N-Acetilglutamato, Deficiencia de …, (N-acetylglutamate synthase deficiency) – NAGS gene.
N-acetylglutamate synthase deficiency, also known as type III hyperammonemia, is a process that results in abnormally high concentrations of ammonia in the blood, which are toxic to the body.
The signs and symptoms of this process are frequently manifested in the first days of life and may include lethargy, difficulty for controlling respiratory rate and body temperature, as well as seizures or unusual body movements. In addition, this process may lead to developmental delay or intellectual disability.
In other individuals, the signs and symptoms do not appear until later. In many affected adults, the disease itself or another type of disorder can trigger episodes of vomiting, lack of coordination, headaches, confusion, changes in behavior or coma.
This process is due to mutations in the NAGS (N-acetylglutamate synthase) gene, located on the long arm of chromosome 17 (17q21.31), which encodes the enzyme N-acetylglutamate synthase. This enzyme is necessary for the urea cycle, which breaks down the excess nitrogen that is produced when the body metabolizes proteins, into a compound called urea. Urea is removed from the body in the urine. Removing excess nitrogen prevents it from accumulating in the form of ammonia, which is toxic in high concentrations, especially for the brain. The enzyme encoded by this gene regulates the production of N-acetylglutamate in mitochondria. N-acetylglutamate is necessary to activate the carbamoyl phosphate synthetase I enzyme. This enzyme regulates the first step of the urea cycle, in which excess nitrogen compounds are incorporated into the cycle to decompose.
More than 40 mutations of the NAGS gene have been identified in people with N-acetylglutamate synthase deficiency, most of which consist of aminoacid changes in the enzyme N-acetylglutamate synthase. It is believed that the abnormal enzyme cannot function properly. Other mutations result in the synthesis of an abnormally short N-acetylglutamate synthase enzyme or inhibit the synthesis of any enzyme. A deficiency of N-acetylglutamate prevents carbamoyl phosphate synthetase I from being activated, which makes it impossible for the urea cycle to begin. As a consequence, ammonia accumulates in the blood. This build-up damages brain tissues and causes neurological problems and other signs and symptoms of N-acetylglutamate synthase deficiency.
This disease is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI we detect mutations associated with N-acetylglutamate synthase deficiency, by means of complete PCR amplification of the exons of the NAGS gene, and their subsequent sequencing.
Recommended samples: blood taken with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).