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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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NAGS Deficiency.

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Very rare; 37 cases from 24 families since 1981.

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Autosomal recessive.

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N-acetylglutamate is synthesized from acetyl-CoA and l-glutamate by mitochondrial N-acetylglutamate synthetase (NAGS) in the liver. Its role is to activate carbamoylphosphate 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.

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Late-Onset Presentation: Long history of chronic hepatogastric symptoms, such as recurrent episodes of vomiting, failure to thrive, and hepatomegaly. Others present a neurologic picture of chronic encephalopathy, behavioral disorders (agitation, delirium, irritability), or Reye-like syndrome following valproate therapy for seizures. 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. 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:

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  • 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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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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Prolonged fasting should be avoided; intravenous glucose (5 or 10% solution) should be administered to prevent protein catabolism; monitor blood glucose, ammonium, and lactates level on regular basis. Hypovolemia must be avoided, especially in patients with altered renal function. If there is risk of nasal, pharyngeal, or gastric bleeding, a gastric tube should be inserted to remove swallowed blood, which may provide a protein load that may trigger acute metabolic decompensation. Prolonged postoperative metabolic monitoring for early diagnosis of acute decompensation.

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This sort of pathology should be borne in mind when dealing with a supposedly “normal” child who does not wake up after uneventful ...

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