Familial Mediterranean fever

Classification according to ICD-10
E85.0	Heredofamily non-neuropathic amyloidosis
ICD-10 online (WHO version 2019)

The familial Mediterranean fever (FMF) - also known as familial recurrent polyserositis called - is an autosomal - recessive inherited disease from the group of periodic fever syndromes , heaped with inhabitants of the eastern Mediterranean region (Turkey, Middle East, North Africa, Arab countries, Armenia, rare Greece and Italy) occurs. This is a chronic disease that is characterized by sporadic attacks of fever with accompanying inflammation of the tunica serosa , which leads to abdominal, chest or joint pain. The most common complication of familial Mediterranean fever is amyloidosis , which shortens the life expectancy of patients.

Epidemiology

Overall, familial Mediterranean fever is a rare disease. However, it has a higher prevalence in the affected ethnic groups . Up to a sixth of North African Jews and up to a seventh of the Armenian population are bearers of characteristics. About 0.2% of these ethnic groups are actually sick. In Turkey, the prevalence of the disease is estimated at around 0.1% of the population.

etiology

In 1997, two consortia described a gene on chromosome 16 ( gene locus 16p13.3) whose mutations cause FMF. The protein product of this MEFV gene has been named marenostrin or pyrin .

It codes for a protein comprising 781 amino acids, which is almost exclusively expressed in blood cells. It has several functions that are not yet fully understood, some of which appear to be relevant in the pathogenesis of FMF.

A pyrin cleavage product translocates into the nucleus (but does not have a DNA binding domain itself), and certain domains also activate NF-κB - a transcription factor that is important for many proinflammatory processes. An interaction of pyrine with tubulin and a colocalization with microtubules has also been shown - the drug colchicine , active in FMF , intervenes pharmacodynamically on microtubules. Furthermore, domains of pyrin bind to the adapter protein Asc , which is a component of the inflammasome . This protein complex plays a crucial role in the production of interleukin-1β , one of the key proteins in the inflammatory response. Pyrin seems to be a negative regulator of this protein complex, so that certain mutations are associated with overactivation (and thus with excessive secretion of interleukin-1-beta). As a result, u. a. to increase blood flow, to influx of granulocytes and to other processes of the inflammatory reaction. The importance of this theory is illustrated by the fact that FMF patients benefit from treatment with the IL-1β antagonist anakinra .

The many different mutations found in the MEFV gene in FMF patients reflect that a uniform molecular biological process cannot completely explain this clinical picture. The further spread of heterozygous patients indicates a selection advantage that can only be speculated about so far.

Clinic and course

Familial Mediterranean fever is a chronic disease that has an intermittent course. The relapses are characterized by a high fever with extreme pain, which is caused by the inflammation of the serosa . This usually affects the peritoneum , less often the pleura or even the inner skin of the joint capsules (the synovial stratum ), which leads to typical abdominal, chest and joint pain. Most patients have their first fever in early childhood and adolescence. 90 percent of the patients had their first attack before the age of 20. The attacks last for about one to three days and then resolve on their own. Between the attacks, the patients are almost symptom-free and feel largely healthy. The main complication of familial Mediterranean fever is progressive AA-type secondary amyloidosis , which occurs in 30–60 percent of patients. Amyloid A is an acute phase protein that is produced by the body during any acute inflammation. In patients with familial Mediterranean fever, a particularly large amount of amyloid is found in the blood during the acute episode , which can be deposited in various organs (especially the kidneys). This leads to organ damage, which is ultimately responsible for the increased mortality of patients with familial Mediterranean fever. Renal insufficiency is another very serious complication .

Diagnosis

In an acute episode there is sometimes an increase in the inflammatory parameters in the blood (leukocytosis with neutrophilia, increase in CRP ). Clinically, it must be differentiated from other periodic febrile diseases. A definitive diagnosis can only be made through a genetic test. It should be noted, however, that genetic diagnostics cannot rule out Mediterranean fever. Large studies have shown that mutations in the MEFV gene are found in only about 80 percent of patients with clinically confirmed familial Mediterranean fever, so that another gene must be assumed which plays a role in the development of familial Mediterranean fever. The great advantage of genetic diagnostics is the possibility that complications of the disease such as amyloidosis are clearly related to certain combinations of mutations. In addition, the clinical picture can thus clearly against other periodic fever syndromes such as hyper-IgD syndrome , cyclic neutropenia , tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS), chronic-infantile-neurological-cutaneous-articular syndrome (CINCA- Syndrome), Muckle-Wells syndrome or PFAPA (periodic fever, aphthae, pharyngitis, adenitis) syndrome.

Metaraminol is also used to provoke a suspected familial Mediterranean fever. The patient is given a single 10 mg dose; if an attack occurs within the next 48 hours, this is an indication of the presence of FMF.

therapy

There is no causal therapy for familial Mediterranean fever. The acute relapses are treated symptomatically with painkillers from the class of opioids (e.g. morphine , oxycodone ) or non-steroidal anti-inflammatory drugs (e.g. acetylsalicylic acid or diclofenac ). As a prophylactic measure , colchicine is administered between the attacks , which can reduce the frequency of the attacks and thereby also prevent the development of amyloidosis . This is explained by the inhibitory effect of this drug on the neutrophil granulocytes. Recently, therapy with the interleukin-1 receptor antagonist anakinra has also been recommended.

literature

• A Livneh, P. Langevitz: Diagnostic and treatment concerns in familial Mediterranean fever . In: Best Pract Res Clin Rheumatol , 2000, 14 (3), pp. 477-498, PMID 10985982 .
• J Rakob et al .: Familial Mediterranean Fever - Clinic and molecular genetic findings in 40 children in Berlin . In: Monthly Pediatric Medicine, 2003, 10, 151, pp. 1064-1071, doi : 10.1007 / s00112-003-0740-z .
• HA. Reiman: Periodic disease. Probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. In: JAMA 1948, 136, pp. 239-244.
• S. Siegal: Benign paroxysmal peritonitis. In: Ann Intern Med , 1945, 23, pp. 1-21.
• Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. In: Cell , 1997, 90, pp. 797-807, PMID 9288758 .
• A candidate gene for familial Mediterranean fever. The French FMF Consortium. In: Nat Genet , 1997, 17, pp. 25-31, PMID 9288094 .

See also

• Mediterranean fever (caused by Brucella melitensis )
• Mediterranean spotted fever (caused by Rickettsia conori )

Individual evidence

1. ^ SL Masters, A. Simon, I. Aksentijevich, DL Kastner: Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). In: Annual review of immunology. Volume 27, 2009, pp. 621-668, doi : 10.1146 / annurev.immunol.25.022106.141627 , PMID 19302049 , PMC 2996236 (free full text) (review).
2. ↑ Barakat MH, El-Khawad AO, Gumaa KA, El-Sobki NI, Fenech FF: Metaraminol provocative test: a specific diagnostic test for familial Mediterranean fever . In: Lancet . 1, No. 8378, 1984, pp. 656-7. PMID 6142351 .
3. ^ Huppertz HI, Michels H: [The metaraminol provocation test in the diagnosis of familial Mediterranean fever] . In: Monthly Children's Health . 136, No. 5, 1988, pp. 243-5. PMID 3405225 .

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