Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia

@article{Caldovic2003NullMI,
  title={Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia},
  author={Ljubica Caldovic and Hiroki Morizono and Maria Panglao and Sabrina F Cheng and Seymour Packman and Mendel Tuchman},
  journal={Human Genetics},
  year={2003},
  volume={112},
  pages={364-368}
}
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. [...] Key Method 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…Expand
Identification of novel mutations of the human N-acetylglutamate synthase gene and their functional investigation by expression studies.
TLDR
In conclusion, overexpression of wild type and mutated NAGS proteins in E. coli provides a suitable tool for functional analysis of N AGS deficiency and provides evidence for the disease-causing nature of mutations. Expand
Mutations and polymorphisms in the human N‐acetylglutamate synthase (NAGS) gene
TLDR
Early, accurate, and specific diagnosis of NAGS deficiency is critical since this condition can be successfully treated with N‐carbamylglutamate (NCG, Carbaglu®; Orphan Europe). Expand
N-acetylglutamate synthase deficiency: Novel mutation associated with neonatal presentation and literature review of molecular and phenotypic spectra
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An infant with NAGS deficiency who presented with neonatal hyperammonemia was found to have a novel homozygous splice-site mutation, c.1097-2A>T, in the NAGs gene, and the clinical course of this infant, who had rapid response to N-carbamylglutamate treatment is described. Expand
Misleading diagnosis of partial N‐acetylglutamate synthase deficiency based on enzyme measurement corrected by mutation analysis
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A Turkish family with an index patient, who died due to hyperammonemia, and another three siblings, who received a prophylactic treatment consisting of arginine hydrochloride, sodium benzoate and phenylbutyrate directly after birth without any deterioration of urea cycle function are reported on. Expand
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Treating NAGS deficiency with N-carbamyglutamate, a stable analog of NAG, can restore deficient urea cycle function and normalize blood ammonia in affected patients. Expand
Late onset N‐acetylglutamate synthase deficiency caused by hypomorphic alleles
TLDR
Study of the purified recombinant mutant proteins revealed deleterious effects on NAGS affinity for substrates, and on the rate of catalysis, and these studies provide a better understanding of the function of NAGs, and the mechanisms for deleteriously effect of mutations causing inherited N AGS deficiency. Expand
N‐carbamylglutamate enhancement of ureagenesis leads to discovery of a novel deleterious mutation in a newly defined enhancer of the NAGS gene and to effective therapy
TLDR
Oral daily NCG therapy restored ureagenesis in this patient, normalizing her biochemical markers, and allowing discontinuation of alternate pathway therapy and normalization of her diet with no recurrence of hyperammonemia. Expand
N-acetylglutamate synthase: structure, function and defects.
TLDR
For either condition, N-carbamylglutamate (NCG), a stable functional analog of NAG, was found to either restore or improve the deficient urea-cycle function. Expand
Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency
  • J. Häberle
  • Medicine
  • Therapeutics and clinical risk management
  • 2011
TLDR
The role of N-carbamyl-L-glutamate for the treatment of acute hyperammonemia due to primary NAGS deficiency is focused on but the current knowledge on the role of the drug is discussed, which is effective in maintaining normal plasma ammonia levels and avoiding the need for additional drug therapy or protein-restricted diet. Expand
Understanding N‐Acetyl‐L‐Glutamate Synthase Deficiency: Mutational Spectrum, Impact of Clinical Mutations on Enzyme Functionality, and Structural Considerations
TLDR
Enzyme activity and stability assays with 12 mutations introduced into pure recombinant Pseudomonas aeruginosa NAGS, together with in silico structural analysis, support the pathogenic role of most NAGSD‐associated mutations found. Expand
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Liver pathology revealed micro- and macrovesicular fat and mitochondria of irregular size and shape with intracristae crystallizations in patients with NAG synthetase deficiency, which suggests an abnormal localization of NAG to the cytoplasm and the likelihood of aberrant cy toplasmic synthesis of this compound. Expand
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