Familial Mediterranean fever

FMF is an autosomal recessive inherited disease due to mutations in the Mediterranean fever (MEFV) gene (mapped to chromosome 16p13.3).[18][19] Most mutations are located on exon 10, and, to date, more than 280 sequence variants have been identified. The registry of hereditary auto-inflammatory disorders mutations Opens in new window

The significance of the major part of these sequence variants is still unknown, even if the association between FMF and mutations such as M694V, M694I, M680I, and V726A has been clearly established, as these mutations are present in more than two-thirds of the cases.[20][21] Evidence suggests that patients who are homozygous for M694V mutations are at higher risk of onset at an early age, arthritis, more frequent attacks, erysipeloid erythema, and amyloidosis.[2] However, controversy exists as to the role of the amino acid substitution E148Q, where glutamine (Q) substitutes for glutamic acid (E). Initially this sequence variation was described as a disease-causing mutation with low penetrance and mild symptoms.[22][23][24] Subsequent studies suggest it may be no more than a benign polymorphism with a high frequency in the general population (up to 30% in some Asian populations).[25][26] The 2015 Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) guideline concludes that the E148Q variant is common, of unknown pathogenic significance, and as the only MEFV variant, does not support a diagnosis of FMF.[26] However, the debate still exists, and some studies report a possible association between a homozygous E148Q genotype and amyloidosis.[27][28][29]

Genetic testing has also shown ancestral relationships among carrier chromosomes that have been separated for centuries.[30] In some cases, FMF could go on to affect multiple generations. This is due to the high carrier rates of high-risk populations, which causes pseudo-dominant inheritance (one parent with the disease + one carrier parent: half of their children develop the disease). True dominant inheritance has also been described in some families, but remains very rare.[31][32][33]

Other considerations:

Some patients with a clinical diagnosis of FMF have no or only one mutation in the MEFV gene.[34][35][36][37] Several scientific and medical reasons could explain this situation, including the possibility of a second - as yet undiscovered - auto-inflammatory gene mimicking FMF.[38] Indeed, the main clinical features (e.g., recurrent fever in the paediatric age group) are rather unspecific, and fever and polyserositis are also common during the other hereditary recurrent fever syndromes. Thus, a clinical misdiagnosis cannot always be excluded. In fact, the proportion of FMF patients without the required genetic mutations is relatively low in populations of Mediterranean descent (20% to 25%), whereas it can be very high in other populations (up to 85%). In some rare families, a true dominant transmission of certain severe mutations could be the explanation, while in other families complex alleles could lead to a more severe form of the disease. A European study supported the idea of gene dosage.[39] But other factors, such as yet unknown molecular mechanisms (i.e., regulation of transcription non-exonic mutations1) are still a possible hypothesis for the development of clinical disease in patients with no or only one mutation in the MEFV gene.
Environmental factors play an important role in triggering FMF attacks, especially stress, viral disease in infancy, extreme exertion, or even drugs such as metaraminol and cisplatin.[40][41]

In 1992, the gene associated with FMF was mapped to the short arm of chromosome 16 and it was cloned in 1997.[19][42] It was called MEFV for MEditerranean FeVer. The full-length transcript of 3.7 Kb encodes a protein called marenostrin/pyrin, consisting of 781 amino acids. MEFV is a gene expressed specifically in myeloid cells, which play important roles in innate immunity. The discovery of MEFV has been very helpful in understanding the mechanisms of FMF.

Several domains of the protein are remarkable: the pyrin domain is a specific domain of 90 amino acids located in the N-terminal region, and defines a novel class of proteins called the pyrin family. A second domain called B30.2 or SPRY is located in the C-terminal region of the protein, and contains the most frequent mutations associated with FMF.

Some pathogenic data related to the functions of these domains have been established. First, it was shown that marenostrin/pyrin can interact with apoptotic speck protein (ASC); ASC mediates both nuclear factor-kappa B and pro-caspase-1 activation with the associated processing and secretion of interleukin (IL)-1beta and apoptosis.[43] The second point derives from the discovery of the inflammasome, a multi-molecular platform activated upon cellular infection or stress, which triggers the maturation of pro-inflammatory cytokines to engage innate immune defences. The inflammasome mediates the activation of pro-caspase-1, which eventually leads to the activation of IL-1beta. Some literature suggests that marenostrin/pyrin modulates the inflammasome by interacting both with the pyrin and SPRY domains.[44][45][46] It has also been shown that pyrin mediates caspase-1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB, a major virulence factor of Clostridium difficile, and thus functions as a specific immune sensor for bacterial modifications of Rho GTPases.[47]

Eurofever Registry and the Paediatric Rheumatology International Trials Organisation classification criteria for familial Mediterranean fever[5]

Presence of confirmatory Mediterranean fever (MEFV) genotype (pathogenic or likely pathogenic variants [heterozygous in autosomal dominant diseases, homozygous or in trans (or biallelic) compound heterozygous in autosomal recessive diseases]) and at least one among the following:

Duration of episodes 1-3 days
Arthritis
Chest pain
Abdominal pain.

Or, presence of not confirmatory MEFV genotype (in trans compound heterozygous for one pathogenic MEFV variants and one variant of uncertain significance [VUS] or biallelic VUS, or heterozygous for one pathogenic MEFV variant) and at least two among the following:

Duration of episodes 1-3 days
Arthritis
Chest pain
Abdominal pain.

These classification criteria are intended for accurate identification of diseases for studies and are not designed for diagnostic purposes.[5]

Pathophysiology

Classification

Eurofever Registry and the Paediatric Rheumatology International Trials Organisation classification criteria for familial Mediterranean fever[5]