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Familial Mediterranean Fever

Disease Details

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Description: Familial Mediterranean Fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and serosal inflammation affecting the abdomen, chest, or joints.
Type: Familial Mediterranean Fever (FMF) is an autoinflammatory disorder. It is typically inherited in an autosomal recessive manner.
Signs And Symptoms: Signs and symptoms of Familial Mediterranean Fever (FMF) include:

- Recurrent fevers
- Abdominal pain
- Chest pain
- Painful, swollen joints, especially in the knees, ankles, and hips
- Red, swollen skin lesions, particularly on the legs
- Muscle aches
- In some cases, amyloidosis, which can lead to kidney damage

These episodes typically last for 1-3 days and can occur without warning.
Prognosis: Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disorder. The prognosis for individuals with FMF is generally good if the disease is properly managed with medications, particularly colchicine, which can prevent attacks and complications such as amyloidosis. Without proper treatment, complications like amyloidosis can lead to more serious health issues, including kidney failure. Regular monitoring and adherence to treatment are crucial for maintaining a good quality of life and long-term health in FMF patients.
Onset: The onset of Familial Mediterranean Fever (FMF) typically occurs in childhood, with most cases presenting before the age of 20. However, it can also manifest later in life.
Prevalence: Familial Mediterranean Fever (FMF) is most commonly found among individuals of Mediterranean descent, including those of Armenian, Arab, Turkish, and Sephardic Jewish backgrounds. The prevalence can vary significantly among different populations: it is estimated to be about 1 in 200 to 1 in 1,000 individuals in these high-risk groups. Among the general population, however, it is much rarer.
Epidemiology: FMF affects groups of people originating from around the Levant or Eastern Mediterranean (hence its name); it is thus most prominent among those from or with ancestry from the regions including Arabs, Armenians, Jews (particularly Sephardi, Mizrahi, and to a lesser degree Ashkenazi Jews), and Turks.
Intractability: Familial Mediterranean Fever (FMF) is a chronic condition that cannot be cured, but it is not considered intractable because it can be effectively managed. The primary treatment involves the use of colchicine, which helps prevent attacks and complications in most patients. With appropriate management, individuals with FMF can lead relatively normal lives.
Disease Severity: Familial Mediterranean Fever (FMF) typically manifests as recurrent episodes of fever and serosal inflammation, which can vary in severity from mild to severe. These episodes can include symptoms such as abdominal pain, chest pain, and arthritis. The severity of the disease can be influenced by the specific gene mutation, with some mutations associated with more severe forms. Chronic untreated FMF can lead to complications such as amyloidosis, which can cause kidney damage and other serious health issues.
Healthcare Professionals: Disease Ontology ID - DOID:2987
Pathophysiology: Virtually all cases are due to a mutation in the Mediterranean Fever (MEFV) gene on the chromosome 16, 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 exons 2, 3, 5 and 10.The function of pyrin has not been completely elucidated, but in short, it is a protein that binds to the adaptor ASC and the pro form of the enzyme caspase-1 to generate multiprotein complexes called inflammasomes in response to certain infections. In healthy individuals, pyrin-mediated inflammasome assembly (which leads to the caspase 1) dependent processing and secretion of the pro-inflammatory cytokines (such as interleukin-18 (IL-18) and IL-1β) is a response to enterotoxins from certain bacteria. The gain-of-function mutations in the MEFV gene render Pyrin hyperactive, and subsequently, the formation of the inflammasomes becomes more frequent.The pathophysiology of familial Mediterranean fever has recently undergone significant advances: at basal state, pyrin is kept inactive by a chaperone protein (belonging to the family of 14.3.3 proteins) linked to pyrin through phosphorylated serine residues. The dephosphoration of pyrin is an essential prerequisite for the activation of the pyrin inflammasome. Inactivation of RhoA GTPases (by bacterial toxins, for example) leads to the inactivation of PKN1 / PKN2 kinases and dephosphoration of pyrin. In healthy subjects, the dephosphorylation step alone does not cause activation of the pyrin inflammasome. In contrast, in FMF patients, the dephosphorylation of serines is sufficient to trigger the activation of the pyrin inflammasome. This suggests that there is a two-level regulation and that the second regulatory mechanism (independent of (de)phosphorylation) is deficient in FMF patients. This deficient mechanism is probably located at the level of the B30.2 domain (exon 10) where most of the pathogenic mutations associated with FMF are located. It is probably the interaction of this domain with the cytoskeleton (microtubules) that is failing, as suggested by the efficacy of colchicine.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). However, steroid hormone catabolites (pregnanolone and etiocholanolone) have been shown to activate the pyrin inflammasome, in vitro, by interacting with the B30.2 domain (coded by exon 10).
Carrier Status: Carrier status for Familial Mediterranean Fever (FMF) typically refers to individuals who have one copy of a mutated gene (MEFV gene) associated with the disease but do not usually exhibit symptoms. These individuals are considered carriers and have a 50% chance of passing the mutated gene to their offspring. For an individual to manifest FMF, they generally need to inherit two copies of the mutated gene, one from each parent.
Mechanism: Familial Mediterranean Fever (FMF) is an autoinflammatory disorder primarily affecting individuals of Mediterranean descent. The mechanism involves mutations in the MEFV gene, which encodes the protein pyrin.

**Molecular Mechanisms:**
1. **MEFV Gene Mutations:** Mutations, particularly M694V, in the MEFV gene disrupt the normal function of pyrin.
2. **Pyrin Dysfunction:** Pyrin is involved in modulating the inflammatory response. Mutant pyrin leads to inappropriate activation of the inflammasome.
3. **Inflammasome Activation:** The inflammasome is a multiprotein complex that activates caspase-1.
4. **Caspase-1 Activation:** Caspase-1 subsequently activates pro-inflammatory cytokines such as interleukin-1β (IL-1β).
5. **Increased IL-1β:** Elevated levels of IL-1β promote inflammation, leading to the characteristic episodes of fever and serosal inflammation seen in FMF.

The inappropriate activation of these inflammatory pathways results in the recurrent fever and serositis typical of FMF.
Treatment: Attacks are self-limiting, and require analgesia and NSAIDs (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. Canakinumab, an anti-interleukin-1-beta monoclonal antibody, has likewise been shown to be effective in controlling and preventing flare-ups in patients with colchicine-resistant FMF and in two additional autoinflammatory recurrent fever syndromes: mevolonate kinase deficiency (hyper-immunoglobulin D syndrome, or HIDS) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS).
Compassionate Use Treatment: For Familial Mediterranean Fever (FMF), compassionate use treatments and off-label or experimental treatments may be considered when standard therapies are ineffective or not tolerated. Here are some examples:

1. **Interleukin-1 Inhibitors**: Drugs like anakinra, canakinumab, and rilonacept are sometimes used off-label. These are primarily used for patients who are resistant to or intolerant of colchicine, the standard treatment.

2. **Anti-TNF Therapy**: Occasionally, anti-TNF drugs such as etanercept or infliximab are considered in refractory cases, although evidence is less robust compared to IL-1 inhibitors.

3. **Thalidomide** and **Lenalidomide**: These immunomodulatory drugs have been explored experimentally in some severe and treatment-resistant cases.

4. **Colchicine Analogs**: Novel colchicine analogs are being studied experimentally, though they are not yet widely available.

5. **Gene Therapy**: This is a very experimental area currently under investigation; it has not yet become a viable treatment option but holds future potential.

It is crucial for these treatments to be managed by a healthcare professional specializing in FMF, given the potential for side effects and the need for close monitoring.
Lifestyle Recommendations: For Familial Mediterranean Fever (FMF), here are some lifestyle recommendations:

1. **Medication Adherence**: Consistently take prescribed medications, such as colchicine, to prevent attacks and complications.

2. **Regular Medical Check-Ups**: Regular follow-up with a healthcare provider to monitor the condition and adjust treatments if necessary.

3. **Diet and Nutrition**: Maintain a balanced diet. Some individuals find that certain foods can trigger attacks, so it may be useful to identify and avoid these triggers.

4. **Hydration**: Drink plenty of water to stay hydrated, as dehydration can sometimes trigger attacks.

5. **Stress Management**: Practice stress-reduction techniques like yoga, meditation, or other relaxation methods to help manage symptoms.

6. **Exercise**: Engage in regular, moderate exercise to maintain overall health, but avoid overly strenuous activities that may trigger symptoms.

7. **Avoiding Triggers**: Identify and avoid individual triggers that may precipitate attacks, such as extreme temperatures or physical overexertion.

8. **Healthy Sleep Patterns**: Ensure adequate and regular sleep to support overall well-being.

9. **Education**: Educate yourself and family members about FMF to better understand and manage the condition.

10. **Support Networks**: Stay connected with support groups or networks for individuals with FMF to share experiences and coping strategies.
Medication: For Familial Mediterranean Fever (FMF), the primary medication used for treatment is Colchicine. Colchicine helps to reduce inflammation and prevent attacks. In cases where Colchicine alone is not effective, other medications that may be used include Anakinra or Canakinumab, which are interleukin-1 inhibitors. Regular use of these medications can help manage symptoms and prevent complications.
Repurposable Drugs: Repurposable drugs for Familial Mediterranean Fever (FMF) include colchicine, which is the primary treatment to prevent attacks and complications. Other repurposable drugs include interleukin-1 inhibitors like anakinra and canakinumab, used for patients who are resistant to or intolerant of colchicine.
Metabolites: Familial Mediterranean Fever (FMF) is an inherited inflammatory disorder. There are specific metabolites associated with FMF that can be detected in the blood or urine, providing diagnostic and prognostic information.

Key metabolites involved include:
1. Increased Serum Amyloid A (SAA): Indicative of acute phase response.
2. Elevated C-reactive protein (CRP): Marker for inflammation.
3. Elevated white blood cells (WBC): Often seen during attacks.
4. Positive levels of fibrinogen.
5. Changes in erythrocyte sedimentation rate (ESR): Typically elevated.

However, direct examination of metabolites specific to FMF in the realm of nanotechnology (nan- signifies "nanotechnology") is not well-documented or standardized as of current medical literature and practice.

Should you have further questions about the metabolites associated with FMF or their diagnostic role, feel free to ask.
Nutraceuticals: Nutraceuticals, or substances that provide medical or health benefits beyond basic nutrition, are not well-established treatments for Familial Mediterranean Fever (FMF). FMF is typically managed with conventional medications such as colchicine to prevent attacks and complications. There is limited scientific evidence supporting the effectiveness of nutraceuticals specifically for FMF. Patients should consult healthcare providers for appropriate treatment plans tailored to their condition.
Peptides: Familial Mediterranean Fever (FMF) is an inherited inflammatory disorder characterized by recurrent episodes of fever and inflammation. The disease is linked to mutations in the MEFV gene, which encodes the protein pyrin. Pyrin is involved in the regulation of the inflammatory response. Treatment primarily involves the use of colchicine to reduce the frequency and severity of acute attacks.