The Urea Cycle Disorders Consortium
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Disorder Definitions

Many of the urea cycle disorders have similar symptoms because they affect the body in the same way. Therefore, descriptions of an individual disorder and the method used to diagnose the disorder may be similar or identical to descriptions of other urea cycle disorders.

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Urea Cycle Diagram Carbamyl Phosphate Synthetase (CPS) Deficiency N-Acetylglutamate Synthase (NAGS) Deficiency Argininosuccinate Synthetase Deficiency (Citrullinemia One) Argininosuccinate Lyase Deficiency Arginase Deficiency (Hyperargininemia) Hyperornithinemia, Hyperammonemia and Homocitrullinuria (HHH) Syndrome Ornithine Transcarbamylase (OTC) Deficiency Citrin Deficiency (Citrullinemia Two)
N-Acetylglutamate Synthetase Deficiency (NAGS)

N-acetylglutamate synthasae deficiency is one of the most severe disorders of the urea cycle. NAGS makes a molecule that is necessary for another enzyme in the urea cycle to do its job (this is called a cofactor). Patients with severe complete NAGS deficiency rapidly develop high ammonia levels in the blood, (hyperammonemia), soon after birth. Patients who are successfully rescued from the crisis of high ammonia levels in the blood are at risk for repeated bouts of hyperammonemia. A new experimental treatment for this disease is currently under investigation through the Urea Cycle Disorders Consortium. Patients with partial NAGS deficiency (milder type of NAGS) can have symptoms appear at almost any time of life with a stressful triggering event such as an infection or a viral illness.

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Carbamoylphosphate Synthetase I Deficiency (CPS-I Deficiency)

Deficiency of CPSI is also one of the most severe types of urea cycle disorders. CPSI is an enzyme that combines ammonia with other molecules to make carbamyl phosphate. This is the first step in the urea cycle which is necessary to get rid of ammonia. Patients with severe complete CPSI deficiency rapidly develop high levels of ammonia in the blood, hyperammonemia, soon after birth. Patients who are successfully rescued from crisis are chronically at risk for repeated bouts of hyperammonemia. Patients with partial CPSI deficiency (milder type of CPSI) can have symptoms appear at almost any time of life with a stressful triggering event such as an infection or a viral illness.

CPSI is an enzyme in the urea cycle found primarily in the liver. CPSI requires another enzyme or cofactor, N-acetylglutamate, to function in the body. Currently, diagnosis of CPSI is based on examination of the enzymes in liver tissue or by identification of pathogenic mutation in a patient’s DNA.

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Ornithine Transcarbamylase (OTC) Deficiency:

OTC deficiency is the one of the most severe of the urea cycle disorders. OTC takes the molecule carbamyl phosphate made by the first part of the urea cycle and combines it with another molecule to make citrulline. If this enzyme cannot work then the carbamyl phosphate builds up which leads to a buildup of ammonia in the blood. Patients with severe complete OTC deficiency (the most severe type of this disorder) rapidly develop high levels of ammonia in the blood, hyperammonemia, soon after birth. Patients who are successfully rescued from crisis are chronically at risk for repeated bouts of hyperammonemia. OTC is located on the X-chromosome which results in the majority of severe patients being male. Females with one abnormal gene in their gene pair may not show evidence of the disorder but like other urea cycle disorders females can also be affected. Patients with partial OTC deficiency (milder type of OTC) can present at almost any time of life with a stressful triggering event such as an infection or a viral illness.

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Argininosuccinate Synthetase Deficiency (ASSD) (Citrullinemia I)

Argininosuccininate Synthetase (also called argininosuccinic acid synthase, ASS) takes the citrulline made by other enzymes in the urea cycle and combines it with aspartate to make argininosuccinate (see the figure). If this enzyme does not work then the molecules that are made before cannot be processed. This leads to a build up of ammonia in the blood. Patients with complete ASSD (most severe type of this disorder) present with extremely high levels of ammonia in the blood, hyperammonemia, soon after birth. A supplement of arginine, an amino acid, is given to these patients. The use of arginine in these patients decreases the amount of ammonia in the blood which makes treatment somewhat easier than other defects in the urea cycle.

Argininosuccinate is formed from citrulline and aspartate. Defects in this enzyme prevent the formation of argininosuccinate. Citrulline levels in these patients can be 100’s of times the normal values. Unlike CPSI, NAGS, and OTC, this enzyme is distributed throughout the body. Diagnosis is by examination of fibroblasts, a cell that is always present in connective tissue and active in making and secreting collagen. Prenatal testing is performed by examining characteristics of the enzymes in the cells of amniotic fluid surrounding the fetus before birth or CVS sample (a procedure used in the first trimester of pregnancy to diagnose genetic diseases) or by identification of a pathogenic mutation in DNA.

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Citrin Deficiency (Citrullinemia II)

Citrin is a protein that gets the raw materials for the urea cycle into the proper part of the liver cells. This type of protein is called a transporter. Citrin transports the amino acid aspartate which is used by other enzymes in the urea cycle pathway to get rid of ammonia. Defects in the function of Citrin (also called Citrullinemia II) can present with high levels of ammonia but often just present with problems with brain function. The majority of patients reported have been Japanese or Asian who share a common mutation in the Citrin gene. These patients can also have the dietary peculiarity of avoiding sugars rather than protein (which most urea cycle patients avoid). Treatment for hyperammonemia is the same as the other urea cycle disorders.

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Argininosuccinate Lyase (AL) Deficiency (Argininosuccinic Aciduria)

Argininosuccinate lyase deficiency affects the body’s ability to clear the nitrogen already incorporated into the urea cycle as argininosuccinate (see: figure). This causes hyperammonemia (an increase of ammonia in the blood). This disorder often presents with rapid-onset hyperammonemia in the newborn period. This enzyme defect is past the point in the metabolic pathway at which all the waste nitrogen (ammonia) has been incorporated into the cycle as argininosuccinate. These patients can also develop trichorrhexis nodosa, a node-like appearance of fragile hair, which usually responds to added arginine [ Batshaw 1984, Brusilow 1985, Batshaw & Berry 1991, Summar 2001, Summar & Tuchman 2001]. Reports exist of affected patients who have never had prolonged coma, but nevertheless have significant developmental disabilities. Clinical trials are underway to determine if the use of nitrogen scavengers will improve the outcome in these patients (see studies you can enroll in >>>).

Diagnosis is based on the presence of large amounts of argininosuccinic acid in the bloodstream and direct enzymatic analysis of fibroblasts. Prenatal diagnosis is available by enzymatic analysis of amniocytes or CVS sample or by identification of pathogenic mutation in DNA.

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Arginase Deficiency (Hyperargininemia)

Arginase takes the amino acid arginine, which is made by the urea cycle, and breaks it into two molecules, urea and ornithine. The urea is disposed of by the kidneys and completes the last step in the urea cycle. Arginase deficiency is not typically characterized by rapid-onset hyperammonemia (high ammonia levels in the blood). These patients often present with the development of progressive problems in muscle control. They can also develop seizures and gradually lose mental function. Growth is usually slow and without therapy they usually do not reach normal adult height. Other symptoms that may present early in life include episodes of irritability, poor appetite, and vomiting. Severe episodes of hyperammonemia are seen infrequently but can occur.

Diagnosis is made by the elevated levels of arginine in the blood and by analysis of enzymatic activity in red blood cells or by identification of pathogenic mutation in DNA.

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Ornithine Translocase Deficiency (HHH Syndrome)

Ornithine Translocase is a protein that moves molecules from one part of the cell to another. OAT moves the molecule ornithine into parts of the liver cell where it can be used for the urea cycle. When OAT does not work properly it causes the urea cycle to not function properly and ammonia builds up in the blood. A number of other molecules build up as well including ornithine. Most patients have intermittent hyperammonemia, elevated levels of ammonia in the blood, accompanied by vomiting, sleepiness and (in extreme cases) coma. Growth is abnormal and learning is affected. Common symptoms are seizures and muscle control problems. Patients that have symptoms beginning in adulthood have partial activity of the transporter (mild type of disorder). They typically self-select low protein diets without being aware they have the disease.

Diagnosis is difficult since the levels of ornithine can appear normal on laboratory examination if the patient is on a protein restricted diet. The presence of hyperammonemia and homocitrullinuria are helpful in the diagnosis of this disorder.

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