Familial Mediterranean Fever (Familial Mediterranean Fever) - Genes MEFV and SAA1.
Familial Mediterranean fever is an inflammatory disorder that primarily affects the population in the Mediterranean basin (in some cases, as among the Armenian, Jewish, Turkish or Arabic, with a very high frequency). It is the most common hereditary disease group characterized by recurrent fever episodes of fever accompanied by signs of inflammation, especially in the abdomen, thorax and joints. Occasionally, episodes of fever accompanied by rash or headaches. Occasionally, inflammation may occur in other parts of the body such as the heart, meninges, spinal cord , and in men in the testes. The main complication associated with familial Mediterranean fever development of renal amyloidosis.
Usually, the first episode of disease familial Mediterranean fever occurs in childhood or adolescence, but in some cases appear much later throughout life. Usually they episodes last from 12 to 72 hours, and can vary in intensity. The time between episodes is also variable and can range from days to years. The diagnosis can be very difficult given the absence of clinical symptoms pathognomonic if onset is delayed in the absence of family history, etc. Methods of molecular biology can contribute greatly facilitate diagnosis, detecting mutations that have asociad with this process. If mutations in the gene involved detected, patients may receive treatment to prevent recurrent episodes and avoid further development of amyloidosis.
This disease is due to mutations in the MEFV and SAA1 gene, located on the short arm of chromosome 16 (16p13.3), and the short arm of chromosome 11 (11p15.1), respectively.
The MEFV gene, encodes a protein of 781 amino acids, called pyrene (or marenostrin), which is expressed primarily on leukocytes (neutrophils, eosinophils and monocytes) and plays an important role in the regulation of innate inflammatory response role. Pyrin contains four domains: PYD (in the N-terminus), B30.2 (located at the C-terminus), CC (Coiled coil) and B-Box (both located between PYD and B30.2 domains) . Through domain PYD pyrin interacts with ASC, an apoptosis associated domain containing caspase recruitment protein, inducing proinflammatory autocatalysis of caspase-1 (converting enzyme interleukin-1-? and responsible for maturation the pro-interleukin-1-? to form proinflammatory and biologically active). Thus, the processing pyrene modulates IL-1-? and therefore the initiation of the inflammatory process by inhibiting the interaction of ASC and caspase-1.
So far, we have identified at least 125 mutations in the MEFV gene associated with familial Mediterranean fever. These mutations were: missense mutations (103), and cutting mutations -splicing- joint (10), regulatory mutations (6), small deletions (2) and small insertions (3). Mutations in the MEFV gene, reduce the activity of the pyrene, thereby controlling the inflammatory process is lost. It has been suggested that the mutated pyrene could cause uncontrolled inflammation in IL-1 production and inhibition of apoptosis. There are differences in the distribution of mutations among different populations, but most cases of this disease are generated by five mutations: E148Q (in exon 2), and M680I, M694I, M694V and V726A (in exón10). In addition, some studies have linked mutations located at codon 694 with a more severe phenotype of the disease with an earlier onset, more frequent episodes and the need for a higher dose of colchicine for treatment. On the other hand, the E148Q mutation is associated with milder forms of the disease.
Meanwhile, the SAA1 gene encodes a protein called serum amyloid A1. This protein is mainly synthesized in the liver and found in low concentrations in the blood. Although its function is not fully understood, serum amyloid A1 appears to play a role in the immune system. The protein can help repair damaged tissues, acting as an antibacterial agent, and noting the migration of cells that fight infection. The concentrations of this protein increases in the blood and other tissues during inflammation. Inflammation occurs when the immune system sends signaling molecules and leukocytes from the blood to a site of injury or disease to combat invading microorganisms and facilitate tissue repair. When this has been accomplished, the body stops the inflammatory response to prevent damage to its own cells and tissues.
Three versions of the protein Serum amyloid A1, known as alpha, beta, and gamma, which differ from each other in one or two amino acids. The frequency of these variants differs between populations. In Caucasian populations, predominantly alpha and gamma version version is rare. However, in the Japanese population, the three versions appear almost equally. Several studies of people with familial Mediterranean fever have indicated that the alpha version of serum amyloid A1 protein increases the risk of amyloidosis as a serious complication. Some studies indicate that people with familial Mediterranean fever having alpha version of the protein having two to seven times more likely to develop amyloidosis people with beta or gamma. During episodes of inflammation it is encoded more protein in the organism, which can lead to the formation of abnormal clusters in organs and tissues. However, it is unclear, how alpha version of the protein increases susceptibility to amyloidosis, or alternatively, how beta and gamma versions can protect against this alteration in people with the disease. 2 mutations have been described in the SAA1 gene, a nonsense mutation and a regulatory mutation.
Familial Mediterranean fever is inherited, in almost all cases, with an autosomal recessive pattern, which means that 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. In rare cases, this alteration appears to be inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to cause disease. In autosomal dominant inheritance, affected individuals usually inherit the mutation from an affected parent. It is believed that some cases of the disease, originally thought to be inherited in an autosomal dominant pattern are due to another form of inheritance would correspond to a genetic mutation that occurs frequently in a population, which can lead to a autosomal recessive disease that appears in multiple generations in a family, with a pattern that mimics the autosomal dominant inheritance. If one parent has the disease (with mutations in both copies of MEFV gene in each cell) and the other parent is an unaffected carrier (with a mutation in one copy of MEFV gene in each cell), it may seem as if the child inherited the disease affected only the affected parent. This aspect of autosomal dominant inheritance, when in fact the pattern is called autosomal recessive pseudodominance.
Tests in IVAMI: in IVAMI perform detection of mutations associated with familial Mediterranean fever, by complete PCR amplification of the exons of the MEFV SAA1 and genes, respectively, and subsequent sequencing. Being more frequent recurrent mutations in exons 2 and 10 of MEFV gene, it offers the possibility of starting the study by these two exons, which if found a mutation in one of them, it would be necessary to conduct the study in other exons, thereby reducing cost and time. In case of negative result of these exons can proceed to full gene sequencing without obtaining a new patient sample.
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).