Ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency
Classification and external resources
Ornithine
ICD-10	E72.4
ICD-9	270.6
OMIM	311250
DiseasesDB	9286
MedlinePlus	000372
eMedicine	ped/2744
MeSH	D020163

Ornithine transcarbamylase deficiency (OTCD), the most common of the urea cycle disorders, 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.

Symptoms

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.

Another symptom of OTC is a buildup of orotic acid in the blood. This is due to an anapleurosis that occurs with carbamoyl phosphate entering the pyrimidine synthesis pathway.

Ornithine transcarbamylase deficiency often becomes evident in the first few days of life, however it can present at middle age.^[1] 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 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.

Genetics

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 while 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.^[2]

Treatment

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). 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 transcarbaylase emzyme ^[3] and its reported ability to reduce ammonia levels in experimental animal studies.^[4]

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.

References

1. ^ Ornithine transcarbamylase deficiency at eMedicine
2. ^ Ornithine transcarbamylase deficiency~followup at eMedicine
3. ^ 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. 
4. ^ 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

External links

• GeneReviews/NCBI/NIH/UW entry on Urea Cycle Disorders Overview
• http://www.nucdf.org