N-acetylglutamate synthetase deficiency




N-acetylglutamate synthase (NAGS) deficiency is type of urea cycle disorder leading to hyperammonaemia. It is an inherited disorder that causes ammonia to accumulate in the blood. The product of NAGS, N-acetylglutamate (NAG), is an allosteric activator of carbamylphosphate synthetase I (CPSI), the enzyme catalysing the first step in ureagenesis. In patients with NAGS deficiency, NAG is not available in sufficient quantities, or is not present at all and, hence, the body levels of ammonia increase.

Ammonia, which is formed when proteins and amino acids are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia. The disorder is very rare and the prevalence is unknown. Only a handful of cases have been described worldwide. 


Onset occurs at any age, but neonatal presentation appears to be the most frequent. The clinical manifestations are variable but common features include:

  • Aggressive behavior
  • Cognitive impairment
  • Coma
  • Confusion
  • Failure to thrive
  • Hyperammonemia
  • Lethargy
  • Respiratory distress
  • Seizures
  • Vomiting

In some affected individuals, especially those with some preserved NAGS activity, signs and symptoms of NAGS deficiency are less severe, and do not appear until later in life. Some people with this form of the disorder cannot tolerate high-protein foods such as meat. 


NAGS deficiency belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is metabolized by the body, to make a compound called urea that is excreted by the kidneys.

The primary disorder is transmitted as an autosomal recessive trait and is caused by mutations in the NAGS gene (17q21.31), leading to a total or partial lack of NAGS activity.


This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Genetic counselling may help in families where the condition occurred previously. 


Diagnosis may be suspected by demonstration of decreased liver NAGS activity and can be confirmed by DNA analysis. The principle differential diagnosis is carbamoylphosphate synthetase deficiency.


Although the severity of the disorder is variable, the prognosis without treatment may be poor with neurological deficit and a potentially fatal outcome.


Glycerol phenylbutyrate (Ravicti) FDA-approved indication: Use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients > or = to 2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements). 


Refer to Research Publications.