Citrulinemias types I and II (Citrullinemia) - Genes ASS1 and SLC25A13.


Citrullinemia is an inherited disorder that causes the ammonia and other toxic substances accumulate in the blood. They described two forms of which differ citrullinemia signs and associated symptoms, as well as genetic cause.


Usually, Type I citrullinemia (also known as classic citrullinemia) is manifested in the first days of life. Affected children are usually normal at birth, but as ammonia accumulates in the body have lethargy, poor feeding, vomiting, seizures and unconsciousness. These are life - threatening medical problems in many cases. Less often, a milder form of type I citrullinemia may develop later in childhood or adulthood. This form of late onset is associated with severe headaches, partial loss of vision, ataxia and lethargy. Some people with genetic mutations associated with type I never manifest signs and symptoms of the disease.


Meanwhile, type II citrullinemia mainly affects the nervous system, resulting in confusion, agitation, memory loss, abnormal behavior (such as aggression, irritability and hyperactivity), convulsions and coma. In some cases, signs and symptoms of type II manifest in early adulthood. These signs and symptoms can be life threatening and can be triggered by certain medications, infections, surgery and intake of alcohol. Citrullinemia characteristics of adult - onset type II can also occur in people who had childhood neonatal intrahepatic cholestasis due to deficiency Citrine (NICCD). This liver disorder also known as type II citrullinemia neonatal onset. NICCD blocks the flow of bile and prevents the body process certain nutrients properly. In many cases, the signs and symptoms of NICCD refer in one year. However, years or even decades later, some of these people develop the characteristics of citrullinemia adult - onset type II.


This process is due to mutations in genes ASS1 and SLC25A13. Citrullinemia belongs to a class of genetic diseases called disturbances urea cycle. The urea cycle is a sequence of chemical reactions that process excess nitrogen that is generated when the protein is metabolized in the body.


The ASS1 gene, located on the long arm of chromosome 9 (9q34.1), encoding an enzyme called argininosuccinate sintatasa 1 involved the third step of the urea cycle. This step combines two amino acids, citrulline and aspartate to form argininosuccinic acid. A number of additional chemical reactions transform argininosuccinic acid in urea.


At least 50 mutations in the gene have been associated ASS1 to citrullinemia type I. Most of these mutations change individual amino acids in the enzyme argininosuccinate synthase 1. These genetic changes are likely to alter the structure of the enzyme, impairing its ability to bind molecules such as citrulline and aspartate. Some mutations result encoding an abnormally short version can not effectively perform its role in the urea cycle. Defects in the argininosuccinate synthase 1 interrupt the third step of the urea cycle, avoiding the liver process excess nitrogen in urea. Consequently, nitrogen (in the form of ammonia) and other byproducts of urea cycle (such as citrulline) accumulate in the bloodstream. Ammonia is toxic, particularly for the nervous system. A buildup of ammonia during the first days of life results in poor feeding, vomiting, convulsions and other signs and symptoms of type citrullinemia I.


The SLC25A13 gene, located on the long arm of chromosome 7 (7q21.3), encoding the protein Citrine. This protein is active mainly in the liver, kidneys and heart. Inside the cells of these organs, citrine is involved in the transport of molecules into and out of mitochondria. Specifically, the amino acid glutamate citrina transported into mitochondria and the amino acid aspartate outside of mitochondria as part of a process called malate aspartate shuttle. An adequate supply of aspartate should be transported out of the mitochondria to participate in the urea cycle. Citrine involved in several other important cellular functions as part of the malate-aspartate shuttle. This protein plays a role in the production and breakdown of simple sugars and protein coding. Also it participates in the production of nucleotides.


They have identified more than 20 mutations in the gene SLC25A13 citrullinemia in people with type II adult onset. Almost all identified mutations result in an unstable encoding protein citrina, which decomposes rapidly, or an abnormally short, nonfunctional version of the protein. A deficiency of functional blocks citrina malate aspartate shuttle, including transport out of mitochondria aspartate. This loss of citrine inhibits normal protein and nucleotide coding. Also it reduces the amount of aspartate available to take part in the urea cycle. Consequently, nitrogen (in the form of ammonia) and other byproducts of urea cycle (such as citrulline), accumulate in the bloodstream. Ammonia is toxic, especially in the nervous system, which explains the development of abnormal behavior and other neurological problems in people with type II citrullinemia adult onset. Mutations in the SLC25A13 gene have also been identified in children with neonatal cholestasis due to deficiency citrin (NICCD).


This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.


Tests performed in IVAMI: in IVAMI perform detection of mutations associated with citrullinemia type I and II, by complete PCR amplification of the exons of ASS1 and SLC25A13, respectively, genes and subsequent sequencing.


Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).