N-acetylglutamate synthase (NAGS) is a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate, an essential allosteric activator of carbamyl phosphate synthetase I, the first enzyme of the urea cycle. Liver NAGS deficiency has previously been found in a small number of patients with hyperammonemia. The mouse and human NAGS genes have recently been cloned and expressed in our laboratory. We searched for mutations in the NAGS gene of two families with presumed NAGS deficiency. The exons and exon/intron boundaries of the NAGS gene were sequenced from genomic DNA obtained from the parents of an infant from the Faroe Islands who died in the neonatal period and from two Hispanic sisters who presented with acute neonatal hyperammonemia. Both parents of the first patient were found to be heterozygous for a null mutation in exon 4 (TGG-->TAG, Trp324Ter). Both sisters from the second family were homozygous for a single base deletion in exon 4 (1025delG) causing a frameshift and premature termination of translation. The finding of deleterious mutations in the NAGS gene confirms the genetic origin of NAGS deficiency. This disorder can now be diagnosed by DNA testing allowing for carrier detection and prenatal diagnosis.
"Under normal physiologic conditions, ammonia is converted to urea in the liver by five enzymes: carbamoyl phosphate synthase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinic acid synthetase (ASS1), argininosuccinic acid lyase (ASL), and arginase (ARG) . A cofactorproducing enzyme, N-acetyl glutamate synthase (NAGS), is also believed to contribute to the urea cycle mechanism according to the finding that a NAGS deficiency yields a phenotype identical to CPS1 deficiency; specifically, it was found that in NAGS absence, CPS1 is rendered inactive . In newborns, hyperammonemia is usually due to severe deficiency or even absence of activity of any of the five enzymes of the urea cycle or the NAGS cofactor. "
[Show abstract][Hide abstract] ABSTRACT: Hyperammonemia related to urea cycle disorders is a rare cause of potentially fatal encephalopathy that is encountered in intensive care units (ICUs). Left undiagnosed, this condition may manifest irreversible neuronal damage. However, timely diagnosis and treatment initiation can be facilitated simply by increased awareness of the ICU staff. Here, we describe a patient with acute severe pancreatitis who developed hyperammonemia and encephalopathy without liver disease. Urea cycle disorder was suspected and hemodialysis was initiated. Following reduction of ammonia levels, subsequent treatment included protein restriction and administration of arginine and sodium benzoate. The patient was discharged to home after 47 days with plasma ammonia within normal range and without neurological symptoms. In clinical care settings, patients with neurological symptoms unexplained by the present illness should be assessed for serum ammonia levels to disclose any urea cycle disorders to initiate timely treatment and improve outcome.
Case Reports in Medicine 08/2013; 2013(4):903546. DOI:10.1155/2013/903546
"These date back to 1981 when CG was first administered to a human NAGSD patient.2,25 Since then, various case reports have been published demonstrating the efficacy of CG treatment for acute and chronic management of NAGSD but with variable morbidity and mortality mostly depending on the clinical course prior to CG administration.4,5,7,8,10,11,14,15,26,27,32 Most authors used a different protocol for initiation and maintenance of CG treatment resulting in varying doses applied. "
[Show abstract][Hide abstract] ABSTRACT: N-acetylglutamate synthase (NAGS) deficiency is a rare inborn error of metabolism affecting ammonia detoxification in the urea cycle. The product of NAGS is N-acetylglutamate which is the absolutely required allosteric activator of the first urea cycle enzyme carbamoylphosphate synthetase 1. In defects of NAGS, the urea cycle function can be severely affected resulting in fatal hyperammonemia in neonatal patients or at any later stage in life. NAGS deficiency can be treated with a structural analog of N-acetylglutamate, N-carbamyl-L-glutamate, which is available for enteral use as a licensed drug. Since NAGS deficiency is an extremely rare disorder, reports on the use of N-carbamyl-L-glutamate are mainly based on single patients. According to these, the drug is very effective in treating acute hyperammonemia by avoiding the need for detoxification during the acute metabolic decompensation. Also during long-term treatment, N-carbamyl-L-glutamate is effective in maintaining normal plasma ammonia levels and avoiding the need for additional drug therapy or protein-restricted diet. Open questions remain which concern the optimal dosage in acute and long-term use of N-carbamyl-L-glutamate and potential additional disorders in which the drug might also be effective in treating acute hyperammonemia. This review focuses on the role of N-carbamyl-L-glutamate for the treatment of acute hyperammonemia due to primary NAGS deficiency but will briefly discuss the current knowledge on the role of N-carbamyl-L-glutamate for treatment of secondary NAGS deficiencies.
"In this report, we describe the first NAGS enhancer mutation, identified in a patient with an unspecified proximal UCD, who despite the absence of any identifiable NAGS mutations by conventional mutation analysis [Caldovic et al., 2007; Haberle et al., 2003], demonstrated a marked response to a short-term trial of NCG. We demonstrate that the mutation ascertained in our patient is indeed deleterious, and results in decreased transcription factor binding and expression of the NAGS gene. "
[Show abstract][Hide abstract] ABSTRACT: N-acetylglutamate synthase (NAGS) cat-alyzes the conversion of glutamate and acetyl-CoA to NAG, the essential allosteric activator of carbamyl phos-phate synthetase I, the first urea cycle enzyme in mam-mals. A 17-year-old female with recurrent hyperammone-mia attacks, the cause of which remained undiagnosed for 8 years in spite of multiple molecular and biochemi-cal investigations, showed markedly enhanced ureagenesis (measured by isotope incorporation) in response to N-carbamylglutamate (NCG). This led to sequencing of the regulatory regions of the NAGS gene and identification of a deleterious single-base substitution in the upstream enhancer. The homozygous mutation (c.-3064C>A), af-fecting a highly conserved nucleotide within the hepatic nuclear factor 1 (HNF-1) binding site, was not found in single nucleotide polymorphism databases and in a screen of 1,086 alleles from a diverse population. Functional as-says demonstrated that this mutation decreases transcrip-tion and binding of HNF-1 to the NAGS gene, while a consensus HNF-1 binding sequence enhances binding to HNF-1 and increases transcription. Oral daily NCG ther-apy restored ureagenesis in this patient, normalizing her biochemical markers, and allowing discontinuation of al-ternate pathway therapy and normalization of her diet with no recurrence of hyperammonemia. Hum Mutat 32:1153–1160, 2011. C 2011 Wiley-Liss, Inc.
Human Mutation 01/2011; 32(10). · 5.14 Impact Factor
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