NORD gratefully acknowledges Stephen Cederbaum, MD, Division of Genetics, UCLA, for assistance in the preparation of this report.
N-acetylglutamate synthetase (NAGS) deficiency is a rare genetic disorder characterized by complete or partial lack of the enzyme N-acetylglutamate synthetase (NAGS). NAGS is one of six enzymes that play a role in the break down and removal of nitrogen from the body, a process known as the urea cycle. The lack of the NAGS enzyme results in excessive accumulation of nitrogen, in the form of ammonia, in the blood (hyperammonemia). Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood, resulting in the symptoms and physical findings of NAGS deficiency. Symptoms include vomiting, refusal to eat, progressive lethargy, and coma. NAGS deficiency is inherited as an autosomal recessive trait.
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.
NAGS deficiency may be associated with complete or partial absence of the NAGS enzyme. Complete lack of the NAGS enzyme results in the severe form of the disorder, in which symptoms occur shortly after birth (neonatal period). Partial lack of the NAGS enzyme results in a milder form of the disorder that occurs later during infancy or childhood or even adulthood in some cases. Specific symptoms can vary from one person to another.
The symptoms of NAGS deficiency are caused by the accumulation of ammonia in the blood. In the most severe cases, the symptoms of NAGS deficiency occur within 24-72 hours after birth. Affected infants may exhibit refusal to eat and poor feeding habits, progressive lethargy, recurrent vomiting, diarrhea, irritability and an abnormally enlarged liver (hepatomegaly). More severe complications can also develop including seizures, confusion, respiratory distress, and the abnormal accumulation of fluid in the brain (cerebral edema),
In some cases, the symptoms of NAGS deficiency may progress to coma due to high levels of ammonia in the blood (hyperammonemic coma). In such cases, the disorder may potentially result in neurological abnormalities including developmental delays, learning disabilities and intellectual disability. The severity of such neurological abnormalities is greater in infants who are in hyperammonemic coma for more than three days. If left untreated, the disorder will result in life-threatening complications.
Some individuals with NAGS deficiency may not exhibit symptoms until later during infancy or childhood or even adulthood because of a partial deficiency of the NAGS enzyme. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), poor growth, avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy, vomiting, and/or diminished muscle tone (hypotonia). Infants and children with the mild form of NAGS deficiency can still experience hyperammonemic coma and life-threatening complications.
NAGS deficiency is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the abnormal gene for the same trait 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, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent.
Investigators have determined that NAGS deficiency is caused by mutations of the NAGS gene located on the long arm (q) of chromosome 17 (17q21.31). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 17q21.31” refers to band 21.31 on the long arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The symptoms of NAGS deficiency develop due to the lack of the enzyme N-acetylglutamate synthetase, which is needed to break down nitrogen in the body. Failure to properly break down nitrogen leads to the abnormal accumulation of nitrogen, in the form of ammonia, in the blood (hyperammonemia). Specifically, the NAGS enzyme is an activator of another enzyme of the urea cycle known as carbamyl phosphate synthetase (CPS).
NAGS deficiency is a rare disorder that affects males and females in equal numbers. In most cases, onset of symptoms occurs at, or shortly following, birth. The estimated frequency of urea cycle disorders collectively is one in 30,000 births. However, because urea cycle disorders like NAGS deficiency 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 NAGS deficiency (or any urea cycle disorder) should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.
A diagnosis of NAGS deficiency can be made following 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, the characteristic finding of urea cycles disorders. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, and fatty acid oxidation disorders. Urea cycles 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.
A diagnosis of NAGS deficiency can be confirmed through molecular genetic testing that reveals a mutation of the NAGS gene that characterizes this disorder.
Treatment of an individual with NAGS deficiency may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticists, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.
The treatment of NAGS deficiency is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy for NAGS deficiency had combined dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).
In March 2010, the U.S. Food and Drug Administration (FDA) approved the use of Carbaglu® (carbamylglutamate) tablets to reduce blood ammonia levels in patients with NAGS deficiency. Carbaglu is manufactured by Orphan Europe. Some individuals who take carbamylglutamic acid may still need to follow dietary restrictions and receive supplemental arginine.
Dietary restrictions in individuals with NAGS deficiency are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with NAGS deficiency are placed a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow's milk formulate, an essential amino acid formula (e.g., UCD-1 Ross, or Cyclinex, Mead Johnson), and a calorie supplement without protein is often used (e.g., MJ80056, Mead Johnson).
Individuals with NAGS deficiency may be treated by medications that stimulate the removal of nitrogen from the body. These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. These medications are unpalatable and often administered via a tube that is placed in the stomach through the abdominal wall (gastrostomy tube) or a narrow tube that reaches the stomach via the nose (nasogastric tube).
The orphan drug sodium phenylbutyrate (Buphenyl®) has been approved by the FDA for the treatment of NAGS deficiency. This drug does not have an offensive odor that is associated with other similar drugs. Buphenyl is manufactured by Ucyclyd Pharma.
Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). The advent of carbaglu therapy has reduced the vulnerability to these episodes. Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some cases, especially those with complete enzyme deficiency, prompt treatment may not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.
Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose. Carbaglu should be continued or given, if the patient is not already on it.
In the past, in individuals where there was no improvement or where hyperammonemic coma developed, the removal of wastes by filtering an affected individual's blood through a machine (hemodialysis) may have been be necessary. However, hemodialysis may be less frequently needed or not needed at all in individuals on carbaglu therapy. Hemodialysis is also used to treat infants, children, and adults who are first diagnosed with NAGS deficiency during hyperammonemic coma.
After diagnosis of NAGS deficiency every effort should be made to take and administer carbaglu. Steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. In addition, elevated levels of an amino acid (glutamine) in the blood often precede the development of hyperammonemia by days or weeks. Affected individuals should receive periodic tests to measure the amount of amino acids such as glutamine in the blood. Detection of elevated levels of ammonia or glutamine may allow treatment before clinical symptoms appear.
Genetic counseling may be of benefit for individuals with NAGS deficiency and their families.
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Contact for additional information about N-acetylglutamate synthetase deficiency:
Stephen Cederbaum, M.D.
635 Charles E. Young Dr. South, Rm 347
Los Angeles, CA 90095-7332
Gessler P, Buchal P, Schwenk HU, Wermuth B. Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency. Eur J Pediatr. 2010;169:197-199.
Krivitzky L, Babikian T, Lee HS, et al. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res. 2009;66:96-101.
Yudkoff M, Ah Mew N, Payan I, et al. Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis. Mol Genet Metab. 2009;98:325-330.
Tuchman M, Caldovic L, Daikhin Y, et al. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic academia as measured by isotopic incorporation and blood biomarkers. Pediatr Res. 2008;64:213-217.
Deignan JL, Cederbaum SD, Grody WW. Contrasting features of urea cycle disorders in human patients and knockout mouse models. Mol Genet Metab. 2008;93:7-14.
Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007;28:754-759.
Caldovic L, Morizono H, Daikhin, et al. Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr. 2004;145:552-554.
Dammers R, Rubio-Gozalbo ME, Robben SG, et al.
N-acetyl-glutamate synthetase deficiency or porto-systemic shunt associated encephalopathy? Acta Paediatr. 2002;91(6):729.
Belanger-Quintana A, Martinez-Pardo M, Garcia MJ, et al. Hyperammonaemia as a cause of psychosis in an adolescent. Eur J Pediatr. 2003 Nov;162(11):773-5.
Lee B, et al. Long-term outcome of urea cycle disorders. J Pediatr. 2000;138:S-62-S71.
Plecko B, et al. Partial N-acetylglutamate synthetase deficiency in a 13-year-old girl: diagnosis and response to treatment with N-carbamylglutamate. Eur J Pediatr. 1998;157:996-98.
Guffon N, et al. A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J Inherit Metab Dis. 1995;18:61-65.
Batshaw ML. Inborn errors of urea synthesis. Ann Neurol. 1994;35:133-41.
Schubiger G, et al. N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication. Eur J Pediatr. 1991;150:353-56.
FROM THE INTERNET
Roth KS. N-acetylglutamate synthetase deficiency. Emedicine Journal, May 19, 2010. Available at: http://emedicine.medscape.com/article/941090-overview Accessed February 20, 2011.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:237310; Last Update:10/17/2007. Available at: http://www.ncbi.nlm.nih.gov/omim/237310 Accessed February 20, 2011.
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