N-Acetylglutamate Synthetase Deficiency

What else is it called?

  • NAGS Deficiency
  • Hyperammonemia due to N-acetylglutamate synthetase deficiency

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What causes it?

This disorder is a urea cycle disorder and is caused by a problem in the NAGS gene. This gene produces the instructions for the N-acetylglutamate synthase enzyme which part of the first step of the urea cycle. This process is needed to breakdown excess protein within the body. When protein is broken down it produces nitrogen; nitrogen then goes through the Urea cycle, where it is broken down into urea which is removed from the body as urine.

If you have a problem in the NAGS gene, you will not produce enough of the NAGS enzyme. Therefore, you will be unable to successfully convert nitrogen into urea, and this causes high levels of nitrogen in the form of ammonia to build up within the blood, which is harmful to the body and can cause an hyperammonemia episode (accumulation of ammonia in the blood).

How common is it?

Urea cycle disorders affect 1 in 300 but N-Acetylglutamate Synthetase Deficiency affects only 1 in 2 million people in the world. It affects both genders equally. It can be difficult to determine a true frequency for these types of disorders as they can often go undiagnosed.

What are the signs and symptoms?

Typically, N-Acetylglutamate Synthetase Deficiency becomes evident within the first few days of life. The symptoms in new-borns are:

  • Poor feeding/appetite
  • Vomiting
  • Changes in body temperature
  • Muscle weakness
  • Drowsiness
  • Abnormal breathing
  • Seizures

In some cases, people with NAGS deficiency may not develop symptoms until the first few months of life and in some rare cases, they may not develop until adulthood. When this happens, symptoms can vary a lot between patients. The most common symptoms are:

  • Abdominal pain
  • Vomiting
  • Low body weight
  • Fatigue
  • Headaches
  • Vision disturbances
  • Uncontrolled movements
  • Confusion
  • Learning difficulties
  • Seizures
  • Coma

In some cases, severe symptoms can appear suddenly in someone who had previously presented as healthy but in some cases less severe symptoms can appear on and off over a longer period. In these cases, it is known as chronic ammonia toxicity.

Symptoms develop when there is added stress to the urea cycle. This can be caused by:

  • Illness
  • Trauma
  • Internal bleeding
  • Surgery
  • Certain medications
  • Increase in dietary proteins
  • Protein avoidance
  • Lengthy physical exercise

If treatment is not given to a patient with N-acetylglutamate Synthetase deficiency then their prognosis will be extremely poor, including neurological problems and in some cases a fatal outcome.

How is it diagnosed?

After symptoms have been noted, a blood test can be taken and a high level of ammonia within the blood can indicate N-acetylglutamate synthetase deficiency. But for a definite diagnosis, urine needs to be examined for elevated levels of organic acids, which is typical of urea cycle disorders. The best way for diagnosis would be molecular genetic testing.

Unfortunately, N-acetylglutamate synthetase deficiency is not tested for in the new-born heel prick test due to its rareness. However, it should be considered in diagnosis when a new-born has an undiagnosed illness with symptoms including vomiting, progressive lethargy and irritability.

Can it be treated?

Long term treatment of N-acetylglutamate synthetase deficiency incudes dietary restrictions and alternative pathways therapy, aimed at converting and excreting nitrogen from the body using alternative methods. The main aim for treatment is to prevent excessive ammonia building up in the blood and removing excessive ammonia during a hyperammonemia episode.

The aim of dietary restrictions is to limit protein intake to avoid excess ammonia being produced, but at the same time ensuring that enough protein is being taken in to ensure proper growth. Infants are placed on a low protein, high in calorie diet supplemented with essential amino acids.

Alternative pathway therapies include the use of nitrogen scavenger such as sodium phenylacetate and sodium benzoate. These drugs help remove excess nitrogen from the body without using the urea cycle. Haemodialysis is another method of removing nitrogen from the blood but is less frequently used.

Carbamylglutamate tablets should be regularly taken as they help to reduce blood ammonia levels. Dietary restrictions should still be followed alongside taking these tablets. Periodic blood tests should be given to monitor ammonia levels within the blood, and this can help catch a rise in ammonia before symptoms begin to present.

Early treatment of N-acetylglutamate synthetase deficiency alongside following treatment plans allows for an excellent quality of life.

Do my family need to be tested?

N-acetylglutamate synthetase deficiency is an autosomal recessive disease, meaning that a fault copy of the gene must be inherited from both parents, giving a 25% chance of the child being born with the disorder. There is a 50% chance that the child will be born carrier, which means that the child will only inherit one copy of the gene and cannot develop N-acetylglutamate synthetase deficiency.

As it is an autosomal recessive disorder, members of your family may be carriers, or they may have the deficiency and do not know. Genetic testing can be done for the disorder and can catch the disorder early on. Identifying carriers within your family can also assist in any family planning.

Relevant Organisations


References are available on request. Please contact Helen Morris by phoning 0845 241 2173 or emailing helen@metabolicsupportuk.org [Resource Library No: AAP002].

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