N-Acetylglutamate synthase deficiency

N-Acetylglutamate synthase deficiency is a urea cycle disorder.

Mechanism
Carbamyl phosphate synthase 1 is an enzyme found in mitochondrial matrix and it catalyzes the very first reaction of the Urea cycle, in which carbamyl phosphate is produced.

Carbamyl Phosphate Synthase 1, abbreviated as CPS1, is activated by its biologically 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-Acetyl Glutamate Synthase or a genetic mutation in the gene coding for the enzyme, will lead to failure of the Urea cycle in which ammonia is not converted to urea, but rather accumulated in blood leading to the condition called Type I Hyperammonemia, severe neonatal disorder with fatal consequences, if not detected immediately upon birth.

Genetics


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 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.

Treatment does exist, but not the cure. The treatment includes injections of structurally similar compound, N-Carbamyl phosphate, an analogue of N-Acetyl Glutamate. Scientists that discovered this compound theorized that injected N-Carbamyl Phosphate could trick the organism into substituting N-Carbamyl Phosphate for N-Acetyl Glutamate and thus activate much required CPS1 enzyme, the catalyst in the very first reaction of the Urea Cycle. This treatment does not cure the disorder but rather 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 lowered, but brain damaged done to the organism is irreversible.

Early symptoms include lethargy, vomiting, and deep coma.

Literature