Ornithine transcarbamylase deficiency
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|Ornithine transcarbamylase deficiency|
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Ornithine transcarbamylase deficiency (OTCD), a urea cycle disorder, is a rare metabolic disorder, occurring in one out of every 80,000 births. OTCD is a genetic disorder resulting in a mutated and ineffective form of the enzyme ornithine transcarbamylase.
Like other urea cycle disorders, OTC affects the body's ability to get rid of ammonia, a toxic breakdown product of the body's use of protein. As a result, ammonia accumulates in the blood causing hyperammonemia. This ammonia travels to the various organs of the body.
Ornithine transcarbamylase deficiency often becomes evident in the first few days of life, however it can present at middle age. Because newborns are usually discharged from the hospital within 1-2 days after birth, the symptoms of a urea cycle disorder are often not seen until the child is at home and may not be recognized in a timely manner by the family and primary-care physician. The typical initial symptoms of a child with hyperammonemia are non-specific: failure to feed, loss of thermoregulation with a low core temperature, and somnolence. Symptoms progress from somnolence to lethargy and coma. Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure upon the brain stem. About 50% of neonates with severe hyperammonemia have seizures. Hyperventilation, secondary to cerebral edema, is a common early finding in a hyperammonemic attack, which causes a respiratory alkalosis. Hypoventilation and respiratory arrest follow as pressure increases on the brain stem. An infant with ornithine transcarbamylase deficiency may be lacking in energy (lethargic) or unwilling to eat, and have poorly-controlled breathing rate or body temperature. Some babies with this disorder may experience seizures or unusual body movements, or go into a coma. In cases where OTC enzyme production is low or non-existent, death can occur within the first days of life. Complications from ornithine transcarbamylase deficiency may include developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen. Other symptoms include irrational behavior (caused by encephalitis), mood swings, and poor performance in school. In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered. by illness or stress at almost any time of life, resulting in multiple mild elevations of plasma ammonia concentration [Bourrier et al 1988]. The hyperammonemia is less severe and the symptoms more subtle. In patients with partial enzyme deficiencies, the first recognized clinical episode may be delayed for months or years. There is an incidence of 1 in 70000 in adults of ornithine transcarbamylase deficiency. In some affected individuals, signs and symptoms of ornithine transcarbamylase may be less severe, and may not appear until later in life. Some female carriers become symptomatic later in life in times of metabolic stress. This can happen as a result of anorexia, starvation, malnutrition, pregnancy or even (in at least one case) as a result of gastric bypass surgery. It is also possible for symptoms to be exacerbated by extreme trauma of many sorts, including, (at least in one case) adolescent pregnancy coupled with severe stomach flu. Despite late presentations in adulthood, hyperammonemia, encephalopathy,cerebral edema, and death can occur.
Ornithine transcarbamylase deficiency is an X-linked recessive disorder caused by a number of different mutations in the OTC gene. Since the gene is on the X chromosome, females are primarily carriers, whereas males with nonconservative mutations rarely survive past 72 hours of birth. Half of those survivors die in the first month, and half of the remaining by age 5. Prognosis is less clear in cases of adult-onset OTCD, as detection of the disease is almost universally post-symptomatic.
Since the disease results in an inability to handle large amounts of nitrogen load, the treatment includes strategies to decrease the intake of nitrogen (low-protein diet), prevention of excessive body protein breakdown during acute illnesses (hydration and nutrition), and administration of medications scavenging nitrogen (sodium benzoate and sodium phenylbutyrate). These form benzoyl-CoA and phenylacetyl-CoA, which help clear glycine (to hippurate) and glutamine (to phenylacetylglutamine), respectively. These conjugates are excreteable and functionally help replace urea as an excretion method. Some patients may need to have supplemental amino acids (arginine, citrulline, valine, leucine, isoleucine). Arginine in particular may be useful due to its role in the urea cycle, but it is also pro-viral and excess nitric oxide (which is synthesized from arginine) can be problematic. Biotin may also be useful due to its stimulatory effect on the ornithine transcarbamylase enzyme  and its reported ability to reduce ammonia levels in experimental animal studies.
In cases where the OTC enzyme production is very low or non-existent, and treatment consisting of low-protein diet and dietary supplementation are inadequate. Liver transplant may become a treatment option.
New efforts to combat the illness starts with prenatal treatment to protect the fetus, which has been identified with OTC deficiency through amniocentesis. There is a case report of success using this approach.
- Ornithine transcarbamylase deficiency at eMedicine
- Ornithine transcarbamylase deficiency~followup at eMedicine
- "google books: Inherited Metabolic Diseases: A Clinical Approach".
- Maeda, Y; Kawata, S; Inui, Y; Fukuda, K; Igura, T; Matsuzawa, Y (1996). "Biotin deficiency decreases ornithine transcarbamylase activity and mRNA in rat liver". The Journal of nutrition 126 (1): 61–6. PMID 8558326.
- Nagamine, T; Saito, S; Kaneko, M; Sekiguchi, T; Sugimoto, H; Takehara, K; Takagi, H (1995). "Effect of biotin on ammonia intoxication in rats and mice". Journal of gastroenterology 30 (3): 351–5. PMID 7647902.
- National Library of Medicine Ornithine transcarbamylase deficiency
- University of Washington, Seattle [url=http://rarediseasesnetwork.epi.usf.edu/ucdc/documents/ucdreview.pdf]