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the 14th letter of the Roman alphabet (同)n

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〈U〉〈C〉(…の)(量・額などの)不足,欠乏《+『of』(『in』)+『名』》 / 〈C〉不足分,不足量,不足額 / 〈C〉(精神・肉体などの)欠陥
nitrogenの化学記号
neodymiumの化学記号

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/11/13 14:45:10」(JST)

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N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.

Mechanism

Carbamoyl phosphate synthase I is an enzyme found in mitochondrial matrix and it catalyzes the very first reaction of the Urea cycle, in which carbamoyl phosphate is produced.

Carbamoyl Phosphate Synthase 1, abbreviated as CPS1, is activated by its natural activator N-Acetyl glutamate, which in turn is synthesized from acetyl-CoA and glutamic acid in the reaction catalyzed by N-Acetyl glutamate synthase, commonly called NAGS. N-Acetyl Glutamate is required for the Urea cycle to take place.

Deficiency in N-Acetylglutamate_synthase or a genetic mutation in the gene coding for the enzyme, will lead to urea cycle failure in which ammonia is not converted to urea, but rather accumulated in blood leading to the condition called Type I Hyperammonemia. This is a severe neonatal disorder with fatal consequences, if not detected immediately upon birth.

Genetics

N-Acetylglutamate synthase deficiency has an autosomal recessive pattern of inheritance.

The chromosome found to be carrying the gene encoding for N-Acetyl Glutamate synthetase is chromosome 17q (q stands for longer arm of the chromosome) in humans and chromosome 11 in mice. In both organisms, the chromosome consists of seven exons and six introns and non-coding sequence.

The figure shows human chromosome 17q and the coding region that encodes the NAGS enzyme. It has seven exons and six introns. The exons are shown as red squares.

The cause for this disorder is a single base deletion that led to frameshift mutation, and thus the error in gene's coding for this specific enzyme.

Presentation and treatment

The symptoms are visible within the first week of life and if not detected and diagnosed correctly immediately consequences are fatal.

Although there is currently no cure, treatment includes injections of structurally similar compound, N-Carbamoyl-L-glutamate, an analogue of N-Acetyl Glutamate. This analogue likewise activates CPS1. This treatment mitigates the intensity of the disorder.

If symptoms are detected early enough and the patient is injected with this compound, levels of severe mental retardation can be slightly lessened, but brain damage is irreversible.

Early symptoms include lethargy, vomiting, and deep coma.

External links

GeneReviews/NCBI/NIH/UW entry on Urea Cycle Disorders Overview
The National Urea Cycle Disorders Foundation

References

Hall L, Metzenberg R, Cohen P (1958). "Isolation and characterization of a naturally occurring cofactor of carbamyl phosphate biosynthesis". J Biol Chem 230 (2): 1013–21. PMID 13525417.

Caldovic L, Morizono H, Panglao M, Cheng S, Packman S, Tuchman M (2003). "Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia". Hum Genet 112 (4): 364–8. doi:10.1007/s00439-003-0909-5. PMID 12594532.

UpToDate Contents

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English Journal

[Perioperative management of the child with a known metabolic disease].

Grosu I, Scholtes JL, Veyckemans F.SourceService d'Anesthésiologie, Cliniques Universitaires St-Luc, Bruxelles, Belgique.
Archives de pédiatrie : organe officiel de la Sociéte française de pédiatrie.Arch Pediatr.2010 Jun;17(6):949-50. doi: 10.1016/S0929-693X(10)70193-7.
PMID 20654975

Carglumic acid: new preparation. An advance in rare urea cycle disorders.

[No authors listed]Abstract(1) Previously, phenylbutyrate sodium was the only product marketed in France for the treatment of diseases caused by enzyme deficiencies affecting the urea cycle. By a non specific action, this drug partially prevents episodes of hyperammonaemia and their potentially severe consequences. (2) Marketing authorization has now been granted, through the European centralised procedure, for carglumic acid (N-carbamyl L-glutamic acid) as replacement therapy for N-acetylglutamate synthetase deficiency, the rarest urea cycle disorder. This enzyme is crucial for the first step of the urea cycle. (3) Thirteen of the 16 patients in the clinical evaluation dossier, who were treated before the onset of permanent sequelae due to hyperammonaemia, had normal growth and psychomotor development. The optimal dose of carglumic acid is not known. (4) No serious adverse effects have been observed, but too few patients have been treated to identify possible rare adverse effects. There are no data on the effects of carglumic acid in pregnant women. (5) In practice, carglumic acid is now the reference treatment for patients with N-acetylglutamate synthetase deficiency, despite several unknowns.
Prescrire international.Prescrire Int.2004 Feb;13(69):3-4.
(1) Previously, phenylbutyrate sodium was the only product marketed in France for the treatment of diseases caused by enzyme deficiencies affecting the urea cycle. By a non specific action, this drug partially prevents episodes of hyperammonaemia and their potentially severe consequences. (2) Market
PMID 15055204