Is there any difference between M694V heterozygote and non-exon 10 mutations on symptoms onset and response to colchicine treatment?

Yıl 2024, Cilt: 17 Sayı: 3, 550 - 559, 05.07.2024

Hatice Adıgüzel Dundar , Serkan Türkuçar , Ceyhun Açarı , Özge Altuğ Gücenmez , Balahan Makay , Erbil Ünsal

https://doi.org/10.31362/patd.1496674

Öz

Purpose: Familial Mediterranean fever (FMF) is the most common inherited autoinflammatory syndrome throughout the world. The most frequent genotype-phenotype correlation is in a certain part of exon 10, especially M694V mutation. There are also a group of patients with non-exon 10 mutations, who have a similar clinical spectrum of the disease. We aim to investigate the genotype-phenotype differences between M694V heterozygote mutations and non-exon 10 mutations.
Materials and methods: Data charts of children (n=431) with FMF from two tertiary hospitals were reviewed. Patients were divided into two groups with regard to having M694V heterozygote or non-exon 10 mutations. Genotype-phenotype features and response to treatment were compared.
Results: There were M694V heterozygote mutations in 128 (29.7%) patients and non-exon 10 mutations in 303 (70.3%) patients. The follow-up period was 54.5 (33-105) months. There was no difference between the age of symptoms onset, the age of diagnosis, and the diagnosis delay time. The family history in patients with M694V heterozygote mutation was statistically positive compared to non-exon 10 mutation group (p=0.001). The symptoms of joint involvement as arthritis and PRAS scores were significantly higher in the M694V heterozygote group (p=0.026 and p=0.001). Additionally, biological agent need due to colchicine unresponsiveness was statistically higher in M694V heterozygote group than group with non-exon 10 mutation (p=0.004).
Conclusion: There is a significant difference between children with M694V and non-exon 10 mutations, even when the M694V mutation is present in one allele only. Family history with FMF, musculoskeletal symptoms, and unresponsiveness to colchicine are main parameters.

Anahtar Kelimeler

Familial Mediterranean Fever, M694V, MEFV mutation, colchicine

M694V heterozigot ve non-ekzon 10 mutasyonları arasında semptomların başlangıcı ve kolşisin tedavisine yanıt açısından fark var mıdır?

Öz

Amaç: Ailesel Akdeniz Ateşi (AAA), tüm dünyada en sık görülen kalıtsal otoinflamatuvar sendromdur. En sık genotip-fenotip korelasyonu ekzon 10'un belirli bir kısmında, özellikle M694V mutasyonundadır. Ekzon 10 mutasyonu olmayan ve benzer klinik spektruma sahip bir grup hasta da bulunmaktadır. Amacımız M694V heterozigot mutasyonları ve ekzon 10 dışı mutasyonlar arasındaki genotip-fenotip farklılıklarını araştırmaktır.
Gereç ve yöntem: İki üçüncü basamak hastaneden AAA'lı çocukların (n=431) veri dosyaları incelendi. Hastalar M694V heterozigot veya non-ekson 10 mutasyonuna sahip olma açısından iki gruba ayrıldı. Genotip-fenotip özellikleri ve tedaviye yanıt karşılaştırıldı.
Bulgular: 128 (%29,7) hastada M694V heterozigot mutasyonu ve 303 (%70,3) hastada non-ekson 10 mutasyonu vardı. Takip süresi 54,5 (33-105) aydı. Semptomların başlama yaşı, tanı yaşı ve tanı gecikme süresi arasında fark yoktu. M694V heterozigot mutasyonu olan hastalarda aile öyküsü, ekzon 10 mutasyonu olmayan gruba kıyasla istatistiksel olarak pozitifti (p=0,001). Artrit olarak eklem tutulumu semptomları ve PRAS skorları M694V heterozigot grubunda anlamlı olarak daha yüksekti (p=0,026 ve p=0,001). Ayrıca, kolşisin yanıtsızlığı nedeniyle biyolojik ajan ihtiyacı M694V heterozigot grupta ekzon 10 mutasyonu olmayan gruba göre istatistiksel olarak daha yüksekti (p=0,004).
Sonuç: M694V mutasyonu sadece bir alelde mevcut olsa bile, M694V ve non-ekson 10 mutasyonu olan çocuklar arasında anlamlı bir fark vardır. AAA ile aile öyküsü, kas-iskelet sistemi semptomları ve kolşisine yanıtsızlık ana parametrelerdir.

Anahtar Kelimeler

Ailevi Akdeniz Ateşi, M694V, MEFV mutasyonu, kolşisin

Kaynakça

• 1. Ben Chetrit E, Touitou I. Familial mediterranean fever in the world. Arthritis Rheum 2009;61:1447-1453. https://doi.org/10.1002/art.24458
• 2. Livneh A, Langevitz P, Zemer D, et al. The changing face of familial Mediterranean fever. Semin Arthritis Rheum 1996;26:612-627. https://doi.org/10.1016/s0049-0172(96)80012-6
• 3. Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 2016;17:914-921. https://doi.org/10.1038/ni.3457
• 4. Yang JL, Xu H, Shao F. The immunological function of familial Mediterranean fever disease protein Pyrin. Sci China Life Sci 2014;57:1156-1161. https://doi.org/10.1007/s11427-014-4758-3
• 5. Infevers: an online database for autoinflammatory mutations. Copyright. Available at: https://infevers.umai-montpellier.fr/. Accessed 25 March 2024
• 6. Sönmez HE, Batu ED, Bilginer Y, Özen S. Discontinuing colchicine in symptomatic carriers for MEFV (Mediterranean FeVer) variants. Clin Rheumatol 2017;36:421-425. https://doi.org/10.1007/s10067-016-3421-8
• 7. Booty MG, Chae JJ, Masters SL, et al. Familial mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum 2009;60:1851-1861. https://doi.org/10.1002/art.24569
• 8. Procopio V, Manti S, Bianco G, et al. Genotype-phenotype correlation in FMF patients: a "non classic" recessive autosomal or "atypical" dominant autosomal inheritance? Gene 2018;641:279-286. https://doi.org/10.1016/j.gene.2017.10.068
• 9. Sönmezgöz E, Özer S, Gül A, et al. Clinical and Demographic Evaluation According to MEFV Genes in Patients with Familial Mediterranean Fever. Biochem Genet 2019;57:289-300. https://doi.org/10.1007/s10528-018-9889-y
• 10. Shohat M, Magal N, Shohat T, et al. Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis. Eur J Hum Genet 1999;7:287-292. https://doi.org/10.1038/sj.ejhg.5200303
• 11. Medlej Hashim M, Delague V, Chouery E, et al. Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Med Genet 2004;5:4. https://doi.org/10.1186/1471-2350-5-4
• 12. Arpacı A, Doğan S, Erdoğan HF, El Ç, Cura SE. Presentation of a new mutation in FMF and evaluating the frequency of distribution of the MEFV gene mutation in our region with clinical findings. Mol Biol Rep 2021;48:2025-2033. https://doi.org/10.1007/s11033-020-06040-y
• 13. Grossman C, Kassel Y, Livneh A, Ben Zvi I. Familial Mediterranean fever (FMF) phenotype in patients homozygous to the MEFV M694V mutation. Eur J Med Genet 2019;62:103532. https://doi.org/10.1016/j.ejmg.2018.08.013
• 14. Açarı C, Bayram M, Yıldız G, Kavukcu S, Soylu A. Demographics, clinical, laboratory findings and treatment results of pediatric patients with IgA vasculitis: single-center experience. Pam Med J 2023;16:73-80. https://dx.doi.org/10.31362/patd.1209784
• 15. Shinar Y, Livneh A, Langevitz P, et al. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol 2000;27:1703-1707.
• 16. Shinar Y, Obici L, Aksentijevich I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis 2012;71:1599-1605. https://doi.org/10.1136/annrheumdis-2011-201271
• 17. Bektas M, Koca N, Oguz E, et al. Characteristics and course of patients with AA amyloidosis: single centre experience with 174 patients from Turkey. Rheumatology (Oxford) 2024;63:319-328. https://doi.org/10.1093/rheumatology/kead465
• 18. Kandur Y, Kocakap DBS, Alpcan A, Tursun S. Clinical significance of MEFV gene variation R202Q. Clin Rheumatol 2022;41:271-274. https://doi.org/10.1007/s10067-021-05906-1
• 19. Dogan H, Faruk Bayrak O, et al. Familial mediterranean fever gene mutations in north-eastern part of Anatolia with special respect to rare mutations. Gene 2015;568:170-175. https://doi.org/10.1016/j.gene.2015.05.045
• 20. Ben Chetrit E, Levy M. Colchicine: 1998 update. Semin Arthritis Rheum 1998;28:48-59. https://doi.org/10.1016/s0049-0172(98)80028-0
• 21. Batu ED, Şener S, Arslanoglu Aydin E, et al. A score for predicting colchicine resistance at the time of diagnosis in familial Mediterranean fever: data from the TURPAID registry. Rheumatology 2024;63:791-797. https://doi.org/10.1093/rheumatology/kead242
• 22. Yalçinkaya F, Ozen S, Ozçakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology 2009;48:395-398. https://doi.org/10.1093/rheumatology/ken509
• 23. Nevzi O, Günöz H, Furman A, ve ark. Türk çocuklarında vücut ağırlığı, boy uzunluğu, baş çevresi ve vücut kitle indeksi referans değerleri. Çocuk Sağlığı ve Hastalıkları Dergisi 2008;51:1-14.
• 24. Pras E, Livneh A, Balow JE Jr, et al. Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet 1998;75:216-219. https://doi.org/10.1002/(sici)1096-8628(19980113)75:2<216::aid-ajmg20>3.0.co;2-r
• 25. Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016;75:644-651. https://doi.org/10.1136/annrheumdis-2015-208690
• 26. Erden A, Batu ED, Sarı A, et al. Erden A, Batu ED, Sarı A, et al. Which definition should be used to determine colchicine resistance among patients with familial Mediterranean fever? Clin Exp Rheumatol 2018;36:97-102.
• 27. Türkuçar S, Adıgüzel H, Yılmaz C, Ünsal E. R202Q gen değişikliğinin ailesel Akdeniz ateşi kliniği üzerine etkisi: tek merkez deneyimi. Pam Med J 2021;14:870-877. https://dx.doi.org/10.31362/patd.885049
• 28. Öztürk K, Coşkuner T, Baglan E, et al. Real-life data from the largest pediatric familial mediterranean fever cohort. Front Pediatr 2022;9:805919. https://doi.org/10.3389/fped.2021.805919
• 29. Türkuçar S, Adıgüzel Dundar H, Koyuncuoğlu Yılmaz C, Unsal E. Exon-2 genotypes may explain typical clinical features of familial mediterranean fever with milder disease activity. Erciyes Med J 2022;44:33-38. https://doi.org/10.14744/etd.2021.15579
• 30. Özen S, Batu ED, Demir S. Familial mediterranean fever: recent developments in pathogenesis and new recommendations for management. Front Immunol 2017;8:253. https://doi.org/10.3389/fimmu.2017.00253 31. Mattit H, Joma M, Al Cheikh S, et al. Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype-genotype correlation. Eur J Med Genet 2006;49:481-486. https://doi.org/10.1016/j.ejmg.2006.03.002
• 32. Tunca M, Akar S, Onen F, et al. Familial Mediterranean Fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine 2005;84:1-11. https://doi.org/10.1097/01.md.0000152370.84628.0c
• 33. Sahin S, Romano M, Guzel F, Piskin D, Poddighe D, Sezer S, et al. Assessment of surrogate markers for cardiovascular disease in familial mediterranean fever-related amyloidosis patients homozygous for M694V mutation in MEFV gene. Life 2022;12:631. https://doi.org/10.3390/life12050631
• 34. Kilic A, Varkal MA, Durmus MS, Yildiz I, Yıldırım ZN, Turunc G, et al. Kilic A, Varkal MA, Durmus MS, et al. Relationship between clinical findings and genetic mutations in patients with familial Mediterranean fever. Pediatr Rheumatol 2015;13:59. https://doi.org/10.1186/s12969-015-0057-1
• 35. Topaloglu R, Batu ED, Yıldız Ç, et al. Familial mediterranean fever patients homozygous for E148Q variant may have milder disease. Int J Rheum Dis 2018;21:1857-1862. https://doi.org/10.1111/1756-185X.12929
• 36. Yoshida S, Sumichika Y, Saito K, et al. Effectiveness of colchicine or canakinumab in japanese patients with familial mediterranean fever: a single-center study. J Clin Med 2023;12:6272. https://doi.org/10.3390/jcm12196272 37. Kişla Ekinci RM, Balci S, Ufuk Altintaş D, Yilmaz M. The influence of concomitant disorders on disease severity of familial mediterranean fever in children. Arch Rheumatol 2017;33:282-287. https://doi.org/10.5606/ArchRheumatol.2018.6488
• 38. Otar Yener G, Yuksel S, Ekici Tekin Z, Türkmen H. Frequency of rheumatic diseases in patients with familial Mediterranean fever. Pam Med J 2023;16:101-109. https://doi.org/10.31362/patd.1213710
• 39. Yildiz M, Adrovic A, Tasdemir E, et al. Evaluation of co-existing diseases in children with familial Mediterranean fever. Rheumatol Int 2020;40:57-64. https://doi.org/10.1007/s00296-019-04391-9
• 40. Aktay Ayaz N, Tanatar A, Karadağ ŞG, Çakan M, Keskindemirci G, Sönmez HE. Comorbidities and phenotype-genotype correlation in children with familial Mediterranean fever. Rheumatol Int 2021;41:113-120. https://doi.org/10.1007/s00296-020-04592-7
• 41. Akbaba TH, Akkaya Ulum YZ, Tavukcuoglu Z, Bilginer Y, Ozen S, Balci Peynircioglu B. Inflammation-related differentially expressed common miRNAs in systemic autoinflammatory disorders patients can regulate the clinical course. Clin Exp Rheumatol 2021;39:109-117. https://doi.org/10.55563/clinexprheumatol/t67tvc
• 42. Ozen S, Aktay N, Lainka E, Duzova A, Bakkaloglu A, Kallinich T. Disease severity in children and adolescents with familial Mediterranean fever: a comparative study to explore environmental effects on a monogenic disease. Ann Rheum Dis 2009;68:246-248. https://doi.org/10.1136/ard.2008.092031
• 43. Khachatryan ZA, Ktsoyan ZA, Manukyan GP, Kelly D, Ghazaryan KA, Aminov RI. Predominant role of host genetics in controlling the composition of gut microbiota. PLoS One 2008;3:e3064. https://doi.org/10.1371/journal.pone.0003064