Citrullinemia
Encyclopedia
Citrullinemia, also called citrullinuria, is an autosomal recessive urea cycle
disorder that causes ammonia
and other toxic substances to accumulate in the blood
.
Two forms of citrullinemia have been described, both having different signs and symptoms, and are caused by mutations in different genes. Citrullinemia belongs to a class of genetic diseases called urea cycle
disorders. The urea cycle is a sequence of chemical reactions that takes place in the liver
. These reactions process excess nitrogen
, generated when protein
is used by the body, to make a compound called urea that is excreted by the kidney
s.
s, and loss of consciousness. These medical problems can be life-threatening in many cases. A milder form of type I citrullinemia is less common in childhood or adulthood. Some people with gene mutations that cause type I citrullinemia never experience signs and symptoms of the disorder.
Type I citrullinemia is the most common form of the disorder, affecting about 1 in 57,000 births worldwide. Mutation
s in the ASS gene
cause type I citrullinemia. The enzyme
made by this gene, argininosuccinate synthetase
, is responsible for one step of the urea cycle. Mutations in the ASS gene reduce the activity of the enzyme, which disrupts the urea cycle and prevents the body from processing nitrogen effectively. Excess nitrogen, in the form of ammonia, and other byproducts of the urea cycle accumulate in the bloodstream, leading to the characteristic features of type I citrullinemia.
. Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. These signs and symptoms can be life-threatening, and are known to be triggered by certain medications, infections, and alcohol
intake in people with type II citrullinemia.
Type II citrullinemia may also develop in people who had a liver
disorder called neonatal cholestasis
during infancy. This condition blocks the flow of bile
and prevents the body from processing certain nutrients properly. In many cases, the signs and symptoms resolve within a year. Years or even decades later, however, some of these people develop the characteristic features of adult type II citrullinemia.
Type II citrullinemia is primarily found in the Japan
ese population, where it occurs in an estimated 1 in 100,000 to 230,000 individuals. Type II has also been reported in people from East Asia
n and Middle Eastern populations. Mutations in the SLC25A13 gene are responsible for type II citrullinemia. This gene makes a protein called citrin
, which normally shuttles certain molecules in and out of mitochondria. These molecules are essential for the urea cycle and are also involved in making proteins and nucleotide
s. Mutations in the SLC25A13 mutation typically prevent the production of any functional citrin, which inhibits the urea cycle and disrupts the production of proteins and nucleotides. The resulting buildup of ammonia and other toxic substances leads to the signs and symptoms of type II citrullinemia. Researchers have determined that many infants with neonatal intrahepatic cholestasis have the same mutations in the SLC25A13 gene as adults with type II citrullinemia.
Urea 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...
disorder that causes ammonia
Ammonia
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...
and other toxic substances to accumulate in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
.
Two forms of citrullinemia have been described, both having different signs and symptoms, and are caused by mutations in different genes. Citrullinemia belongs to a class of genetic diseases called urea cycle
Urea 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...
disorders. The urea cycle is a sequence of chemical reactions that takes place in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. These reactions process excess nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
, generated when 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...
is used by the body, to make a compound called urea that is excreted by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s.
Type I
Type I citrullinemia usually becomes evident in the first few days of life. Affected infants typically appear normal at birth, but as ammonia builds up in the body they develop a lack of energy (lethargy), poor feeding, vomiting, seizureSeizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, and loss of consciousness. These medical problems can be life-threatening in many cases. A milder form of type I citrullinemia is less common in childhood or adulthood. Some people with gene mutations that cause type I citrullinemia never experience signs and symptoms of the disorder.
Type I citrullinemia is the most common form of the disorder, affecting about 1 in 57,000 births worldwide. Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the ASS gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
cause type I citrullinemia. The enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
made by this gene, argininosuccinate synthetase
Argininosuccinate synthetase
Argininosuccinate synthase is an enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartateASS is responsible for the third step of the urea cycle and one of the reactions of the Citrulline-NO cycle.-Gene:...
, is responsible for one step of the urea cycle. Mutations in the ASS gene reduce the activity of the enzyme, which disrupts the urea cycle and prevents the body from processing nitrogen effectively. Excess nitrogen, in the form of ammonia, and other byproducts of the urea cycle accumulate in the bloodstream, leading to the characteristic features of type I citrullinemia.
Type II
The signs and symptoms of type II citrullinemia ( and ) usually appear during adulthood and mainly affect the nervous systemNervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. These signs and symptoms can be life-threatening, and are known to be triggered by certain medications, infections, and alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
intake in people with type II citrullinemia.
Type II citrullinemia may also develop in people who had a liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
disorder called neonatal cholestasis
Neonatal cholestasis
Neonatal cholestasis defines persisiting conjugated hyperbilirubinemia in the newborn with conjugated bilirubin levels exceeding 15% of total bilirubin level. The disease is either due to defects in bile excretion from hepatocytes or impaired bile flow.The incidence has been found to be about...
during infancy. This condition blocks the flow of bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
and prevents the body from processing certain nutrients properly. In many cases, the signs and symptoms resolve within a year. Years or even decades later, however, some of these people develop the characteristic features of adult type II citrullinemia.
Type II citrullinemia is primarily found in the Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
ese population, where it occurs in an estimated 1 in 100,000 to 230,000 individuals. Type II has also been reported in people from East Asia
East Asia
East Asia or Eastern Asia is a subregion of Asia that can be defined in either geographical or cultural terms...
n and Middle Eastern populations. Mutations in the SLC25A13 gene are responsible for type II citrullinemia. This gene makes a protein called citrin
Citrin
Citrin also known as solute carrier family 25, member 13 or SLC25A13 is a protein which in humans is encoded by the SLC25A13 gene.Citrin is associated with type II citrullinemia....
, which normally shuttles certain molecules in and out of mitochondria. These molecules are essential for the urea cycle and are also involved in making proteins and nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s. Mutations in the SLC25A13 mutation typically prevent the production of any functional citrin, which inhibits the urea cycle and disrupts the production of proteins and nucleotides. The resulting buildup of ammonia and other toxic substances leads to the signs and symptoms of type II citrullinemia. Researchers have determined that many infants with neonatal intrahepatic cholestasis have the same mutations in the SLC25A13 gene as adults with type II citrullinemia.