Ornithine translocase deficiency is an inherited disorder that causes ammonia and other substances to build up (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 translocase deficiency varies widely in its severity and age of onset. Affected infants show signs and symptoms of ornithine translocase deficiency within days after birth. In most affected individuals, however, signs and symptoms of ornithine translocase deficiency do not appear until later in life, with health problems first appearing anytime from childhood to adulthood. Later-onset forms of ornithine translocase deficiency are usually less severe than the infantile form.

Infants with ornithine translocase deficiency may lack energy (be lethargic), refuse to eat, vomit frequently, or have poorly controlled breathing or body temperature. Seizures or unusual body movements are common in these individuals. Some people with this condition have intellectual disability or developmental delay, but others have normal intelligence. Severe cases may result in coma.

Some people with later-onset ornithine translocase deficiency have episodes of vomiting, lethargy, problems with coordination (ataxia), vision problems, episodes of brain dysfunction (encephalopathy), developmental delay, learning disabilities, or stiffness caused by abnormal tensing of the muscles (spasticity). Affected individuals may have chronic liver problems and mild abnormal bleeding.

Individuals with ornithine translocase deficiency often cannot tolerate high-protein foods, such as meat. Occasionally, high-protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase of ammonia likely leads to the signs and symptoms of ornithine translocase deficiency.

While the signs and symptoms of ornithine translocase deficiency can vary greatly among affected individuals, proper treatment can prevent some complications from occurring and may improve quality of life.

Mutations in the SLC25A15 gene cause ornithine translocase deficiency. The SLC25A15 gene provides instructions for making a protein called mitochondrial ornithine transporter 1. This protein participates in the urea cycle, which is a sequence of biochemical reactions that occurs in liver cells. The urea cycle breaks down excess nitrogen, made when protein is broken down by the body, to make a compound called urea that is excreted by the kidneys in urine.

Mitochondrial ornithine transporter 1 is located within the mitochondria (the energy-producing centers in cells), where the protein transports a molecule called ornithine so it can participate in the urea cycle.

Mutations in the SLC25A15 gene cause the production of a mitochondrial ornithine transporter 1 with reduced or absent function. As a result, ornithine transport is impaired and the urea cycle cannot proceed normally. This causes, nitrogen to accumulate in the bloodstream in the form of toxic ammonia instead of being converted to less toxic urea and being excreted. Ammonia is especially damaging to the brain, and excess ammonia causes neurological problems and other signs and symptoms of ornithine translocase deficiency. Byproducts of impaired ornithine transport in people with this condition include the accumulation of a substance called ornithine in the blood (hyperornithinemia) and the excretion of a substance called homocitrulline in the urine (homocitrullinuria).

Another version of the mitochondrial ornithine transporter protein is produced by a different gene. While this protein is not as abundant as mitochondrial ornithine transporter 1, it is thought that this other version of the protein may partially compensate for the loss of mitochondrial ornithine transporter 1 and contribute to the late age of onset and mild signs and symptoms in some affected individuals. Other factors, many unknown, also contribute to the variable severity of ornithine translocase deficiency.

Because ornithine translocase deficiency is caused by problems with the urea cycle, it belongs to a class of genetic diseases called urea cycle disorders.

Normal Function

The SLC25A15 gene provides instructions for making a protein called mitochondrial ornithine transporter 1. This protein participates in the urea cycle, which is a sequence of biochemical reactions that occurs in liver cells. The urea cycle breaks down excess nitrogen, made when protein is broken down by the body, to make a compound called urea that is excreted by the kidneys in urine. Excreting the excess nitrogen prevents it from accumulating in the form of ammonia, which is toxic, especially to the nervous system.

Mitochondrial ornithine transporter 1 is needed to move a molecule called ornithine within the mitochondria (the energy-producing centers in cells). Specifically, this protein transports ornithine across the inner membrane of mitochondria to the region called the mitochondrial matrix, where it participates in the urea cycle.

Health Conditions Related to Genetic Changes

Ornithine translocase deficiency

At least 35 mutations in the SLC25A15 gene have been identified in individuals affected by ornithine translocase deficiency, which is characterized by abnormally high levels of ammonia in the blood. This condition can cause extreme tiredness (lethargy), difficulty feeding, problems controlling breathing or body temperature, and seizures in infancy. Affected adults can have episodes of vomiting, difficulty with movements, liver problems, or neurological problems.

The most common mutation found in people with ornithine translocase deficiency deletes the protein building block (amino acid) phenylalanine at position 188 (written as Phe188del or F188del). This mutation is seen in 30 to 50 percent of affected individuals and most commonly occurs in the French-Canadian population. Another common mutation replaces the amino acid arginine with a premature stop signal in the instructions for making the protein (written as Arg179Ter or R179X). This mutation is found in about 15 percent of affected individuals and most commonly occurs in Japanese and Middle Eastern populations.

Mutations in the SLC25A15 gene cause the production of a mitochondrial ornithine transporter 1 with reduced or absent function. As a result, ornithine transport is impaired and the urea cycle cannot proceed normally. Without a normally functioning urea cycle, nitrogen accumulates in the bloodstream in the form of toxic ammonia instead of being converted to less toxic urea and being excreted. Ammonia is especially damaging to the brain, and excess ammonia causes neurological problems and other signs and symptoms of ornithine translocase deficiency.

Other Names for This Gene

• D13S327
• HHH
• ORC1
• ornithine transporter 1
• ORNT1
• ORNT1_HUMAN
• OTTHUMP00000042249
• solute carrier family 25 (mitochondrial carrier; ornithine transporter) member 15

Genomic Location

Ornithine translocase deficiency is a genetic condition. Babies inherit it from their biological (birth) parents.

• Ornithine translocase deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking SLC25A15 gene to their baby. Only babies with two nonworking SLC25A15 genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the SLC25A15 gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the SLC25A15 gene, they have a 1 in 4 chance of having a child with Ornithine translocase deficiency.
  • Carriers for Ornithine translocase deficiency often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with Ornithine translocase deficiency.
  • Parents who already have a child with Ornithine translocase deficiency still have a 1 in 4 chance of having another child with Ornithine translocase deficiency. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of ornithine translocase deficiency can vary widely and may appear anytime from infancy to childhood. These signs may be triggered by eating foods high in protein, going a long time without eating (prolonged fasting), illnesses, and infections.

Signs of the condition may include the following:

• High ammonia in the blood (hyperammonemia)
• High homocitrulline in the urine (homocitrullinuria)
• Poor feeding/refusing to eat
• Vomiting
• Lack of energy (lethargy)
• Seizures
• Liver problems
• Problems with coordination (ataxia)

Newborn screening for Ornithine translocase deficiency requires collecting a small amount of blood from your baby’s heel. Screening measures how much ornithine is in your baby’s blood. Babies with high levels of ornithine might have Ornithine translocase deficiency.

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

If your baby’s blood spot screening result for Ornithine translocase 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 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 develop serious problems in infancy if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen.

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 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 certain proteins
• Special formula or food
• Supplements or medications

Children who receive early and ongoing treatment for ornithine translocase deficiency can lead healthier lives.

Ornithine translocase deficiency is a very rare disorder. More than 100 affected individuals have been described in the scientific literature.