Hemophagocytic lymphohistiocytosis family (Familial hemophagocytic lymphohistiocytosis) - Genes and UNC13D PRF1.

Family hemophagocytic lymphohistiocytosis is a disorder in which the immune system encodes excess T cells, B cells and cytokines histiocytes. This overactivation of the immune system causes fever and damage to the liver and spleen, causing enlargement of these organs. This disease leads to a process called haemophagocytosis, which destroys the blood -forming cells in the bone marrow. As a result, affected individuals have anemia and a reduction in the number of platelets. A reduction in platelets can cause bruising and abnormal bleeding. In addition, the brain can also be affected resulting in irritability, delayed closure of the cranial bones in infants, neck stiffness, abnormal muscle tone, paralysis, blindness, seizures and coma. In addition to neurological problems, the disease can cause abnormalities in the heart, kidneys and other organs and tissues. Affected individuals also have a higher risk of developing leukemia and lymphoma.

In general, the signs and symptoms of the disease become evident during childhood. Usually they occur when the immune system launches an exaggerated response to an infection, but can also occur in the absence of infection. Without treatment, most people with hemophagocytic lymphohistiocytosis family survive a few months.

This disease is due to mutations in several genes. Approximately 40% and 60% of cases are caused by mutations in genes PRF1 and UNC13D. Fewer cases are caused by mutations in other genes known. In some affected individuals, the genetic cause of the disease is unknown.

PRF1 gene, located on the long arm of chromosome 10 (10q22), and UNC13D gene, located on the long arm of chromosome 17 (17q25.1), encoding proteins involved in cytolysis and immune system regulation. They are important components of cytolytic granules within T cells and NK cells. One of the main ways in which T cells and NK cells kill other the cells is transported and secreting these cytolytic granules containing proteins cell killing on the membranes of target cells. These proteins, allow cytolytic proteins enter the cell and cause it to self - destruct. This cytolytic mechanism also helps regulate the immune system by destroying T cells are not necessary. Controlling the number of T cells prevents immune cytokine overproduction of proteins that lead to inflammation and, in excess, causing tissue damage.

There are more than 90 mutations in the gene PRF1 and more than 50 mutations in the gene UNC13D in people with hemophagocytic lymphohistiocytosis family. These mutations lead to faulty coding and non - functional proteins or protein - coding prevent. The resulting decrease in functional protein prevents carry out their role in the destruction of cells and regulation of the immune system, leading to exaggerated immune response characteristic of the disease. People with genetic mutations in PRF1 gene have an increased risk of developing leukemia and lymphoma because mutations impair the ability of immune cells to destroy abnormal system, allowing them to grow and divide uncontrollably.

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 in IVAMI: in IVAMI perform detection of mutations associated with hemophagocytic lymphohistiocytosis family, by complete PCR amplification of the exons of the genes and UNC13D PRF1, respectively, 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).