Urea cycle disorder

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Urea cycle disorder
ICD-10 E72.2
ICD-9 270.6
MedlinePlus 000372

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An urea cycle disorder or urea cycle defect is a genetic disorder caused by a deficiency of one of the enzymes in the urea cycle which is responsible for removing ammonia from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is removed from the blood and converted to urea. Normally, the urea is transferred into the urine and removed from the body. In urea cycle disorders, the nitrogen accumulates in the form of ammonia, a highly toxic substance, and is not removed from the body.

Urea cycle disorders are included in the category of inborn errors of metabolism. There is no cure.


Inborn errors of metabolism are generally considered to be rare but represent a substantial cause of brain damage and death among newborns and infants. Because many cases of urea cycle disorders remain undiagnosed and/or infants born with the disorders die without a definitive diagnosis, the exact incidence of these cases is unknown and underestimated. It is believed that up to 20% of Sudden Infant Death Syndrome cases may be attributed to an undiagnosed inborn error of metabolism such as urea cycle disorder. In April 2000, research experts at the Urea Cycle Consensus Conference estimated the incidence of the disorders at 1 in 10000 births. This represents a significant increase in case diagnosis in the last two years.


The neonatal period

Children with severe urea cycle disorders typically show symptoms after the first 24 hours of life. The baby may be irritable at first, followed by vomiting and increasing lethargy. Soon after, seizures, hypotonia (poor muscle tone), respiratory distress, and coma may occur. If untreated, the child will die. These symptoms are caused by rising ammonia levels in the blood. Acute neonatal symptoms are most frequently seen in, but not limited to, boys with OTC Deficiency.


Children with mild or moderate urea cycle enzyme deficiencies may not show symptoms until early childhood, or may be diagnosed subsequent to identification of the disorder in a more severely affected relative or through newborn screening. Early symptoms may include hyperactive behavior, sometimes accompanied by screaming and self-injurious behavior, and refusal to eat meat or other high-protein foods. Later symptoms may include frequent episodes of vomiting, especially following high-protein meals; lethargy and delirium; and finally, if the condition is undiagnosed and untreated, coma and death. Children with this disorder may be referred to child psychologists because of their behavior and eating problems. Childhood episodes of hyperammonemia (high ammonia levels in the blood) may be brought on by viral illnesses including chicken pox, high-protein meals, or even exhaustion. The condition is sometimes misdiagnosed as Reye’s Syndrome. Childhood onset can be seen in both boys and girls.


Recently, the number of adult individuals being diagnosed with urea cycle disorders has increased at an alarming rate. Recent evidence has indicated that these individuals have survived undiagnosed to adulthood, probably due to less severe enzyme deficiencies. These individuals exhibit stroke-like symptoms, episodes of lethargy, and delirium. These adults are likely to be referred to neurologists or psychiatrists because of their psychiatric symptoms. However, without proper diagnosis and treatment, these individuals are at risk for permanent brain damage, coma, and death. Adult-onset symptoms have been observed following viral illnesses, childbirth, and use of valproic acid (an anti-epileptic drug).

The six urea cycle disorders

There are six disorders of the urea cycle. Each is referred to by the initials of the missing enzyme.

Location Abb. Enyzme Disorder Measurements
Mitochondria NAGS N-Acetylglutamate synthetase N-Acetylglutamate synthase deficiency +Ammonia
Mitochondria CPS1 Carbamoyl phosphate synthetase I Carbamoyl phosphate synthetase I deficiency +Ammonia
Mitochondria OTC Ornithine transcarbamylase Ornithine transcarbamylase deficiency +Ornithine, +Uracil, +Orotic acid
Cytosol AS Argininosuccinic acid synthetase "AS deficiency" or citrullinemia +Citrulline
Cytosol AL Argininosuccinase acid lyase "AL deficiency" or argininosuccinic aciduria (ASA) +Citrulline, +Argininosuccinic acid
Cytosol AG Arginase "Arginase deficiency" or argininemia +Arginine

Individuals with childhood or adult onset disease may have a partial enzyme deficiency. All of these disorders are transmitted genetically as autosomal recessive genes - each parent contributes a defective gene to the child, except for one of the defects, Ornithine Transcarbamylase Deficiency. This urea cycle disorder is acquired in one of three ways: as an X-linked trait from the mother, who may be an undiagnosed carrier; in some cases of female children, the disorder can also be inherited from the father's X-chromosome; and finally, OTC deficiency may be acquired as a "new" mutation occurring in the fetus uniquely. Recent research has shown that some female carriers of the disease may become symptomatic with the disorder later in life, suffering high ammonia levels. Several undiagnosed women have died during childbirth as a result of high ammonia levels and on autopsy were determined to have been unknown carriers of the disorder.


The treatment of urea cycle disorders consists of balancing dietary protein intake in order that the body receive the essential amino acids responsible for cell growth and development, but not so much protein that excessive ammonia is formed. This protein restriction is used in conjunction with medications which provide alternative pathways for the removal of ammonia from the blood. These medications are usually given by way of tube feedings, either via gastrostomy tube (a tube surgically implanted in the stomach) or nasogastric tube through the nose into the stomach. The treatment may also include supplementation with special amino acid formulas developed specifically for urea cycle disorders, multiple vitamins and calcium supplements. Frequent blood tests are required to monitor the disorders and optimize treatment, and frequently hospitalizations are necessary to control the disorder.

At the most extreme end of the spectrum, a few liver transplants have been done successfully as a cure to the disorder. This treatment alternative must be carefully evaluated with medical professionals to determine if potential of success as compared to the potential for new medical concerns.


In 2003, the National Institutes of Health began a research initiative including the creation of a Rare Diseases Clinical Research Network, including 10 consortia studying more than 50 rare diseases. The Urea Cycle Disorders Consortium, under the direction of Mark Batshaw, M.D. at Children's National Medical Center, and in combination with eight other academic centers, began longitudinal studies of the urea cycle disorders. Within the past year there has also been an explosion of research involving the connection between urea cycle disorders and other major diseases, such as cancer, AIDS and sickle cell anemia.

Researchers have found at least two major areas of interest in relation to urea cycle disorders. The first connection involves changes in urea cycle enzyme production in cancer patients with bone marrow transplants undergoing chemotherapy. Because the production of urea cycle enzymes takes place in the liver, drugs toxic to the liver, such as those used in chemotherapy, are observed to be causing changes in the urea cycle. Thus, these bone marrow transplant patients are developing the same accumulation of ammonia (hyperammonemia) seen in children with urea cycle disorders. Another study has found changes (polymorphisms) in these enzymes in large populations. This raises questions as to the significance of these variations on the overall health of the individual.The second connection relates to the drugs that were developed through the Orphan Drug Act for treating the children with of urea cycle disorders. These drugs, pioneered by children with urea cycle disorders, are now being used in Phase II clinical trials at major cancer research institutions across the nation. The drugs appear to halt the production of cancer cells in numerous cancers, including melanoma and lymphoma.

Other large research institutions are now looking at urea cycle disorders, a previously limited disease, as a new key to developing treatments in other areas of medicine. This new interest will bring more resources to bear for urea cycle research, and our ultimate goal of a cure for the children suffering from these devastating disorders.

Recent advancements in technologies such as tandem mass spectrometry have made it possible to screen all newborns for argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase, and arginase deficiency. Research into screens for OTC and CPS deficiencies has been initiated. We believe that comprehensive newborn screening will help prevent brain damage and other severe consequences of delayed diagnoses and save children’s lives.

See also


Initial article taken verbatim from the National Urea Cycle Disorders Foundation with permission (from Cynthia Le Mons). The Foundation has played a key role in initiating and funding the research at Johns Hopkins for the current medication being used in treating urea cycle disorders, Buphenyl, and was also instrumental in lobbying the United States Congress for the medication.

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