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Disorder DefinitionsThe following definitions are provided as a reference for physicians. A list of definitions for patients and family has also been provided - click here. Please choose from the menu below:
N-Acetylglutamate Synthetase Deficiency (NAGS)N-acetylglutamate synthetase deficiency affects the body’s ability to make n-acetylglutamate (NAG) which is a required cofactor for the function of carbamyl phosphate synthetase I. Without NAG, CPSI cannot convert ammonia into carbamyl phosphate. Along with OTC deficiency and CPSI, deficiency of N-acetylglutamate is the most severe of the urea cycle disorders. Patients with complete NAGS deficiency rapidly develop hyperammonemia in the newborn period. Patients who are successfully rescued from crisis are chronically at risk for repeated bouts of hyperammonemia. A new experimental treatment for this disease is currently under investigation through the Urea Cycle Disorders Consortium using the compound carbamyl glutamine. Patients with partial NAGS deficiency can present at almost any time of life with a stressful triggering event. Information from the National Center for Biotechnology Information Join the Registry for this Disorder | Find a Study | Back to Top Download: UCDC Contact Registry Paper Form Carbamoylphosphate synthetase I deficiency (CPS-I Deficiency)Carbamylphosphate synthetase I deficiency affects the livers ability to convert nitrogen to urea. This enzyme takes ammonia and through the use of bicarbonate and ATP produces carbamyl phosphate. This enzyme requires the presence of its cofactor n-acetylglutamate. Along with OTC deficiency and NAGS, deficiency of CPSI is the most severe of the urea cycle disorders. Patients with complete CPSI deficiency rapidly develop hyperammonemia in the newborn period. Patients who are successfully rescued from crisis are chronically at risk for repeated bouts of hyperammonemia. Patients with partial CPSI deficiency can present at almost any time of life with a stressful triggering event. CPSI is the first enzyme in the urea cycle and is found primarily in the liver. It requires the cofactor N-acetylglutamate to function. Currently, diagnosis is based on enzymatic assay of liver tissue. Sequence analysis is available on a research basis only.Information from the National Center for Biotechnology Information Join the Registry for this Disorder | Find a Study | Back to Top Download: UCDC Contact Registry Paper Form Ornithine Transcarbamylase (OTC) Deficiency:Ornithine Transcarbamylase deficiency affects the livers ability to convert ammonia into urea. OTC combines carbamyl phosphate with ornithine to make citrulline which is subsequently processed to urea (see: cycle diagram). Along with CPSI and NAGS deficiency, OTC deficiency is the most severe of the urea cycle disorders. Patients with complete OTC deficiency rapidly develop hyperammonemia in the newborn period. 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. Carrier females can also be affected (unlike the other urea cycle disorders) due to switching off on one of the X chromosomes in females. Patients with partial OTC deficiency can present at almost any time of life with a stressful triggering event. Information from the National Center for Biotechnology Information Join the Registry for this Disorder | Find a Study | Back to Top Download: UCDC Contact Registry Paper Form Argininosuccinate Synthetase Deficiency (ASSD) (Citrullinemia I)Defects in argininosuccinate synthetase (ASS) affect the ability to incorporate ammonia into urea. This enzyme combines citrulline with aspartate to form argininosuccinate. Patients with complete ASSD present with severe hyperammonemia in the newborn period. The use of arginine in these patients allows some nitrogen (ammonia) to be incorporated into the urea cycle which makes treatment somewhat easier than other defects in the cycle. 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 enzymatic assay of fibroblasts. Prenatal testing is performed by enzymatic analysis of amniocytes or CVS sample. Information from the National Center for Biotechnology Information Join the Registry for this Disorder | Find a Study | Back to Top Download: UCDC Contact Registry Paper Form Citrin Deficiency (Citrullinemia II)Citrullinemia II is an autosomal disorder that results in decreased activity in the liver of a transport molecule for aspartate. This results in limitation of activity for the enzyme argininosuccinic acid synthase which combines aspartate and citrulline to make argininosuccinic acid. Citrin (the defective protein) is an aspartate glutamate transporter across the mitochondrial membrane. This defect can present with classic newborn hyperammonemia but is more likely to present with insidious neurologic findings in adulthood. The majority of patients reported have been Japanese or Asian who share a common mutation. These patients can also have the dietary peculiarity of avoiding carbohydrates rather than protein. This probably is due to the overlap of this disorder with glucose metabolism. Treatment for hyperammonemia is the same as the other urea cycle disorders. Information from the National Center for Biotechnology Information (Neo-Natal Onset) Information from the National Center for Biotechnology Information (Adult Onset) Join the Registry for this Disorder | Find a Study | Back to Top Download: UCDC Contact Registry Paper Form Argininosuccinate Lyase Deficiency (Argininosuccinic Aciduria)Argininosuccinate Lyase Deficiency affects the body’s ability to clear the nitrogen already incorporated into the urea cycle as argininosuccinate. This causes hyperammonemia. 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 has been incorporated into the cycle as argininosuccinate (see figure). Treatment of these patients is based on a reduction in nitrogen intake and supplementation with arginine to complete a partial cycle. This disorder is marked by chronic hepatic enlargement and elevation of transaminases. Biopsy of the liver shows enlarged hepatocytes, which may over time progress to fibrosis, the etiology of which is unclear. These patients can also develop trichorrhexis nodosa, a node-like appearance of fragile hair, which usually responds to arginine supplementation [ 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. Deficiency of this enzyme prevents the conversion of argininosuccinate to the amino acid arginine which affects the urea cycle and other biochemical pathways. 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.Information from the National Center for Biotechnology Information Join the Registry for this Disorder | Find a Study | Back to Top Download: UCDC Contact Registry Paper Form Arginase Deficiency (Hyperargininemia)Arginase deficiency is not typically characterized by rapid-onset hyperammonemia. These patients often present with the development of progressive spasticity with greater severity in the lower limbs. They also develop seizures and gradually lose intellectual attainments. 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, anorexia and vomiting. Severe episodes of hyperammonemia are seen infrequently with this disorder, but can be fatal. Diagnosis is made by the elevated levels of arginine in the blood and by analysis of enzymatic activity in red blood cells. Treatment is identical to other urea cycle disorders, with limitation of protein, use of essential amino acid supplements and diversion of ammonia from the urea cycle with sodium benzoate or sodium phenylbutyrate.Information from the National Center for Biotechnology Information Join the Registry for this Disorder | Find a Study | Back to Top Download: UCDC Contact Registry Paper Form Ornithine Translocase Deficiency (HHH Syndrome)The HHH (Hyperornithinemia, Hyperammonemia, Homocitrullinuria) syndrome is an autosomal recessive inherited disorder described in more than 50 patients. The clinical symptoms are related to the hyperammonemia and resemble those of the urea cycle disorders. Plasma ornithine concentrations are extremely high. The defect in ornithine translocase results in diminished ornithine transport into the mitochondria with ornithine accumulation in the cytoplasm and reduced intramitochondrial ornithine causing impaired ureagenesis and orotic aciduria. Homocitrulline is thought to originate from transcarbamylation of lysine. Most patients have intermittent hyperammonemia accompanied by vomiting, lethargy and coma (in extreme cases). Growth is abnormal and intellectual development is affected. Spasticity is common as are seizures. Adult patients are found with partial activity of the enzyme. They typically self-select low protein diets. Diagnosis is complicated since plasma ornithine levels can normalize on a protein restricted diet. The presence of hyperammonemia and homocitrullinuria are helpful. Information from the National Center for Biotechnology Information Join the Registry for this Disorder | Find a Study | Back to Top Download: UCDC Contact Registry Paper Form |
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