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Congenital mitochondrial disorder of the metabolism of ammonium (hyperammonemia) leading to an anomaly in the urea cycle.
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Very rare; 56 cases from 42 families since 1981.
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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.
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Elevated blood ammonium (NH4) level in a lethargic or comatose patient. A liver needle biopsy is necessary to confirm the diagnosis.
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Two clinical presentations, depending on complete or partial lack of NAGS.
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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.
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Precautions before anesthesia
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Check blood glucose and NH4 levels. Make sure sodium benzoate, sodium phenylbutyrate, and L-arginine are available for emergency treatment of hyperammonemia.
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Anesthetic considerations
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Prolonged fasting should be avoided; intravenous glucose (5 ...