Inborn errors of urea synthesis
Related Terms
ALD, ammonia, ARG, arginase, arginine, arginosuccinase acid lyase, argininosuccinic acid synthetase, ASD, carbamyl phosphate synthetase, carbamylglutamate, citrin, citrulline, citrullinemia, CPS, encephalopathy, HHH syndrome, hyperammonemia, inborn errors of metabolism, inborn errors of urea synthesis, N-acetylglutamate synthetase (NAGS), N-acetylglutamate synthetase deficiency, ornithine transcarbamylase deficiency, ornithine translocase deficiency, OTC, sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, urea cycle.
Background
Urea cycle disorders are conditions in which the body cannot properly dispose of ammonia, a waste product of protein digestion. Six enzymes are involved in the urea cycle, a process that converts the toxic substance ammonia into urea, which is excreted in the urine.
The six enzymes in the urea cycle are ornithine transcarbamylase (OTC), argininosuccinic acid synthetase (ASD), arginase (ARG), arginosuccinase acid lyase (ALD), carbamyl phosphate synthetase (CPS), and N-acetylglutamate synthetase (NAGS). These enzymes are found in the liver, where they process nitrogen-containing waste products (such as ammonia) into urea. Deficiencies in any of these enzymes, also known as inborn errors of urea synthesis, can lead to urea cycle disorders.
Urea cycle disorders can also occur from defects in transporter proteins that move or transport a specific substance involved in the urea cycle in and out of various parts of a cell. The two known defects are citrin deficiency (citrullinemia II) and ornithine translocase deficiency.
If an enzyme or transporter in the urea cycle is deficient, ammonia may build up in the blood and reach toxic levels. An elevated ammonia level (hyperammonemia) disrupts normal brain and central nervous system function. Some of the physical symptoms may include lack of appetite, irritability, heavy or rapid breathing, low energy, vomiting, disorientation, and combativeness. If left untreated, high ammonia levels may lead to coma, swelling of the brain, brain damage, and death. In a urea cycle disorder, ammonia levels may be increased after a meal high in protein, viral illness, childbirth, and certain prescription medications.
It is estimated that as a group, urea cycle disorders occur at a rate of one in 10,000 births. OTC deficiency is the most common of the disorders and is estimated to occur in one in 30,000 births. NAGS deficiency is the rarest of the urea cycle disorders, with only a handful of cases reported worldwide each year.
Signs and symptoms
General: Symptoms of urea cycle disorders are caused by elevated ammonia levels in the blood (hyperammonemia). An elevated ammonia level can disrupt normal brain and central nervous system function. Some of the physical symptoms of an elevated ammonia level may include tremor, lack of appetite,
irritability, heavy or rapid breathing, low energy, vomiting, disorientation, and combativeness. If the elevated ammonia levels are left untreated and are high enough to reach the central nervous system, the brain and spinal cord may swell, causing irreversible brain damage (encephalopathy), seizures, coma, and death. Signs and symptoms of an elevated ammonia level usually appear early during childhood, but in cases of mild deficiency, the person may not develop symptoms until as late as 40-50 years old. Some common signs of a urea cycle disorder not related to hyperammonemia may include skin lesions, brittle hair, and progressive liver disease.
Newborn period: Onset of symptoms at birth usually indicates a severe deficiency or complete absence of enzymes. In some cases, symptoms may occur within 24 to 72 hours of birth. Signs and symptoms may include vomiting, refusing to eat, restlessness, difficultly waking, tiredness, difficulty breathing, coma, and seizures. Physicians often misdiagnose this as sepsis.
Childhood: Mild to moderate cases of enzyme deficiency typically appear during childhood. Symptoms usually represent a lack of protein intake, and may be worsened after eating a high-protein meal. The signs and symptoms can be the same as the newborn period but may also include poor growth, loss of appetite, delirium, tremors, inconsolable crying, hyperactive behavior, and irritability.
Adulthood: In cases of mild deficiency, a person may go undiagnosed until adulthood. Signs and symptoms may include cycles of vomiting, delirium, lethargy, and worsening of symptoms with high-protein meals. Episodes of hyperammonemia often result in permanent brain damage and serious mental deficits. Ammonia levels may be increased by a viral illness, childbirth, certain cancer treatments, and prescription medications like divalproex sodium (Depakote?).
Diagnosis
General: A urea cycle disorder should be suspected in any patient with unexplained abnormal behavior that may include tremor, lack of appetite,
irritability, heavy or rapid breathing, low energy, vomiting, disorientation, and combativeness. These symptoms may indicate an elevated ammonia level. Blood ammonia levels should be tested especially in young children. A lab result of plasma ammonia greater than 150 mmol/L is a good indicator of a possible urea cycle disorder.
Several routine lab tests, such as those that measure serum electrolytes and blood gases, may aid in the diagnosis of a urea cycle disorder. Low blood urea nitrogen and abnormal blood sugar levels also support a diagnosis of UCD.
Specific tests for urea cycle disorders, such as blood amino acid analysis, urine orotic acid level, urine amino acid level, urine organic acid, enzyme testing, DNA testing, and liver biopsy, are helpful in diagnosis. Orotic acid is produced when there is an increase in available carbamoyl phosphate.
Amino acid testing: Blood and urine levels of amino acids may be increased or decreased depending on the type of urea cycle disorder. Levels of citrulline may be low in carbamyl phosphate synthetase (CPS) and ornithine transcarbamylase (OTC) deficiency but elevated in argininosuccinic acid synthetase (ASD), arginosuccinase acid lyase (ALD), and arginase (ARG) deficiency. Each UCD may have a decreased arginine level except for ARG deficiency. An increased arginine level of 5-7 times above normal indicates ARG deficiency.
DNA testing: DNA testing may be performed to confirm the presence and the type of UCD. Each UCD has a known mutation that is specific to the type of disease. In cases of a family history of a UCD, genetic testing may also be used to identify a carrier. If UCD is suspected, a cytogenetic test may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for a defect or mutation in any of the known urea cycle disorder genes.
Enzyme testing: An enzyme assay may be used to make a definitive diagnosis of the type of urea cycle disorder based upon the levels of the six enzymes involved in the urea cycle. Enzyme activity may be measured from a blood or urine sample that is combined with a substrate specific to the target enzyme. The target enzyme can be OTC, ASD, AG, ALD, CPS, and N-acetylglutamate synthetase (NAGS).
Prenatal testing: If there is a family history of a UCD, prenatal testing may be performed to determine if the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can help diagnose a UCD. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks associated with these procedures with a medical professional.
During amniocentesis, a long, thin needle is inserted through the abdominal wall into the uterus and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.
During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th week of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for the mutation responsible for one of the urea cycle disorders. Miscarriage occurs in about 0.5-1% of women who undergo this procedure.
Genetic counseling: Before and after genetic testing, it is recommended that patients meet with genetic counselors. These professionals can help patients understand the risks of having a child with a urea cycle disorder. A genetic counselor can also explain the different types of genetic tests, including their potential risks and benefits. These counselors can also help patients understand and interpret genetic test results.
Complications
Brain: Normal brain function may be maintained if a urea cycle disorder is mild or diagnosed early. Frequent episodes of an elevated ammonia level can disrupt normal brain and central nervous system function.
Other: Some of the physical symptoms of an elevated ammonia level may include lack of appetite, irritability, heavy or rapid breathing, low energy, vomiting, disorientation, and combativeness. If the elevated ammonia levels are left untreated and are high enough to reach the central nervous system, the brain and spinal cord may swell, causing irreversible brain damage (encephalopathy), seizures, coma, and death.
Treatment
General: There is currently no known cure for urea cycle disorders, but treatment can help to reduce symptoms and improve quality of life for a patient. Current treatment options focus on reducing protein intake, reducing ammonia levels, and providing amino acid supplementation. Patients with a diagnosed urea cycle disorder need to be routinely checked for ammonia and amino acid levels.
Amino acid supplementation: Researchers have used arginine and citrulline to treat certain urea cycle disorders. The goal of treatment is to supply a missing component of the urea cycle. These amino acids are not useful in the treatment of arginase deficiency because the disorder is characterized by increased arginine levels and arginine supplementation will worsen the disease.
Dialysis: The most effective way to reduce ammonia levels rapidly is through dialysis. When the kidneys begin to fail, patients can undergo dialysis to restore filtering function. In hemodialysis, a patient's blood is circulated into an external filter and cleaned. The filtered blood is then returned to the body. In peritoneal dialysis, a fluid containing dextrose is introduced into the abdomen through a tube. This solution absorbs the wastes in the body and is then removed. Ammonia is removed from the blood during the filtration process of dialysis.
Medication: Researchers have used sodium phenylacetate, sodium benzoate, and sodium phenylbutyrate to target nitrogen compounds in order to help eliminate and reduce ammonia levels. These medications are also called "alternative pathway therapy" because they can remove nitrogen without the use of the urea cycle. Administration into a blood vessel has been found to help in acute management of hyperammonemia. These medications have been used for long-term management of urea cycle disorders when given by mouth.
Nutrition counseling: A nutritionist may be consulted to provide a patient with a carefully balanced diet. A diet too low or too high in protein can cause an elevated ammonia level. Controlling the amount of ammonia that is produced during protein breakdown is a key component of preventing symptoms and exacerbations of a urea cycle disorder. The majority of urea cycle disorders appear before puberty. Therefore, the diet should be carefully tailored to account for growth rate and energy requirements so as not to disrupt the normal development of a child with a urea cycle disorder.
Transplant: Because urea cycle disorders are caused by decreased enzyme production in the liver, a liver transplant may be an option, particularly when nutritional and amino acid supplementation fail or in cases of neonatal ornithine transcarbamylase (OTC) and carbamyl phosphate synthetase (CPS) deficiency. There are risks associated with transplantation that need to be assessed by the appropriate medical professional. After a transplant, an infection may develop from the procedure or the body may attack and reject the transplanted liver. These complications can be life-threatening and patients should be closely followed by a healthcare professional after transplantation. Due to the severity and rapid onset of OTC and CPS deficiency at birth, a liver transplant is often needed.
Other: The use of an N-acetylglutamate analog, carbamylglutamate, has been reported with the treatment of N-acetylglutamate synthetase deficiency. The only known treatment for arginase deficiency is protein restriction, which typically only delays the disease.
Integrative therapies
Note: Currently, there is a lack of scientific data on the use of integrative therapies for the treatment or prevention of urea cycle disorders. The therapies listed below have been studied for related conditions, and should be used only under the supervision of a qualified healthcare provider, not in replacement of other proven therapies.
Strong scientific evidence:
Arginine: In patients with inborn errors of urea synthesis, high blood ammonia levels may occur due to a deficiency or absence of necessary enzymes in the urea cycle. Arginine is an essential amino acid in the urea cycle that may be helpful by providing a necessary component of the cycle, but should be avoided in patients with hyperargininemia (high arginine levels) and arginase deficiency. In arginase deficiency, the enzyme needed to break down arginine is absent or deficient and supplementing with arginine will worsen the disease. The use of arginine for a urea cycle disorder should be supervised by a qualified healthcare professional.
Arginine should be avoided if there is a history of stroke, liver disease, or kidney disease. Avoid if pregnant or breastfeeding. Use caution if taking blood-thinning drugs (like warfarin or Coumadin?) and blood pressure drugs or herbs or supplements with similar effects. It is important to check blood potassium levels.
Unclear or conflicting scientific evidence:
Creatine: Ornithine is a byproduct formed in the liver. Some individuals are born with a genetic disorder that prevents them from appropriately breaking down ornithine, and blood levels of ornithine become too high. High amounts of ornithine can lead to blindness, muscle weakness, and reduced storage of creatine in muscles and the brain. Although there is only limited research in this area, early evidence suggests that long-term, daily creatine supplementation may help replace missing creatine and slow vision loss.
Avoid if allergic to creatine or with diuretics (like hydrochlorothiazide, furosemide (Lasix?)). Use cautiously with asthma, diabetes, gout, kidney, liver, or muscle problems, stroke, or a history of these conditions. Avoid with dehydration. Avoid if pregnant or breastfeeding.
Traditional or theoretical uses lacking sufficient evidence:
Citrulline: Levels of citrulline tend to be decreased in some people with urea cycle disorders. It is not clear, however, whether supplementation with citrulline is useful for urea cycle disorders. Scientific safety and efficacy data are lacking, and additional study is needed before any recommendations may be made.
Prevention
General: Urea cycle disorders are inherited genetic conditions that currently have no known means of prevention. However, genetic screening and counseling may reduce the risks of having children with a urea cycle disorder.
Genetic testing and counseling: Individuals with a family history of urea cycle disorders or who currently have a urea cycle disorder may meet with genetic counselors to discuss the risks of having children with the disease.
Known carriers of a urea cycle disorder may undergo genetic counseling before they conceive a child. Genetic counselors can explain the options and the associated risks of various tests, including pre-implantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).
Pre-implantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for a urea cycle disorder, and only the embryos that are free of the urea cycle disorder mutations may be implanted. This procedure is considered controversial.
Author information
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
Bibliography
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Causes
General: Urea cycle disorders are diseases caused by deficiencies in any of the enzymes or transporters involved in the conversion of ammonia to urea. A gene is a portion of DNA that is responsible for the production of a specific protein (enzyme or transporter). Enzymes are proteins that stimulate the conversion of one substance into another within a cell. The job of a transporter is to move a specific substance in and out of various parts of a cell. The absence or abnormal formation of a urea cycle disorder enzyme or transporter protein disrupts the normal function of the urea cycle. The urea cycle is an important process that helps remove waste products, such as ammonia, from the blood stream. Excess levels of ammonia can lead to brain damage and death.
When proteins or amino acids are broken down, nitrogen is produced. This nitrogen is normally present in the form of ammonia (NH3). Ammonia is toxic, so it is removed from the blood and converted to a less toxic substance called urea. Urea is then excreted from the body in the urine.
The liver produces the six enzymes needed for the urea cycle. These enzymes are ornithine transcarbamylase (OTC), argininosuccinic acid synthetase (ASD), arginase (AG), arginosuccinase acid lyase (ALD), carbamyl phosphate synthetase (CPS), and N-acetylglutamate synthetase (NAGS). The two transporter proteins involved in the urea cycle are citrin and ornithine translocase. A gene mutation for each of the UCD enzymes and transporter proteins has been identified.
N-acetylglutamate synthetase (NAGS) deficiency: NAGS deficiency is caused by a mutation of the NAGS gene on chromosome 17 at position 21.31.
Carbamyl phosphate synthetase(CPS) deficiency: CPS deficiency is caused by a mutation of the CPS1 gene on chromosome 2 at position 35.
Ornithine transcarbamylase(OTC) deficiency: OTC deficiency is caused by a mutation of the OTC gene on the X-chromosome at position 21.1.
Argininosuccinic acid synthetase (ASD) deficiency: ASD deficiency is caused by a mutation of the ASS1 gene on chromosome 9 at position 34.1.
Argininosuccinase acid lyase(ALD) deficiency: ALD deficiency is caused by a mutation of the ASL gene located on chromosome 7 at position 11.2.
Arginase(ARG) deficiency: ARG deficiency is caused by a mutation of the ARG1 gene located on chromosome 6 at position 23.
Citrin deficiency: Citrin deficiency is caused by a mutation of the SLC25A13 gene on chromosome 7 at position 21.3. Citrin deficiency is more common in east-Asian populations.
Ornithine translocase deficiency: Ornithine translocase deficiency is caused by a mutation of the SLC25A15 gene on chromosome 13 at position 14.
Autosomal recessive inheritance: All of the urea cycle disorders are autosomal recessive except for OTC deficiency. In a recessive genetic disorder a person must inherit two copies of the genetic mutation (one copy from each parent) to develop a urea cycle disorder. People who inherit a mutation from only one parent are called "carriers," and they may pass the mutation to their children.
If one parent only has one copy of the mutated gene, then each child will have a 50% chance of inheriting one mutated gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two mutated genes, a 50% chance of inheriting only one mutation, and a 25% chance of inheriting neither of the mutations.
X-linked recessive inheritance: OTC deficiency is an X-linked recessive inherited genetic condition. Normal individuals have two copies of most genes (one inherited from the father and one from the mother). In a recessive genetic disorder, both copies of a certain gene need to be defective for the condition to manifest itself.
Females have two copies of the X chromosome, but males have one X chromosome and one Y chromosome. Males inherit an X chromosome from the mother and a Y chromosome from the father, so a male can only inherit OTC deficiency from the mother. Therefore, a female needs to inherit two mutant copies to develop OTC deficiency (one from each parent), whereas a male only needs to inherit one mutant copy to develop the condition.
Because females need to inherit two mutant copies to develop the condition, whereas males only need to inherit one mutant copy, OTC deficiency is more common in males that females. Females who inherit only one mutant copy are called "carriers." Females who are carriers may exhibit some mild symptoms.
Random occurrence: It is rare for OTC deficiency to occur due to a spontaneous mutation during fetal development. Development of OTC deficiency in these cases can happen without a family history or other risk factors for the disease.
Risk factors
It is estimated that as a group, urea cycle disorders occur at a rate of one in 10,000 births. Ornithine transcarbamylase deficiency is the most common of the disorders and is estimated to occur in one in 30,000 births. N-acetylglutamate synthetase deficiency is the rarest of the urea cycle disorders, with only a handful of cases reported worldwide each year. Urea cycle disorders are typically inherited. Therefore, individuals with a family history of these diseases may have increased risks of developing a similar condition. Citrin deficiency is more common in east-Asian populations.
Autosomal recessive inheritance: All of the urea cycle disorders are autosomal recessive except for OTC deficiency. To inherit a recessive genetic disorder, a person must receive two copies of the genetic mutation (one copy from each parent). People who inherit a mutation from only one parent are called "carriers" and they may pass the mutation to their children.
If one parent only has one copy of the mutated gene, then each child will have a 50% chance of inheriting one mutated gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two mutated genes, a 50% chance of inheriting only one mutation, and a 25% chance of inheriting neither of the mutations. Thus, if both parents are carriers, approximately one out of every four children will have a urea cycle disorder.
X-linked recessive inheritance: OTC deficiency is an X-linked recessive inherited genetic condition. Normal individuals have two copies of most genes (one inherited from the father and one from the mother). In a recessive genetic disorder, both copies of a certain gene need to be defective for the condition to manifest itself.
Females have two copies of the X chromosome, but males have one X chromosome and one Y chromosome. Males inherit an X chromosome from the mother and a Y chromosome from the father, so a male can only inherit OTC deficiency from the mother. Therefore, a female needs to inherit two mutant copies to develop OTC deficiency (one from each parent), whereas a male only needs to inherit one mutant copy to develop the condition.
Because females need to inherit two mutant copies to develop the condition, whereas males only need to inherit one mutant copy, OTC deficiency is more common in males than females. Females who inherit only one mutant copy are called "carriers." Females who are carriers may exhibit some mild symptoms.
Random occurrence: It is rare for OTC deficiency to occur due to a spontaneous mutation during fetal development. Development of OTC deficiency in these cases can happen without a family history or other risk factors for the disease.
Types of the disease
Enzyme deficiency disorders:
N-acetylglutamate synthetase(NAGS) deficiency: NAGS deficiency is caused by a mutation of the NAGS gene that may decrease the production of the NAGS enzyme. The NAGS enzyme is responsible for controlling the process of creating N-acetylglutamate. N-acetylglutamate is an amino acid that is necessary to activate carbamyl phosphate synthetase (CPS). A deficiency of NAGS may lead to a secondary CPS deficiency due to the role of NAGS in the urea cycle. The presentation of NAGS and CPS deficiency are often similar.
Carbamoyl phosphate synthetase(CPS) deficiency: CPS deficiency is caused by a mutation of the CPS1 gene that may result in a decrease or absence of CPS enzyme production. CPS is the enzyme that starts the first step in converting nitrogen products to urea in the urea cycle. A deficiency or absence of CPS may lead to a decrease in conversion of toxic nitrogen products into the compound carbamoyl phosphate, a necessary component of the urea cycle.
Ornithine transcarbamylase(OTC) deficiency: OTC deficiency is caused by a mutation of the OTC gene that may decrease the production of the OTC enzyme. This is the most common mutation of a urea cycle enzyme. The role of the OTC enzyme in the urea cycle is to control the combination of carbamoyl phosphate and ornithine to form citrulline. This is the second step in the urea cycle.
Argininosuccinic acid synthetase(ASD) deficiency: Also called citrullinemia, ASD deficiency is caused by a mutation of the ASS1 gene that may decrease the production of the ASD enzyme. ASD is the enzyme that controls the third step of the urea cycle. ASD regulates the combination of two amino acids, citrulline and aspartate, into argininosuccinic acid.
Argininosuccinase acid lyase(ALD) deficiency: ALD deficiency is caused by a mutation of the ASL gene that may decrease production of the ALD enzyme. The ALD enzyme controls the fourth step of the urea cycle disorder. In this step, argininosuccinic acid is converted into arginine.
Arginase(ARG) deficiency: ARG deficiency is caused by a mutation of the ARG1 gene that may decrease the production of the ARG enzyme. The enzyme arginase controls the last step of the urea cycle. In this step, urea is produced by removing nitrogen from arginine. Once the nitrogen from arginine is removed, the product that is left is ornithine, which is needed for the formation of citrulline.
Transporter defects:
Citrindeficiency(citrullinemia II): Citrin deficiency is caused by a mutation of the SLC25A13 gene that may decrease the production of citrin. In the urea cycle, citrin is a transporter protein of aspartate. Aspartate is an amino acid that is required in the urea cycle for the formation of argininosuccinic acid. A deficiency in available aspartate may lead to an increase in ammonia levels. Citrin deficiency is more common among the east-Asian population.
Ornithine translocase deficiency: Ornithine translocase deficiency is caused by a mutation of the SLC25A15 gene that may decrease the production of the ornithine translocase transporter protein. This is a rare syndrome with currently only about 50 known cases. In the last step of the urea cycle, the nitrogen component of arginine is removed. The products of this step are urea and ornithine. In order for the urea cycle to continue, ornithine must be transported back into another part of the cell. A defect in this transporter protein results in an elevated level of ornithine in the wrong part of the cell. Without ornithine re-entering into the urea cycle, ammonia will start to accumulate. Ornithine translocase deficiency is sometimes referred to as Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome. The syndrome is named HHH syndrome because the lab findings of ornithine translocase deficiency are usually elevated ornithine, ammonia, and homocitrulline levels.