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Hyperammonemia due to N-acetylglutamate synthase deficiency
A rare disorder of urea cycle metabolism causing a deficit of ammonia detoxification and arginine synthesis, and characterized by hyperammonemia of variable severity. Manifestations range from neonatal presentation of poor feeding, vomiting, lethargy, tachypnea, convulsions and coma to adult-onset headaches, hazy gastrointestinal symptoms, seizures, behavioral/psychiatric problems, confusion and lethargy.
ORPHA:927
To date, approximately 100 cases have been reported worldwide.
Onset occurs at any age... The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhea, poor feeding, seizures, hypotonia, global development delay, psychiatric symptoms and respiratory distress. The hyperammonemia might be severe and may lead to hyperammonemic coma.
The primary disorder is caused by mutations in the NAGS gene (17q21.31), leading to a total or partial lack of activity in the encoded protein, N-acetylglutamate synthase (NAGS). NAGS is an allosteric activator of carbamylphosphate synthetase I (CPSI), the enzyme catalyzing the first step in ureagenesis. NAGS deficiency may also be secondary to certain organic acid disorders, defects in fatty acid metabolism or valproic acid treatment.
Besides the hyperammonemia, diagnosis is evoked by a rise in glutamine coupled with decrease of citrulline/arginine and absence of urinary orotic acid. Confirmation by DNA analysis is mandatory. If the latter is not conclusive, enzymatic NAGS activity upon liver biopsy can help in the definite diagnosis.
The principle differential diagnosis is carbamoyl phosphate synthetase 1 deficiency.
The primary disorder is transmitted as an autosomal recessive trait. The risk to siblings of inheriting the disease is 25%. Offspring of affected individuals are obligate carriers.
Acute treatment of hyperammonemia of unknown etiology consists in high glucose perfusion (with withdrawal of proteins and lipids) and administration of ammonia scavengers (sodium benzoate and/or sodium phenylbutyrate), L-Arginine and N-carbamylglutamate. Once definite diagnosis of NAGS deficiency is established, daily administration of N-carbamylglutamate, a structural analogue of NAGS that activates CPSI, might be sufficient as a unique treatment without protein restriction.
In most cases, early treatment with N-carbamylglutamate (i.e. before the onset of permanent neurological sequelae) allows normal global development and an excellent quality of life without diet. Although the severity of the disorder is variable, the prognosis without treatment may be poor with neurological deficit and a potentially fatal outcome.
Last update: May 2022 - Expert reviewer(s): Dr Dries DOBBELAERE
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