NORD gratefully acknowledges Nicholas Ah Mew, MD, Assistant Professor of Pediatrics, Children's National Medical Center, 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 break down 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 case to case, even within the same family. A severe form of the disorder affects some male infants shortly after birth (neonatal period). A milder form of the disorder affects some males later during infancy. Both males and females may develop symptoms of OTC deficiency during childhood. Most carrier females are healthy, but may be prone to severe headaches following protein intake.
Children and adults with mild forms of the disorder may only have a partial enzyme deficiency and therefore a greater tolerance to protein in the diet. Male infants with 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. In some cases, hyperammonemia may not develop until later during infancy. 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 exhibit the accumulation of fluid (edema) within the brain.
If left untreated, infants with the severe form of OTC deficiency may fall into coma and may potentially develop neurological abnormalities such as mental retardation, developmental delays, and cerebral palsy. The longer an infant remains in hyperammonemic coma the greater the chance neurological abnormalities may develop. In most cases, the longer an infant is in hyperammonemic coma the more severe these neurological abnormalities become. If left untreated, hyperammonemic coma may result in life-threatening complications.
Some infants and children may have a milder form of OTC deficiency. These infants and children may not exhibit symptoms of OTC deficiency until later during life. Children who develop OTC deficiency later during life often express the disorder during an episode of hyperammonemia. These episodes recur, alternating between periods of wellness.
During a hyperammonemic episode, affected children may experience vomiting, lethargy, and irritability. Additional symptoms may include confusion or delirium, hyperactivity, self-mutilation such as biting oneself, 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 exhibit migraines; nausea; difficulty forming words (dysarthria); an impaired ability to coordinate voluntary movements (ataxia); confusion; hallucinations; and blurred vision.
OTC deficiency is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. However, approximately 20% of female carriers of the OTC gene are symptomatic. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease. Many males with OTC deficiency have an abnormal OTC gene as the result of a new mutation as opposed to a mutation inherited from the mother.
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 X-linked disorders is able to reproduce, he will pass the defective gene to all of 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 offspring.
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, but may also occur with onset at 40-50 years of age. Approximately 20% of carrier females have mild symptoms of the disorder and rarely may be severely affected in childhood. Some women who are carriers may not experience 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 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 should be considered in any newborn 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 characterize 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 or abnormal organic acids. In urea cycle disorders, urinary organic acids are normal.
The study of blood plasma and urine is used to differentiate OTC deficiency from other urea cycle disorders. Individuals with OTC deficiency usually have both low levels of citrulline 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 testing is available to confirm the diagnosis and mutations 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 is possible if the disease-causing mutation has been identified in an affected family member.
Newborn screening for OTC deficiency is not currently available.
Treatment of an individual with OTC deficiency may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticist, 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 pathways therapy).
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 a low protein, high calorie diet 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 (e.g., UCD Anamix Junior, Nutricia, or Cyclinex, Mead Johnson), and a calorie supplement without protein is often used (e.g., 80056, Mead Johnson or Pro-Phree, Abbott).
In addition to dietary restrictions, individuals with OTC deficiency are treated by 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 and 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).
The orphan drug sodium phenylbutyrate (Buphenyl), manufactured by Hyperion Therapeutics, has been approved by the Food and Drug Administration (FDA) for the treatment of chronic hyperammonemia in OTC deficiency. In 2013, a new medication, glycerol phenylgutyrate (Ravicti), also manufactured by Hyperion Therapeutics, was approved by the FDA for treatment of chronic hyperammonemia in patients with urea cycle disorders. Ammonul (sodium phenylacetate and sodium benzoate), manufactured by Ucyclyd Pharma, is the only FDA-approved adjunctive therapy 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 in order to maintain a normal rate of 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 cases, 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 a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose or lipids (fat).
In cases where there is no improvement or in cases where hyperammonemic coma develops, the removal of wastes by filtering an 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.
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 in order to assure 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 cases, liver transplantation, either cadaveric or from a 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 medications life-long for immunosuppression.
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Contacts for additional information about ornithine transcarbamylase deficiency:
Nicholas Ah Mew, MD
Assistant Professor of Pediatrics
Children’s National Health System
Mendel Tuchman, MD
Chief Research Officer
Scientific Director, Children’s Research Institute
Professor of Pediatrics, Biochemistry, Molecular Biology & Integrative System Biology
Children’s National Health System
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