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what causes fmf ?

Familial Mediterranean Fever

Familial Mediterranean Fever is also known as familial paroxysmal polyserositis or FMF.

polyserositis recurring

Familial Mediterranean Fever Subdivisions

Mediterranean fever type 1 is a kind of familial Mediterranean fever.

Mediterranean fever type 2 is a kind of familial Mediterranean fever.

Discussion in General

Summary

FMF is an inherited autoinflammatory disease marked by recurring episodes (attacks) of fever and acute inflammation of the membranes lining the gut, joints, and lungs. Affected persons may get skin rashes (erysipelas, similar to erythema) on their lower legs in some circumstances. Inflammation of the membranes lining the heart or covering the brain and spinal cord occurs less frequently. Some people may develop amyloidosis, a dangerous illness in which specific proteins called amyloid accumulate in numerous body tissues. Amyloid builds up in the kidneys (renal amyloidosis) in FMF patients.

The Nature of the Illness

FMF most commonly affects children. Inflammatory bouts can last anywhere from a few hours to several days. Patients who are treated early on have a good outcome. Although FMF episodes can occur without warning and for no apparent reason, in rare situations, specific triggers have been found. Infection, trauma, strenuous exercise, and stress are all examples of these triggers. An episode can be triggered by the start of a woman’s period (menses).
Symptoms and Signs
Even within family members, the symptoms and severity of FMF might vary substantially. Short, recurring episodes (attacks) of inflammation are a hallmark of the typical form of FMF. These bouts can last anywhere from one to four days and are usually unprovoked. The length and severity of episodes (in various people and even the same person) can vary greatly.

The commencement of an episode of FMF is preceded by a feeling of ill health or unpleasantness in around 50% of people with FMF. A prodrome, or prodromal phase, is the term for this period. Fatigue, stress, or physical exertion can all induce attacks.

The first indication of FMF is frequently recurrent fevers in early childhood. Temperatures can quickly rise, reaching 100–104 degrees Fahrenheit (or >40 degrees Celsius) in extreme cases. Fever can occur on its own or in combination with any or all of the symptoms listed below. Fevers might develop without any other symptoms during mild episodes. Recurrent fevers during childhood may be the only symptom associated with FMF in some people.

Serositis is another prevalent symptom, along with prolonged episodes of fever.

Approximately 90% of people with FMF have abdominal symptoms, which can vary from minor bloating to inflammation of the gut lining (peritonitis). The beginning of abdominal symptoms can happen at the same time as the onset of a fever. Abdominal pain or tenderness is prevalent, and the abdominal muscles are often stiff and tight, with a “board-like” appearance. Swelling in the abdomen is common (distended). During an abdominal episode, some people may experience constipation, which is sometimes followed by diarrhea after the incident is over. Affected people are frequently misdiagnosed with acute abdomen (peritonitis) and have unneeded surgery as a result.

Due to inflammation of the membrane (synovium) lining the joints, approximately 75% of those affected have joint pain (arthralgia) and inflammation (arthritis). The pain, which is often accompanied by swelling, can be excruciating.

Some people who are affected may also have chest pain as a result of inflammation of the thin membrane that lines the lungs (pleura) (pleuritis). Episodes usually start out abruptly and end within 48 hours. On the affected side of the lungs, affected people may suffer uncomfortable breathing and reduced breathing noises. Breathing problems such as shortness of breath and quick, shallow breathing are also possible.

Causes

Mutations in the MEFV gene are the cause of FMF. The disease is passed down through the generations as an autosomal recessive characteristic. The mix of genes for a certain trait on the chromosomes obtained from the father and mother determines hereditary disorders.
When a child receives a defective gene from each parent, he or she develops recessive genetic illnesses. If a person is born with one normal gene and one illness gene, he or she will be a carrier for the disease but will not display symptoms. With each pregnancy, there is a 25% chance that two carrier parents will both carry the faulty gene and, as a result, have an afflicted child. It’s a 50/50 chance of having a child who is a carrier like their parents.

Despite the fact that FMF is an autosomal recessive disorder, some people who have only one defective gene (heterozygotes) will exhibit inflammatory symptoms that are remarkably similar to FMF. Other inflammatory disorders, such as Bechet’s disease and Crohn’s disease, are also more common in these people than in the general population. The severity of the disease in these people is generally comparable to that of those who have two disease genes (homozygotes) or two distinct mutations (compound heterozygotes), and they usually need therapy (see Standard Therapies below). The reason why some people with a single altered gene show symptoms is unknown. More research is needed to figure out why this happens and whether these cases are linked to a specific illness pattern..

Affected Populations

Males and females are equally affected by FMF, while some research imply a slight male bias. Individuals of any ethnic group can be affected by FMF, however the rates are substantially greater among particular Mediterranean communities, such as those of Armenian, Turkish, Arabic, and North African Jewish origin. The prevalence in these populations is estimated to be 1 in 200.

Related Disorders

The following illnesses have symptoms that are comparable to FMF. For a differential diagnosis, comparisons can be informative.

Autoinflammatory syndromes are a set of rare diseases defined by recurrent episodes of inflammation caused by innate immune system abnormalities. Periodic fevers, rash, stomach pain, joint pain, bone pain, and other symptoms associated with chronic inflammation are common in these syndromes. Cryopyrin-associated periodic syndromes (familial cold autoinflammatory disease, Muckle-Wells syndrome, and NOMID/CINCA), mevalonate kinase deficiency (MKD), and TNF receptor-associated periodic syndrome are examples of these conditions (TRAPS). (To learn more about these conditions, use the name of the disorder as a search keyword in the Rare Disease Database.

Diagnosis

A diagnosis of FMF is made based on the presence of specific symptoms, a thorough patient history, a thorough clinical examination, and a variety of specialist testing. These tests can help with diagnosing FMF and determining the severity of the condition. In FMF, early diagnosis is critical to avoid misdiagnosis and unneeded surgery (as many children are misdiagnosed as having appendicitis).

Clinical Testing and Work-Up

A blood test termed as an erythrocyte sedimentation rate may be performed during an episode. The sedimentation rate is the time it takes for red blood cells (erythrocytes) to settle in a test tube over a defined length of time. Many people who have FMF have a high sedimentation rate, which is a sign of inflammation. Raised white blood cell levels, which indicate an immune system response, elevated C-reactive protein, which is elevated during periods of inflammation, and/or elevated fibrinogen levels can all be detected through blood tests (a substance that helps stop bleeding). These tests, however, are only effective for an episode of FMF, and when the episode concludes, they return to normal or near normal.

Standard Therapies

Treatment

Although there is no cure for FMF, there are effective therapies available. Treatments are tailored to the exact symptoms that each person exhibits.

Colchicine, a complex chemical that lowers inflammation, is the cornerstone medicine used to treat many people. More than 90% of those who take the medicine see a significant reduction in the length and frequency of their episodes. Colchicine is also useful in avoiding amyloid build-up in the kidneys. Colchicine, on the other hand, necessitates stringent daily compliance and does not treat an episode once it has begun. As a result, increasing the dose during an episode isn’t a good idea. Colcrys, an oral colchicine medication, was approved by the FDA in 2009 to treat FMF.

Even if it is ineffective at treating FMF assaults, colchicine can prevent the development of renal amyloidosis. Renal amyloidosis can be reversed in its early stages. Some people who have FMF and amyloidosis develop end-stage renal disease (ESRD), which necessitates a kidney transplant. Affected individuals may need dialysis at first. Dialysis is a treatment in which a machine performs some of the duties of the kidney, such as filtering waste items from the bloodstream, assisting with blood pressure control, and ensuring adequate levels of vital chemicals like potassium. Because ESRD is irreversible, patients will eventually need a kidney transplant. The rate at which kidney dysfunction progresses to end-stage renal disease (ESRD) varies substantially from one person to the next. Since the introduction of colchicine treatment.

Investigational Therapies

Anakinra has been used to treat those who haven’t responded to colchicine therapy (Kineret). Anakinra is an interleukin-1 (IL1) receptor antagonist that inhibits interleukin-1 activity. According to early findings, this medicine is a safe and effective alternative for people who don’t respond to colchicine. More research is needed to determine anakinra’s long-term safety and effectiveness in people with FMF. Ilaris and Arcalyst are two more IL1-blockades that can be employed.

Rilonacept (Arcalyst), a medication developed by Regeneron Pharmaceuticals and authorized by the FDA for the treatment of autoinflammatory disorders such cold autoinflammatory syndrome, is being investigated as a potential therapy for FMF patients. More research is needed to determine the medication’s long-term safety and usefulness in the treatment of FMF patients.

Thalidomide, etanercept, interferon alpha, and sulphasalazine are some of the other medications that have been used in people who haven’t responded to colchicine. To evaluate the long-term safety and effectiveness of these prospective FMF therapies, more research is needed.

Resources

RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.

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