''N''-Acetylglutamate synthase deficiency is an autosomal recessive

urea cycle disorder Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important r ...

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 A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

found to be carrying the

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

encoding for N-acetyl glutamate synthase is

chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...

q (q stands for longer arm of the

) in humans and chromosome 11 in mice. In both organisms, the chromosome consists of seven exons and six

introns An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...

and

non-coding sequence Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, microRNA, piRNA, ribosomal RNA, and regul ...

. 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.

Mechanism

Carbamoyl phosphate synthase I is an enzyme found in

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...

and it catalyzes the very first reaction of the

urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of Biochemistry, biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle ...

, in which

carbamoyl phosphate Carbamoyl phosphate is an anion of biochemical significance. In land-dwelling animals, it is an intermediary metabolite in nitrogen disposal through the urea cycle and the synthesis of pyrimidines. Its enzymatic counterpart, carbamoyl phosphate sy ...

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 Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...

is not converted to urea, but rather accumulated in blood leading to the condition called type I

hyperammonemia Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary. Ammonia is a substance that contains nitrogen. It i ...

. 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, 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 Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

can be slightly lessened, but brain damage 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 Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

, and deep coma.

References

* *

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