Normal N-acetylglutamate concentration measured in liver from a new patient with N-acetylglutamate synthetase deficiency: Physiologic and biochemical implications

Vockley, Jerry; Vockley, Catherine M.Walsh; Lin, Shaun-Pei; Tuchman, Mendel; Wu, Jia‐Feng; Lin, Ching-Yuang; Seashore, Margretta R.

doi:10.1016/0885-4505(92)90006-k

Cited by 21 publications

(21 citation statements)

References 17 publications

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“…In these patients, the diagnosis of NAGS deficiency was based on fairly nonspecific clinical and biochemical presentation that included hyperammonemia, elevated plasma glutamine, reduced or absent plasma citrulline, and normal urinary orotate [Bachmann et al, 1981[Bachmann et al, , 1982a[Bachmann et al, , 1988Burlina et al, 1992;Elpeleg et al, 1990;Forget et al, 1999;Guffon et al, 1995;Hinnie et al, 1997;Morris et al, 1998;Pandya et al, 1991;Plecko et al, 1998;Schubiger et al, 1991;Vockley et al, 1992]. Diagnosis of the NAGS deficiency also relied on the measurements of enzymatic activity in the liver biopsies of patients with presumed NAGS deficiency.…”

Section: Molecular Diagnosis Strategiesmentioning

confidence: 99%

“…Diagnosis of the NAGS deficiency also relied on the measurements of enzymatic activity in the liver biopsies of patients with presumed NAGS deficiency. These measurements showed variable enzymatic activity, ranging from undetectable to normal activity that is unresponsive to arginine [Bachmann et al, 1981;Burlina et al, 1992;Elpeleg et al, 1990;Forget et al, 1999;Grody et al, 1994;Guffon et al, 1995;Hinnie et al, 1997;Morris et al, 1998;Pandya et al, 1991;Plecko et al, 1998;Vockley et al, 1992]. Since the establishment of a molecular diagnostic test for NAGS deficiency in 2002, the condition has been diagnosed in at least 18 reported families.…”

Section: Molecular Diagnosis Strategiesmentioning

confidence: 99%

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Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene

2007

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Section: Molecular Diagnosis Strategiesmentioning

confidence: 99%

Section: Molecular Diagnosis Strategiesmentioning

confidence: 99%

Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene

2007

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“…Several putative cases of NAGS deficiency have been reported [Bachmann et al, 1982;Bachmann et al, 1989;Epleleg et al, 1990;Schubiger et al, 1991;Vockley et al, 1992;Plecko et al, 1998]. All cases have included hyperammonemia but otherwise have had variable clinical presentations.…”

Section: Isolated Hyperammonemia-n-acetylglutamate Synthetase [Nags] mentioning

confidence: 99%

“…Activity of NAGS from liver biopsies of these patients has ranged from none to approximately 60% of normal [Bachmann et al, 1989;Epleleg et al, 1990;Plecko et al, 1998]. Despite having only 10% of normal NAGS activity, the liver of the one patient in whom it was measured had normal NAG content [Vockley et al, 1992]. Tuchman and Holzknecht have noted that measurements of NAG content and NAGS activity in the liver may be inaccurate as a result of the indirect assays employed [1990].…”

Section: Isolated Hyperammonemia-n-acetylglutamate Synthetase [Nags] mentioning

confidence: 99%

Disorders of glutamate metabolism

Kelly

Stanley

2001

Ment. Retard. Dev. Disabil. Res. Rev.

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The significant role the amino acid glutamate assumes in a number of fundamental metabolic pathways is becoming better understood. As a central junction for interchange of amino nitrogen, glutamate facilitates both amino acid synthesis and degradation. In the liver, glutamate is the terminus for release of ammonia from amino acids, and the intrahepatic concentration of glutamate modulates the rate of ammonia detoxification into urea. In pancreatic beta-cells, oxidation of glutamate mediates amino acid-stimulated insulin secretion. In the central nervous system, glutamate serves as an excitatory neurotransmittor. Glutamate is also the precursor of the inhibitory neurotransmittor GABA, as well as glutamine, a potential mediator of hyperammonemic neurotoxicity. The recent identification of a novel form of congenital hyperinsulinism associated with asymptomatic hyperammonemia assigns glutamate oxidation by glutamate dehydrogenase a more important role than previously recognized in beta-cell insulin secretion and hepatic and CNS ammonia detoxification. Disruptions of glutamate metabolism have been implicated in other clinical disorders, such as pyridoxine-dependent seizures, confirming the importance of intact glutamate metabolism. This article will review glutamate metabolism and clinical disorders associated with disrupted glutamate metabolism.

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“…NAGSD is transmitted as an autosomal recessive trait. The clinical presentation is variable, comprising cases with early onset and fulminant neonatal hyperammonemia, as well as late presentations [Bachmann et al, 1988;Schubiger et al, 1991;Vockley et al, 1992;Guffon et al, 1995;Hinnie et al, 1997;Plecko et al, 1998;Elpeleg et al, 2002]. In suspected patients, the amino acid profiles in plasma and the excretion of orotic acid in the urine cannot discriminate between deficiencies of either CPS1 or NAGS.…”

Section: Introductionmentioning

confidence: 99%

Mutation analysis in patients with N-acetylglutamate synthase deficiency

et al. 2003

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N-acetylglutamate synthase (NAGS) is the key enzyme for the regulation of the hepatic urea cycle and is also highly expressed in kidney and gut. The reaction product, N-acetylglutamate, is an allosteric activator of carbamylphosphate synthetase 1 in the liver, catalyzing the initial step of ammonia detoxification. NAGS deficiency is a rare inborn error of metabolism inherited as an autosomal recessive trait leading to hyperammonemia. Using homology search based on genetic information of ascomycetes, we identified the human gene for NAGS on chromosome 17q21.31. There is a distinct pattern of organospecific expression of transcripts in liver, small intestine, and kidney similar to the other mitochondrially located enzymes of the urea cycle. The encoded 534 amino acid polypeptide has a consensus sequence for a 49 amino acid mitochondrial leader peptide. We identified private mutations of the NAGS gene in patients with severe early onset of clinical symptoms (IVS3-2A>T, c.1306_1307insT, c.971G>A/W324X, c.1289T>C/L430P, c.1299G>C/E433S, c.1450T>C/W484R), as well as in a case with late onset (c.835G>A/A279P). Four out of seven mutations were detected on exon 6. This is the first report of mutation analysis in a series of families affected with deficiency of NAGS. Molecular analysis of patients and reliable antenatal diagnostics for affected families are now feasible.

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Normal N-acetylglutamate concentration measured in liver from a new patient with N-acetylglutamate synthetase deficiency: Physiologic and biochemical implications

Cited by 21 publications

References 17 publications

Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene

Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene

Disorders of glutamate metabolism

Mutation analysis in patients with N-acetylglutamate synthase deficiency

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