''N''-Acetylglutamate synthase deficiency is an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

Signs and symptoms

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

Genetics

The chromosome found to be carrying the gene encoding for N-acetyl glutamate synthase 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 An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

and six introns and non-coding sequence. The cause for this disorder is a single base deletion that led to

frameshift mutation A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature ...

, and thus the error in gene's coding for this specific enzyme.

Mechanism

Carbamoyl phosphate synthase I Carbamoyl phosphate synthetase I is a ligase enzyme located in the mitochondria involved in the production of urea. Carbamoyl phosphate synthetase I (CPS1 or CPSI) transfers an ammonia molecule to a molecule of bicarbonate that has been phosphor ...

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 Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...

and

glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

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.

Diagnosis

Treatment

Although there is currently no cure, treatment includes injections of structurally similar compound,

carglumic acid Carglumic acid, sold under the brand name Carbaglu among others, is used for the treatment of hyperammonaemia. Carglumic acid is a carbamoyl phosphate synthetase 1 (CPS 1) activator. The most common adverse effects include vomiting, abdominal ...

, 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 Neurotrauma, brain damage or brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating t ...

is irreversible. Also: hemodialysis for emergent hyperammonemic crisis, Na benzoate, Na phenylacetate, Na phenylbutyrate, low-protein diet supplemented with essential amino acid mixture and arginine, citrulline, experimental attempts at gene therapy, liver transplantation (which is curative), and also N-carbamylglutamate supplementation. Early symptoms include lethargy, vomiting, and deep

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...

References

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External links

GeneReviews/NCBI/NIH/UW entry on Urea Cycle Disorders Overview
{{Amino acid metabolic pathology Amino acid metabolism disorders Autosomal recessive disorders Rare diseases