Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Autoimmune lymphoproliferative syndrome ... (ALPS: Autoimmune lymphoproliferative syndrome) - Genes FAS and FASLG

The autoimmune lymphoproliferative syndrome (ALPS), is an inherited process in which the body can not regulate the life of lymphocytes, and thus affected have a high number of lymphocytes (lymphoproliferation), which accumulate in various organs and can trigger autoimmune phenomena, damaging cells and tissues of our body.

The onset of symptoms, when there lymphoproliferation, no autoimmune phenomena, it's early, just a few months after birth. It manifests with generalized lymphadenopathy, splenomegaly and, less frequently, hepatomegaly, due to accumulation of lymphocytes in these places. Other manifestations include cutaneous involvement (urticaria, panniculitis), joints (arthritis), vascular (vasculitis), oral (ulcerations), ovarian (ovarian failure), (brain syndrome, headaches, seizures, dementia, ...) nervous system. Autoimmune disorders are also features of ALPS, and are due to attack several types of cells, tissues or organs by the immune system. Most Immune changes ALPS damage blood cells, such as erythrocytes, causing autoimmune hemolytic anemia. Sometimes damage to leukocytes (autoimmune neutropenia), or platelets (autoimmune thrombocytopenia). It can also damage the kidneys (glomerulonephritis), liver (autoimmune hepatitis), eyes (uveitis), nerves (Guillain-Barré syndrome), or connective tissue (systemic lupus erythematosus).

This process has been classified into several types according to their genetic cause. In the most common form, called the classical form, lymphoproliferation can appear early in childhood. Autoimmune affectations are presented belatedly, almost always as hemolytic anemia and thrombocytopenia (Evans syndrome). Additionally, individuals with this syndrome have an increased susceptibility for the development of neoplasms, particularly hematologic malignancies (lymphomas, especially Hodgkin lymphoma). Other associated cancers include hepatic carcinoma, thyroid adenoma and lung, etc. Other types of ALPS are very rare. In some affected individuals, severe lymphoproliferation starts around birth, while autoimmune disorders and lymphoma develop at an early age. People with this pattern of signs and symptoms do not usually live beyond childhood. Another way involves ALPS lymphocyte proliferation and the tendency to develop systemic lupus erythematosus. Individuals with this form have an enlarged spleen. Some people have signs and symptoms that resemble those of ALPS syndrome, but the specific pattern of these signs and symptoms or genetic causes may be different in other ways. It is unclear whether these individuals should be considered as affected ALPS syndrome or a separate process.

The molecular defect which causes the autoimmune lymphoproliferative syndrome (ALPS) is generated in about 75% of the cases by mutations in the FAS gene and fewer cases by genetic alterations in FASLG. ALPS may also be due to mutations in additional genes, as CASP10, CAP8, KRAS and NRAS are. Mutations in these genes other represent each a small percentage of cases.

FAS gene, located on the long arm of chromosome 10 (10q24.1) also known as TNFRSF (Receptor Superfamily Tumor Necrosis Factor) belongs to the family of genes CD (CD molecules), and the family of genes TNFRSF (Tumor Necrosis Factor receptor Superfamily). This gene encodes the FAS (CD95 / APO1 / TNFRSF6), which can be located in the plasma membrane of cells, and is involved in lymphocyte apoptosis protein when they have been activated and proliferated in response to antigenic induction. Apoptosis is essential for the homeostasis of mature lymphocytes. For apoptosis to occur, expression of the FAS molecule on the membrane of the activated cell is necessary, inducing cell death upon binding of its ligand (FASLG). There are more than 100 mutations in the FAS gene in individuals with autoimmune lymphoproliferative syndrome. FAS mutations produce an abnormal protein that interferes with apoptosis. This produces a defective apoptosis of lymphocytes causing an alteration of organic homeostasis to not eliminated autoreactive T cells (lymphocytes). The defect in apoptosis causes an accumulation of cells in secondary lymphoid organs resulting in lymphoproliferative manifestations (lymphadenopathy, splenomegaly, hepatomegaly).

Unlike many other diseases and genetic syndromes in autoimmune lymphoproliferative syndrome there is a correlation between genotype and clinical phenotype. The most severe phenotype homozygous patients present it generated a complete deficiency of FAS protein. The impact is greater in families with mutations in the intracellular domain that families have mutations in the extracellular region.

Meanwhile, the FASLG gene (Fas Ligand) (= TNFSF6: Superfamily Tumor Necrosis Factor, member 6), located on the long arm of chromosome 1 (1q23), encodes a protein which is the ligand of the FAS protein. Both proteins, FASLG and FAS, are transmembrane proteins, and the interaction is needed between the two to generate the lymphocyte apoptosis. This apoptosis mediated TNFRSF6 / FAS interaction may have an important role in the induction of immunological tolerance, and would prevent lymphocytes could trigger autoimmune phenomena.

In most people with ALPS, including most of those with mutations in the FAS gene, the process is inherited as an autosomal dominant, which means that a copy of an altered in every cell gene is sufficient to express the syndrome. In these cases, an affected person inherits the mutation usually an affected parent. Other cases are due to new genetic mutations that occur early embryonic development in people with no history of disease in your family. In a small number of cases, including some cases caused by mutations in the FAS gene, ALPS is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations to be expressed alteration . 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. ALPS can also arise from a somatic mutation in cells that are not inherited but occurs during the life of an individual.

Tests in IVAMI: in IVAMI perform detection of mutations associated with autoimmune lymphoproliferative syndrome (ALPS), by complete PCR amplification of the exons of the FAS gene, and subsequent sequencing. We recommend starting the study by exon 9, where most of the genetic alterations are located, with the probable cost reduction and runtime. If not detected any mutation in this region would proceed to study the other 8 exons.

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).