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| OTC deficiency is the most common cause of hyperammonemia, which is a toxically high level of ammonia in the blood.(13) This is caused by a mutation in the X hromosome that does not allow OTC to be properly produced, thus, it is transmitted as an X-linked trait. Neonatal onset is seen in males. In females, symptoms appear later and the course is more variable. This is based on the Lyon hypothesis of random inactivation of the X chromosome. (14) In the presence of OTC ornithine combines with carbamoyl phosphate to form citrulline in the mitochondria. Citrulline is then transported out of the mitochondria to continue the urea cycle. (14) The urea cycle is a cycle of biochemical reactions occurring in the liver of many animal organisms that produces urea from ammonia (NH4+). Urea is much less toxic than ammonia, therefore, organisms that cannot easily and quickly remove ammonia usually have to convert it to urea or uric acid. (15) Ammonia is a by product of the metabolism of proteins, so it essentially cannot be avoided. Without OTC’s proper functioning, enough ammonia will not be converted into urea. Just a 140 mmol/L increase in ammonia concentration can be toxic in humans and alter the function of the central nervous system. Increased levels of ammonia can lead to ATP depletion, increases in brain levels of lactate, pyruvate, glutamine, and free glucose, and decreases in brain levels of glycogen, ketone bodies, and glutamate. Ammonia also increases the transport of aromatic amino acids across the blood-brain barrier. This leads to an increase in the level of serotonin, which is the basis for anorexia in hyperammonemia. Coma and cerebral edema are the major causes of death in hyperammonemia. The survivors of coma have a high incidence of intellectual impairment. (14) In one case in 1998, an Austrian woman was given a liver transplant from a male cadaver who, unknown to the surgeons, had a mutation in his single ornithine transcarbamoylase gene. The woman's blood level of ammonia shot up, and she died a few days later. (16) Treatment of hyperammonemia includes a low protein, high carbohydrate diet possibly with arginine or citrulline supplements. In the worst conditions, liver transplant is the only hope. (14) |
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