damage may also occur.

In some affected individuals, signs and symptoms of ornithine transcarbamylase deficiency may be less severe, and may not appear until later in life. The late-onset form of the disorder occurs in both males and females. People with late-onset ornithine transcarbamylase deficiency may experience episodes of altered mental status, such as delirium, erratic behavior, or a reduced level of consciousness. Headaches, vomiting, aversion to protein foods, and seizures can also occur in this form of the disorder.

Mutations in the OTC gene cause ornithine transcarbamylase deficiency. The OTC gene provides instructions for making the ornithine transcarbamylase enzyme.

Ornithine transcarbamylase deficiency belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. It processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys. The ornithine transcarbamylase enzyme starts a specific reaction within the urea cycle.

In ornithine transcarbamylase deficiency, as its name suggests, the ornithine transcarbamylase enzyme is damaged or missing. The urea cycle cannot proceed normally, and nitrogen accumulates in the bloodstream in the form of ammonia.

Ammonia is especially damaging to the nervous system, so ornithine transcarbamylase deficiency causes neurological problems as well as eventual damage to the liver.

Normal Function

The OTC gene provides instructions for making the enzyme ornithine transcarbamylase. This enzyme participates in the urea cycle, a series of reactions that occurs in liver cells. The urea cycle processes excess nitrogen, generated when protein is used by the body, into a compound called urea that is excreted by the kidneys. Excreting the excess nitrogen prevents it from accumulating in the form of ammonia, which is toxic, especially to the nervous system.

The specific role of the ornithine transcarbamylase enzyme is to control the reaction in which two compounds, carbamoyl phosphate and ornithine, form a new compound called citrulline.

Health Conditions Related to Genetic Changes

Ornithine transcarbamylase deficiency

More than 500 OTC gene mutations have been identified in people with ornithine transcarbamylase deficiency, an inherited disorder that causes ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

The OTC gene mutations that cause ornithine transcarbamylase deficiency result in an ornithine transcarbamylase enzyme that is shorter than normal or the wrong shape, or prevent any enzyme from being produced. The shape of an enzyme affects its ability to control a chemical reaction. If the ornithine transcarbamylase enzyme is misshapen or missing, it cannot fulfill its role in the urea cycle. Excess nitrogen is not converted to urea for excretion, and ammonia accumulates in the body. Accumulation of ammonia causes neurological problems and other signs and symptoms of ornithine transcarbamylase deficiency.

Other Names for This Gene

• MGC129967
• MGC129968
• OCTD
• ornithine carbamoyltransferase precursor
• ornithine transcarbamylase
• OTC_HUMAN

Genomic Location

OTC deficiency follows X-linked inheritance. This is because the gene responsible for causing OTC deficiency is located on the X chromosome, one of the two sex chromosomes.

X-linked diseases more commonly occur in males, who have only one X chromosome (and one Y chromosome). Having a mutation in a gene on their X chromosome is enough to cause the disease. Females have two X chromosomes, so if they have a mutation on one of them, they still have one X chromosome without the mutation and are much less likely to have the disease. In some cases however, females with only one mutation in the OTC gene will have symptoms of OTC deficiency. Females with mutations in the gene on both chromosomes will have the disease.

If a mother has a mutation that causes OTC deficiency and the father does not, the risk to each of her children depends on whether they are male or female.

• Each son has a 50% chance to inherit the mutation and have OTC deficiency.
• Each daughter has a 50% chance to inherit the mutation and may or may not develop symptoms, like the mother.

If a father has OTC deficiency and the mother does not have a mutation, all sons will not inherit the mutation, and all daughters will inherit the mutation. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

People with personal questions about the inheritance of this condition are encouraged to speak with a genetic counselor or other genetics professional. A genetics professional can help by:

• Thoroughly evaluating the family history.
• Addressing questions and concerns.
• Assessing recurrence risks.
• Facilitating genetic testing if desired.
• Discussing reproductive options.

• Episodes of delirium, erratic behavior, or reduced consciousness.
• Headaches.
• Vomiting.
• An aversion to foods high in protein.
• Seizures.

Newborn screening for OTC deficiency requires collecting a small amount of blood from your baby’s heel. Screening measures how much citrulline is in your baby’s blood. Citrulline is one of the products of the urea cycle and does not form when the OTC enzyme is not working. Babies with very low levels of citrulline might have OTC deficiency.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for OTC deficiency is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen. Screening samples collected too early (before the baby is 24 hours of age) may cause false positive results. Babies with other conditions that have low citrulline levels may also be detected through this screening. An example of another condition that may be detected is carbamoyl phosphate synthetase I deficiency.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Diet low in protein
• Special foods or formulas
• Arginine and citrulline supplements to help lower ammonia levels
• Medications to get rid of extra ammonia in the body
• Dialysis to get rid of extra ammonia in the body
• Liver transplant

Early and ongoing treatment for OTC deficiency can be lifesaving and can lead to better growth and development in affected children.

Estimates of the prevalence of ornithine transcarbamylase deficiency have ranged from 1 in 14,000 to 1 in 77,000 people. Individuals with the neonatal-onset form of the disorder are more likely to be counted in these estimates, because people with the late-onset form are less likely to come to medical attention.