N-Acetylglutamate synthase deficiency

N-Acetylglutamate synthase deficiency
N-Acetylglutamic acid
Classification and external resources
OMIM	237310
DiseasesDB	29823
eMedicine	ped/10

N-Acetylglutamate synthase (or synthetase) 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.

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.

External links

Inborn error of amino acid metabolism (E70–E72, 270)

K→acetyl-CoA

Lysine/straight chain	Glutaric acidemia type 1 type 2 Hyperlysinemia Pipecolic acidemia Saccharopinuria

Leucine	3-hydroxy-3-methylglutaryl-CoA lyase deficiency 3-Methylcrotonyl-CoA carboxylase deficiency 3-Methylglutaconic aciduria 1 Isovaleric acidemia Maple syrup urine disease

Tryptophan	Hypertryptophanemia

G→pyruvate→citrate

Glycine	D-Glyceric acidemia Glutathione synthetase deficiency Sarcosinemia Glycine→Creatine: GAMT deficiency Glycine encephalopathy

G→glutamate→
α-ketoglutarate

Histidine	Carnosinemia Histidinemia Urocanic aciduria

Proline	Hyperprolinemia Prolidase deficiency

Glutamate/glutamine	SSADHD

G→propionyl-CoA→
succinyl-CoA

Valine	Hypervalinemia Isobutyryl-CoA dehydrogenase deficiency Maple syrup urine disease

Isoleucine	2-Methylbutyryl-CoA dehydrogenase deficiency Beta-ketothiolase deficiency Maple syrup urine disease

Methionine	Cystathioninuria Homocystinuria Hypermethioninemia

General BC/OA	Methylmalonic acidemia Methylmalonyl-CoA mutase deficiency Propionic acidemia

G→fumarate

Phenylalanine/tyrosine

Phenylketonuria	6-Pyruvoyltetrahydropterin synthase deficiency Tetrahydrobiopterin deficiency

Tyrosinemia	Alkaptonuria/Ochronosis Type I tyrosinemia Type II tyrosinemia Type III tyrosinemia/Hawkinsinuria

Tyrosine→Melanin	Albinism: Ocular albinism (1) Oculocutaneous albinism (Hermansky–Pudlak syndrome) Waardenburg syndrome

Tyrosine→Norepinephrine	Dopamine beta hydroxylase deficiency reverse: Brunner syndrome

G→oxaloacetate

Urea cycle/Hyperammonemia (arginine aspartate)	Argininemia Argininosuccinic aciduria Carbamoyl phosphate synthetase I deficiency Citrullinemia N-Acetylglutamate synthase deficiency Ornithine transcarbamylase deficiency/translocase deficiency

Transport/
IE of RTT

Other

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