Introduction ============ Familial Mediterranean Fever (FMF) is the most common autoinflammatory disease in people with Turkish ancestry. With a prevalence of 1/1000 in the general population, FMF is characterized by self-limiting, episodic attacks of fever and serositis, typically lasting 12 to 36 hours with high intensity \[[@B1]\]. FMF may also result in amyloidosis, which is a life-threatening condition secondary to the deposition of amyloid fibrils derived from serum amyloid A (SAA), a reactive protein in response to inflammation \[[@B2]\]. It is estimated that FMF affects a total of 1 million individuals worldwide \[[@B3]\]. FMF is seen in all ethnic groups and it is also reported that this disease may not be limited to the Mediterranean region. A literature search was carried out using PubMed and Google Scholar databases. Search terms included \"FMF\", \"Mediterranean\", \"gene\", \"Tay-Sachs\", \"nephropathia\", \"meningoencephalitis\", and \"amyloidosis\". Only English language and human studies published in the last three decades were included. Data were reviewed and summarized. FMF as an Autoinflammatory Disease ================================== Autoinflammatory diseases are disorders characterized by abnormally increased activity of the innate immune system and its response to various stimuli and are not caused by immune responses to infectious agents or foreign antigens \[[@B4]\]. In 2005, there were only about 30 identified autoinflammatory diseases, including FMF \[[@B5]\]. These are uncommon conditions which usually have early onset and can be lethal if not treated. Autoinflammatory diseases include the periodic fever syndromes, such as FMF, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and hyperimmunoglobulinemia D syndrome \[[@B6]\]. In FMF, approximately 85% of FMF patients carry a pathogenic mutation in the MEFV gene (Mediterranean fever). To date, more than 150 mutations in the MEFV gene have been identified as pathogenic and more than 140 mutations have been defined as nonpathogenic \[[@B7]\]. Mutations in the Mediterranean fever gene lead to the excessive production and release of SAA protein, leading to amyloidosis in patients \[[@B8]\]. The only known treatment in patients with FMF is colchicine \[[@B9]\]. The management of FMF, however, can be very challenging, particularly in patients with undiagnosed or treatment-resistant FMF or amyloidosis. MEFV gene and Causative Mechanism ================================= The FMF gene (also called Mediterranean fever, periodical fever, and marenostrin), is located on the short arm of chromosome 16 (16p13.3) \[[@B10],[@B11]\]. This gene encodes a 781-amino acid protein called pyrin or marenostrin \[[@B12]\]. Pyrin contains a unique amino terminal B30.2 domain, which is a sequence containing a repeated eight-residue motif, with a highly conserved structure between different species. This protein binds to SAA, which is encoded by another gene located on chromosome 1, and this may be the mechanism by which the protein regulates inflammation \[[@B13]\]. Nine MEFV mutations have been defined as the causative for FMF ([Table 1](#T1){ref-type="table"}) \[[@B14]\]. Patients with FMF typically have one MEFV mutation, usually the E148Q, M680I, and V726A mutations. The pyrin gene plays a key role in the innate immune system and is closely related to the interleukin (IL)-1 pathway \[[@B15]\]. One of the primary inflammatory proteins associated with FMF is SAA. SAA is an acute phase reactant, and is a major component of the normal plasma protein fraction in humans. It is synthesized primarily in the liver and is secreted into the plasma in response to various inflammatory stimuli. In addition to being an acute phase reactant, SAA is also known to activate CD8 T-cells, which results in tissue injury during inflammation and autoimmunity \[[@B16]\]. The SAA protein is implicated in amyloidosis. In FMF patients, it is present in a range of 10-200 µg/ml. Several studies have shown that a polymorphism at position 42 of the SAA protein can cause it to precipitate, leading to the formation of amyloid fibrils that are highly insoluble and resistant to proteolysis \[[@B17]\]. The *SAA1* gene is located at chromosome 11q12-13 \[[@B18]\] and it has two polymorphisms: the *SAA1*-3′-UTR C\>G polymorphism, or -3 gene conversion \[[@B19],[@B20]\], and a polymorphism in the *SAA1* coding region (AAG/GGG) \[[@B21]\]. The serum amyloid A protein is encoded by the *SAA1* gene, which has been found to be overexpressed in FMF patients with M694V \[[@B22]\]. FMF and Colchicine Therapy ========================== The treatment of FMF has been based on colchicine, which is a tricyclic heterocyclic lactone. It is a cytotoxic drug that has been known to inhibit microtubule polymerization in various cells. The effects of colchicine include prevention of microtubule polymerization, which causes cell membrane disruption and inhibition of leukocyte function \[[@B23]\]. The exact cause of FMF is unknown, although it is most likely related to mutations in the pyrin gene and the MEFV gene on chromosome 16p. The gene encodes pyrin or marenostrin. It is a 781 amino acid protein that has a role in innate immunity and the inflammatory response. The *MEFV* gene was cloned and sequenced in 1997 \[[@B11]\]. This gene encodes a protein named pyrin, which is believed to be an integral part of the innate immune system. The gene has also been implicated in a rare autoinflammatory condition, periodic fever syndromes, and may also play a role in systemic AA amyloidosis \[[@B24],[@B25]\]. The MEFV gene is mapped on chromosome 16 (16p13.3) \[[@B10],[@B11]\] and consists of 10 exons with its promoter on chromosome 1. A total of 120 variants have been identified to date, and mutations in the *MEFV* gene are responsible for FMF \[[@B26]\]. The FMF is inherited in an autosomal-recessive fashion. A carrier of FMF has 50% risk to develop FMF \[[@B27]\]. These factors make the disease difficult to diagnose \[[@B28]\]. As the first-line treatment, colchicine should be administered within the first 3 days of the onset of FMF symptoms to prevent irreversible destruction of the renal parenchyma. Colchicine inhibits phagocytosis and the function of neutrophils, macrophages, and T-cells. The efficacy of colchicine in FMF treatment is well known. In cases of amyloidosis, colchicine should be administered even after renal damage. This treatment reduces the rate of progression to renal failure and is effective in delaying it \[[@B29]\]. Other Drugs That May Be Used to Treat FMF ========================================= In patients who do not respond to colchicine, other therapies are available: Colchicine and corticosteroids in combination should be considered the first-line therapy. The aim is to control the chronic disease. After a 6- to 12-week trial of colchicine (2.0 mg per day), if colchicine does not relieve the symptoms, it should be replaced by corticosteroids, administered for 2 to 4 weeks. Corticosteroids used for this purpose are prednisone (1 mg/kg/day or 20 mg/day for adults), deflazacort (4 mg/day for children), or dexamethasone (0.3-1.0 mg/kg/day for children) \[[@B30]\]. Hydroxychloroquine is used in some patients with colchicine resistance or secondary FMF, especially in children and adolescents, and results in considerable improvement of the clinical picture. In the case of inadequate response to colchicine and/or steroids, hydroxychloroquine at a dose of 5 mg/kg/day divided twice daily can be added to the regimen. Sodium aurothiomalate was also successfully used to treat patients with FMF \[[@B31]\]. Immunosuppressants, such as azathioprine, cyclophosphamide, and mycophenolate mofetil, may be prescribed in some patients. However, the exact indication for the use of these agents is not clear. Mycophenolate mofetil is an immunosuppressant that acts on T and B lymphocytes. It also inhibits the production of IL-2 and IL-3. There are some studies of success with mycophenolate mofetil in cases of refractory FMF \[[@B32]\]. In our study, 3-amino-9-ethylcarbazole was used for electron microscopy of a renal biopsy specimen \[[@B33]\]. It was reported that there were no deposits in the subendothelial region or mesangium, which was similar to previous studies \[[@B34],[@B35]\]. Amyloidosis as a Progressive Complication ========================================= Amyloidosis is the extracellular deposition of an insoluble fibrillar protein \[[@B36]\]. Amyloidosis is caused by many conditions and causes a significant morbidity and mortality. The amyloid is seen in different organs, such as the heart, liver, spleen, kidneys, nervous system, and other tissues \[[@B37]\].