Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder that affects groups of patients originating from around the Mediterranean Sea (hence its name). It is prominently present in the Armenian people (up to 1 in 7 affected), Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), people from Turkey, the Arab countries and Lebanon. The following codes are used with International Statistical Classification of Diseases and Related Health Problems. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... A genetic disorder, or genetic disease is a disease caused by abnormal expression of one or more genes in a person causing a clinical phenotype. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ... Satellite image The Mediterranean Sea is a part of the Alanic Ocean almost completely enclosed by land, on the north by Europe, on the south by Africa, and on the east by Asia. ... Sephardim (ספרדי, Standard Hebrew Səfardi, Tiberian Hebrew ardî; plural Sephardim: ספרדים, Standard Hebrew Sfaradim, Tiberian Hebrew ) are a subgroup of Jews, generally defined in contrast to Ashkenazim and/or . ... Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim (אַשְׁכֲּנָזִי אַשְׁכֲּנָזִים Standard Hebrew, Aškanazi,Aškanazim, Tiberian Hebrew, ʾAškănāzî, ʾAškănāzîm, pronounced sing. ...

Clinical symptoms

Attacks

There are seven types of attacks. 90% of all patients have their first attack before they are 20 years old. All develop over 2-4 hours and last anytime between 6 hours and 4 days. Most attacks involve fever: Hyperthermia: Characterized on the left. ...

1. Abdominal attacks, featuring abdominal pain affecting the whole abdomen with all signs of acute abdomen (e.g. appendicitis). They occur in 95% of all patients and may lead to unnecessary laparotomy. Incomplete attacks, with local tenderness and normal blood tests, have been reported.
2. Joint attacks, occurring in large joints, mainly of the legs. Usually, only one joint is affected. 75% of all FMF patients experience joint attacks.
3. Chest attacks with pleuritis (inflammation of the pleural lining) and pericarditis (inflammation of the pericardium). Pleuritis occurs in 40%, but pericarditis is rare.
4. Scrotal attacks due to inflammation of the tunica vaginalis. This occurs in up to 5% and may be mistaken for acute scrotum (i.e. testicular torsion)
5. Myalgia (rare in isolation)
6. Erysipeloid (a skin reaction on the legs, rare in isolation)
7. Fever without any symptoms (25%)

Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. ... Appendicitis is a condition characterised by inflammation of the appendix. ... A laparotomy is a surgical maneuver involving an incision through the abdominal wall to gain access into the abdominal cavity. ... ... In anatomy, the pleural cavity is the potential space between the lungs and the chest wall. ... Pericarditis is inflammation of the pericardium. ... The pericardium is a double-walled sac that contains the heart and the roots of the great vessels. ... The scrotum (human variant shown) is a thin extension of the abdomen that contains the testes and helps regulate their temperature. ... In testicular torsion the spermatic cord that provides the blood supply to a testicle is twisted, cutting off the blood supply, often causing orchalgia. ... Myalgia means muscle pain and is a symptom of many diseases and disorders. ... Erysipelas is a streptococcus bacterial skin infection, resulting in inflammation and characteristically extending into underlying fat tissue. ...

Complications

AA-amyloidosis with renal failure is a complication and may develop without overt crises. AA (amyloid protein) is produced in very large quantities during attacks and at a low rate between them, and accumulates mainly in the kidney, as well as the heart, spleen, gastrointestinal tract and the thyroid. Amyloid describes various types of protein aggregations that share specific traits when examined microscopically. ... Renal failure is the condition where the kidneys fail to function properly. ... Kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... The heart and lungs (from an older edition of Grays Anatomy) The heart (Latin cor) is a hollow, muscular organ that pumps blood through the blood vessels by repeated, rhythmic contractions. ... The spleen is a ductless, vertebrate gland that is not necessary for life but is closely associated with the circulatory system, where it functions in the destruction of old red blood cells and removal of other debris from the bloodstream, and also in holding a reservoir of blood. ... The gastrointestinal or digestive tract, also referred to as the GI tract or the alimentary canal or the gut, is the system of organs within multicellular animals which takes in food, digests it to extract energy and nutrients, and expels the remaining waste. ...

There appears to be an increase in the risk for developing particular vasculitis-related diseases (e.g. Henoch-Schoenlein purpura), spondylarthropathy, prolonged arthritis of certain joints and protracted myalgia. In medicine, vasculitis (plural: vasculitides) is a group of diseases featuring inflammation of the wall of blood vessels. ... In medicine (rheumatology and pediatrics) Henoch-Schönlein purpura (HSP, also known as allergic purpura) is a form of vasculitis that mainly affects children. ... Arthritis (from Greek arthro-, joint + -itis, inflammation) is a group of conditions that affect the health of the bone joints in the body. ...

Diagnosis

The diagnosis is essentially made on the basis of the history of typical attacks, especially in patients from the ethnic groups in which FMF is more highly prevalent. An acute phase response is present during attacks, with high C-reactive protein levels, an elevated white blood cell count and other markers of inflammation. In patients with a long history of attacks, monitoring the renal function is of importance in predicting chronic renal failure. Acute phase proteins are a class of proteins that are synthetized in the liver in response to inflammation. ... C-reactive protein (CRP) is a plasma protein, an acute phase protein produced by the liver. ... White blood cells (also called leukocytes or immune cells) are a component of blood. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ... In medicine (nephrology) renal function is an indication of the state of the kidney and its role in physiology. ...

Disease mechanism

Pathophysiology

Virtually all cases are due to a mutation in the MEFV gene, which codes for a protein called pyrin or marenostenin. This was discovered in 1997 by two different groups. Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur in exons 2, 3, 5 and 10. 1997 is a common year starting on Wednesday of the Gregorian calendar. ... Exons are the regions of DNA within a gene that are not spliced out from the transcribed RNA and are retained in the final messenger RNA (mRNA) molecule. ...

The function of pyrin has not been completely elucidated, but it appears to be a suppressor of the activation of caspase 1, the enzyme that stimulates production of interleukin 1β, a cytokine central to the process of inflammation. It is not conclusively known what exactly sets off the attacks, and why overproduction of IL-1 would lead to particular symptoms in particular organs (e.g. joints or the peritoneal cavity). Ribbon diagram of the catalytically perfect enzyme TIM. Factor D enzyme crystal prevents the immune system from inappropriately running out of control. ... Interleukin-1 (IL-1) is secreted by the macrophages, monocytes and dendritic cells. ... Cytokines are small protein molecules that are the core of communication between immune system cells, and even between these cells and cells belonging to other tissue types. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ...

Genetics

The MEFV gene is located on the 16th chromosome (16p13). The disease inherits in an autosomal recessive fashion. Therefore, two asymptomatic carrier parents have a 25% chance of a child with the disorder. FMF patients who marry a carrier or another FMF patient have a 50% and 100% chance, respectively, in having a child with FMF. Figure 1: Chromosome. ... In genetics, the term recessive gene refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele). ...

Treatment

Attacks are self-limiting, and require analgesia and non-steroidal anti-inflammatory drugs (such as diclofenac). For other uses of painkiller, see painkiller (disambiguation) An analgesic (colloquially known as painkiller) is any member of the diverse group of drugs used to relieve pain. ... Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. ... Diclofenac (marketed as Voltaren®, Voltarol® and Cataflam®) is a non-steroidal anti-inflammatory drug (NSAID) taken to reduce inflammation, such as in arthritis or acute injury. ...

Since the 1970s, colchicine, a drug otherwise mainly used in gout, has been shown to decrease attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side-effects (such as abdominal pain and muscle pains), it may markedly improve quality of life in patients. The dosage is typically 1-2 mg a day. Development of amyloidosis is delayed with colchicine treatment. Interferon is being studied as a therapeutic modality. This article provides extensive lists of events and significant personalities of the 1970s. ... Colchicine is a highly poisonous alkaloid, originally extracted from plants of the genus Colchicum (Autumn crocus, also known as the Meadow saffron). Originally used to treat rheumatic complaints and especially gout, it was also prescribed for its cathartic and emetic effects. ... Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. ... Myalgia means muscle pain and is a symptom of many diseases and disorders. ... Interferons (IFNs) are natural proteins produced by the cells of the immune systems of most animals in response to challenges by foreign agents such as viruses, bacteria, parasites and tumour cells. ...

History

A New York allergist, Dr Sheppard Siegal, first described the attacks of peritonitis in 1945; he termed this "benign paroxysmal peritonitis", as the disease course was essentially benign. Dr Hobart Reimann, working in the American University in Beirut, described a more complete picture which he termed "periodic disease". State nickname: Empire State Other U.S. States Capital Albany Largest city New York City Governor George Pataki (R) Senators Charles Schumer (D) Hillary Rodham Clinton (D) Official languages None (English is de facto) Area 141,205 km² (27th)  - Land 122,409 km²  - Water 18,795 km² (13. ...

References

• Livneh A, Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever. Baillieres Best Pract Res Clin Rheumatol 2000;14(3):477-98. PMID 10985982.
• Reiman HA. Periodic disease. Probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. JAMA 1948;136:239-44.
• Siegal S. Benign paroxysmal peritonitis. Ann Intern Med 1945;23:1-21.
• The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90:797-807. PMID 9288758.
• The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17:25-31. PMID 9288094.

JAMA is the acronym for the Journal of the American Medical Association, a leading medical journal. ...

External links

• OMIM 249100 and OMIM 608107
• The FMF Community Online: Providing support, validation, resources and connections for those living with FMF (www.fmfcommunity.org)
• Information, support and advice to anyone with Amyloidosis, secondary to FMF (www.amyloidosisaustralia.org)