Periodic fever syndromes: beyond the single gene paradigm

Abstract

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease in Canada and is characterized by a clinical syndrome of episodic inflammatory symptoms. Traditionally, the disease is defined by autosomal recessive inheritance of MEFV gene variants, yet FMF also not uncommonly manifests in individuals with only one identified disease-associated allele. Increasing availability and affordability of gene sequencing has led to the identification of multiple MEFV variants; however, they are often of unknown clinical significance. Variants in other genes affecting overlapping or distinct inflammatory signaling pathwaystogether with gene-environment interactions including epigenetic modulationlikely underlie the significant genetic and phenotypic heterogeneity seen among patients with this disease. We review recent evidence of the expanding spectrum of FMF genotype and phenotype and suggest that current drug funding schemes restricting biologic agents to patients with homozygous mutations have not kept pace with our biological understanding of the disease.

Mediterranean fever gene variants modify clinical phenotypes of idiopathic multi-centric Castleman disease

“…Previous results from a pyrin knock‐in mouse suggested that autoinflammatory conditions were caused by a gain‐of‐function of pyrin [ 19 ]. Furthermore, MEFV variants confer susceptibility to other inflammatory diseases—including adult‐onset Still’s disease, Henoch–Schönlein purpura, polyarteritis nodosa and Behçet’s disease—and modify clinical phenotypes of yet other inflammatory diseases, including Crohn’s disease, rheumatoid arthritis and systemic lupus erythematosus [ 20 ]. Therefore, deregulation of the innate immune system and subsequent activation of the innate response, owing to these MEFV variants, may promote the development of various inflammatory diseases or modify their pathologies.…”

Children with systemic autoinflammatory diseases have multiple, mixed ethnicities that reflect regional ethnic diversity

“…Eligible patients were enrolled between January 2016 and December 2019 and clinical information was entered into a BCCH SAID registry (15). Parents/guardians were asked to report the ethnicity of an affected child's four biologic grandparents, i.e.…”

TRIM E3 Ubiquitin Ligases in Rare Genetic Disorders

“…This disorder is prevalent in Arabic, Turkish, Armenian, and Sephardic Jewish populations, hence the name, and the ancestral M694 V mutation account for the majority of the mutated alleles. The pathogenetic variants fall into two clusters, one at the N-terminus and one within the PRY-SPRY domain and depending on whether monoallelic or biallelic mutations are detected they are involved in the dominant or recessive form, respectively [84]. They are mainly missense mutations suggesting that the periodic nature of inflammatory attacks in FMF is consistent with a protein that functions adequately at steady state but decompensates under stress.…”