N-Acetylglutamate Synthase Deficiency

Baby Detect > Metabology > N-Acetylglutamate Synthase Deficiency

NAGS gene

Also known as: NAGS deficiency, Hyperammonemia due to N-acetylglutamate synthetase deficiency; N-acetylglutamate synthetase deficiency

OMIM#237310 https://omim.org/entry/237310

1. The disease

N-acetylglutamate synthase (NAGS) deficiency is a urea cycle disorder leading to hyperammonemia. The primary disorder 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.

2. The Symptoms

Onset occurs at any age, but neonatal presentation appears to be the most frequent. Lack of early signs or symptoms does not exclude the diagnosis.

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 hyperammonemia is often severe and may lead to hyperammonemic coma.

3. Actions to take in case of early diagnosis

  • Babies with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the gene NAGS) should continue breastfeeding and avoid baby formulas.
  • Early treatment is essential in preventing chronic symptoms.
  • Biochemical correlation is essential for confirming diagnosis with plasma quantitative amino acids (very low citrulline and arginine with high glutamine), ammonia levels (very high) and urinary organic acids (normal orotic acid). Biochemical NBS with tandem mass spectrometry can also help.
  • NAGS deficiency is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician, a part from a multidisciplinary approach to care.
  • The established treatment for patients with NAGS activity is daily administration of N-carbamoyl-L-glutamic acid (NCG) a synthetic analogue of N-acetyl glutamate (NAG) that works effectively as a cofactor for carbamoyl phosphate synthase 1 and enhances ureagenesis by activating the urea cycle. NCG (brand name, Carbaglu) is EMA approved.
  • NCG has favorable pharmacological features including better bioavailability compared to NAG. The clinical use of NCG has proven to be so effective as to make dietary protein restriction unnecessary for patients with NAGS deficiency.
  • Valproic acid should be avoided.
  • In most cases, early treatment with NGC (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.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

 4. For more information

Orphanet: https://www.orpha.net/consor4.01/www/cgi-bin/Disease_Search.php?lng=EN&data_id=3370&Disease_Disease_Search_diseaseGroup=NAGS-deficiency&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Hyperammonemia-due-to-N-acetylglutamate-synthase-deficiency&title=Hyperammonemia%20due%20to%20N-acetylglutamate%20synthase%20deficiency&search=Disease_Search_Simple

Biblio:

  • https://www.ncbi.nlm.nih.gov/books/NBK1217/
  • Chapel-Crespo CC, Diaz GA, Oishi K. Efficacy of N-carbamoyl-L-glutamic acid for the treatment of inherited metabolic disorders. Expert Rev Endocrinol Metab. 2016;11(6):467-473. PMID: 30034506.