Genetic and clinical features of Familial Mediterranean Fever in a cohort of patients with kidney failure

First author: Ahmed Sheyyab

Journal: Journal of Nephrology

Link to the article: doi.org/10.1007/s40620-025-02272-y

Author of the abstract: Rim BOURGUIBA

Introduction

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. In its classic form, it is mainly associated with mutations in exon 10 of the MEFV gene. AA amyloidosis is the most severe complication of FMF.

The aim of this study was to compare the frequency of MEFV variants in hemodialysis patients versus healthy controls in a Mediterranean country, Jordan.

Methods

This was a cross‑sectional study including 78 patients with end‑stage kidney disease on hemodialysis and 201 healthy controls in Jordan. All patients underwent Sanger sequencing for the main MEFV variants. The following variants were tested: p.E148Q, p.P369S, p.F479L, p.M680I (G/C), p.M680I (G/A), p.I692del, p.M694V, p.M694I, p.K695R, p.V726A, p.A744S, and p.R761H.

Patients carrying a variant were then clinically assessed according to the Tel‑Hashomer criteria. Five underwent rectal biopsy to detect amyloidosis.

Results

Among dialysis patients, 16% had at least one MEFV variant versus 12.9% in the control group (not significant). The two most frequent mutations in the hemodialysis group were M694V (p = 0.035) and V726A (p = 0.009). The variants detected in both groups are summarized in Table 1. In the control group without renal failure, 22 individuals were heterozygous for the E148Q variant. Three patients met diagnostic criteria for FMF, and one case of AA amyloidosis was confirmed by biopsy.

Conclusion

FMF is the most common autoinflammatory disease in Mediterranean countries, yet it remains underdiagnosed even in high‑risk populations. This diagnostic delay leads to complications, notably AA amyloidosis. This study shows that 4% of hemodialysis patients were diagnosed with FMF. It also confirms the non‑pathogenic nature of the E148Q variant, which was detected in 22 healthy, asymptomatic individuals.

Overall, these findings underscore the importance of testing for MEFV mutations in patients with AA amyloidosis in countries where FMF is highly prevalent, in order to offer appropriate treatment to prevent AA amyloidosis and progression to renal failure.

Genetic and clinical features of familial Mediterranean fever in a cohort of patients with.

Download • 572KB

An update on autoinflammatory diseases

First author: S. Georgin-Lavialle

Abstract:

Autoinflammatory diseases (AIDs) are defined as disorders of innate immunity. They were initially defined in opposition to autoimmune diseases, due to the absence of involvement of the adaptive immune system and circulating autoantibodies. The 4 IADs first described are known as the “historic” IADs and include: familial Mediterranean fever (associated with mutations in the MEFV gene), cryopyrinopathies (associated with mutations in NLRP3), tumor necrosis factor receptor-associated periodic syndrome (associated with mutations in TNFRSF1A) and mevalonate kinase deficiency (associated with mutations in MVK). Over the past 10 years, more than 50 new monogenic IBDs have been discovered thanks to advances in genetics. Diagnosis is facilitated by personal and family history-taking and detailed analysis of the signs and symptoms associated with febrile attacks, which must be associated with the presence of elevated blood biomarkers of inflammation. Increasingly powerful genetic analysis techniques can help refine the diagnosis. This chapter describes the main types of IJD, and helps to guide the clinician in the suspicion and diagnosis of IJD.

MAi en français.pdf

Download PDF • 1.35MB

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation

First author: Camille Cosson and al.

Link to article: DOI: 10.1084/jem.20231200

Abstract

NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations associated with CAPS autoinflammation. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments.

Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors.

We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses.

Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.

Functional diversity of NLRP3.pdf

Download PDF • 10.21MB