Hemophilia A and B (Deficiencies of factor VIII and IX - Disease of Christmas-) (Hemophilia A and B) - Genes F8 and F9
Hemophilia is a bleeding disorder that slows the blood clotting process. Affected individuals have hemorrhages or prolonged bleeding following injury, surgery or tooth extraction. In severe cases, bleeding occurs after minor or even in the absence of injury (spontaneous bleeding) trauma. Serious complications may be due to bleeding in joints, muscles, brain or other internal organs. Milder forms of hemophilia not necessarily involve a spontaneous bleeding, and alteration can not manifest until bleeding after surgery or serious injury occurs.
The main types of the disease are Hemophilia A, also known as classical hemophilia or factor VIII deficiency, and hemophilia B, also known as Christmas disease or Factor IX deficiency. Although both types have very similar signs and symptoms are caused by mutations in different genes. People with a rare form of hemophilia B, known as hemophilia B Leyden, bleeding episodes occur during childhood, but have few bleeding problems after puberty.
Hemophilia is caused by mutations in genes F8 and F9. Changes in gene F8 are responsible for hemophilia A, while mutations in the F9 gene result hemophilia B. The coagulation system maintains vascular integrity by balancing clot formation and its inhibition. Proteases and protein cofactors that generate the coagulation cascade are present as inactive precursors. After injury, activation may occur to form the fibrin clot, to thereby activating or exponential amplification of the protease cascade which requires, inter alia, factors VIII and IX is required. These factors activate the coagulation factor X, and X active factor, in turn, activates more factors VIII and IX. The factor VIII acts as a cofactor and as a protease factor IX. Deficiency or dysfunction of either factor causes hemophilia.
The F8 gene, located on the long arm of chromosome X (Xq28), encoding coagulation factor VIII. This is a rather large gene comprising a sequence coding exons 26 and about 186,000 base pairs (186 Kb). They have been identified over 1300 mutations in this gene responsible for hemophilia A. These genetic alterations may be point mutations, insertions and deletions. The most frequent mutation in people with severe hemophilia A is an investment that deleted the carboxyl terminus of factor VIII. The inversion occurs as a consequence of intrachromosomal recombination between sequences located in intron 22 of the F8 gene and homologous sequences telomeric to F8. As a result of this and other anomalies in the F8 gene enzyme activity of coagulation factor VIII it is affected in direct proportion to the clinical severity of the disease. Thus, in cases of mild or moderate haemophilia A the most likely genetic cause is a point mutation that causes a nucleotide substitution of one amino acid for another and which may result in a decrease -generally partially of secretion and, therefore its coagulant function.
The F9 gene, located on the long arm of chromosome X (Xq27.1-q27.2) encoding factor IX clotting. There are more than 900 changes in this gene result in hemophilia B. The most frequent mutations change base pairs in the gene. A small percentage of mutations eliminate or multiple pairs inserted or rearranged DNA segments within the gene. Mutations in the F9 gene result encoding an abnormal version of factor IX clotting or reduce the amount of this protein encoded. The altered or missing protein can not effectively participate in the process of blood coagulation. Consequently they can not adequately formed blood clots in response to injury. Mutations that reduce but do not eliminate the activity of the protein usually cause moderate or mild hemophilia. Several mutations near the beginning of the sequence F9 gene cause an unusual form of hemophilia known as hemophilia B Leyden. Individuals with these mutations are born with very low amounts of clotting factor IX functional, but hormonal changes make this protein concentrations gradually increase during puberty. As a result, adults with hemophilia B Leyden rarely present bleeding.
Hemophilia A and hemophilia B are inherited in an X - linked recessive pattern in males, who have only one X chromosome, an altered copy of the gene in each cell is sufficient to express the disease. In females, having two X chromosomes, the mutation should occur in both copies of the gene to express the alteration. Because it is unlikely that women have two altered copies of this gene is very rare that women presenting hemophilia. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome. In X - linked recessive inheritance, a woman with an altered copy of the gene in each cell is called a carrier. Female carriers have about half of the usual amount of clotting factor VIII or IX clotting factor, which is generally sufficient for normal blood clotting. However, approximately 10% of female carriers have less than half the normal amount of one of these clotting factors; These people are at risk of abnormal bleeding, especially after an injury, surgery or tooth extraction.
Tests in IVAMI: in IVAMI perform detection of mutations associated with haemophilia, by complete PCR amplification of the exons of the F8 and F9, respectively, and subsequent sequencing genes.
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). In case of prenatal diagnosis, amniotic fluid.