N-acetylglutamate synthase deficiency

Roland Posset MD (Dr. Posset of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Georg F Hoffmann MD (Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Barry Wolf MD PhD, editor. (Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.)
Originally released March 27, 1995; last updated May 6, 2020; expires May 6, 2023

This article includes discussion of N-acetylglutamate synthase deficiency (NAGSD), also known NAGS deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


N-acetylglutamate synthase deficiency is an inherited urea cycle disorder that causes hyperammonemia and neurologic sequelae, and most importantly, intellectual disability and early death. N-acetylglutamate synthase (NAGS) plays a determinant role in regulating the urea cycle at the entry point and connects energy metabolism with nitrogen disposal. Primary genetic enzyme deficiency almost invariably results in hyperammonemic coma within the first weeks of life (≤ 28 days; neonatal/early onset), whereas presentation at a later stage of life (> 28 days; late onset) has very rarely been reported so far. Biochemical markers include elevated plasma glutamine and normal to reduced L-arginine and/or L-citrulline concentrations on amino acid analysis. Diagnosis is established by molecular genetic analysis or, rarely, by enzymatic testing. Treatment consists of long-term oral therapy with N-carbamylglutamate. It should be noted, however, that a successful therapeutic trial with N-carbamylglutamate is not diagnostic of primary N-acetylglutamate synthase deficiency because the drug may also lower elevated ammonia concentrations in some patients with organic acidurias or carbamylphosphate synthetase 1 deficiency, especially when added to the emergency treatment. N-carbamylglutamate is potentially of use in the treatment of other secondary conditions that interfere with N-acetylglutamate synthase activity. Secondary functional deficiencies occur whenever the synthesis of either of the substrates, acetyl-CoA or glutamate, is insufficient or when other substrates (eg, pathological acyl-CoAs) interfere or compete with acetyl-CoA for NAGS activity. This is the case if intermediates of amino and/or fatty acid metabolism or certain drugs (eg, valproate or pivalate-ester antibiotics) accumulate.

Currently, international networks for rare metabolic diseases (UCDC, E-IMD, JUCDC) aim to more completely describe the natural history, especially the initial and long-term evolving clinical phenotype of patients with urea cycle disorders, such as N-acetylglutamate synthase deficiency. Furthermore, they want to determine if the natural disease course can be favorably modulated by diagnostic and therapeutic interventions. These networks collect systematic data to improve the clinical knowledge, develop guidelines, and provide patients and professionals with reliable data on disease manifestation, complications, as well as long-term outcomes of urea cycle disorders. These networks include the Urea Cycle Disorders Consortium (UCDC), established in 2006, the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD), established in 2011, and the Japanese Urea Cycle Disorders Consortium (JUCDC), established in 2012 (Summar et al 2014).

Key points


• N-acetylglutamate synthase deficiency is a rare urea cycle disorder that causes hyperammonemia, neurologic sequelae, and intellectual disability.


• Disease manifestations occur most often within the first days of life (early onset ≤ 28 days) and less commonly after the neonatal period (late onset > 28 days).


• Neurologic outcome depends on noninterventional parameters, eg, intrinsic disease severity (reflected by onset type and initial peak plasma ammonium concentration during first metabolic decompensation). The impact of interventional parameters, eg, diagnostic and therapeutic interventions, on clinical outcome remains to be elucidated.


• Therapy is based on principles of acute and long-term management including administration of N-carbamylglutamate.

Historical note and terminology

N-acetylglutamate synthase deficiency (NAGSD) was first described in 1981 in a male baby and had presumably occurred in 2 of his siblings who had died in the neonatal period (Bachmann et al 1981). N-acetylglutamate synthase deficiency was considered and the patient successfully treated with benzoate, and later with carbamylglutamate and arginine. N-acetylglutamate synthase deficiency is caused by a deficiency of N-acetylglutamate synthase, which catalyzes the synthesis of N-acetylglutamate from acetyl-CoA and glutamate.

Diagram of ammonia detoxification through its conversion to urea by enzymes Image: Ammonia is detoxified through its conversion to urea by the enzymes in the small boxes
N-acetylglutamate is the required allosteric activator of carbamoylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle (Ah Mew and Caldovic 2011).

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