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Hyperammonemia due to N-acetylglutamate synthase deficiency

Synonym(s) NAGS deficiency
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset All ages
  • E72.2
MeSH -
MedDRA -


N-acetylglutamate synthase (NAGS) deficiency is a urea cycle disorder leading to hyperammonaemia. The disorder is very rare but the prevalence is unknown. Onset occurs at any age, but neonatal presentation appears to be the most frequent. The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhoea, poor feeding, seizures, hypotonia, delayed psychomotor development and respiratory distress. The hyperammonaemia is often severe and may lead to hyperammonaemic coma. 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. The product of NAGS, N-acetylglutamate (NAG), is an allosteric activator of carbamylphosphate synthetase I (CPSI), the enzyme catalysing the first step in ureagenesis. NAGS deficiency may also be secondary to certain organic acid disorders, defects in fatty acid metabolism or valproic acid treatment. 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 (see this term). The established treatment for patients with NAGS activity is daily administration of N-carbamyl-L-glutamate (NCLG), a structural analogue of NAG that activates CPSI. NCLG has held EU marketing authorisation as an orphan drug treatment for NAGS deficiency since 2003. In most cases, early treatment with NCLG (i.e. before the onset of permanent neurological sequelae) allows normal psychomotor development and an excellent quality of life. Although the severity of the disorder is variable, the prognosis without treatment may be poor with neurological deficit and a potentially fatal outcome.

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  • Pr Pascale DE LONLAY

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