NAGS – Urea Cycle Disorder

N-acetylglutamate synthase (NAGS) deficiency is an autosomal recessive urea cycle disorder characterized by impaired production of N-acetylglutamate, the essential allosteric activator of carbamoylphosphate synthetase 1 (PMID:15878741). The gene–disease relationship is classified as Definitive based on decades of reports involving over 56 patients from 42 families, prenatal diagnoses, and concordant functional studies (PMID:27037498; PMID:15164414).

1. Genetic Evidence

Inheritance is autosomal recessive. More than 56 affected individuals from 42 unrelated families have been reported, including neonatal and late-onset presentations (PMID:27037498). Segregation in at least 2 multiplex families confirms homozygosity or compound heterozygosity for pathogenic variants (PMID:2044610). Case series describe neonatal hyperammonemia and adult encephalopathy with biallelic splice-site and missense variants. Notably, the recurrent intronic splice-site mutation c.1097-2A>T was identified in a neonate with rapid response to N-carbamylglutamate (PMID:27570737).

2. Variant Spectrum

Pathogenic alleles include >36 missense changes and multiple splice-site and frameshift variants distributed across the gene. A representative variant is c.344C>T (p.Ala115Val), identified in an adult with late-onset headaches and confirmed by biochemical rescue (PMID:29364180). Variants lead to absent or severely reduced enzyme activity in vitro.

3. Functional Evidence

Missense mutations c.598T>C (p.Cys200Arg), c.1228T>C (p.Ser410Pro), and c.1552G>A (p.Ala518Thr) showed markedly decreased enzyme activity in bacterial expression assays, establishing pathogenicity (PMID:15878741). Noncoding variants in the enhancer region (e.g., c.-3026C>T) reduce NAGS expression in HepG2 cells (PMID:30337552). An AAV-mediated gene therapy in Nag-/- mice fully rescued hyperammonemia, underscoring the requirement of L-arginine–dependent activation of NAGS for ureagenesis (PMID:33574402).

4. Clinical Presentation & Management

Presentation ranges from catastrophic neonatal hyperammonemia with coma to adult encephalopathy, headaches, vomiting, nausea, reduced consciousness, and atypical behavior. Early diagnosis via molecular testing or measurement of ammonia is critical. Specific therapy with N-carbamylglutamate restores ureagenesis and normalizes biochemical parameters, reducing the need for protein restriction and improving outcomes.

5. Integration and Take-Home Message

The NAGS–urea cycle disorder association is Definitive. Genetic and functional data robustly support pathogenicity of diverse NAGS variants. Targeted therapy exists, making early molecular diagnosis essential for improving patient outcomes.

Key Take-Home: Early recognition of NAGS deficiency enables effective treatment with N-carbamylglutamate, transforming a severe metabolic crisis into a manageable condition.

References

• European Journal of Pediatrics • 1991 • N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication PMID:2044610
• Molecular Genetics and Metabolism Reports • 2016 • N-acetylglutamate synthase deficiency: Novel mutation associated with neonatal presentation and literature review of molecular and phenotypic spectra PMID:27570737
• 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
• Prenatal Diagnosis • 2004 • Genetic approach to prenatal diagnosis in urea cycle defects PMID:15164414
• 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

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