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N-acetylglutamate synthetase (NAGS) deficiency

What is N-acetylglutamate synthetase (NAGS) deficiency?

N-acetylglutamate synthetase (NAGS) deficiency is a rare genetic disorder caused by either the complete or partial absence of the enzyme N-acetylglutamate synthetase (NAGS). The NAGS enzyme is part of the urea cycle. The urea cycle is a biochemical pathway in the body that involves several steps in which nitrogen is converted into urea and removed from the body by the kidneys through the urine. Nitrogen is a normal waste product of protein metabolism. When people cannot breakdown nitrogen due to a urea cycle defect such as NAGS deficiency, nitrogen builds up in the body in the form of ammonia. Ammonia is a neurotoxin, a substance that can damage the brain and the nervous system.

 

Synonyms

  • NAGS deficiency
  • hyperammonemia due to N-acetylglutamate synthetase deficiency

N-acetylglutamate synthetase (NAGS) deficiency is a rare genetic disorder caused by either the complete or partial absence of the enzyme N-acetylglutamate synthetase (NAGS). The NAGS enzyme is part of the urea cycle. The urea cycle is a biochemical pathway in the body that involves several steps in which nitrogen is converted into urea and removed from the body by the kidneys through the urine. Nitrogen is a normal waste product of protein metabolism. When people cannot breakdown nitrogen due to a urea cycle defect such as NAGS deficiency, nitrogen builds up in the body in the form of ammonia. Ammonia is a neurotoxin, a substance that can damage the brain and the nervous system.

Acknowledgement of N-acetylglutamate synthetase (NAGS) deficiency has not been added yet.

N-acetylglutamate synthase deficiency is an extremely rare disorder with an estimated annual incidence of 1/1,000,000. Only several cases have been reported worldwide; the disorder is most likely under-recognized and underdiagnosed.

Name Abbreviation
NAGS deficiency NAGS deficiency
hyperammonemia due to N-acetylglutamate synthetase deficiency NAGS deficiency

NAGS deficiency is caused by mutations in the NAGS gene. When a gene is mutated, it can lead to the abnormal production of a protein product, which may be inefficient, faulty, deficiency, or almost nearly absent.

NAGS deficiency is inherited in an autosomal recessive manner, which means both parents must carry a copy of the mutated gene. For each pregnancy, there is a 25% chance that a child will inherit one mutated gene from each parent, what is required to develop the disorder. The parents, however, do not show the signs and symptoms of this condition.

NAGS deficiency can refer to either a complete or a partial lack of the NAGS enzyme. A severe or complete lack results in a severe form of NAGS deficiency, where the symptoms occur within 24-72 hours after birth. Symptoms include refusal to eat, progressive lethargy, vomiting, diarrhea, enlarged liver (hepatomegaly), respiratory distress, seizures, and abnormal accumulation of fluid in brain (cerebral edema). Symptoms can progress to coma and will become life-threatening if left untreated.

When a partial lack of the NAGS enzyme occurs, symptoms may not appear until later in childhood or even adulthood. However, individuals are still at risk for repeated bouts of elevated levels of ammonia in the blood and hyperammonemic episodes. Symptoms include failure to grow and weight gaining during early childhood, inability to coordinate voluntary movements (ataxia), lethargy, vomiting, and diminished muscle tone (hypotonia).

If a newborn demonstrates symptoms such as vomiting, irritability, and progressive lethargy, a diagnosis of urea cycle disorder may be suspected. Some things to be considered for a diagnosis are patient and family history, identification of characteristic findings, and specialized tests such as blood tests or molecular genetic testing.

A blood test can reveal the ammonia level in blood. A plasma ammonia concentration higher than 50 μmol/L can be indicative of a urea cycle disorder. To distinguish between different urea cycle disorders, plasma quantitative amino acid analysis is needed.

Molecular genetic testing can confirm a diagnosis of NAGS deficiency by identifying a mutation in the NAGS gene that causes the disorder.

The goal of treatment is to prevent excessive ammonia from forming and to remove the excessive ammonia that has formed. Long-term therapy includes dietary restrictions and alternative methods for converting and excreting nitrogen from body. The dietary restriction consists of limiting the intake of protein, which will lower the levels of nitrogen produced in the body.

Carglumic acid tablets were approved by the U.S. Food and Drug Administration (FDA) in 2010 and are used to reduce blood ammonia in individuals suffering from NAGS. Individuals may still need to follow dietary restrictions and may also need supplemental arginine in addition to taking Carglumic acid tablets.

A severe hyperammonemic episode is a medical emergency that will require hospitalization and can potential require dialysis and hemofiltration to reduce plasma ammonia concentration. Hemofiltration is a process of removing blood from the body, purifying it by filtering out impurities such as ammonia, and returning it to the body. Dialysis and hemofiltration are no longer required frequently because of the develop of treatment with Carglumic acid tablets.

The symptoms are visible within the first week of life and if not detected and diagnosed correctly immediately consequences can potentially prove fatal. However, if diagnosed and treated promptly before the onset of permanent neurological damage, even individuals with a severe lack of the NAGS enzyme can experience normal psychomotor development and excellent quality of life.

People with NAGS deficiency should avoid fasting, starvation, and excessively high (or low) dietary intake of protein.

Genetic counseling is recommended for individuals and their families.

Evaluation of at-risk relatives should be considered in order to identify the disorder before the onset of symptoms and to allow for dietary therapy and other preventive measures.

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