Última actualización:
7/17/2025
Años publicados: 1986, 1987, 1990, 1992, 1993, 1996, 2001, 2011, 2014, 2017, 2025
NORD gratefully acknowledges Nicholas Ah Mew, MD, Associate Professor of Pediatrics, Children’s National Hospital, for assistance in the preparation of this report.
Ornithine transcarbamylase (OTC) deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is one of six enzymes that play a role in the breakdown and removal of nitrogen the body, a process known as the urea cycle. The lack of the OTC enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood, resulting in the symptoms and physical findings associated with OTC deficiency. Symptoms include vomiting, refusal to eat, progressive lethargy and coma.
The severity and age of onset of OTC deficiency vary from person to person, even within the same family, especially with the milder forms of the disorder. A severe form of the disorder affects some infants, typically males, shortly after birth (neonatal period). A milder form of the disorder affects some children or adults later in life. Both males and females may develop symptoms of OTC deficiency. Most carrier females are healthy; however, some may be prone to headaches following protein intake, may have some difficulty with short-term memory or may have difficulty with planning and organizing.
Children and adults with mild forms of the disorder may only have a partial OTC enzyme deficiency and therefore a greater tolerance to protein in the diet. Male infants who develop symptoms due to the severe form of the disorder often have a complete lack of the OTC enzyme.
The severe form of OTC deficiency occurs in some affected males anywhere between 24 hours to a few days after birth, usually following a protein feeding. Initial symptoms may include refusal to eat, poor suck, vomiting, progressive lethargy and irritability. The disorder may rapidly progress to include seizures, diminished muscle tone (hypotonia), an enlarged liver (hepatomegaly) and respiratory abnormalities. Affected infants and children may also have an accumulation of fluid (edema) within the brain.
If left untreated, infants with the severe form of OTC deficiency may fall into a coma and may potentially develop neurological abnormalities such as intellectual disability, developmental delays and cerebral palsy. The longer an infant remains in hyperammonemic coma the greater the chance neurological abnormalities may develop. Also, in most children, the longer an infant is in hyperammonemic coma the more severe these neurological abnormalities become. If left untreated, hyperammonemic coma may be life-threatening.
Some children and adults may have a milder form of OTC deficiency. These individuals may not have symptoms of OTC deficiency until later in life. People who have symptoms of OTC deficiency later in life often develop them during an episode of illness or prolonged fasting, and first experience hyperammonemia at that time. These episodes can recur, alternating between periods of wellness.
During a hyperammonemic episode, affected individuals may experience vomiting, lethargy and irritability. Additional symptoms may include confusion or delirium, hyperactivity and an impaired ability to coordinate voluntary movements (ataxia). If left untreated a hyperammonemic episode may progress to coma and life-threatening complications.
OTC deficiency may not become apparent until adulthood. Adults who have OTC deficiency may have migraines, nausea, difficulty forming words (dysarthria), an impaired ability to coordinate voluntary movements (ataxia), confusion, hallucinations and blurred vision.
OTC deficiency is caused by changes (variants) in the OTC gene.
OTC deficiency is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome and mostly affect males. Females who have a disease-causing gene variant on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the gene variant. However, approximately 20% of female carriers of an OTC gene variant develop symptoms. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
Many males with OTC deficiency have an OTC gene variant as the result of a new (de novo) variant as opposed to a variant inherited from the mother.
OTC deficiency affects males more often than females and is fully expressed in males only. In males, symptoms typically begin during the first few days of life. Late-onset OTC deficiency can present later in childhood or in adulthood. Approximately 20% of carrier females have mild symptoms of the disorder and rarely may be severely affected in childhood. Some females who are carriers may not have abnormally high levels of ammonia (hyperammonemia) until pregnancy or delivery.
The estimated frequency of OTC deficiency is 1/50,000 – 80,000. The estimated frequency of all urea cycle disorders collectively is 1/35,000. However, because urea cycle disorders like OTC deficiency often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.
A diagnosis of OTC deficiency or other metabolic disorder should be considered in any individual that has an undiagnosed illness characterized by vomiting, progressive lethargy and irritability.
Blood tests may reveal excessive amounts of ammonia in the blood, the characteristic finding of urea cycles disorders. However, high levels of ammonia in the blood may also be seen in other disorders such as the organic acidemias, congenital lactic acidosis and fatty acid oxidation disorders. Urea cycle disorders can be differentiated from these disorders through the examination of urine for elevated levels of organic acids and examination for alterations in plasma amino acids and plasma acylcarnitines.
The laboratory investigation of blood plasma and urine is used to differentiate OTC deficiency from other urea cycle disorders. Individuals with OTC deficiency usually have low levels of citrulline and high glutamine in the blood and high levels of orotic acid in the urine.
In rare cases, OTC deficiency may be detected by surgical removal (biopsy) and microscopic examination of tissue samples from the liver, duodenum and rectum where deficient enzyme activity may be seen.
Molecular genetic (DNA) testing is available to confirm the diagnosis. Variants in the OTC gene have been identified in approximately 80% of individuals with a documented enzyme deficiency.
Carrier testing and prenatal diagnosis of OTC deficiency are possible if the disease-causing variant has been identified in an affected family member.
Newborn screening for OTC deficiency is not currently routinely available and is only offered in 10 states.
Treatment
Treatment of an individual with OTC deficiency may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticists, dieticians and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language and physical therapists may be needed to treat children with developmental disabilities.
The treatment of OTC deficiency is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy for OTC deficiency combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathway therapies).
Dietary restrictions in individuals with OTC deficiency are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with OTC deficiency are placed on a low protein, high calorie diet often supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula, and a calorie supplement without protein is often used. Essential amino acid supplements may also be used.
In addition to dietary restrictions, individuals with OTC deficiency are treated with medications that stimulate the removal of nitrogen from the body. These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. These medications are unpalatable to many patients and are often administered via a tube that is placed in the stomach through the abdominal wall (gastrostomy tube) or a narrow tube that reaches the stomach via the nose (nasogastric tube). These medications include oral glycerol phenylbutyrate, sodium phenylbutyrate and sodium benzoate. An intravenous form of combined sodium phenylacetate and sodium benzoate is also available for the treatment of acute hyperammonemia in patients with urea cycle disorders.
Individuals with OTC deficiency benefit from treatment with arginine, or its precursor citrulline, which are needed to maintain normal protein synthesis. Multiple vitamins and calcium supplements may also be used in the treatment of OTC deficiency.
Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some individuals, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.
Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and an intravenous combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose or lipids (fat).
In people who do not improve or if hyperammonemic coma develops, the removal of ammonia by filtering the affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children and adults who are first diagnosed with OTC deficiency during hyperammonemic coma.
Preventive Care
After diagnosis of OTC deficiency, steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. In addition, elevated levels of an amino acid (glutamine) in the blood often precede the development of hyperammonemia by days or weeks. Affected individuals should receive periodic tests to measure the amount of amino acids such as glutamine in the blood. Detection of elevated levels of ammonia or glutamine may allow treatment before clinical symptoms appear. Blood tests should also be performed to monitor phenylbutyrate levels to ensure a proper dose is used and to avoid a potential overdose.
Genetic counseling is recommended for individuals with OTC deficiency and their families.
In some people, liver transplantation, either from a deceased or living donor, may be an appropriate treatment option. Liver transplantation can cure the hyperammonemia in OTC deficiency. However, this operation is risky and may result in post-operative complications. Also, after liver transplantation, patients will need to take life-long medications for immunosuppression.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contact for additional information about ornithine transcarbamylase deficiency:
Nicholas Ah Mew, MD
Associate Professor of Pediatrics
Children’s National Hospital
TEXTBOOKS
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