Urea cycle disorders

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.

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.

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®).

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.

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.