Ornithine transcarbamylase deficiency
Encyclopedia
Ornithine transcarbamylase deficiency (OTCD), the most common of the urea cycle disorder
s, 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
.
, 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. 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 swing
s, 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.
, female
s are primarily carriers while male
s 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.
, 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 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.
Urea cycle disorder
An urea cycle disorder or urea cycle defect is a genetic disorder caused by a deficiency of one of the enzymes in the urea cycle which is responsible for removing ammonia from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein...
s, is a rare metabolic disorder, occurring in one out of every 80,000 births. OTCD is a genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
resulting in a mutated and ineffective form of the enzyme ornithine transcarbamylase
Ornithine transcarbamylase
Ornithine transcarbamoylase is an enzyme that catalyzes the reaction between carbamoyl phosphate and ornithine to form citrulline and phosphate...
.
Symptoms
Like other urea cycle disorders, OTC affects the body's ability to get rid of ammoniaAmmonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
, a toxic breakdown product of the body's use of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
. As a result, ammonia accumulates in the blood causing hyperammonemia
Hyperammonemia
Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to encephalopathy and death. It may be primary or secondary....
. 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. 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
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
. 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
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
. Progressive liver damage, skin lesions, and brittle hair may also be seen. Other symptoms include irrational behavior (caused by encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
), mood swing
Mood swing
-Associated disorders:Mood swings are commonly associated with mood disorders including bipolar disorder and depression. In patients with cases of bipolar disorder, the patient experiences serious mood swings that last for days or even weeks...
s, 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
Female
Female is the sex of an organism, or a part of an organism, which produces non-mobile ova .- Defining characteristics :The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male...
carriers become symptomatic later in life in times of metabolic stress. This can happen as a result of anorexia
Anorexia nervosa
Anorexia nervosa is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight. Although commonly called "anorexia", that term on its own denotes any symptomatic loss of appetite and is not strictly accurate...
, starvation
Starvation
Starvation is a severe deficiency in caloric energy, nutrient and vitamin intake. It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ damage and eventually, death...
, malnutrition
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
, pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
or even (in at least one case) as a result of gastric bypass surgery
Gastric bypass surgery
Gastric bypass procedures are any of a group of similar operations that first divides the stomach into a small upper pouch and a much larger lower "remnant" pouch and then re-arranges the small intestine to allow both pouches to stay connected to it. Surgeons have developed several different ways...
. 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 chromosomeChromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
, female
Female
Female is the sex of an organism, or a part of an organism, which produces non-mobile ova .- Defining characteristics :The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male...
s are primarily carriers while male
Male
Male refers to the biological sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilization...
s with nonconservative mutations rarely survive past 72 hours of birth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
. 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.
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 cycleUrea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
, but it is also pro-viral and excess nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(which is synthesized from arginine) can be problematic. Biotin
Biotin
Biotin, also known as Vitamin H or Coenzyme R, is a water-soluble B-complex vitamin discovered by Bateman in 1916. It is composed of a ureido ring fused with a tetrahydrothiophene ring. A valeric acid substituent is attached to one of the carbon atoms of the tetrahydrothiophene ring...
may also be useful due to its stimulatory effect on the ornithine transcarbaylase emzyme 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.
External links
- GeneReviews/NCBI/NIH/UW entry on Urea Cycle Disorders Overview
- http://www.nucdf.org