Ornithine transcarbamylase deficiency
Ornithine transcarbamylase deficiency is a disorder in which there is a failure of the body to properly process ammonia, which can lead to coma and death if left untreated.
Persons with ornithine transcarbamylase deficiency (OTC deficiency) have a problem with nitrogen metabolism. Too much nitrogen in the blood in the form of ammonia can cause brain damage, coma, and death. Ammonia is made up of nitrogen and hydrogen. Ammonia found in humans mostly comes from the breakdown of protein, either protein broken down from muscles, organs, and tissues already in the body, or excess protein that is eaten in the diet. Since excess ammonia is harmful, it is immediately excreted in normal humans after passing through the urea cycle and becoming urea. Ornithine transcarbamylase is a gene involved in the urea cycle–the process of making ammonia into urea, which occurs in the liver.
It is important to make urea, because, unlike ammonia, urea an be excreted by the kidney into the urine. Ammonia, on the other hand, cannot be effectively excreted by the kidney. So, if the ornithine transcarbamylase (OTC) function is reduced or impaired, ammonia builds up in the bloodstream. This buildup of ammonia in the bloodstream can lead to consequences as severe as coma and death. The amount of ammonia found in the bloodstream, and the severity of the disorder, depend on how well the OTC gene functions. If it functions reasonably well, the person should have a minor form of the disorder or no disorder. If the gene functions extremely poorly, or not at all, the disorder will be severe.
Synonyms for ornithine transcarbamylase deficiency include Hyperammonemia Type II, Ornithine carbamyl transferase deficiency, OTC deficiency, UCE, Urea cycle disorder, OTC Type, and Hyperammonemia due to ornithine transcarbamylase deficiency.
OTC deficiency is an X-linked recessive disorder. This means that it is found on the X chromosome (specifically, it is located on the short arm at Xp21.1) Recessive disorders require that only abnormal genes, and no normal genes, be present. For non-sex chromosomes, this means that both copies of a gene (one received from each parent) must be abnormal in order for that person to have the disorder.
In X-linked recessive disorders, however, only one abnormal copy of a gene must be present to cause the disorder in males. Males possess only one X chromosome, from thier mother, and one Y chromosome, which they receive from their father. If the mother is a carrier for the disorder (she has one normal gene and one abnormal gene), a male child would have a 50% chance of receiving an abnormal gene from her. If he receives the abnormal gene, he will have the disorder. So male children of a female carrier have a 50% chance of having the disorder.
A female child of a female carrier is much less likely to have the disorder. Unless the father has OTC deficiency, a female child will have one normal and one abnormal gene. Since recessive disorders require that both genes be mutated, the female child cannot have the disorder. Females with only one mutant OTC gene may have a mild form of the disorder because it is not purely recessive. Usually, the normal copy of the gene can sufficiently compensate for the poor functioning of the second, abnormal gene.
Some females do have the full-blown disorder, probably because of a phenomenon called X-inactivation. Although females have two X chromosomes in each cell, only one is active. Therefore, it is possible a female could have the disorder because only the abnormal gene was active in each cell of the liver, which is where OTC function takes place. Not enough is known about X-inactivation to speculate on the likelihood of this occuring. Overall, many more men than women have the disease. This means that OTC disease due to X-inactivation is not very common.
If the father has the gene for the disorder, he cannot pass it on to his male child (he does not give the male child an X chromosome, only a Y). He can give his female child one copy of the gene, which might result in a mild form of the disorder or the full-blown disorder due to X-inactivation.
OTC affects infants at the rate of approximately one birth in every 70,000. As expected with an X-linked disorder, the disorder is more common in males.
Signs and symptoms
Before birth there are no symptoms of OTC deficiency because the exchange of nutrients and fluids between the mother and fetus allows the excess ammonia to leave the infant's blood and go into the mother's blood. The mother is then able to get rid of the ammonia as urea because she either lacks the disorder or her ammonia levels are medically well-controlled.
The most severe cases of OTC deficiency usually present in infants before they are a week old, typically in males. It may take several days for symptoms to appear, since it takes that long for protein, and therefore ammonia levels, to build up in the infant. Affected infants generally show periods of inactivity, a failure to feed, and vomiting. Unfortunately, many other disorders may also present with these same general symptoms, and new parents may not recognize these as abnormal in an infant. These symptoms are always accompanied in OTC deficiency by hyperammonemia, or high levels of ammonia in the blood.
Hyperammonemia is the most important symptom for identification and treatment of ornithine transcarbamylase deficiency. It is the cause of all other symptoms seen in OTC deficiency. Additionally, hepatomegaly (an enlarged liver), and seizures may also be present. If the disorder, or at least the hyperammonemia, is not recognized and treated, the symptoms may progress into coma and eventually, death. A failure to quickly resolve the hyperammonemia once an infant lapses into a coma may also lead to severe mental retardation or death.
Patients with milder forms of the disorder may show symptoms later in life such as failure to grow at a normal rate or they may experience developmental delay. Developmental delay is an inability to reach recognized milestones like speaking or grasping objects at an appropriate age. These milder symptoms would be accompanied by hyperammonemia, but the levels of ammonia would be much lower than in an episodic attack of hyperammonemia or in the severely ill infant. Other persons with mild forms of the disorder may have no symptoms, or may only experience nausea after a meal with a large protein content.
Persons with a mild form of the disorder and no other symptoms may also learn they have the disorder from an episode of acute hyperammonemia. Acute conditions are brief and immediate, whereas chronic conditions are long-lasting.
An episodic attack of acute hypperammonemia, then, is a an episode where levels of ammonia climb above what may be already high levels of ammonia. A person with an episode of acute hyperammonemia can have symptoms including some, or all, of the following: vomiting, lack of apetite, drowsiness, hepatomegaly, seizures, coma, and death. These episodes can be life-threatening and may require hospitalization depending on their severity and response to medication.
These episodic attacks are probably related to a large increase in the amount of protein being broken down in the body, which results in too much ammonia being produced. This ammonia cannot be immediately excreted, which results in hyperammonemia. The most common reasons for a change in the amount of protein broken down are probably starvation, illness, and surgery. Even persons with no previous symptoms can experience a fatal episode of acute hyperammonemia brought on by an increase in protein breakdown. Since an episodic attack of hyperammonemia can be fatal without any previous symptoms, persons who have at least one family member with OTC deficiency should consider testing to determine whether they have the gene for the disorder. If the disorder is known to be present, an episode of hyperammonemia might be anticipated and its effect lessened.
A definitive diagnosis of OTC deficiency is made by laboratory tests, since physical synptoms are very general and common to a large number of disorders. A high level of ammonia in the blood is the hallmark of this disorder and other disorders that affect the urea cycle. In the short term, the levels of two amino acids in the urine, orotate and citrulline, should distinguish between OTC deficiency and other urea cycle deficiencies. In OTC deficiency, citrulline levels are normal or low, and orotate levels are usually high. In the long term, however, the most definitive diagnosis can be made through DNA analysis, or through a test of OTC activity in a small piece of liver tissue (a biopsy) taken from the patient.
Prenatal diagnosis of the disorder is difficult and not indicated unless there is an affected family member with the disorder. In that case, if the mutation is known, DNA analysis would reveal the same mutation as in the family member with OTC deficiency. If the mutation is not known, a method called linkage analysis may be used. In linkage analysis, the OTC gene itself is not analyzed, but the DNA near the gene is analyzed. The "near DNA" can then be compared to the "near DNA" of the affected family member. If the DNAs are different, then the fetus should not have the disorder. If they are the same, then the fetus probably has the disorder.
The severity of the disorder is the most important factor in determining long-term treatment of OTC deficiency. The most severely affected individuals, usually infant males, should have liver transplants. As previously mentioned, the urea cycle and OTCs function occur in the liver. The transplantation immediately corrects OTC deficiency. Episodes of life-threatening ammonemia are prevented, although monitoring of tissue levels of ammonia is suggested. Another important benefit is that the transplant allows the child to develop and grow in a normal manner, without the threat of developmental delay or mental retardation. Transplants are now recommended even for children less than one year of age with a severe form of the disorder.
Two problems with liver transplants exist, however. First, it is difficult to obtain a liver from among the limited supply of donors, especially if the child is not currently hospitalized. The second problem arises from the way in which organs are assigned. Persons who are critically ill receive priority in organ donor lists. This means children whose disease is manageable may not be able to receive a transplant.
Second, children with transplants must have their immune system suppressed. The immune system fights off, and lets one recover from infections like colds, flus, and chicken pox. However, it also fights the introduction of an organ from someone else's body, even a relative—except identical twins. Thus, as long as a person has a transplant, that person must have their immune system suppressed so that the transplanted organ is not killed by the body it is in. The problem with immune suppression is that a person is much more likely to become sick. This disadvantage is far outweighed by the advantages of normal mental development and the prevention of death in patients with severe OTC deficiency.
Patients in rural areas, or areas where there is no immediate access to a hospital equipped to care for a patient with an acute attack of hyperammonemia, should also be strongly considered for a liver transplant if the patient is predisposed to attacks of life-threatening hyperammonemia.
For less severely affected children, or children unable to obtain a liver transplant, long-term therapy consists of a combination of drugs, usually oral, sodium phenylbutyrate, and diet. This bypasses the normal process of the breakdown of protein into urea in the liver, which is the usual way that ammonia leaves the body. Children with OTC deficiency are placed on a low protein diet so their protein breakdown system does not become overwhelmed and lead to hyperammonemia. Children with OTC deficiency are also given arginine, an amino acid, which, for reasons that are unclear, causes more nitrogen, which is part of ammonia, to be excreted in the urine, and lowers blood ammonia. Dietary regimens vary from patient to patient based on their age, size, and the severity of the disorder. A nutrition expert must be consulted when developing an appropriate diet. The most strict diet consists of vitamin supplements and no protein other than essential amino acids. Essential amino acids are those that cannot be made by the body and must be obtained through food. Since proteins are made up of amino acids, and only amino acids, that means this diet is extremely restrictive. It also means that very little ammonia is left in the bloodstream since most of the otherwise free ammonia is tied up in the synthesis of the non-essential amino acids, amino acids made by the body itself.
Any chronic disease is stressful for a family. Parents and patients should consider support and information groups like the National Urea Cycle Disorders Foundation.
Short-term management of attacks of crisis hyperammonemia (severe acute hyperammonemia) consists of dialysis and drug therapy. Dialysis and large doses of the drugs sodium benzoate and sodium phenylacetate and doses of arginine are used to decrease the levels of ammonia in the blood. These methods are used together due to their synergistic effect.
Dialysis is a process where a toxic substance is removed from the blood. This can best be understood by pouring a small amount of cola into a glass. Now pour a large amount of water into it. In this way, the cola is "watered down" or diluted. Ammonia is diluted in a similar way using dialysis. Blood is removed from a patient and run through a hose. At one point, this hose runs through a tank made up of liquid that contains all
The future treatment of OTC deficiency probably will come from experiments in gene therapy. OTC deficiency is a disorder particularly amenable to gene therapy because only one gene is affected and only one organ, the liver, would need the new gene. However, as of 2001, gene therapy has not been successfully demonstrated in human beings. Many technical problems must still be solved in order to successfully treat OTC deficiency and other disorders like it with gene therapy.
Only 50% of the most severely affected patients live beyond the time they first attend school. Of those receiving liver transplants, 82% of patients survive five years after receiving the transplant. Children with the severe disorder that receive drug therapy are much more likely to experience mental retardation, developmental delay, and a lack of growth. Also, many infants who experience hyperammonemic comas have severe mental damage.
For individuals not identified at birth or soon after, the prognosis varies widely. The consequences of the disorder are affected by the severity of the disorder and how it is managed, although anyone with the disorder may experience life-threatening attacks of acute hyperammonemia. In terms of long-term survival, puberty appears to be a difficult time for those with OTC deficiency, and persons who survive until after puberty have improved outcomes. The prognosis for this disorder can vary from quite hopeful to very distressing based upon its severity and how well the disorder can be controlled. A severe disorder that is well-controlled may still have a positive outcome.
Maestri, Nancy E., et al. "The Phenotype of Ostensibly Healthy Women Who Are Carriers for Ornithine Transcarbamylase Deficiency." Medicine 77, no. 6 (November 1998): 389.
National Urea Cycle Disorders Foundation. 4841 Hill Street, La Canada, CA 91011. (800) 38NUCDF. <http://www.NUCDF.org/>.
"Ornithine transcarbamylase deficiency." NORD—National Organization for Rare Diseases. <http://www.rarediseases.org>.
"Ornithine transcarbamylase deficiency." Aim for Health. <http://www.aim4health.com/family/otc.htm>.
Michael V. Zuck, Ph D