July 31, 2017
Years published: 1986, 1987, 1990, 1992, 1995, 1996, 1997, 2001, 2011, 2017
NORD gratefully acknowledges Marshall L. Summar, MD, Chief, Genetics and Metabolism, Margaret O’Malley Professor of Genetic Medicine, Professor of Pediatrics, George Washington University, for assistance in the preparation of this report.
Carbamoyl phosphate synthetase 1 deficiency (CPSID) is a rare inherited disorder characterized by complete or partial lack of the carbamoyl phosphate synthetase (CPS) enzyme. This is one of five enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of the CPSI enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Affected children may experience vomiting, refusal to eat, progressive lethargy, and coma. CPSID is inherited as an autosomal recessive genetic disorder.
The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood.
CPSID may be associated with complete or partial absence of the CPS enzyme. Complete lack of the CPS enzyme results in the severe form of the disorder, in which symptoms occur shortly after birth (neonatal period). Partial lack of the CPS enzyme results in a milder form of the disorder that can occur at any time during the life of the patient.
The symptoms of CPSID are caused by the accumulation of ammonia in the blood. The severe form of CPSID occurs within 24-72 hours after birth, regardless of exposure to dietary protein. This form of CPSID is initially characterized by refusal to eat, lethargy, lack of appetite, vomiting, and irritability. Shortly thereafter, affected infants may also experience seizures, respiratory distress, and abnormal movements and postures, The symptoms are mostly attributable to the swelling of the brain (cerebral edema) caused by hyperammonemia.
In neonatal cases, untreated CPSID progresses to coma due to high levels of ammonia in the blood (hyperammonemic coma). In such cases and even with effective treatment, the disorder may potentially result in neurological abnormalities, including developmental delays and intellectual disability. The neurological abnormalities are more severe in infants who are in hyperammonemic coma for a prolonged period (days). If left untreated, the disorder will typically results in death of the patient.
Those with the milder form of CPSID show symptoms later during infancy, childhood, or adulthood. Symptoms are often triggered by a secondary illness such as a viral infection or other stress. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy, vomiting, and/or diminished muscle tone (hypotonia). Patients with the milder form of CPSID may still experience hyperammonemic coma and life-threatening complications.
CPSID is inherited as an autosomal recessive genetic disorder and is caused by mutations in the CPSI gene. Mutations in the CPSI gene result in production of an abnormal carbamoyl phosphate synthetase enzyme.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
The estimated frequency of CPSID is 1 in 150-200,000 births. The estimated frequency of urea cycle disorders collectively is one in 30,000. However, because urea cycle disorders like CPSID often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.
A diagnosis of a urea cycle disorder, such as CPSID, should be considered in any newborn who has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.
A diagnosis of CPSID involves a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Blood tests may reveal excessive amounts of ammonia in the blood, which is the main criterion for a diagnosis of urea cycle disorders including CPSID. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, liver disease, and fatty acid oxidation disorders. Urea cycle disorders can be differentiated from these disorders through the examination of urine for elevated levels of, or abnormal, organic acids. In urea cycle disorders, urinary organic acids are normal except for the presence of orotic acid in OTCD. Genetic sequencing of the CPSI gene is the main form of diagnosis at this time (typically combined with sequence of the other urea cycle enzymes). Measurement of CPSID1 enzyme activity on cells obtained from a liver biopsy can confirm the diagnosis but is rarely employed currently.
Treatment is very complex and should be coordinated by a metabolic specialist at a center experienced in the care of urea cycle patients. Therapy is based on reducing plasma ammonia concentration, preventing excess ammonia from being formed, and reducing the amount of nitrogen in the diet while supplying enough for growth.
Reduction of plasma ammonia concentration is accomplished by dialysis and several different methods are available.
The nitrogen scavenger drugs sodium phenylacetate and sodium benzoate provide an alternative pathway for removing excess nitrogen. Intravenous and oral forms of these medications are available (Ammonul and Ucephan). Phenylbutyrate (Buphenyl) has a less offensive odor than the other medications but is available as oral therapy only.
Dietary restrictions in individuals with CPSID are aimed at limiting the amount of protein intake. Children with CPSID are placed on a low-protein, high calorie diet, supplemented by essential amino acids. Treatment may also include citrulline or arginine, to maintain a normal rate of protein formation (synthesis).
Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can sometimes prevent coma and severe neurological symptoms. However, in some cases, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications. In many centers liver transplantation is offered as a more permanent solution to severe CPSID.
Consensus treatment guidelines are available online at the NIH sponsored urea cycle disorders consortium website.
Seizures are treated with phenobarbital or carbamazepine. Valproic acid and intravenous steroids should be avoided, as it can increase blood ammonia levels. Prednisone and other similar steroid compounds should also be avoided because they will trigger a protein catabolic state and hyperammonemia. Inhaled steroids are somewhat safer if necessary.
Of note, the chemotherapy drug cyclophosphamide appears to directly inhibit CPSI.
Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. Excessive levels of ammonia should be promptly treated.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about carbamyl phosphate synthetase deficiency:
Marshall L. Summar, MD
Chief, Genetics and Metabolism
Margaret O’Malley Professor of Genetic Medicine
Professor of Pediatrics, George Washington University
Children’s National Medical Center
111 Michigan Avenue, N.W., Suite 4800
Washington, DC 20010
P: (202) 476-5291
F: (202) 476-5650
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Ah Mew N, Simpson KL, Gropman AL, et al. Urea Cycle Disorders Overview. 2003 Apr 29 [Updated 2017 Jun 22]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.Available from: https://www.ncbi.nlm.nih.gov/books/NBK1217/ Accessed July 31, 2017.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Carbamoyl phosphate synthetase I deficiency; Entry No: 237300. Last update: 06/21/2016 Available at: http://www.ncbi.nlm.nih.gov/omim/237300 Accessed July 31, 2017.
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