Familial Mediterranean fever (FMF), a genetic disease with autosomal recessive transmission, has an estimated prevalence of 1-5/10,000 in populations living in the Mediterranean basin. A cluster of families affected by FMF has been identified in the Apulia region, in the Murgia area of Altamura-Matera, with atypical manifestations for genetics, symptoms, and age of onset (1-3).
The localization in these areas dates back to the influence of groups of populations that historically populated those areas (Jews, Turks, Greeks, Arabs, Armenians, etc.). The disease is included in the list of rare diseases attached to the DPCM January 12, 2017 with code RC0241. Despite the fact that the diagnosis of disease is usually made in childhood or adolescence, in the Apulian cluster cases have been diagnosed already in adulthood and even in old age. In fact, the case of a patient with the highest seniority reported at diagnosis has been recently reported by our group.
The peculiarity of the clinical presentation of the Apulian patients is also evident for the data observed in our case series that about 35% of patients had undergone, following serositis symptoms with predominant abdominal localization, surgery (cholecystectomy, appendectomy, laparoscopy) obviously without clinical improvement, in absence of specific colchicine therapy.
Moreover, considering the considerable number of cases diagnosed in the cluster mentioned above (60 patients currently in follow-up at the Medical Clinic “Murri” of the University of Bari), the available data on the prevalence of the disease suggest that, precisely because of the atypical characteristics detected, there may be numerous cases not adequately diagnosed and managed in the Apulia region.
In consideration of the complex pathophysiological picture that links the genetic alterations typical of FMF to the variable clinical expression (with a probable role for local environmental factors), a complete and exhaustive assessment of this disease cannot disregard the formulation of study protocols that involve simultaneously different professionals (geneticists, molecular biologists, pathologists, clinicians) and that are aimed at improving not only the understanding of pathophysiological mechanisms and diagnostic possibilities but also therapy, follow-up and quality of life of patients affected by FMF and their relatives.
The present project aims to rationalize and improve the assessment and management of FMF patients through multidisciplinary studies in FMF, a model of autoinflammatory disease particularly recurrent in our territory.
Background Familial Mediterranean Fever (FMF) is a genetic disease with autosomal recessive transmission, common among populations of the Mediterranean basin. It falls into the group of hereditary recurrent fevers and has an estimated prevalence of 1-5/10,000.
The MEFV gene (Mediterranean Fever), located on chromosome 16, encodes a protein of 86 kDa (called pyrin or marenostrin, or TRIM20) expressed mainly in cells of the myeloid series (neutrophils, monocytes, eosinophils, dendritic cells and synovial fibroblasts). The lack of physiological function of pyrin, through the activation of the innate immunity cell lines, is able to activate an abnormal and purposeless inflammatory response, with periodic attacks of fever and serositis related to the activation of the inflammasome, the production of caspases and the release of interleukin 1β (IL-1 β) and IL-18, even in the absence of antigenic stimuli bacterial, viral or of other nature.
To date, at least 365 variants have been identified on the 10 exons among which the coding sequence of the MEFV gene is distributed (https://infevers.umai-montpellier.fr/web/search.php?n=1). However, for many of them the causative role in the pathogenesis of FMF has not yet been fully clarified. Moreover, based on recent studies that have evaluated, in vitro, the activation of the inflammasome associated with different genotypes, it is possible that the onset and severity of symptoms is related to a mechanism of genes with dose effect.
The onset of the disease usually occurs before the age of twenty, especially in some populations of the Mediterranean basin, which are those most affected and with more intense phenotypic expression: non-Ashkenazi Jews, Turks, Armenians and Arabs. Due to the passage of various populations and the local diffusion of mutations, FMF is also found in Italy (with an incremental gradient of prevalence north-south) and in Greece, Japan, United States. In particular, the Medical Clinic “A. Murri” of the University of Bari has identified a cluster of families in the Murgia area located between the municipalities of Altamura and Matera, which has allowed to accumulate a considerable casuistry and the publication of works that report atypical manifestations for genetics, symptoms and age of onset (geriatric) of the disease.
Depending on the penetrance of the genetic mutation, in fact, the phenotypic manifestation of FMF can vary enormously from subject to subject, complicating and delaying an adequate diagnostic formulation. Further variability in the phenotypic manifestations of FMF could also derive from particular (local) gene-environment interactions that involve alterations of environmental matrices, altered epigenetic mechanisms, alterations of intestinal microbiota (the latter able to modulate the immune axis in case of dysbiosis, bacterial contamination and alteration of intestinal permeability).
In this context, it is of particular interest to search for information useful to improve the knowledge of the pathophysiological mechanisms proper to FMF and its expressions phenotypic but also the possibilities of confirmation of diagnostic suspicions, the therapeutic choices FEVER PROJECT APULIAE more appropriate to adopt in patients affected by FMF (today mainly based on use by colchicine, with risks especially for possible long-term toxicity) and follow-up by cases already diagnosed and family members of patients, orienting it towards possibilities of prevention primary and secondary. All this, considering the particular complexity of the pathology, requires inevitably the involvement of different professional figures with skills in the field of genetic, biological-molecular, and clinical.
Discover our publications about the research project of FMF