Hyperammonemia due to N-acetylglutamate synthase deficiency

Hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency is an extremely rare inherited disorder of the urea cycle, also known as NAGS deficiency or N-acetylglutamate synthetase deficiency. The urea cycle is the metabolic pathway in the liver responsible for converting toxic ammonia into urea for excretion. NAGS produces N-acetylglutamate (NAG), which is an essential activator of carbamoyl phosphate synthetase 1 (CPS1), the first enzyme in the urea cycle. When NAGS is deficient, CPS1 cannot function properly, leading to the accumulation of ammonia (hyperammonemia) in the blood, which is highly toxic to the brain and central nervous system. The disease typically presents in the neonatal period with severe hyperammonemia, though later-onset forms with milder or episodic symptoms have been described. Neonatal-onset patients may develop poor feeding, vomiting, lethargy, hypothermia, hyperventilation, seizures, and progressive encephalopathy that can rapidly lead to coma and death if untreated. Later-onset forms may present in infancy, childhood, or even adulthood with episodic hyperammonemia triggered by illness, stress, or high protein intake, manifesting as recurrent vomiting, confusion, ataxia, and behavioral changes. The brain is the primary organ affected by ammonia toxicity, and intellectual disability or developmental delay may result from hyperammonemic episodes. NAGS deficiency is unique among urea cycle disorders because it has a specific pharmacological treatment: carglumic acid (N-carbamylglutamate, brand name Carbaglu), a synthetic structural analog of NAG that can directly activate CPS1, bypassing the enzymatic defect. Carglumic acid is considered the first-line treatment and can dramatically reduce ammonia levels. Additional management includes dietary protein restriction, ammonia scavenger medications (such as sodium benzoate or sodium phenylbutyrate), and emergency treatment of acute hyperammonemic crises with hemodialysis if necessary. With early diagnosis and appropriate treatment, outcomes can be significantly improved compared to other urea cycle disorders.

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