The urea cycle is a sequence of chemical reactions that takes place in liver cells. The reactions remove ammonia from the blood and convert it into urea. Ammonia is a natural by-product of the metabolism of proteins from our diet and from the normal turnover of proteins in our cells. Urea can then be passed out of the body in the urine. The urea cycle also produces an amino acid called arginine.
A specific chemical, or enzyme, is responsible for each of the reactions that make up the urea cycle. The cycle also relies on a 'co-factor', or compound that one of the enzymes needs to be able to carry out its reaction.
In urea cycle disorders one of the enzymes within the cycle is not working properly or the co-factor is not available. As a result, ammonia cannot be converted into urea and ammonia levels in the body will begin to rise ("hyperammonemia"). Ammonia can then reach the brain through the blood, where it can cause irreversible brain damage, coma and/or death.
Genes contain the instructions for how to make each of the enzymes and the co-factors of the urea cycle. Therefore, the urea cycle disorders are a group of genetic disorders. The estimated incidence of UCDs is 1 in 30,000 births. UCDs occur in all racial and ethnic backgrounds.
The different urea cycle disorders are named for the part of the cycle that is not working properly. For example, if the enzyme carbamoyl phosphate synthetase 1 (CPS1) is not working, the urea cycle disorder is "CPS1 deficiency" or "carbamoyl phosphate synthetase 1 deficiency". A list of the classic urea cycle disorders and the genes associated with them is below.
|Urea Cycle Disorder||Alternate Name||Gene|
|Carbamoyl phosphate synthetase 1 deficiency||CPS1|
|Ornithine transcarbamylase deficiency||OTC|
|Argininosuccinic acid synthetase deficiency||Citrullinemia type 1||ASS1|
|Argininosuccinic acid lyase deficiency||Argininosuccinic Aciduria||ASL|
|N-acetylglutamate synthetase deficiency||NAGS|
The UCDs are caused by mutations (or alterations) in the genes that tell our cells how to make the enzymes and the co-factor of the urea cycle. A mutation causes a gene to not function at all or not to function as well as it should. Most often these altered genes are inherited from parent(s), but they may also occur spontaneously.
When discussing how genetic conditions are passed on in a family, it is important to understand that we have two copies of most genes, with one copy inherited from our mother and one copy inherited from our father. This is not the case for the genes that are on our sex chromosomes (the "X" and "Y" chromosomes). These are different in men and women: men have one X chromosome and one Y chromosome, while women have two X chromosomes. Because men have only one X chromosome they have only one copy of each of the genes on the X chromosome, while women have two copies. A father passes on his X chromosome to all of his daughters and his Y chromosome to all of his sons. A mother passes on one of her X chromosomes to each of her children.
These UCDs are inherited or passed on in an autosomal recessive pattern. 'Autosomal' means that males and females are equally likely to inherit the disorder and 'recessive' means that both copies of the relevant gene are altered. Most often, the affected person has inherited one copy of the altered gene from their mother and the other from their father. In this case, the parents are "carriers" of the disorder, meaning that they have one altered copy and one working copy of the gene; carriers of autosomal recessive UCDs do not show signs and symptoms of the disorder.
OTC deficiency is inherited in an X-linked pattern. The OTC gene is on the X chromosome and, as noted above, males have only one copy of this gene while females have two copies of the gene. Males are usually more severely affected than females because they do not have a second working copy of the OTC gene. Some female "carriers" of OTC deficiency (who have one working copy and one altered copy of the OTC gene) have some signs and symptoms of the disorder; this is unlike the carriers of the autosomal recessive UCDs who are asymptomatic.
A male with OTC deficiency may have inherited an altered OTC gene from his mother (in which case his mother is a carrier who may or may not have symptoms of the disorder herself) or the OTC gene mutation may have occurred spontaneously in him (in which case he is the first one in the family to have the mutation). A female with OTC deficiency may have inherited an altered OTC gene from either her mother or her father, or the OTC gene mutation may have occurred spontaneously in her.
The chance that someone else in the family has the same UCD as their relative depends on the inheritance pattern of the UCD, whether the at-risk family member is male or female (in the case of OTC deficiency), and the rest of the family history (how many relatives have been diagnosed with the disorder already and whether genetic testing has been performed in other relatives). In some cases the age of the at-risk family member and whether or not they have shown any signs or symptoms of the disorder is helpful in estimating the chances that they also have the disorder.
We recommend talking to your metabolic specialist and/or genetic counselor to determine those relatives who may be at risk for having a UCD and for coordination of genetic testing, when appropriate. We are happy to talk with you about this.
UCDs can be diagnosed in newborns, children, or young adults. In general, the earlier someone develops symptoms of a UCD, the more severe their disorder. The severity of symptoms is generally based (1) the position of the defective enzyme within the urea cycle (the beginning vs. the end of the cycle) and (2) whether or not there is any functional enzyme or co-factor being produced. However, other environmental and genetic factors may play a role in determining the severity of symptoms for a given patient.
Severe deficiency (a complete lack) of any one of the first four enzymes in the urea cycle (CPS1, OTC, ASS and ASL) or the co-factor (NAGS) generally causes a rapid onset of symptoms related to hyperammonemia in the first few days of life. The symptoms may not be present until after a newborn goes home from the hospital and may not be recognized by the parents or primary care provider. Initial symptoms due to rising ammonia levels are generally not specific to UCDs and can include seizures, vomiting, loss of appetite/inability to eat, altered breathing (abnormally slow and/or shallow or abnormally fast and/or deep breathing), sluggishness, low core body temperature, abnormal posturing and coma. If untreated, a severe UCD will ultimately lead to death.
Individuals who have a mild or moderate UCD due to partial enzyme or co-factor deficiency may not be diagnosed until childhood or later. The specific gene alteration(s) dictates whether or not some functional enzyme or co-factor is still being produced. All of the UCDs may therefore occur in a mild or moderate form. Symptoms due to mild elevations in ammonia, often triggered by illness or stress at any age, include failure to thrive, loss of appetite, avoidance of high-protein foods, cyclical vomiting, lethargy and behavioral problems. Diagnosis and treatment are critically important for patients with mild or moderate UCDs because ammonia levels may rise enough to cause permanent brain damage, coma and death. Deficiency of arginase (the 5th enzyme in the cycle) is marked by mostly neurologic symptoms. For reasons that are not clearly understood, patients with ARG deficiency are less likely to develop hyperammonemia than other UCD patients.
In a symptomatic patient, the diagnosis of a UCD is based on clinical and biochemical data and review of family history. In some cases, genetic testing may also be used to reach a diagnosis.
Newborn screening in some states includes testing for ASS1 deficiency (Citrullinemia) and ASL deficiency. Some cases of ARG1 deficiency may be detected on newborn screening.
Genetic testing is available for all classic urea cycle disorders. In almost all cases, the first person in the family to have genetic testing should be someone who has received a clinical diagnosis of a UCD. Carrier and diagnostic testing can then be offered to other relatives, including in a prenatal setting.
Treatment of UCDs can be tailored to the specific disorder once a diagnosis is made. In general, the goals of treatment for a patient who is acutely ill with symptoms of hyperammonemia are to (1) quickly lower the ammonia concentration via some form of dialysis, (2) block the production of additional ammonia by use of intravenous and oral medications, (3) carefully manage the patient's diet to limit excess nitrogen (a key component of ammonia) by balancing the calories delivered by protein, carbohydrate and fat, and (4) reduce the risk of neurologic damage through the use of IV fluids and cardiac monitoring.
In a UCD patient who is not currently symptomatic, a restricted diet that includes specialized formulas and medications is used to minimize future hyperammonemic episodes that may be triggered by eating too much protein. It is also very important to minimize the risk of illnesses and other stressors that can cause the body to break down the proteins within cells. Recommendations therefore include immunizations against respiratory and gastrointestinal illnesses, other usual immunizations, and multivitamin and fluoride supplementation.
A doctor who specializes in metabolic disorders should see patients with UCDs on a regular basis. Severely affected patients will likely be seen on a more frequent basis than mild or moderately affected patients.
Unfortunately there is currently no cure for any of the UCDs. Ongoing research is focused on treatment for UCDs and on better understanding the natural history and mechanisms that underlie these disorders.
Last Reviewed; August 7, 2014