NAGS Deficiency

What is NAGS deficiency? NAGS deficiency is one of the urea cycle disorders (UCD). UCD are inherited metabolic disorders resulting from a deficiency in one of the six enzymes involved in urea synthesis, which leads to hyperammonaemia. Accumulation of ammonia in the body causes irreversible brain damage, coma, and eventually death. The first hepatic enzyme N-Acetyl Glutamate Synthase (NAGS) activates the urea cycle. In case of NAGS deficiency the activity of this enzyme could be completely (severe, early onset) or partially (late onset, less severe) affected. What causes NAGS deficiency? NAGS deficiency is transmitted by a recessive autosomal mechanism. The gene coding for NAGS in located on the chromosome 17. Urea cycle disorders are estimated to affect 1 in every 25,000 to 50,000 births. NAGS deficiency is the rarest among the UCD. Clinical presentation of NAGS deficiency The NAGS deficiency can clinically present as: Early onset NAGS deficiency. When there is a null mutation of the NAGS gene, it usually manifests a few hours after babys delivery. Initial symptoms of hyperammonaemia in the newborn are non-specific; failure to feed, inability to maintain normal body temperature with a low core body temperature, and drowsiness. Symptoms will progress from sleepiness to abnormal drowsiness and coma. In the newborn that appears normal the progression of symptoms may be very rapid and may lead to cerebral oedema. Late onset NAGS deficiency. In contrast to the early onset forms of NAGS deficiency, the clinical picture and development of late onset forms vary widely. They may occur in the first months of life or in adulthood, and may involve episodes of acute decompensation or chronic gastrointestinal, neurological or psychiatric signs. Many patients present with symptoms in early childhood triggered by other factors like infections, stress, trauma, etc. There are even documented cases of adults becoming symptomatic after a traumatic event, such as childbirth. How to diagnose NAGS deficiency? There are specific tests for each type of UCD. The NAGS deficiency is detected by checking a blood ammonia level and amino acid levels. The diagnosis is usually confirmed by liver biopsy and/or DNA test. Treatment of NAGS deficiency The aim of the treatment of UCD is to increase the elimination of excessive ammonia. Specific therapy of NAGS deficiency is with carglumic acid, a functional analogue of N-Acetyl Glutamate, which restores the urea cycle by activating the enzyme CPS (carbamylphosphate synthetase). The treatment with carglumic acid controls ammonia level in blood to physiologically acceptable levels. Some patients additionally to the treatment with carglumic acid may also need: dietary protein restriction with hypercaloric value, provision of arginine to enhance availability of ornithine, in emergency situations, when ammonia levels are not controlled, haemodialysis should be implemented. It is necessary to highlight that ammonia scavengers can not be administered for long period. Extremely low protein diet for many days could lead to increase endogenous ammonia.