Ornithine transcarbamylase (OTC) deficiency

Patients with ornithine transcarbamylase deficiency are born with a genetic change that causes deficient or absent activity of an enzyme. This absence/deficiency will remain throughout a child’s life. A child will not "grow out" of the disease. The severity of their clinical condition, however, may change with age.

Since this ornithine transcarbamylase deficiency is a genetic disease affecting one of the most important pathways in the body, a cure is very difficult. Liver transplantation fixes many of the problems with this disease but has its own effects and consequences. Part of the work of the Urea Cycle Disorders Consortium (UCDC) is to develop and test new treatments and therapies.

Liver transplantation is sometimes the best therapeutic option for these patients with ornithine transcarbamylase deficiency. However, there are substantial risks to the procedure and long-term medical issues. The decision to transplant a patient is best made working closely with a metabolic specialist.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website. A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

Ornithine transcarbamylase deficiency (OTC) is an X-linked recessive disorder. A condition is considered X-linked if the disease causing gene is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Men who have OTC will pass the disease causing gene change on the X chromosome to all their daughters and none of their sones. Some females with only one altered copy of the OTC gene also show signs and symptoms of ornithine transcarbamylase deficiency. Whether they have symptoms or not, there is a 50% for a woman with a gene change that causes OTC to pass it on to each of her children, male or female.

To learn more about the inheritance of OTC and testing, it can be helpful to talk with a genetics professional. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

The National Urea Cycle Disorders Foundation has a mentor program as well as a family-networking program. You can learn more about these on their website at: http://nucdf.org/support.htm.

Treatment is best provided by a clinical geneticist and a metabolic dieticican experienced in the treatment of metabolic disease. Treatment of hyperammonemic coma should be provided by a team coordinated by a metabolic specialist in a care center experienced in the management of ornithine transcarbamylase deficiency. Complications of OTC including ADHD and learning/intellectual disability are treated according to the standard of care for these conditions by specialist such a occupational, speech language, and physical therapists. Liver transplant specialists may be added to the team in some situations.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website. A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

The abbreviation for Ornithine Transcarbamylase Deficiency is OTC.

While the life expectancy of many of the most severely affected patients with ornithine transcarbamylase deficiency is shortened, new improvements in diagnosis and treatment may improve their outcome. Many are surviving because of improved medical management, so it is suspected that the survival is much better now. The survival for the late onset cases seems to be quite good, but there is still a significant risk of a life-threatening or debilitating hyperammonemic episode, so symptoms should always be taken seriously. It is expected that the outcome for patients diagnosed through newborn screening will be better than that of children diagnosed after they become ill.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website. A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

Ornithine Transcarbamylase Deficiency (OTC) is an inherited disorder that results in high levels of ammonia in the blood. In its most severe and life-threatening form, OTC can present in boys and (rarely) in girls in the first 2-3 days of life and requires early and rapid recognition and treatment to prevent death. Many of these babies affected by the most severe form of OTC will need a liver transplant in the first 6 months of life to stabilize their health. A serious, but less medically catastrophic form of OTC, partial deficiency, can begin any time of life from infancy to later childhood, adolescence, or adulthood. No matter how mild the disease, dangerously high ammonia levels in the blood can occur by events such as a illness and become a life-threatening event at any age. Even with treatment, the high levels of ammonia in the blood that occur in OTC can lead to developmental delay, learning disabilities, intellectual disability, and attention deficit hyperactivity disorder (ADHD).

Health problems to look for in a child with ornithine transcarbamylase deficiency include looking to see if your baby is lacking in energy, unwilling to eat, is difficult to wake, or has a poorly controlled breathing rate and body temperature.

Older individuals with OTC may have similar symptoms to those in the more severe form and/or the appearance of a psychiatric condition with altered mental status, erratic behavior, or a reduced level of consciousness. Headaches, vomiting, aversion to protein foods, and seizures can also occur in this form of OTC. In many cases onset is unexpected. For example, it can present in a seemingly healthy woman who falls into a coma after delivery of a baby.

Ornithine transcarbamylase deficiency (OTC) belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occur in liver cells. It processes excess nitrogen generated when protein is used by the body to make a compound called urea which is excreted by the kidneys. In OTC, the enzyme that starts a specific reaction within the urea cycle 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 OTC causes neurological problems as well as eventual damage to the liver.

Mutations in the OTC gene cause Ornithine Transcarbamylase Deficiency. The OTC gene provides instructions for making the enzyme ornithine transcarbamylase. This enzyme helps the body identify and dispose of extra nitrogen in the body through the urea cycle. Excreting the excess nitrogen prevents it from storing up in the form of ammonia, which is poisonous, especially to the brain and nerves.

When the lab is testing a gene, they "read" each "letter" in the gene to see if there are any changes or variants in the "letters" that the gene should have. Sometimes they find a change in the gene that causes no problems or is "benign". Sometimes they find a gene change that causes the disease or is "pathogenic". Sometimes they find a gene change that they do not know if it causes "no problems" or if it causes the disease. This is called a variant of unknown significance (VUS), because the lab does not know what it does. By studying the family history or looking at what the gene change would do to the protein made by the gene, sometimes the lab can figure out the significance of the VUS.

When the lab is testing the OTC to determine if someone is at risk to have Ornithine Transcarbamylase Deficiency (OTC), they "read" each "letter" in the gene to see if there are any changes in the "letters" that the gene should have. Sometimes they find a change in the gene that causes no problems (benign variant). Sometimes they find a gene change that causes the disease (pathogenic variant). Sometime they find a gene change and they do not know if it is benign or if it causes the disease. This is called a variant of unknown significance (VUS), because the lab does not know how it affects the body. Most families have gene changes that are unique to them. By studying the family history or looking at what the gene change would do to the protein made by the gene, sometimes the lab can figure out the significance of the VUS.

To learn more about testing for OTC is can be helpful to talk with a genetics professional. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Women who have one pathogenic variant that causes Ornithine Transcarbamylase deficiency (OTC) are at risk of becoming catabolic and going into a coma during pregnancy, especially in the postpartum period right after birth. Those who are symptomatic need to be treated throughout pregnancy as necessary; those who are asymptomatic need to avoid catabolism in the peripartum and postpartum periods and should be treated as needed.

Anything that places increased stress on the body of someone with ornithine transcarbamylase deficiency can trigger an hyperammonemic episode. Viral infections are probably the most common cause, but episodes can be triggered by physical or emotional stress, dehydration, trauma, broken bones, the menstrual cycle, certain medications (like Valproic acid), pregnancy and delivery, and changes in the diet.

An infant with ornithine transcarbamylase deficiency (OTC) will have too much ammonia in the blood (hyperammonemia) and may be lacking in energy or unwilling to eat, and have poorly controlled breathing rate or body temperature. Some babies with this disorder may experience seizures or unusual body movements, or go into a coma. Complications from OTC may include developmental delay and intellectual disability. Progressive liver damage, skin lesions, and brittle hair may also be seen.

Older individuals with OTC may have similar symptoms to those in the more severe form and/or the appearance of a psychiatric condition with altered mental status, erratic behavior, or a reduced level of consciousness. Headaches, vomiting, aversion to protein foods, and seizures can also occur in this form of OTC. In many cases onset is unexpected. For example, it can present in a seemingly healthy woman who falls into a coma after delivery of a baby.

Since most infants with ornithine transcarbamylase deficiency (OTC) are not diagnosed until after a life-threatening illness (ammonia levels are severely elevated), rescue therapy is begun immediately. The fastest method for lowering the ammonia level is hemodialysis. A neonate should not be hemodialysed longer than four hours and should then be switched to hemofiltration for stabilization to prevent a rebound of the ammonia level. An older individual can be dialysed longer and should also be switched to hemofiltration for stabilization.

Ammonia scavenger therapy treatment allows an alternative pathway for the excretion of excess nitrogen. Nitrogen scavenger therapy is available as an intravenous infusion of a mixture of sodium phenylacetate and sodium benzoate for acute management and as an oral preparation of phenylbutyrate or sodium benzoate for long-term maintenance therapy.

If an older or seemingly asymptomatic individual is diagnosed with OTC, they will work closely with metabolic dietitians and medical geneticists as they learn more about the individual and do additional blood tests to develop the best treatment and monitoring plan for that individual which may include following a low protein diet and taking medicines such as citrulline.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website. A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

Most small community hospitals cannot deal with a major hyperammonemic episodes related to ornithine transcarbamylase deficiency (OTC). However, with the advent of regional patient transport systems most patients can be moved to a large hospital with the proper facilities and personnel very rapidly. It is important that the hospital that treats your child has intravenous benzoate/phenylacetate available in the case of hyperammonemic crisis.

To connect a local team with an expert in OTC, a medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website. A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

Because ornithine transcarbamylase deficiency is an X-linked genetic disorder, there is an increased risk for siblings of children having the disorder. A condition is considered X-linked if the disease causing gene is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Men who have OTC will pass the disease causing gene change on the X chromosome to all their daughters and none of their sons. Some females with only one altered copy of the OTC gene will show signs and symptoms of ornithine transcarbamylase deficiency. Whether they have symptoms or not, there is a 50% for a woman with a gene change that causes OTC to pass it on to each of her children, male or female. Prenatal testing is available for this disorder. Working with a metabolic specialist, a genetic counselor can help individuals determine what type of testing makes the most sense, and when it should be done.

To learn more about the inheritance and testing for OTC is can be helpful to talk with a genetics professional. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Many families worry about the placement of a gastrostomy tube in children with ornithine transcarbamylase deficiency. These tubes can be a real stress reliever if there are issues around feeding. It is very common for children with OTC
(OTC) disorder to have eating problems. While ideally it is best for your child to eat by mouth, that is not always possible. If they is not gaining weight, eating becomes the focus of the family’s life, or taking medications by mouth becomes a constant battle, the gastrostomy tube (G-tube) may be the answer. It can provide an effective alternative means of feeding and providing medication. There are certain risks in inserting and maintaining a G-tube and these should be discussed with your doctor. In general, however, children with this disorder require G-tubes have benefited from them with improved weight gain, better metabolic control, and less behavior problems.

The interaction between ammonia and the brain is not well understood. Sometimes it makes a child sleepy and sometimes it makes them agitated. Both can be signs of an onset of hyperammonemia. In general, however, agitation and hyperactivity tend to precede lethargy in a hyperammonemic episode.

In children with ornithine transcarbamylase deficiency (OTC), with developmental intervention programs and careful medical management, these patients can catch up with their peers. However, most patients who experience a severe hyperammonemic episode will have some degree of developmental delay. In addition to developmental delay, some patients are also at risk for milder disabilities such as attention deficit disorder or learning disabilities. If a child has this disorder, their metabolic treatment team should arrange periodic assessment by a developmental specialist. Children should be enrolled in an appropriate developmental intervention program at an early age based on their medical condition or developmental assessment.

The basic tests to make the diagnosis a urea cycle disorder such as ornithine transcarbamylase deficiency are blood ammonia, plasma amino acids, and urine organic acids. These laboratory tests measure substances that reflect how well the urea cycle is working. When there is a block in one of the enzymes in the urea cycle, certain chemical compounds build up behind the block and others are not adequately formed beyond the block. It is like the effects of a dam.

Children with Ornithine Transcarbamylase Deficiency(OTC) will face many challenges in life living with OTC. The outcome and the effect on their life will depend a great deal on how sick they were when they were diagnosed and how severe the defect in the urea cycle. Most patients presenting with a hyperammonemic coma have some degree of delay in their development. Their daily routine will be complicated but they can grow up and participate in school, play, and work. Later onset cases can have normal intelligence and may live a fairly normal life. They may, however, need to practice protein restriction and take medications throughout their life. While most children with later onset are not severely intellectually disabled, many have mild disabilities such as attention deficit hyperactivity disorder or learning disabilities.

To determine if other children may be at risk for ornithine transcarbamylase deficiency (OTC), the issue should be discussed with a metabolic specialist who can arrange any testing that is needed for family members. This disorder is a genetic condition; therefore there may be a risk for other members in an affected individual’s family. In the case of OTC, which is usually passed on from the mother, there may be risks for other children, the mother’s sisters or their families and testing should be arranged.

To learn more about the inheritance of OTC and testing for OTC is can be helpful to talk with a genetics professional. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Penetrance for ornithine transcarbamylase (OTC) deficiency is complete in males since the gene that causes OTC deficiency is on the X chromosome and males only have one X chromosome; OTC is X-linked in inheritance. Having said this, there have been females with only one non-functional gene who become symptomatic in the first days of life. Males and females may have a partial enzyme deficiency and have a milder, but still life threatening form of the condition.

Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely females) and as a late-onset disease in males and females. Males with severe neonatal-onset OTC deficiency are typically normal at birth but become symptomatic from hyperammonemia on day to three of life and are usually catastrophically ill by the time they come to medical attention. Accordingly, families may report multiple baby boys in a family history that passed away a few days after birth. Later onset versions of OTC may have unusual features such as spontaneous refusal to eat meat from a young age, intermittent of episodes that resemble psychiatric illness, and women falling into an unexpected coma after the birth of a child.

Most state screening panels do not include screening for ornithine transcarbamylase deficiency (OTC). In 2019, states that DO include OTC deficiency on their state mandated newborn screening panel or will pick it up while screening for a similar condition include:

Infants with Ornithine Transcarbamylase deficiency (OTC) are diagnosed through symptoms soon after birth or newborn screening in some states. Further testing to confirm a diagnosis will be done. This will include testing the blood and urine for substances that are abnormally elevated in people with OTC.

Genetic testing can be used to confirm a diagnosis of OTC These tests involve studying the OTC gene for changes that cause the disorder. This can include targeted mutation analysis, where specific, known changes in a gene are looked for; single-gene testing, where the OTC gene is studied for any changes; or, deletion/duplication analysis, where missing or extra regions of DNA are looked for within a specific gene.

To learn more about testing for OTC is can be helpful to talk with a genetics professional. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

The best place to look for any ongoing clinical research for ornithine transcarbamylase deficiency can be found on the website [link url="Clinicaltrials.gov” target=”_blank”>Clinicaltrials.gov. Individuals may also reach out to the primary OTC support group National Urea Cycle Disorders Foundation who often has up-to-date information about clinical trials.

Treatment of Ornithine Transcarbamylase Deficiency (OTC) has two phases: during severe episodes of illness with very high levels of ammonia in the blood and daily maintenance therapy to keep levels stable.

During the illness episodes, it is critical to rapidly lower blood ammonia levels with:

A mutation in the gene encoding Ornithine Carbamoyltransferase causes ornithine transcarbamylase deficiency.

Prenatal testing is available for ornithine transcarbamylase deficiency. Working with a metabolic specialist, a genetic counselor or your obstetrician can help you determine what type of testing is best, and when it should be done. It is recommended that you contact a counselor either before you are pregnant or as soon as you know so that testing can be more easily arranged.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website. A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

DNA testing is available to test for ornithine transcarbamylase deficiency, but it is not used as a general screening test. If the plasma amino acids and urine tests do not make the diagnosis, more specialized testing is done. This may include obtaining blood to measure the suspected missing enzyme or performing DNA analysis on blood to identify the specific mutation or error causing the enzyme defect. The enzyme and DNA tests are usually done if the disorder is strongly suspected and as yet undiagnosed. The DNA testing may also be done to help in genetic counseling of other family members or in prenatal diagnosis.

To learn more about testing for OTC is can be helpful to talk with a genetics professional. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

We all need some protein for our bodies to grow and repair our tissues. There are many amino acids (subunits of protein) that the body cannot make on its and must get from protein in the diet. Without these outside sources of protein and amino acids the body will break down its own protein. This break down of body protein releases ammonia, which can cause hyperammonemia as bad as or worse than too much protein in the diet. The balance is difficult to achieve and changes in protein intake should be made in close consultation with the metabolic treatment team for patients with ornithine transcarbamylase deficiency.

A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

The Urea Cycle Disorders Consortium created a page on their website specifically on information for physicians that you can give to your doctor at: http://www.rarediseasesnetwork.org/UCDC/physicians/index.htm.

For patients with ornithine transcarbamylase deficiency, their metabolic specialist should determine how frequently a child’s ammonia levels and amino acid levels be monitored. Depending on the severity of the disease and the age of the child, this can vary from weekly to several times a year.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website. A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

Ornithine transcarbamylase deficiency (OTC) is an X-linked recessive disorder. A condition is considered X-linked if the disease causing gene is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Men who have OTC will pass the disease causing gene change on the X chromosome to all their daughters and none of their sons. Some females with only one altered copy of the OTC gene also show signs and symptoms of ornithine transcarbamylase deficiency. Whether they have symptoms or not, there is a 50% for a woman with a gene change that causes OTC to pass it on to each of her children, male or female.

Some patients get symptomatic at moderate ammonia levels (over 50-60 micromoles/liter) while others only become symptomatic at much higher levels (in the 100s or more). In general, the fewer symptomatic hyperammonemic episodes, the better the developmental outcome. Also, the better the long-term metabolic control of the disorder the better the outcome. Whenever children become symptomatic or may be at risk (such as during a viral illness), the metabolic team should be consulted and usually an ammonia level checked.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website. A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

An ornithine transcarbamylase deficiency(OTC) diagnosis usually begins with clinical manifestations and laboratory studies during an illness episode that is affecting brain function (encephalopathy). During an episode abnormal lab values can include:

Starting a support group is a challenging and rewarding experience. Support organizations, such as the National Urea Cycle Disorders Foundation, can help connect you with other families in your area. Clinics that serve people with ornithine transcarbamylase deficiency often have social workers or genetic counselors that can help you start a support group. The National Organization for Rare Disorders provides tools to help you with starting your own organization at: http://rarediseases.org/for-patients-and-families/connect-others/start-patient-organization/.

You can donate to the National urea Cycle Disorders Foundation at: http://nucdf.org/support_our_mission.html or to the National Organization for Rare Disorders (NORD) at: https://salsa3.salsalabs.com/o/51076/donate_page/donate-now.

Go to [link url="www.ClinicalTrials.gov” target=”_blank”>ClinicalTrials.gov to find clinical research in Ornithine Transcarbamylase Deficiency. Individuals may also reach out to the primary OTC support group National Urea Cycle Disorders Foundation who often has up-to-date information about clinical trials.

You can learn about clinical centers participating in the Urea Cycle Disorders Consortium at: http://www.rarediseasesnetwork.org/UCDC/centers/index.htm.

Ornithine transcarbamylase deficiency (OTC) is thought to be the most common urea cycle disorder.

The estimated prevalence of OTC is 1 in 14,000 live births with worldwide prevalence estimates range between 1/56,500 to 1/113,000 live births. However some studies report a lower incidence of OTC deficiency in Italy, Finland, and New South Wales, Australia, of 1 in 70,000, 1 in 62,000, and 1 in 77,000 live births, respectively.

Given that males and females with partial OTC deficiency may manifest symptoms at any age, prevalence numbers are likely biased toward the earliest and most severe presentations.

To determine the difference between a hyperammonemic episode from too much protein intake as opposed to insufficient protein intake in patients with ornithine transcarbamylase deficiency, testing is best done by examination of the amino acid levels in the blood stream. If certain amino acid levels are low or high, a metabolic doctor can determine if the patient is breaking down protein from the body or taking too much in. Surprisingly, more patients probably become hyperammonemic from breaking down their own protein than from overdosing in their diet.

To discuss best practices for protein in a diet, a metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

A patient with ornithine transcarbamylase deficiency needs both a pediatrician and a specialist. Ideally, a physician experienced in this disorder should do the initial testing and the acute treatment for this disorder. This metabolic specialist is often a pediatric geneticist and works in a hospital based metabolic clinic that often has a nutritionist, genetic counselor and social worker. The metabolic team can then work with your pediatrician to provide ongoing care in a collaborative fashion.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website. A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

For ornithine transcarbamylase deficiency, blood or saliva can be used for genetic testing but most labs prefer blood.

Anything that places increased stress on the body can trigger an ornithine transcarbamylase deficiency (OTC) episode. Viral infections are probably the most common cause, but episodes can be triggered by physical or emotional stress, dehydration, trauma, broken bones, the menstrual cycle, certain medications (like valproic acid), pregnancy and delivery, and changes in the diet.

In severe cases of Ornithine Transcarbamylase Deficiency, liver transplantation is typically performed by age six months to prevent further crises from ammonia and neurodevelopmental deterioration. This is considered in individuals who have frequent episodes.

Other names for Ornithine Transcarbamylase Deficiency include:

The National Urea Cycle Disorders Foundation has a mentor program as well as a family-networking program. You can learn more about these on their website at: http://nucdf.org/support.htm.

In some affected individuals, signs and symptoms of ornithine transcarbamylase deficiency may be less severe, and may not appear until later in life. In this case, it may look like a psychiatric condition with altered mental status, erratic behavior, or a reduced level of consciousness particularly after eating a high protein meal, infections, or stress.

Ornithine Transcarbamylase Deficiency can look much like other conditions that affect the urea cycle and lead to high levels of waste products like ammonia in the blood. These can include: