Urea cycle disorders are conditions in which the body cannot properly dispose of ammonia, a waste product of protein digestion. Six enzymes are involved in the urea cycle, a process that converts the toxic substance ammonia into urea, which is excreted in the urine.
The six enzymes in the urea cycle are ornithine transcarbamylase (OTC), argininosuccinic acid synthetase (ASD), arginase (ARG), arginosuccinase acid lyase (ALD), carbamyl phosphate synthetase (CPS), and N-acetylglutamate synthetase (NAGS). These enzymes are found in the liver, where they process nitrogen-containing waste products (such as ammonia) into urea. Deficiencies in any of these enzymes, also known as inborn errors of urea synthesis, can lead to urea cycle disorders.
Urea cycle disorders can also occur from defects in transporter proteins that move or transport a specific substance involved in the urea cycle in and out of various parts of a cell. The two known defects are citrin deficiency (citrullinemia II) and ornithine translocase deficiency.
If an enzyme or transporter in the urea cycle is deficient, ammonia may build up in the blood and reach toxic levels. An elevated ammonia level (hyperammonemia) disrupts normal brain and central nervous system function. Some of the physical symptoms may include lack of appetite, irritability, heavy or rapid breathing, low energy, vomiting, disorientation, and combativeness. If left untreated, high ammonia levels may lead to coma, swelling of the brain, brain damage, and death. In a urea cycle disorder, ammonia levels may be increased after a meal high in protein, viral illness, childbirth, and certain prescription medications.
It is estimated that as a group, urea cycle disorders occur at a rate of one in 10,000 births. OTC deficiency is the most common of the disorders and is estimated to occur in one in 30,000 births. NAGS deficiency is the rarest of the urea cycle disorders, with only a handful of cases reported worldwide each year.
ALD, ammonia, ARG, arginase, arginine, arginosuccinase acid lyase, argininosuccinic acid synthetase, ASD, carbamyl phosphate synthetase, carbamylglutamate, citrin, citrulline, citrullinemia, CPS, encephalopathy, HHH syndrome, hyperammonemia, inborn errors of metabolism, inborn errors of urea synthesis, N-acetylglutamate synthetase (NAGS), N-acetylglutamate synthetase deficiency, ornithine transcarbamylase deficiency, ornithine translocase deficiency, OTC, sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, urea cycle.
types of the disease
Enzyme deficiency disorders
(NAGS) deficiency: NAGS deficiency is caused by a mutation of the NAGS gene that may decrease the production of the NAGS enzyme. The NAGS enzyme is responsible for controlling the process of creating N-acetylglutamate. N-acetylglutamate is an amino acid that is necessary to activate carbamyl phosphate synthetase (CPS). A deficiency of NAGS may lead to a secondary CPS deficiency due to the role of NAGS in the urea cycle. The presentation of NAGS and CPS deficiency are often similar.
Carbamoyl phosphate synthetase
(CPS) deficiency: CPS deficiency is caused by a mutation of the CPS1 gene that may result in a decrease or absence of CPS enzyme production. CPS is the enzyme that starts the first step in converting nitrogen products to urea in the urea cycle. A deficiency or absence of CPS may lead to a decrease in conversion of toxic nitrogen products into the compound carbamoyl phosphate, a necessary component of the urea cycle.
(OTC) deficiency: OTC deficiency is caused by a mutation of the OTC gene that may decrease the production of the OTC enzyme. This is the most common mutation of a urea cycle enzyme. The role of the OTC enzyme in the urea cycle is to control the combination of carbamoyl phosphate and ornithine to form citrulline. This is the second step in the urea cycle.
Argininosuccinic acid synthetase
(ASD) deficiency: Also called citrullinemia, ASD deficiency is caused by a mutation of the ASS1 gene that may decrease the production of the ASD enzyme. ASD is the enzyme that controls the third step of the urea cycle. ASD regulates the combination of two amino acids, citrulline and aspartate, into argininosuccinic acid.
Argininosuccinase acid lyase
(ALD) deficiency: ALD deficiency is caused by a mutation of the ASL gene that may decrease production of the ALD enzyme. The ALD enzyme controls the fourth step of the urea cycle disorder. In this step, argininosuccinic acid is converted into arginine.
(ARG) deficiency: ARG deficiency is caused by a mutation of the ARG1 gene that may decrease the production of the ARG enzyme. The enzyme arginase controls the last step of the urea cycle. In this step, urea is produced by removing nitrogen from arginine. Once the nitrogen from arginine is removed, the product that is left is ornithine, which is needed for the formation of citrulline.
(citrullinemia II): Citrin deficiency is caused by a mutation of the SLC25A13 gene that may decrease the production of citrin. In the urea cycle, citrin is a transporter protein of aspartate. Aspartate is an amino acid that is required in the urea cycle for the formation of argininosuccinic acid. A deficiency in available aspartate may lead to an increase in ammonia levels. Citrin deficiency is more common among the east-Asian population.
Ornithine translocase deficiency: Ornithine translocase deficiency is caused by a mutation of the SLC25A15 gene that may decrease the production of the ornithine translocase transporter protein. This is a rare syndrome with currently only about 50 known cases. In the last step of the urea cycle, the nitrogen component of arginine is removed. The products of this step are urea and ornithine. In order for the urea cycle to continue, ornithine must be transported back into another part of the cell. A defect in this transporter protein results in an elevated level of ornithine in the wrong part of the cell. Without ornithine re-entering into the urea cycle, ammonia will start to accumulate. Ornithine translocase deficiency is sometimes referred to as Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome. The syndrome is named HHH syndrome because the lab findings of ornithine translocase deficiency are usually elevated ornithine, ammonia, and homocitrulline levels.