Familial Mediterranean Fever: A Comprehensive Review of Pathogenesis, Genetics, and Epigenetic Regulation

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory periodic fever syndrome globally.
• It stems from pathogenic variants in the MEFV gene, causing immune dysregulation and chronic inflammation.
• Current understanding of MEFV mutation effects on inflammation is incomplete, and clinical heterogeneity suggests factors beyond simple Mendelian inheritance.

Purpose of the Study:

• To provide a comprehensive review of genetic, molecular, and epigenetic factors in FMF.
• To highlight existing controversies and knowledge gaps in FMF pathogenesis.
• To propose future research directions for better understanding and managing FMF.

Main Methods:

• Literature review of genetic, molecular, and epigenetic studies on FMF.
• Analysis of existing data on MEFV gene variants and their clinical impact.
• Synthesis of evidence regarding epigenetic mechanisms (DNA methylation, histone modifications, microRNAs) in FMF.

Main Results:

• Pathogenic MEFV variants are established causes of FMF, leading to innate immune system dysregulation.
• Clinical heterogeneity (incomplete penetrance, variable expressivity) is significant.
• Emerging evidence points to epigenetic modifications as contributors to FMF variability, though data are limited and conflicting.

Conclusions:

• FMF pathogenesis is complex, influenced by genetic and potentially epigenetic factors.
• Further research into epigenetic mechanisms is crucial for understanding FMF variability and improving patient outcomes.
• Addressing unresolved controversies and focusing on future research priorities will advance FMF management.