Chicago Center for Jewish Genetics Disorders - Sephardic Disorders

Sephardi Disorders

Gene: Familial Mediterranean Fever is caused by a mutation in the MEVF gene, which is located at 16p13. This gene encodes the protein pyrin, which is hypothesized to help control inflammation.

Mutations and testing: 17 mutations have been detected and all result in less active pyrin protein. The three most common mutations are M694V, E148Q, and V726A. DNA testing detects 95% of mutations seen in North African Jews, 80% of mutations seen in Iraqi Jews, and 90% of the mutations seen in Ashkenazi Jews.

M694V: 80-90% of African Jewish patients have at least one M694V allele. There is a significant association of development of amyloidosis with the presence of this allele and this likelihood increases with homozygosity. An earlier age of onset and a higher frequency of arthritis and pleuritis have also been associated with this mutation.
E148Q: This mutation is the predominant mutation seen Ashkenazi Jews with FMF. It is generally associated with a mild form of the disease. When a individual is homozygous for E148Q or is a compound heterozygote for E148Q and any other mutation besides M694V, they may be asymptomatic and have a low risk for developing amyloidosis. It is considered to have low penetrance.
V726A: It is not clear if a specific phenotype is associated with this mutation. It is considered to have low penetrance.

Traits: Pyrin is expressed only in granulocytes, which are immune cells acting as the first line of defense against foreign invaders and damage. During an FMF attack, these cells accumulate in massive numbers at the site of the affected body part. This triggers inflammation and results in redness, swelling, heat, and pain. Pryin is believed to shut down or dampen the inflammatory response when it is not needed, and in FMF patients, this reaction is out of control. FMF is described as having 2 subtypes and either can be seen between and within families.

Type I is characterized by recurrent short episodes (from 1-3 days) of inflammation and serositis (inflammation of the fluid-secreting membranes that cover the insides of body cavities). Serositis most commonly occurs as peritonitis (abdominal pain seen in 90% of patients), synovitis (joint pain seen in 75% of patients), and pleuritis (seen in 45% of patients). Pericarditis can also occur, but is rare.
Type II is characterized by amyloidosis as the first symptom. Amyloidosis is a condition in which insoluble protein fibers (amyloids) are deposited extracellularly in tissues and organs, thereby damaging them and interfering with their function. In FMF, it is frequently associated with renal failure.

Treatment: Regular administration of colchicine is the main treatment for patients with symptomatic FMF, and is effective in ~90% of cases. It reduces the number of inflammatory attacks and effectively prevents amyloidosis. It is hypothesized to work by blocking the movement of neutrophils to the areas that would otherwise become inflammed. For patients with one or two M694V mutations, colchicine is given presymptomatically.

Familial Mediterranean Fever from eMedicine
http://www.emedicine.com/med/topic1410.htm

Familial Mediterranean Fever from Geneclinics.org

Reviewed by Dr. Joel Charrow, Children's Memorial Hospital.
1/03

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This page last updated on January 10, 2003.