Dataset Information

N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region.

ABSTRACT: N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive disorder of the urea cycle that results from absent or decreased production of N-acetylglutamate (NAG) due to either decreased NAGS gene expression or defective NAGS enzyme. NAG is essential for the activity of carbamylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle. NAGSD is the only urea cycle disorder that can be treated with a single drug, N-carbamylglutamate (NCG), which can activate CPS1 and completely restore ureagenesis in patients with NAGSD. We describe a novel sequence variant NM_153006.2:c.-3026C?>?T in the NAGS enhancer that was found in three patients from two families with NAGSD; two patients had hyperammonemia that resolved upon treatment with NCG, while the third patient increased dietary protein intake after initiation of NCG therapy. Two patients were homozygous for the variant while the third patient had the c.-3026C?>?T variant and a partial uniparental disomy that encompassed the NAGS gene on chromosome 17. The c.-3026C?>?T sequence variant affects a base pair that is highly conserved in vertebrates; the variant is predicted to be deleterious by several bioinformatics tools. Functional assays in cultured HepG2 cells demonstrated that the c.-3026C?>?T substitution could result in reduced expression of the NAGS gene. These findings underscore the importance of analyzing NAGS gene regulatory regions when looking for molecular causes of NAGSD.

SUBMITTER: Williams M

PROVIDER: S-EPMC6194121 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region.

Williams Monique M Burlina Alberto A Rubert Laura L Polo Giulia G Ruijter George J G GJG van den Born Myrthe M Rüfenacht Véronique V Haskins Nantaporn N van Zutven Laura J C M LJCM Tuchman Mendel M Saris Jasper J JJ Häberle Johannes J Caldovic Ljubica L

Scientific reports 20181018 1

N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive disorder of the urea cycle that results from absent or decreased production of N-acetylglutamate (NAG) due to either decreased NAGS gene expression or defective NAGS enzyme. NAG is essential for the activity of carbamylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle. NAGSD is the only urea cycle disorder that can be treated with a single drug, N-carbamylglutamate (NCG), which ...[more]

PMID: 30337552

Similar Datasets

Project description:BACKGROUND:N-Acetylglutamate synthase (NAGS) deficiency is an extremely rare autosomal recessive metabolic disorder affecting the urea cycle, leading to episodes of hyperammonemia which can cause significant morbidity and mortality. Since its recognition in 1981, NAGS deficiency has been treated with carbamylglutamate with or without other measures (nutritional, ammonia scavengers, dialytic, etc.). We conducted a systematic literature review of NAGS deficiency to summarize current knowledge around presentation and management. METHODS:Case reports and case series were identified using the Medline database, as well as references from other articles and a general internet search. Clinical data related to presentation and management were abstracted by two reviewers. RESULTS:In total, 98 cases of NAGS deficiency from 79 families, in 48 articles or abstracts were identified. Of these, 1 was diagnosed prenatally, 57 were neonatal cases, 34 were post-neonatal, and 6 did not specify age at presentation or were asymptomatic at diagnosis. Twenty-one cases had relevant family history. We summarize triggers of hyperammonemic episodes, diagnosis, clinical signs and symptoms, and management strategies. DNA testing is the preferred method of diagnosis, although therapeutic trials to assess response of ammonia levels to carbamylglutamate may also be helpful. Management usually consists of treatment with carbamylglutamate, although the reported maintenance dose varied across case reports. Protein restriction was sometimes used in conjunction with carbamylglutamate. Supplementation with citrulline, arginine, and sodium benzoate also were reported. CONCLUSIONS:Presentation of NAGS deficiency varies by age and symptoms. In addition, both diagnosis and management have evolved over time and vary across clinics. Prompt recognition and appropriate treatment of NAGS deficiency with carbamylglutamate may improve outcomes of affected individuals. Further research is needed to assess the roles of protein restriction and supplements in the treatment of NAGS deficiency, especially during times of illness or lack of access to carbamylglutamate.

Dataset Information

N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region.

Publications

N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets