NAGS – Hyperammonemia due to N-acetylglutamate synthase deficiency

N-acetylglutamate synthase (NAGS, HGNC:17996) deficiency is a rare autosomal recessive urea cycle disorder that manifests as hyperammonemia due to impaired activation of carbamoyl phosphate synthetase I (MONDO:0009377). Affected individuals present with severe neonatal or later-onset hyperammonaemic crises and variable neurological impairment. Diagnosis relies on identification of biallelic pathogenic NAGS variants or on a positive therapeutic trial with N-carbamylglutamate. Over 98 unrelated individuals from 79 families have been reported worldwide ([PMID:33036647]).

Case reports and multi-patient studies have described more than 36 distinct NAGS mutations, including missense, nonsense, frameshift, splice-site, and regulatory variants. Inheritance is autosomal recessive, with probands harboring homozygous or compound heterozygous alleles. Segregation analyses in multiple families confirm co-segregation of biallelic variants with disease, including two affected siblings in a Hispanic kindred ([PMID:12594532]). Case-level data document 56 NAGS-deficient patients harboring 36 mutations across diverse populations ([PMID:27037498]).

In vitro expression of NAGS missense variants, such as p.Cys200Arg, p.Ser410Pro, and p.Ala518Thr, in NAGS-deficient Escherichia coli systems revealed severe enzyme activity reduction ([PMID:15878741]). NAGS knockout mice rescued by adeno-associated virus gene transfer of wild-type but not L-arginine activation–deficient NAGS demonstrate the physiological necessity of enzyme activation for ureagenesis ([PMID:33574402]). Reporter assays of intronic and enhancer variants further corroborate the impact of noncoding changes on gene expression ([PMID:34510628]).

Therapeutically, N-carbamylglutamate normalizes plasma ammonia levels in neonatal and late-onset cases, supports liberalized protein intake, and improves neurodevelopmental outcomes. Early NCG trials serve both diagnostic and therapeutic roles, distinguishing NAGS deficiency from other proximal urea cycle disorders and guiding lifelong management.

No studies have disputed the NAGS–hyperammonemia association. Phenotypic variability correlates with residual enzymatic activity, but pathogenicity of reported variants is consistently supported by genetic segregation and functional assays.

Overall, genetic and experimental evidence definitively supports NAGS deficiency as the cause of hyperammonemia due to NAGS deficiency. Molecular testing enables early diagnosis, family screening, and prenatal testing, while functional studies inform variant interpretation and genotype–phenotype correlations.

Key take-home: NAGS genetic testing and N-carbamylglutamate responsiveness provide a robust diagnostic and therapeutic framework for hyperammonemia due to NAGS deficiency.

References

• Orphanet journal of rare diseases • 2020 • Presentation and management of N-acetylglutamate synthase deficiency: a review of the literature. PMID:33036647
• Human mutation • 2003 • Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. PMID:12594532
• Human mutation • 2016 • Understanding N-Acetyl-L-Glutamate Synthase Deficiency: Mutational Spectrum, Impact of Clinical Mutations on Enzyme Functionality, and Structural Considerations. PMID:27037498
• Biochimica et biophysica acta • 2005 • Identification of novel mutations of the human N-acetylglutamate synthase gene and their functional investigation by expression studies. PMID:15878741
• Scientific reports • 2021 • Gene delivery corrects N-acetylglutamate synthase deficiency and enables insights in the physiological impact of L-arginine activation of N-acetylglutamate synthase. PMID:33574402
• Human mutation • 2021 • Noncoding sequence variants define a novel regulatory element in the first intron of the N-acetylglutamate synthase gene. PMID:34510628

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