Last updated:
9/26/2024
Years published: 1986, 1987, 1990, 1992, 1993, 1997, 1998, 2001, 2011, 2016, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Stephen Cederbaum, MD, Division of Genetics, UCLA, for assistance in the preparation of this report.
Summary
N-acetylglutamate synthetase (NAGS) deficiency is a rare genetic disorder caused by a complete or partial lack of the enzyme N-acetylglutamate synthetase (NAGS). NAGS is one of six 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 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 in an autosomal recessive pattern.
Treatment may include preventing excessive ammonia and may include dietary restrictions and medication such as carbamylglutamate (Carbaglu).
Introduction
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 people. Specific symptoms can vary from one person to another.
The symptoms of NAGS deficiency are caused by the accumulation of ammonia in the blood.
Severe form (complete NAGS enzyme deficiency)
In the most severe cases, symptoms appear within 24-72 hours after birth. These include:
If untreated, the high levels of ammonia in the blood can lead to a hyperammonemic coma. This can result in:
Life-threatening complications are likely if the disorder remains untreated.
Milder form (partial NAGS enzyme deficiency)
Some people may have a milder form of NAGS deficiency where symptoms appear later in infancy, childhood, or even adulthood. Symptoms can include:
Even with this milder form, there is still a risk of hyperammonemic coma and potentially life-threatening complications if the condition is not managed.
NAGS deficiency is caused by changes (variants) in the NAGS gene. Variants in the NAGS gene result in deficiency of the enzyme N-acetylglutamate synthetase. The symptoms of NAGS deficiency develop due to the lack of this enzyme 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).
Inheritance is autosomal recessive. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
NAGS deficiency is a rare disorder that affects males and females in equal numbers. In most people, 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. NAGS deficiency is the rarest defect of the urea cycle, with an incidence of less than one in 2,000,000 livebirths.
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 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 disease-causing variants in the NAGS gene.
Treatment
People affected with NAGS deficiency require a team of specialists to ensure proper care. This team may include pediatricians, neurologists, geneticists, dieticians and doctors who specialize in metabolic disorders. For children with developmental delays, additional support from occupational, speech and physical therapists may be necessary.
The focus of treatment for NAGS deficiency is to:
Historically, treatment for NAGS deficiency involved a combination of:
In 2010, the U.S. Food and Drug Administration (FDA) approved carbamylglutamate (Carbaglu) to lower ammonia levels in patients with NAGS deficiency. Carbaglu helps activate the urea cycle, allowing the body to process ammonia. However, some individuals on Carbaglu may still need dietary restrictions and supplemental arginine.
Managing the diet of people affected with NAGS deficiency is essential. The goal is to limit protein intake to prevent ammonia buildup while ensuring enough protein is consumed for proper growth, especially in infants. The typical diet plan includes:
Dietary management should be supervised by a trained metabolic dietician.
Nitrogen scavenger drugs help remove excess nitrogen from the body. These include:
In young children, these medications are often given through a gastrostomy tube (placed through the abdominal wall into the stomach) or a nasogastric tube (through the nose to the stomach).
During a severe hyperammonemic episode (extremely high ammonia levels), immediate treatment is critical to prevent coma and neurological damage. Key steps include:
In the past, when there was no response to treatment or people developed coma, hemodialysis (a process where blood is filtered through a machine) was used to remove ammonia. However, with Carbaglu therapy, the need for hemodialysis has been greatly reduced.
After a diagnosis of NAGS deficiency, ongoing care is essential to prevent ammonia buildup:
By detecting early signs of elevated ammonia or glutamine, doctors can start treatment before symptoms appear.
Genetic counseling can be helpful for families affected by NAGS deficiency, providing information about the disorder, inheritance patterns and options for family planning.
Recent studies on gene therapy show promising potential for treating NAGS deficiency. Using adeno-associated virus (AAV) vectors, researchers successfully delivered functional NAGS genes to animal models (mice in the laboratory). This method could correct enzyme deficiency and help control ammonia levels in the future.
These studies found that L-arginine is very important in activating the NAGS enzyme. Research on animals with a form of NAGS that cannot bind to L-arginine shows high ammonia levels, even when the NAGS enzyme is restored. This highlights the role of L-arginine in the urea cycle and suggests future therapies may focus on enhancing L-arginine activation.
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Singh, R.H., Bourdages, MH., Kurtz, A. et al. The efficacy of Carbamylglutamate impacts the nutritional management of patients with N-Acetylglutamate synthase deficiency. Orphanet J Rare Dis. 2024; 19:168. https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03167-0
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.
INTERNET
Roth KS. N-acetylglutamate synthetase deficiency. Medscape. Feb 18, 2019. Available at: https://emedicine.medscape.com/article/941090-overview Accessed Sept 26, 2024.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:237310; Last Update: 04/22/2024. Available at: https://www.ncbi.nlm.nih.gov/omim/237310 Accessed Sept 26, 2024.
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