The Effect of E148Q Variant on Disease Severity in Familial Mediterranean Fever Patients with Compound Heterozygous Mutation

Yıl 2023, Cilt: 11 Sayı: 3, 111 - 115, 15.10.2023

Müge Sezer Elif Çelikel Zahide Ekici Tekin Vildan Güngörer Nilüfer Tekgöz Cüneyt Karagöl Serkan Coşkun Melike Mehveş Kaplan Nimet Öner Merve Cansu Polat Banu Acar

Öz

Aim: In this study, we aimed to evaluate the demographic and clinical findings of familial Mediterranean fever (FMF) patients carrying a compound heterozygous mutation and to investigate the effect of the E148Q variant on disease severity.
Methods: Patients between the ages of 0-18 years diagnosed with FMF and carrying a compound heterozygous mutation were included in the study. Disease severity was assessed using the international severity scoring for FMF (ISSF). Patients were divided into two groups according to mutation type: those with exon 10/E148Q compound heterozygous mutation (Group 1) and exon 10/exon 10 compound heterozygous mutation (Group 2).
Results: A total of 317 FMF patients with compound heterozygous mutations had a male/female ratio of: 1.07, median age at diagnosis was 6.7 (IQR:6.3) years. The most common symptom was abdominal pain (85.8%). The median age at diagnosis was 6 years in Group 2 (n=219) and 8.2 years in Group 1 (n=98) (p=0.005). Fever (75.8%) was more common in patients with two exon 10 mutations (75.8%) (p=0.001). The presence of more than two different attack types, more than two findings in an attack and an attacks lasting longer than 72 hours were more frequent in patients in Group 2 (p=0.021, p<0.001, p=0.043, respectively). The ISSF score of Group 2 was higher than the other group (p<0.001).
Conclusion: Patients with two exon 10 mutations have more severe disease than patients with other compound heterozygous mutations including the E148Q mutation. ISSF score is lower in patients with E148Q mutation in one allele.

Anahtar Kelimeler

Familial Mediterranean fever, E148Q variant, ISSF score

Bileşik Heterozigot Mutasyonu Olan Ailevi Akdeniz Ateşi Hastalarında E148Q Varyantının Hastalık Ağırlığına Etkisi

Öz

Amaç: Bu çalışmada bileşik heterozigot mutasyon taşıyan AAA hastalarının demografik, klinik bulgularının değerlendirilmesi ve E148Q varyantının hastalık ağrılığı üzerine etkisinin araştırılması amaçlandı.
Yöntemler: 0-18 yaşları arasında, Yalçınkaya-Özen kriterlerine göre AAA tanısı konulmuş olan ve bileşik heterozigot mutasyon saptanmış olan hastalar çalışmaya alındı. Klinik ve demografik verileri kaydedildi. Hastalık ağırlığı AAA için uluslararası şiddet skorlama sistemi (ISSF) ile değerlendirildi. Hastalar mutasyon tipine göre ekzon 10/E148Q bileşik heterozigot mutasyonu olanlar (Grup 1) ile ekzon 10/ekzon 10 bileşik heterozigot mutasyonu olanlar (Grup 2) olarak iki gruba ayrılarak değerlendirildi.
Bulgular: Toplam 317 bileşik heterozigot mutasyona sahip AAA hastalarında kadın/erkek oranı: 1.07, ortanca tanı yaşı 6.7 (IQR: 6.3) yıldı. En sık görülen semptom %85.8 oranında karın ağrısı idi. Grup 2’de (n=219) yer alan hastaların ortanca tanı yaşı 6 yıl, Grup 1’dekilerin (n=98) ise 8.2 yıldı (p=0.005). İki ekzon 10 mutasyonu olan hastalarda ateş (%75.8) diğer gruba göre daha sık görüldü (p=0.01). İkiden fazla farklı atak tipi, atakta ikiden fazla bulgu ve 72 saatten uzun süren atak varlığı Grup 2’deki hastalarda daha sıktı (sırasıyla p=0.021, p<0.001, p=0.043). Tüm hastalarda toplam ISSF skoru ortanca 2 (IQR:3) olarak bulunurken Grup 2’nin ISSF skoru diğer gruba göre daha yüksekti (p<0.001).
Sonuç: İki ekzon 10 mutasyonu olan hastalar, E148Q mutasyonunu içeren diğer bileşik heterozigot mutasyonu olan hastalara göre daha şiddetli hastalığa sahiptir. ISSF skoru bir alelinde E148Q mutasyonu olan hastalarda daha düşüktür.

Anahtar Kelimeler

Ailevi Akdeniz ateşi, E148Q varyant, ISSF skoru

Kaynakça

• 1. Ayaz NA, Tanatar A, Karadağ ŞG, Çakan M, Keskindemirci G, Sönmez HE. Comorbidities and phenotype–genotype correlation in children with familial Mediterranean fever. Rheumatol Int. 2021;41(1):113-20.
• 2. Padeh S, Bilginer Y, Ozen S. Familial mediterranean fever. Textbook of Autoinflammation. 2019:293-313.
• 3. Coşku S, Kurtgöz S, Keskin E, Sönmez F, Bozkurt G. Frequency of mutations in Mediterranean fever gene, with gender and genotype–phenotype correlations in a Turkish population. J Genet. 2015;94:629-35.
• 4. Kunt SŞ, Aydın F, Çakar N, Özdel S, Yalçınkaya F, Özçakar ZB. The effect of genotype on musculoskeletal complaints in patients with familial Mediterranean fever. Postgrad Med. 2020;132(2):220-4.
• 5. Ozdogan H, Ugurlu S. Familial mediterranean fever. La Presse Médicale. 2019;48(1):e61-e76.
• 6. Barut K, Sahin S, Adrovic A, Sinoplu AB, Yucel G, Pamuk G, et al. Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int. 2018;38:67-74.
• 7. Gangemi S, Manti S, Procopio V et al. Lack of clear and univocal genotype‐phenotype correlation in familial Mediterranean fever patients: A systematic review. Clin Genet. 2018;94(1):81-94.
• 8. Yalçınkaya F, Özen S, Özçakar ZB et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology. 2009;48(4):395-8.
• 9. Demirkaya E, Acikel C, Hashkes P et al. Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF). Ann Rheum Dis. 2016;75(6):1051-6.
• 10. Özdel S, Özçakar ZB, Kunt SŞ, Elhan AH, Yalçınkaya F. Late-onset disease is associated with a mild phenotype in children with familial Mediterranean fever. Clin Rheumatol. 2016;35:1837-40.
• 11. Caglayan AO, Demiryilmaz F, Ozyazgan I, Gumus H. MEFV gene compound heterozygous mutations in familial Mediterranean fever phenotype: a retrospective clinical and molecular study. Nephrol Dial Transplant. 2010;25(8):2520-3.
• 12. Balta B, Erdogan M, Kiraz A, Akalın T, Baştug F, Bayram A. A comprehensive molecular analysis and genotype–phenotype correlation in patients with familial mediterranean fever. Mol Biol Rep. 2020;47:1835-43.
• 13. Tunca M, Ozdogan H, Kasapcopur O et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005;84(1):1-11.
• 14. Yaşar Bilge NŞ, Sari I, Solmaz D et al. The distribution of MEFV mutations in Turkish FMF patients: multicenter study representing results of Anatolia. Turk J Med Sci. 2019; 49(2), 472-477.
• 15. Ece A, Çakmak E, Uluca Ü et al. The MEFV mutations and their clinical correlations in children with familial Mediterranean fever in southeast Turkey. Rheumatol Int. 2014;34:207-12.
• 16. Jarjour RA. Familial Mediterranean fever in Syrian patients: MEFV gene mutations and genotype–phenotype correlation. Mol Biol Rep. 2010;37:1-5.
• 17. Giancane G, Ter Haar NM, Wulffraat N et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015;74(4):635-41.
• 18. Kilic A, Varkal MA, Durmus MS et al. Relationship between clinical findings and genetic mutations in patients with familial Mediterranean fever. Pediatr Rheumatol. 2015;13(1):1-9.
• 19. Ozcan G, Cayci S, Celikel Acar B et al. Is the performance of the international severity scoring system for familial mediterranean fever in children better than other scoring systems? Int J Clin Pract. 2021;75(11):e14678.
• 20. Bilge NŞY, Bodakçi E, Bilgin M, Kaşifoğlu T. Comparison of clinical features in FMF patients according to severity scores: An analysis with the ISSF scoring system. Eur J Rheumatol. 2020;7(2):68.
• 21. Sönmez HE, Esmeray P, Batu ED et al. Is age associated with disease severity and compliance to treatment in children with familial Mediterranean fever? Rheumatol Int. 2019;39:83-7.
• 22. Tanatar A, Karadağ ŞG, Çakan M, Sönmez HE, Ayaz NA. Age of onset as an influencing factor for disease severity in children with familial Mediterranean fever. Mod Rheumatol. 2021;31(1):219-22.