Familial Mediterranean fever without MEFV mutations: a case–control study

Abstract

BackgroundAlthough familial Mediterranean fever (FMF) was originally defined as an autosomal recessive disorder, approximately 10–20% of FMF patients do not carry any FMF gene (MEFV) mutations. Fine phenotype characterization may facilitate the elucidation of the genetic background of the so called “FMF without MEFV mutations”. In this study we clinically and demographically characterize this subset.MethodsMEFV mutation-negative FMF and control patients were recruited randomly from a cohort followed in a dedicated FMF clinic. The control subjects comprised 2 groups: 1. typical population of FMF, consisting of genetically heterogeneous patients manifesting the classical spectrum of FMF phenotype and 2. a severe phenotype of FMF, consisting of FMF patients homozygous for the p.M694V mutation.ResultsForty-seven genetic-negative, 60 genetically heterogeneous and 57 p.M694V homozygous FMF patients were enrolled to the study. MEFV-mutation negative FMF patients showed a phenotype closely resembling that of the other 2 populations. It differed however from the p.M694V homozygous subset by its milder severity (using Mor et al. scoring method), as determined by the lower proportion of patients with chest and erysipelas like attacks, lower frequency of some of the chronic manifestations, lower colchicine dose and older age of disease onset.ConclusionsMEFV mutation-negative FMF by virtue of its classical FMF phenotype is probably associated with a genetic defect upstream or downstream to MEFV related metabolic pathway.

Autoinflammatory diseases: update on classification diagnosis and management

“…It should be noted that this patient did not experience an inflammatory phenotype prior to FMF development, and, therefore, this clinically silent variant is unlikely to be always pathogenic, despite reports to the contrary 57. In line with these findings, clinical characterisation of 47 FMF mutation-negative patients (ie, no detectable mutation using PCR for common mutations in MEFV ), compared with those heterozygous for the disease, saw that the mutation-negative patients were less likely to experience joint attacks 58. As the reported phenotypes were only marginally distinctive, a number of conclusions could be derived; for example, there could be epigenetic modifications of the MEFV gene product, which could suggest the involvement of other, unknown genes.…”

Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF)

“…This aspect of the tool has been used extensively to show ethnic variability in the severity of FMF30 (eg, patients from North African Jewish ancestry express a more severe disease as compared with Iraqi Jewish or Ashkenazi patients), phenotype–genotype correlation31 (eg, patients with homozygous M694V MEFV genotype have the most severe phenotype, while other genetic combinations may be graded in a decreasing severity order), the association between certain features of the disease with disease severity32 33(eg, late onset, carriage of only one mutation, genetic negative disease and response to low colchicine dose as inherent features of mild disease) and environmental effects on disease expression17 (Turkish children in Germany vs in Turkey). It is expected that the ISSF will promote and facilitate further comparisons of genetically, clinically and ethnically different subpopulations under unified measure.…”

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“…The disease is transmitted in an autosomal recessive pattern and predominately affects people from the Mediterranean basin, including, Turks, Arabs, Armenians and Sephardic Jews [1,6]. The overall prevalence of the disease in the Turkish population is estimated as 1/1,073.…”

“…FMF is caused by mutations in the MEFV gene, which is located on chromosome 16p13 and contains 3505 nucleotides. About 30 mutations associated with FMF have been defined, the five most common of which are M694V, M680I, M694I, E148Q and V726A, generally clustered on exon 10 [6,9]. The most frequent mutation in Turkish patients is M694V, followed by M680I and V726A [3].…”