Information on the following diseases can be found in the Related Disorders section of this report:

• Organic Acidemias
• Reye Syndrome
• Urea Cycle Disorders

N-acetylglutamate synthetase 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.

The symptoms of NAGS deficiency are caused by the accumulation of ammonia in the blood. In most cases, NAGS deficiency occurs within 24-72 hours after birth, usually following a protein feeding. Affected infants may exhibit refusal to eat, progressive lethargy, vomiting, and irritability. Affected infants may also experience seizures, respiratory distress, the abnormal accumulation of fluid in the brain (cerebral edema), and an abnormally large liver (hepatomegaly).

In some cases, 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 and mental retardation. The severity of such neurological abnormalities is more severe in infants who are in hyperammonemic coma for more than three days. If left untreated, the disorder will result in life-threatening complications.

Some with NAGS deficiency may not exhibit symptoms until later during infancy or childhood 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), 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 may still experience hyperammonemic coma and life-threatening complications.
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N-acetylglutamate synthetase deficiency is inherited as an autosomal recessive trait. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.

In recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

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).
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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.
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Symptoms of the following disorders may be similar to those of NAGS deficiency. Comparisons may be useful for a differential diagnosis:

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. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly) in some cases. In severe cases, life-threatening complications may result. In addition to NAGS deficiency, the other urea cycle disorders are: argininosuccinate synthetase deficiency (citrullinemia); argininosuccinase acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and carbamylphosphate synthetase (CPS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)

Reye syndrome is a rare childhood disorder characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia), and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered by the use of aspirin in children recovering from chicken pox or influenza. Deficiencies of the urea cycle enzymes are thought to play a role in the development of Reye syndrome. Symptoms include vomiting, diarrhea, rapid breathing, irritability, fatigue, and behavioral changes. Neurological symptoms may be life-threatening and include seizures, stupor, and coma. (For more information on this disorder, choose "Reye" as your search term in the Rare Disease Database.)

Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to break down (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy, and seizures. If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon.
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Diagnosis
A diagnosis of NAGS deficiency 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 confirmed by 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.

Treatment
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 combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).

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;x).

In addition to dietary restrictions, individuals with NAGS deficiency benefit from supplemental treatment with carbamylglutamate and arginine, which are needed in order to maintain a normal rate of protein breakdown (synthesis).

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 Food and Drug Administration (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). Prompt treatment can avoid hyperammonemic coma and associated 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.

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.

In cases where there is no improvement or in cases where hyperammonemic coma develops, the removal of wastes by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children, and adults who are first diagnosed with NAGS deficiency during hyperammonemic coma.

Preventive Care
After diagnosis of NAGS deficiency, 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 be may be of benefit for individuals with NAGS deficiency and their families.
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Enzyme replacement therapy shows potential promise for treatment of urea cycle disorders including NAGS deficiency. Research on this type of therapy is in a preliminary stage. More research is necessary to determine the long-term safety and effectiveness of this treatment for CPS deficiency.

The drug carbamylglutamic acid has received an orphan drug designation for its use in the treatment of NAGS deficiency. More studies are needed to determine the long-term safety and effectiveness of this drug for the treatment of NAGS deficiency. For more information, contact:

Orphan Europe
Immeuble "Le Guillaumet"
60 Avenue du President Wilson
92046 Paris France

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:237310; Last Update:4/12/00.

TEXTBOOKS
Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:935-37.

Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:350-55.

Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:12-14.

Menkes JH, au., Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995:46-52.

Urea Cycle Disorders. In: Gellis and Kagan (Eds.), Current Pediatric Therapy, 17th Ed., WB Saunders and Co.

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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.

Elpeleg ON, et al. Late-onset form of partial N-acetylglutamate synthetase deficiency. Eur J Pediatr. 1990;149:634-44.

Brusilow SW, Disorders or the urea cycle. Hosp Prac. 1985;305:65-72.