Authors: Mai Labani , Talal ALAnzi , Anwar Almughyiri , Moeenaldeen AlSayed ,

Abstract

Background: N-acetylglutamate synthase deficiency (NAGSD) is the rarest urea cycle disorder and a potentially treatable cause of neonatal hyperammonemia. Because it may not be detected by routine newborn screening, delayed diagnosis can result in irreversible neurological injury.

Objective: To describe the clinical, biochemical, and molecular findings of two related patients with NAGSD and to highlight the importance of early recognition and treatment.

Methods: We report two related patients with clinically and molecularly confirmed NAGSD. Clinical presentation, biochemical results, neuroimaging, genetic findings, and treatment outcomes were reviewed.

Results: Both patients presented in the neonatal period with hyperammonemia and later developed recurrent metabolic decompensation and seizures. Biochemical evaluation showed elevated glutamine with normal citrulline and normal acylcarnitine profiles, making early biochemical recognition challenging. Whole exome sequencing identified a homozygous pathogenic splice-site variant in the NAGS gene, c.427-2A>T, in both patients. Despite treatment with carglumic acid and dietary management, both developed significant neurodevelopmental delay, likely secondary to early hyperammonemic brain injury. Neuroimaging findings were consistent with metabolic encephalopathy. After diagnosis and treatment, no further hyperammonemic crises were reported.

Conclusion: NAGSD should be considered in any neonate with unexplained hyperammonemia, even when newborn screening and citrulline levels are normal. Early empirical treatment with carglumic acid may be life-saving and can reduce the risk of permanent neurological damage, especially in high-consanguinity populations.

Keywords: N-acetylglutamate synthase deficiency, NAGS deficiency; hyperammonemia, urea cycle disorder, carglumic acid, neonatal onset, whole-exome sequencing, neurodevelopmental outcome.