Familial Mediterranean fever
Encyclopedia
Familial Mediterranean fever (FMF) is a hereditary
inflammatory
disorder. FMF is an autoinflammatory disease caused by mutations in MEFV
, a gene which encodes a 781–amino acid protein denoted pyrin.
The disorder has been given various names including familial paroxysmal polyserositis, periodic peritonitis, recurrent polyserositis, benign paroxysmal peritonitis, periodic disease or periodic fever, Reimann periodic disease or Reimann's syndrome, Siegal-Cattan-Mamou disease, and Wolff periodic disease. Note that "periodic fever" can also refer to any of the Periodic fever syndrome
s.
(hence its name). It is prominently present in the Armenia
n people, Sephardi Jews
(and, to a much lesser extent, Ashkenazi Jews), Greeks
, Turks and Arabs.
.
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 thyroid
.
There appears to be an increase in the risk for developing particular vasculitis
-related diseases (e.g. Henoch-Schönlein purpura
), spondylarthropathy, prolonged arthritis
of certain joints and protracted myalgia.
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
.
A genetic test is also available to detect mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.
A specific and highly sensitive test for FMF is the "Metaraminol
Provocative Test (MPT)," whereby a single 10 mg infusion of Metaraminol is administered to the patient. A positive diagnosis is made if the patient presents with a typical, albeit milder, FMF attack within 48 hours. As MPT is more sensitive than specific, it does not identify all cases of FMF. Although a positive MPT can be very useful.
, which codes for a protein called pyrin or marenostrin. Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur mainly in exon
s 2, 3, 5 and 10.
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
. In other words an ineffective pyrin doesn't inhibit inflammation normally, resulting in inflammatory episodes of membranes at differing sites. 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).
The MEFV
gene is located on the short arm of chromosome 16
(16p13). The disorder inherits in an autosomal recessive fashion. Therefore, two asymptomatic carrier
parents have a 25% chance of a child with the disorder, a 50% chance of a child who is an asymptomatic carrier and a 25% chance of a child who does not carry the disorder. FMF patients who have children with a carrier or another FMF patient have a 50% and 100% chance, respectively, of having a child with FMF.
s (such as diclofenac
).
Colchicine
, a drug otherwise mainly used in gout
, decreases 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. Some advise discontinuation of colchicine before and during pregnancy, but the data are inconsistent, and others feel it is safe to take colchicine during pregnancy.
Approximately 5-10% of FMF cases are resistant to colchicine therapy alone. In these cases, adding anakinra
to the daily colchicine regimen has been successful.
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".
Colchicine has been used as a treatment since the 1970s.
The link to the MEFV gene was discovered in 1997 by two different groups, each working independently - the French FMF Consortium, and the International FMF Consortium.
gene.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
disorder. FMF is an autoinflammatory disease caused by mutations in MEFV
MEFV
MEFV is a human gene that provides instructions for making a protein called pyrin . Pyrin is produced in certain white blood cells that play a role in inflammation and in fighting infection...
, a gene which encodes a 781–amino acid protein denoted pyrin.
The disorder has been given various names including familial paroxysmal polyserositis, periodic peritonitis, recurrent polyserositis, benign paroxysmal peritonitis, periodic disease or periodic fever, Reimann periodic disease or Reimann's syndrome, Siegal-Cattan-Mamou disease, and Wolff periodic disease. Note that "periodic fever" can also refer to any of the Periodic fever syndrome
Periodic fever syndrome
The periodic fever syndromes are a set of disorders, many of which are genetic disorders in which the mechanisms which initiate and control inflammation are disturbed, leading to uncontrolled inflammation throughout the body...
s.
Epidemiology
FMF affects groups of people originating from around the Mediterranean SeaMediterranean Sea
The Mediterranean Sea is a sea connected to the Atlantic Ocean surrounded by the Mediterranean region and almost completely enclosed by land: on the north by Anatolia and Europe, on the south by North Africa, and on the east by the Levant...
(hence its name). It is prominently present in the Armenia
Armenia
Armenia , officially the Republic of Armenia , is a landlocked mountainous country in the Caucasus region of Eurasia...
n people, Sephardi Jews
Judaism
Judaism ) is the "religion, philosophy, and way of life" of the Jewish people...
(and, to a much lesser extent, Ashkenazi Jews), Greeks
Greeks
The Greeks, also known as the Hellenes , are a nation and ethnic group native to Greece, Cyprus and neighboring regions. They also form a significant diaspora, with Greek communities established around the world....
, Turks and Arabs.
Attacks
There are seven types of attacks. Ninety percent of all patients have their first attacks before they are 18 years old. All develop over 2–4 hours and last anywhere from 6 hours to 4 days. Most attacks involve feverFever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
.
- Abdominal attacks, featuring abdominal painAbdominal painAbdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, affect the whole abdomen with all signs of peritonitis (inflammation of abdominal lining), and acute abdominal pain like appendicitisAppendicitisAppendicitis is a condition characterized by inflammation of the appendix. It is classified as a medical emergency and many cases require removal of the inflamed appendix, either by laparotomy or laparoscopy. Untreated, mortality is high, mainly because of the risk of rupture leading to...
. They occur in 95% of all patients and may lead to unnecessary laparotomyLaparotomyA laparotomy is a surgical procedure involving a large incision through the abdominal wall to gain access into the abdominal cavity. It is also known as coeliotomy.- Terminology :...
. Incomplete attacks, with local tenderness and normal blood tests, have been reported. - Joint attacks mainly occur in large joints, especially in the legs. Usually, only one joint is affected. Seventy-five percent of all FMF patients experience joint attacks.
- Chest attacks include pleuritis (inflammation of the pleura) and pericarditisPericarditisPericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...
(inflammation of the pericardiumPericardiumThe pericardium is a double-walled sac that contains the heart and the roots of the great vessels.-Layers:...
). Pleuritis occurs in 40% of patients, and makes it difficult to breathe or lie flat, but pericarditis is rare. - ScrotalScrotumIn some male mammals the scrotum is a dual-chambered protuberance of skin and muscle containing the testicles and divided by a septum. It is an extension of the perineum, and is located between the penis and anus. In humans and some other mammals, the base of the scrotum becomes covered with curly...
attacks due to inflammation of the tunica vaginalisTunica vaginalisThe tunica vaginalis is the serous covering of the testis.It is a pouch of serous membrane, derived from the processus vaginalis of the peritoneum, which in the fetus preceded the descent of the testis from the abdomen into the scrotum....
occurs in up to 5% and may be mistaken for acute scrotum (i.e. testicular torsionTesticular torsionTesticular torsion is when the spermatic cord to a testicle twists, cutting off the blood supply. The most common symptom is acute testicular pain and the most common underlying cause is a congenital malformation known as a "bell-clapper deformity". The diagnosis is often made clinically but if it...
). - MyalgiaMyalgiaMyalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
(rare in isolation) - ErysipeloidErysipelasErysipelas is an acute streptococcus bacterial infection of the deep epidermis with lymphatic spread.-Risk factors:...
(a skin reaction on the legs, rare in isolation) - Fever without any of the other symptoms listed above (25%)
Complications
AA-amyloidosis with renal failureRenal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
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
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, as well as the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
and thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
.
There appears to be an increase in the risk for developing particular vasculitis
Vasculitis
Vasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis...
-related diseases (e.g. Henoch-Schönlein purpura
Henoch-Schönlein purpura
Henoch–Schönlein purpura is a disease of the skin and other organs that most commonly affects children. In the skin, the disease causes palpable purpura ; often with joint and abdominal pain...
), spondylarthropathy, prolonged arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
of certain joints and protracted myalgia.
Diagnosis
The diagnosis is clinically 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 proteinC-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
levels, an elevated white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
count and other markers of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. In patients with a long history of attacks, monitoring the renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
is of importance in predicting chronic renal failure
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
.
A genetic test is also available to detect mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.
A specific and highly sensitive test for FMF is the "Metaraminol
Metaraminol
Metaraminol is a potent sympathomimetic amine used in the prevention and treatment of hypotension, particularly as a complication of anesthesia.It is an α1-adrenergic receptor agonist with some β effect....
Provocative Test (MPT)," whereby a single 10 mg infusion of Metaraminol is administered to the patient. A positive diagnosis is made if the patient presents with a typical, albeit milder, FMF attack within 48 hours. As MPT is more sensitive than specific, it does not identify all cases of FMF. Although a positive MPT can be very useful.
Pathophysiology
Virtually all cases are due to a mutation in the MEFV gene on the sixteenth chromosomeChromosome 16 (human)
125px|rightChromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs and represents just under 3 % of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic...
, which codes for a protein called pyrin or marenostrin. Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur mainly in exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s 2, 3, 5 and 10.
The function of pyrin has not been completely elucidated, but it appears to be a suppressor of the activation of caspase 1
Caspase 1
Caspase 1 is an enzyme that proteolytically cleaves other proteins, such as the precursor forms of the inflammatory cytokines interleukin 1-β and interleukin 18, into active mature peptides...
, the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that stimulates production of interleukin 1β
IL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...
, a cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
central to the process of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. In other words an ineffective pyrin doesn't inhibit inflammation normally, resulting in inflammatory episodes of membranes at differing sites. 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).
Genetics
MEFV
MEFV is a human gene that provides instructions for making a protein called pyrin . Pyrin is produced in certain white blood cells that play a role in inflammation and in fighting infection...
gene is located on the short arm of chromosome 16
Chromosome 16 (human)
125px|rightChromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs and represents just under 3 % of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic...
(16p13). The disorder inherits in an autosomal recessive fashion. Therefore, two asymptomatic carrier
Asymptomatic carrier
An asymptomatic carrier is a person or other organism that has contracted an infectious disease, but who displays no symptoms. Although unaffected by the disease themselves, carriers can transmit it to others...
parents have a 25% chance of a child with the disorder, a 50% chance of a child who is an asymptomatic carrier and a 25% chance of a child who does not carry the disorder. FMF patients who have children with a carrier or another FMF patient have a 50% and 100% chance, respectively, of having a child with FMF.
Treatment
Attacks are self-limiting, and require analgesia and NSAIDNon-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
s (such as diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
).
Colchicine
Colchicine
Colchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
, a drug otherwise mainly used in gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
, decreases 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
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
and muscle pains
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
), 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
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
is being studied as a therapeutic modality. Some advise discontinuation of colchicine before and during pregnancy, but the data are inconsistent, and others feel it is safe to take colchicine during pregnancy.
Approximately 5-10% of FMF cases are resistant to colchicine therapy alone. In these cases, adding anakinra
Anakinra
Anakinra is a drug used to treat rheumatoid arthritis.-Mechanism:Anakinra is an interleukin-1 receptor antagonist...
to the daily colchicine regimen has been successful.
History
A New YorkNew York
New York is a state in the Northeastern region of the United States. It is the nation's third most populous state. New York is bordered by New Jersey and Pennsylvania to the south, and by Connecticut, Massachusetts and Vermont to the east...
allergist, Dr Sheppard Siegal, first described the attacks of peritonitis
Peritonitis
Peritonitis is an inflammation of the peritoneum, the serous membrane that lines part of the abdominal cavity and viscera. Peritonitis may be localised or generalised, and may result from infection or from a non-infectious process.-Abdominal pain and tenderness:The main manifestations of...
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
American University of Beirut
The American University of Beirut is a private, independent university in Beirut, Lebanon. It was founded as the Syrian Protestant College by American missionaries in 1866...
, described a more complete picture which he termed "periodic disease".
Colchicine has been used as a treatment since the 1970s.
The link to the MEFV gene was discovered in 1997 by two different groups, each working independently - the French FMF Consortium, and the International FMF Consortium.
External links
information about the MEFVMEFV
MEFV is a human gene that provides instructions for making a protein called pyrin . Pyrin is produced in certain white blood cells that play a role in inflammation and in fighting infection...
gene.