Autoimmune lymphoproliferative syndrome – FAS and FASLG genes

Autoimmune lymphoproliferative syndrome (ALPS), also known as Canale-Smith syndrome, is a hereditary process in which the body cannot regulate the life of lymphocytes, and therefore those affected have a high number of lymphocytes (lymphoproliferation), which accumulate in several organs and can trigger autoimmune phenomena, damaging cells and tissues of the body.

The onset of symptoms of lymphoproliferation without autoimmune phenomena is early, just a few months after birth. It manifests with generalized lymphadenopathy, splenomegaly and, less frequently, hepatomegaly, due to the accumulation of lymphocytes in these places. Other manifestations include: skin involvement (urticaria, panniculitis), joint (arthritis), vascular (vasculitis), oral (ulcerations), ovaries (ovarian failure), nervous system (cerebral syndrome, headaches, seizures, dementia...). Autoimmune abnormalities are also characteristic of ALPS and are due to attack on various types of cells, tissues or organs by the immune system. The most common immune disorders include autoimmune hemolytic anemia, and autoimmune neutropenia and thrombocytopenia. Other organs that can be also damaged are the kidney (glomerulonephritis), liver (autoimmune hepatitis), eyes (uveitis), nerves (Guillain-Barré syndrome), or connective tissue (systemic lupus erythematosus.

Some people have signs and symptoms that resemble those of ALPS, such as lymphoproliferation, lymphadenopathy, splenomegaly and low blood counts, but the specific pattern of these signs and symptoms or the genetic cause may be different. It is not clear whether individuals with these nonclassical forms should be considered to have ALPS or an isolated disease.

This process has been classified into several types, according to their genetic cause. In the most frequent form, called the classical form, lymphoproliferation can manifest itself early in childhood. Autoimmune disorders occur later, usually as hemolytic anemia and thrombocytopenia (Evans syndrome). In addition, individuals with this syndrome have a greater susceptibility to the development of neoplasms, particularly hematologic malignancies (lymphomas, especially Hodgkin lymphoma). Other types of cancer associated include liver carcinoma, thyroid cancer and lung adenomacarcinoma, among others. In some affected individuals severe lymphoproliferation begins around birth, while autoimmune abnormalities and lymphoma develop at an early age. People with this pattern of signs and symptoms generally do not live beyond childhood.

The molecular defect that causes this syndrome is generated due to mutations in the FAS (Fas cell surface death receptor) gene in approximately 75% of cases, and in a smaller number of cases due to genetic alterations in the FASLG (Fas ligand) gene. ALPS may also be due to mutations in additional genes, such as CASP10, CTLA4, MAGT1, PIK3CD, STAT3, KRAS and NRAS. Mutations in these other genes represent a small percentage of cases.

The FAS gene, located on the long arm of chromosome 10 (10q23.31) also called TNFRSF (Superfamily Tumor Necrosis Factor Receptor), belongs to the family of CD (CD molecules) genes, and the family of TNFRSF (Tumor Necrosis Factor Superfamily receiver) genes. This gene encodes the FAS protein (CD95/APO1/TNFRSF6), which can be located in the plasma membrane of lymphocytes and is involved in their apoptosis when they have been activated and proliferated in response to an antigenic induction. Apoptosis is essential for homeostasis of mature lymphocytes. The expression of the FAS molecule on the activated cell membrane is necessary for apoptosis to take place, inducing cell death after binding of its ligand (FASLG). More than 115 mutations in the FAS gene have been identified in individuals with ALPS. FAS mutations produce an abnormal protein that interferes with apoptosis. This generates a defective apoptosis of the lymphocyte, which causes an alteration of organic homeostasis by not eliminating the autoreactive T cells (lymphocytes). The defect in apoptosis causes an accumulation of lymphocytes in the secondary lymphoid organs, resulting in lymphoproliferative manifestations (adenomegaly, splenomegaly, and hepatomegaly).

Unlike many other diseases and syndromes of genetic origin, in ALPS there is a correlation between genotype and clinical phenotype. The most severe phenotype is presented by homozygous patients who generate a complete deficiency of the FAS protein. The involvement is greater in families with mutations in the intracellular domain than in families with mutations in the extracellular region.

The FASLG gene, also called TNFSF6 (Tumor Necrosis Factor Superfamily, member 6), located on the long arm of chromosome 1 (1q23), encodes a protein that is the ligand of the FAS protein. Both proteins, FASLG and FAS, are transmembrane proteins, and interaction between them is needed to generate lymphocyte apoptosis. This apoptosis mediated by the TNFRSF6/FAS interaction may have an important role in inducing immunological tolerance, since it would prevent lymphocytes from triggering autoimmune phenomena.

In most people with ALPS, including most people with mutations in the FAS gene, the process is inherited with an autosomal dominant pattern, which means that one copy of an altered gene in each cell is sufficient to express the syndrome. In these cases, an affected person usually inherits the mutation of an affected parent. Other cases are due to new genetic mutations that occur at the beginning of embryonic development in people with no history of the disease in their family. In a small number of cases, including some cases due to mutations in the FAS gene, ALPS is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. ALPS can also arise from a somatic mutation in lymphocytes that is not inherited but occurs during the life of an individual.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with autoimmune lymphoproliferative syndrome (ALPS), by means of the complete PCR amplification of the exons of the FAS and FASLG genes, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).