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At a glance

Congenital mitochondrial disorder of the metabolism of ammonium (hyperammonemia) leading to an anomaly in the urea cycle.


NAGS Deficiency.


Very rare; 56 cases from 42 families since 1981.

Genetic inheritance

Autosomal recessive.


N-acetylglutamate synthatase (NAGS) deficiency is caused by homozygous or compound heterozygous mutation in the NAGS gene on chromosome 17q21. N-acetylglutamate is synthesized from acetyl-CoA and L-glutamate by mitochondrial NAGS in the liver. Its role is to activate carbamoyl phosphate synthetase, one of the enzymes of the urea cycle. Impairment of the urea cycle produces hyperammonemia.


Elevated blood ammonium (NH4) level in a lethargic or comatose patient. A liver needle biopsy is necessary to confirm the diagnosis.

Clinical aspects

Two clinical presentations, depending on complete or partial lack of NAGS.

  • Neonatal Presentation: Starting within the first 4 days of life: refusal to drink, irritability, persistent vomiting, and mild respiratory alkalosis, followed rapidly by neurologic deterioration leading to coma, convulsions, and hypotonia.

  • Infant Presentation: Long history of chronic hepatogastric symptoms, such as recurrent episodes of vomiting, failure to thrive. A gastrointestinal cause to these problems is commonly sought before establishing the diagnosis.

  • Late-Onset Presentation: A neurologic picture of chronic encephalopathy, behavioral disorders (agitation, delirium, irritability), or Reye-like Syndrome following valproate therapy for seizures are the hallmarks of a late presentation in childhood and adolescence. Death may occur during a metabolic crisis precipitated by an infection, surgery, increased catabolism, or a protein-rich diet. In case of seizures, sodium valproate should not be used because it may precipitate acute metabolic decompensation. Liver transplantation is curative. The basic treatment is a low-protein diet carefully calculated and adapted to the child’s needs and metabolic tolerance, but may not be essential if treated with N-carbamyl glutamate. N-carbamyl glutamate can be given orally at a dose of 100 to 300 mg/kg/day divided into three to six doses, usually before feedings. In case of hyperammonemia:

    • Stop protein intake and restrict fluid volume if there is any concern about cerebral edema. Provide a high-energy intake orally or intravenous (IV) (glucose 10-20%).

    • Use alternative pathways for nitrogen elimination: give sodium benzoate up to 500 mg/kg/day, sodium phenylbutyrate up to 600 mg/kg/day, and L-arginine 300 mg/kg/day orally or IV. These drugs lead to significant potassium losses, so potassium blood levels should be monitored. Treat sepsis and convulsions aggressively.

Precautions before anesthesia

Check blood glucose and NH4 levels. Make sure sodium benzoate, sodium phenylbutyrate, and L-arginine are available for emergency treatment of hyperammonemia.

Anesthetic considerations

Prolonged fasting should be avoided; intravenous glucose (5 ...

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