Genotype-Phenotype and Genotype-Origin Correlations in Children with Mediterranean Fever in Germany – an AID-Net Study

Abstract

Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children.

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

“…These findings support the accuracy of our screening methodology of MEFV genetic analysis to detect mutation negative FMF patients, and confirm with high certainty that our cohort is a true subset of patients with unaffected MEFV , and not a group of patients in whom MEFV mutations have been missed. Secondly, our genetically heterogeneous control group represents the typical phenotype of FMF, as reported in various cohorts around the world, with regard to disease severity, manifestations of attacks, family history of FMF and colchicine treatment [15,21,22]. The frequency of different MEFV mutations is also comparable to that of the general FMF population seen in Israel [19].…”

Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever

“…Wide clinical and genetic heterogeneity exists within FMF . The most frequently detected mutation is p.M694V, and patients who are p.M694V homozygotes are regarded as having a more severe clinical phenotype compared to those carrying other genotypes . Homozygous p.M694V‐positive patients with FMF present with more frequent joint and skin involvement, higher acute‐phase reactant levels during clinically inactive disease, and a higher rate of secondary amyloidosis, and also require a higher dose of colchicine .…”

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

“…In these studies authors used different primary outcome measures such as attack frequency,18–20 ‘abortion’ of the attacks,21 severity of the attacks as defined by the patient,22–24 QOL scales and the serum levels of acute-phase reactants 20 24. The same problem can also be seen in observational clinical and epidemiological studies 16 25–27. Because of the absence of validated uniform instrument to use in these studies it is too difficult to perform meta-analysis or systematic reviews 28 29.…”

“…The most commonly used criteria were those developed by Pras et al 5 and Mor et al 6 However, neither Pras nor Mor criteria were validated and both were developed for adult patients. Moreover, low agreement between the two sets of criteria has been previously shown 7 16. There has been a paediatric attempt to develop a modified severity criteria; however, this has not been widely used 17.…”