Familial Mediterranean fever is an inherited condition characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints. These episodes are often accompanied by fever and sometimes a rash or headache. Occasionally inflammation may occur in other parts of the body, such as the heart; the membrane surrounding the brain and spinal cord; and in males, the testicles. In about half of affected individuals, attacks are preceded by mild signs and symptoms known as a prodrome. Prodromal symptoms include mildly uncomfortable sensations in the area that will later become inflamed, or more general feelings of discomfort.

The first episode of illness in familial Mediterranean fever usually occurs in childhood or the teenage years, but in some cases, the initial attack occurs much later in life. Typically, episodes last 12 to 72 hours and can vary in severity. Episodes generally occur once a month, and in affected women of reproductive age, attacks often correspond with menstruation or ovulation. However, the length of time between episodes can range from days to years. During these periods, affected individuals usually have no signs or symptoms related to the condition. However, without treatment to help prevent attacks and complications, a buildup of protein deposits (amyloidosis) in the body's organs and tissues may occur, especially in the kidneys, which can lead to kidney failure.

Familial Mediterranean Fever (FMF) is an inherited disease, characterized by recurrent attacks of fever, inflammation of the abdominal lining (peritonitis), inflammation of the lining surrounding the lungs , painful, swollen joints, and a characteristic ankle rash.

What is Familial Mediterranean Fever?

FMF is considered a rare disease worldwide. However, it is very common in people of Sephardic (non-Ashkenazi) Jewish, Armenian, Arab and Turkish heritage. Among people with these backgrounds, about 1 in 200 has FMF. The availability of genetic testing has helped identify numerous cases among several additional populations with Mediterranean roots, including: Ashkenazi Jews, Italians, Greeks, Spaniards, and Cypriots, and occasional cases in a broad range of other ethnicities (Northern Europeans and Japanese).

FMF is characterized by relatively short, usually 1- to 3-day, episodes of fever accompanied with serositis, synovitis or skin rash. In some patients, attacks begin in infancy or very early childhood, but 80 to 90 percent of patients experience their first episode by age 20. Young children sometimes present with recurrent fevers alone. The frequency of FMF attacks is highly variable, both among groups of patients or for any individual patient, with the interval between attacks ranging from days to years. Moreover, the type of attack - whether abdominal, pleural or arthritic - may also vary over time. Between attacks, people commonly are symptom-free.

Other symptoms that may occur include inflammation of the lining surrounding the heart (pericarditis), inflammation of the testis (orchitis), benign, recurrent inflammation of the membrane that surrounds the brain and spinal chord (meningitis), headaches and amyloidosis. Amyloidosis occurs when a particular protein, called amyloid, builds up in various tissues of the body, primarily the kidney. Potentially, it is the most serious complication of FMF, causing kidney failure. In some cases the amyloidosis can develop even without overt attacks of FMF.

This condition is also sometimes referred to as recurrent polyserositis or familial paroxysmal polyserositis.

What do we know about heredity and Familial Mediterranean Fever?

Familial Mediterranean Fever (FMF) is an autosomal recessive inherited disease, which means it appears only in individuals who received two copies of the mutant (altered) gene that causes FMF, one from each parent. As many as 1 in 5 people of Sephardic (non-Ashkenazi) Jewish, Armenian, Arab and Turkish heritage have one mutant copy of the gene and are therefore carriers of FMF, which means they carry the mutant gene but do not suffer from FMF themselves.

Located on the short (p) arm of chromosome 16, MEFV (MEditerranean FeVer) is the gene that, when mutated, causes FMF. This gene provides the instructions (codes) for creating a protein, called pyrin (also known as marenostrin), which is found in the white blood cells (granulocytes), which are important in the immune response, and myeloid bone marrow precursors. Although the precise function of pyrin is as yet unknown, researchers believe it most likely plays a role in keeping inflammation under control, possibly by inhibiting the immune inflammatory response. There are more than 30 mutations in the MEFV gene known to cause FMF, but four of them are very common in the patients of Middle Eastern ancestry.

How is Familial Mediterranean Fever diagnosed?

In making a diagnosis of Familial Mediterranean Fever (FMF), doctors take all of these factors into account:

• Whether or not the patient has the clinical symptoms common for the disease and whether the symptoms are recurrent.

• How he or she responds to colchicine treatment (see "How is Familial Mediterranean Fever treated?" below).

• Usually a positive family history in people of Middle Eastern ancestry.

• The results of genetic testing.

Also helpful in establishing a correct diagnosis of FMF is the patient's ancestry. Testing for the following can also be helpful:

• Elevated white blood cell count, which is an indication of an immune response.

• Elevated erythrocyte sedimentation rate (ESR), which is an indication of an inflammatory response.

• Elevated plasma fibrinogen, which helps stop bleeding. An elevated amount would indicate that something might be wrong with this mechanism.

• Elevated serum haptoglobin, which would indicate that red blood cells are being destroyed, a common occurrence in rheumatic diseases, such as FMF.

• Elevated C-reactive protein, which is a special type of protein, produced by the liver, that is only present during episodes of acute inflammation.

• Elevated albumin in the urine, which is demonstrated by urinalysis. The presence of the protein albumin in the urine can be a symptom of kidney disease, along with microscopic hematuria (very small - microscopic - amounts of blood or blood cells in the urine), during attacks.

Is there a test for Familial Mediterranean Fever?

Since the gene mutations responsible for this condition have been identified, there are a few labs in the United States and Canada and a few more in Europe and the Middle East that are offering molecular or DNA testing for Familial Mediterranean Fever (FMF). Most centers, however, only test for a subset of the mutations that cause FMF, particularly those common in FMF patients.

How is Familial Mediterranean Fever treated?

At present, there is no known cure for Familial Mediterranean Fever (FMF). Physicians can only treat the symptoms of the disease.

A common therapy for FMF is daily use of the drug colchicine, a medicine that reduces inflammation. This therapy has been successful in preventing attacks of fever in 75 percent of patients who take the drug regularly, and over 90 percent of patients demonstrate a marked improvement. Even if colchicine does not prevent the fever attacks, it does prevent the amyloidosis. However, compliance in taking colchicine every day is very important. If a patient stops taking the drug, an attack can occur within a couple of days.

Since the gene that causes FMF codes for the protein pyrin, researchers hope that by studying how this protein works they will ultimately develop improved treatments for FMF, and possibly for other conditions involving excess inflammation.

Familial Mediterranean fever is caused by variants (also known as mutations) in the MEFV gene. The MEFV gene provides instructions for making a protein called pyrin (also known as marenostrin), which is found in white blood cells. This protein is involved in the immune system, helping to regulate the process of inflammation. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this process is complete, the body stops the inflammatory response to prevent damage to its own cells and tissues.

Variants in the MEFV gene reduce the activity of the pyrin protein, which disrupts control of the inflammation process. An inappropriate or prolonged inflammatory response can result, leading to fever and pain in the abdomen, chest, or joints.

Normal variations in the SAA1 gene may modify the course of familial Mediterranean fever. Some evidence suggests that a particular version of the SAA1 gene (called the alpha variant) increases the risk of amyloidosis among people with familial Mediterranean fever.

Normal Function

The MEFV gene provides instructions for making a protein called pyrin (also known as marenostrin). Although pyrin's function is not fully understood, it likely assists in keeping the inflammation process under control. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this has been accomplished, the body stops the inflammatory response to prevent damage to its own cells and tissues.

Pyrin is produced in certain white blood cells (neutrophils, eosinophils, and monocytes) that play a role in inflammation and in fighting infection. Pyrin may direct the migration of white blood cells to sites of inflammation and stop or slow the inflammatory response when it is no longer needed. Pyrin also interacts with other molecules to assemble themselves into structures called inflammasomes, which are involved in the process of inflammation. Research indicates that pyrin helps regulate inflammation by interacting with the cytoskeleton, the structural framework that helps to define the shape, size, and movement of a cell.

Health Conditions Related to Genetic Changes

Familial Mediterranean fever

More than 80 MEFV gene variants (also known as mutations) have been found to cause familial Mediterranean fever. A few variants delete small amounts of DNA from the MEFV gene, which can lead to an abnormally small, nonfunctional protein. Most MEFV gene variants, however, change one of the protein building blocks (amino acids) used to make pyrin. The most common variant replaces the amino acid methionine with the amino acid valine at protein position 694 (written as Met694Val or M694V). Among people with familial Mediterranean fever, this particular variant is also associated with an increased risk of developing amyloidosis, a complication in which abnormal protein deposits can lead to kidney failure. Some evidence suggests that normal variations in another gene, called SAA1, can further modify the risk of developing amyloidosis among people with the M694V change.

MEFV gene variants lead to reduced amounts of pyrin or a malformed pyrin protein that cannot function properly. As a result, pyrin cannot perform its presumed role in controlling inflammation, leading to an inappropriate or prolonged inflammatory response. Fever and inflammation in the abdomen, chest, joints, or skin are signs of familial Mediterranean fever.

Other Names for This Gene

• FMF
• marenostrin
• Mediterranean fever
• MEF
• MEFV_HUMAN
• MRST
• pyrin
• TRIM20

Genomic Location

FMF is almost always inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a:

• 25% chance to have the condition
• 50% chance to be a carrier like each of the parents
• 25% chance to not have the condition and not be a carrier

As many as 1 in 5 people of Sephardic Jewish, Armenian, Arab and Turkish heritage is a carrier of FMF.

In rare cases, FMF appears to be inherited in an autosomal dominant manner. This means that to be affected, a person needs to have a mutation in only one copy of the responsible gene in each cell. In some cases, an affected person inherits the mutation from an affected parent. Other cases may result from new (de novo) mutations in the gene. A person with autosomal dominant FMF has a 50% chance to pass the mutated gene on to each child.

In some cases, FMF may appear to be autosomal dominant when it is actually autosomal recessive. This phenomenon is called pseudodominance.

• whether a person has symptoms of FMF and whether the symptoms are recurrent
• how a person responds to colchicine treatment
• family medical history and ancestry
• results of genetic testing

• Elevated white blood cell count, which is an indication of an immune response.
• Elevated erythrocyte sedimentation rate (ESR), which is an indication of an inflammatory response.
• Elevated plasma fibrinogen, which helps stop bleeding. An elevated amount would indicate that something might be wrong with this mechanism.
• Elevated serum haptoglobin, which would indicate that red blood cells are being destroyed, a common occurrence in rheumatic diseases, such as FMF.
• Elevated C-reactive protein, which is a special type of protein produced by the liver that is only present during episodes of acute inflammation.
• Elevated albumin in the urine, which can be a symptom of kidney disease, along with microscopic hematuria (microscopic amounts of blood in the urine).

The goal of treatment for familial Mediterranean fever (FMF) is to control symptoms because there is no cure for the condition.

Treatment of an acute episode may include:

• intravenous saline for hydration
• nonsteroidal anti-inflammatory drugs (NSAIDs) for fever and inflammatory episodes
• NSAIDs, paracetamol or dipyrone for pain relief
• routine treatment of end-stage renal disease (kidney failure), including renal transplantation

Depending on disease severity or the presence of specific mutations, lifelong treatment with colchicine may be needed. Colchicine prevents inflammatory attacks and the deposition of amyloid. Those who are only mildly affected (with infrequent inflammatory attacks) may either be treated with colchicine or be monitored every six months for the presence of protein in the urine (proteinuria). Others may only be treated with colchicine if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis. Those who are unresponsive to oral colchicine may respond to intravenous colchicine, or one of several other medications. Colchicine is not effective as treatment for an acute FMF attack.

People with FMF who are compliant with daily colchicine can probably expect to have a normal lifespan, if colchicine is started before proteinuria develops. Even with amyloidosis, the use of colchicine, dialysis, and kidney transplantation should extend a patient's life beyond 50 years of age.