Pyrin-associated autoinflammatory disease with p.Thr577Ala MEFV somatic mutation.

Alexandre Terré,  Magnotti, Jean-Maxime Piot, Guilaine Boursier, Sophie Georgin-Lavialle.

Liink to article: ​https://doi.org/10.1016/j.ejim.2023.11.014

Summary:

The mutations responsible for the classic form of familial Mediterranean fever (FMF) (recessive, requiring 2 mutations) are located in exon 10 of the MEFV gene.

Mutations in the same MEFV gene have also been reported to be associated with dominant autoinflammatory diseases such as that at position 577, with clinical presentations that differ from classic FMF. The name pyrin-associated autoinflammatory disease (PAAD) was therefore chosen to include all diseases caused by pyrin defects or mutations in the MEFV gene.

Our team has identified a new form of PAAD associated with a dominant somatic mutation of MEFV in a 28-year-old woman of French origin on 3 of her grandparents and Algerian on one. There were no other cases in her family. Since the age of 2, she had suffered recurrent episodes of fever, abdominal pain, erythema of the limbs, particularly the ankles, and joint and muscle pain, with a permanent biological inflammatory syndrome that worsened during febrile crises, with a CRP > 100 mg/L.

​In view of the digestive and joint manifestations, and in the absence of joint destruction or any formal element of classification, she was labelled as having atypical Crohn's disease with atypical spondyloarthritis.

A pathogenic Thr577Ala mutation in the MEFV gene with an allele frequency of 16% was found in her; family members were neither carriers nor affected. Somatic mutations are rare "post-zygotic" genetic events occurring after fertilisation. They can occur at any time in life. Mutations are therefore not found in every cell in the body.

This is the first description of a somatic mutation in exon 8 of the MEFV gene responsible for a pyrin-related autoinflammatory dominant disease sensitive to colchicine. She had no further episodes of fever, joint symptoms, abdominal pain or diarrhoea on this treatment. The patient's diagnosis was only made possible by advanced genetic techniques such as high-throughput sequencing and thanks to the expertise of the Montpellier genetics laboratory belonging to the Centre de Référence des Maladies Autoinflammatoires et des Amyloses (CEREMAIA).

Référence :

Alexandre Terré et al. Pyrin-associated autoinflammatory disease with p.Thr577Ala MEFV somatic mutation, European Journal of Internal Medicine.

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Gut microbiota alterations are associated with phenotype and genotype in Familial Mediterranean Fever

Marion Delplanque1,2,3,†, Nicolas Benech2,3,†, Nathalie Rolhion2,3, Cyriane Oeuvray2,3, Marjolène Straube2,3, Chloé Galbert2,3, Loic Brot2,3, Thomas Henry 4 , Yvan Jamilloux4 , Le´ a Savey1 , Gilles Grateau1 , Harry Sokol 2,3,5, Sophie Georgin-Lavialle1,2,3,*

Link to article: https://pubmed.ncbi.nlm.nih.gov/37402619/

Summary: 

The intestinal microbiota has attracted growing interest in recent years due to its involvement in a number of diseases. In Familial Mediterranean Fever (FMF), its role was suspected because certain digestive bacterial infections caused attacks of the disease, such as Helicobacter pylori in the stomach. With the help of Professors Georgin-Lavialle and Sokol from the "Microbiota and Immunity" Avenir Team (INSERM U938 unit), and all the patients and their relatives who agreed to take part, Dr Marion Delplanque, Assistant Clinical Head of the FMF National Reference Centre at Tenon Hospital, conducted research over a year to compare the composition of the intestinal microbiota of patients with FMF with a control group of healthy subjects. The technique used to study the genetic content of the intestine is called metagenomics; it enables the microorganisms present in the faeces to be identified.The faecal microbiota of 119 patients with FMF was compared with that of 61 healthy subjects. Of the FMF patients, 88 carried 2 pathogenic mutations in the MEFV gene and 31 carried a single mutation. Twenty-seven patients (22.7%) were resistant to colchicine, 17 had inflammatory amyloidosis, also known as AA amyloidosis (14.2%) and 10 were on anti-interleukin-1 biotherapy.

We demonstrated an imbalance in the intestinal flora (known as dysbiosis) in patients with FMF compared with healthy subjects. Bacterial diversity, measured by the number of different species present in the intestine, was reduced in patients with FMF. In addition, certain inflammation-promoting bacteria were predominant in FMF patients. In patients with severe FMF, defined by the presence of AA amyloidosis and/or colchicine resistance, inflammation-promoting bacteria were significantly more abundant than in less severe patients. Finally, the composition of the microbiota differed according to the response to colchicine: colchicine-resistant patients had a different structure and composition to colchicine-sensitive patients, and the connectivity of their bacterial network was reduced.

Overall, this is the most important study to date of stool composition in FMF. It confirms that there is an imbalance in the composition of the intestinal flora (or dysbiosis) in patients with FMF compared with healthy controls. Further work is needed to determine whether the intestinal flora could be a therapeutic target in FMF, particularly in the case of colchicine-resistant forms or severe complications such as AA amyloidosis.

Référence :

Delplanque M et al. Gut microbiota alterations are associated with phenotype and genotype in familial Mediterranean fever. Rheumatology (Oxford).  2023 Jul 4 (ahead print). PMID : 37402619

Hip involvement in familial Mediterranean fever

First author : François Rodrigues et al

Journal: European Journal of Internal Medicine, 10.1016/j.ejim.2022.11.008

Link to article: https://pubmed.ncbi.nlm.nih.gov/36435696/

Introduction: 

Familial Mediterranean Fever (FMF) is a monogenic autoinflammatory disorder that is linked to homozygous mutations of the MEFV gene. The field of FMF is expanding as many patients with FMF phenotype are heterozygous with monoallelic variants. Arthritis is a frequent manifestation of FMF, involving 50 to 75% of patients.

The hip is the third most commonly affected joint after the knee andankle. Aseptic necrosis of the femoral head caused by disruption of local blood supply has also been reported in FMF patients. Meanwhile, hip inflammation or coxitis can be caused by axial spondyloarthritis, which develops at an increased rate in FMF patients. Therefore, the literature is controversial as to whether coxitis in FMF is a distinct entity or a manifestation of an associated axial spondyloarthritis. Our objectives were to describe the clinical, functional and radiological features of hip involvement in FMF.

Hip involvement in familial Mediterranean fever.pdf

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