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

Abstract

Introduction:

Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.

Methods:

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.

Results:

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.

Conclusion:

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.

Zusammenfasstung

Einleitung:

Das Familiäre Mittelmeerfieber (FMF) ist die häufigste vererbliche autoinflammatorische Erkrankung (AID) mit Mutationen im MEFV(MediterraneanFeVer)-Gen.

Methodik:

Zur Bestimmung des Erkrankungs­schweregrades bei FMF-Patienten in Deutschland benutzten wir die für Kinder modifizierten Scores nach Mor et al. bzw. Pras et al. und das C-reaktive Protein (CRP). Wir untersuchten die Übereinstimmung der beiden Scores für die Erkrankungsaktivität und korrelierten zu Her­kunft, Phenotyp und Genotyp.

Ergebnisse:

Bei 242 Patienten (Alter im Median: 5 Jahre zum Diagnosezeitpunkt) erfassten wir insgesamt 431 Pyrinmutationen mit 22 verschiedenen Sequenzvariationen, einschließlich einer neuen Mutation (p.Gly488Asp). Die 5 häufigsten Mutationen waren p.Met694Val (55,2%), p.Met680lle (11,8%), p.Val726Ala (10%), p.Glu148Gln (7,9%) und p.Met694IIe (2.3%). Die vorwiegende ethnische Herkunft von 223 Fällen war türkisch (82,5%) oder libanesisch (8%). P.Met694Val homozygot (30,2%) trat signifikant häufiger in Verbindung mit einem schwereren Erkrankungsgrad (nach Mor) sowie einem höheren mittleren CRP-Wert (74 mg/l) im Vergleich zu Patienten mit anderen Mutationen auf. Allerdings waren Mor- und Pras-Score nicht konsistent miteinander. Obwohl eine typische Mutationsverteilung in den verschiedenen ethnischen Gruppen auffiel, konnte dies aufgrund der niedrigen Patientenanzahl nicht statistisch nachge­wiesen werden.

Zusammenfassung:

Der Genotyp p.Met694Val homozygot war in unserer deutschen FMF-Kinderkohorte mit einer schwereren Erkran­kungsaktivität assoziiert. Beide bekannten Scores für die Erkrankungsschweregrade waren für Kinder inkonsist­ent.

Key words

FMF - AID - MEFV gene - pyrin - phenotype - HRF

Schlüsselwörter

FMF - AID - MEFV-Gen - Pyrin - Phänotyp - HRF

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