Familial Mediterranean fever: genotype-phenotype correlations in Japanese patients
Kiyoshi Migita1, Kazunaga Agematsu, Masahide Yazaki
1From the Clinical Research Center (KM, YJ), Nagasaki Medical Center, Omura, Nagasaki; Department of Infection and Host Defense (KA), Graduate School of Medicine, Shinshu University, Matsumoto; Departments of Medicine (Neurology and Rheumatology) (M. Yazaki, AN, DK), Shinshu University School of Medicine, Matsumoto; Department of Rheumatology (FN, KE), Sasebo City General Hospital, Sasebo; Department of Pediatrics (TT, AY), School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa; Department of Public Health (RU, Y. Nakamura), Jichi Medical University, Tochigi; Department of Pathology (JM), Ehime University Graduate School of Medicine and Proteo-Science Center, Toon, Ehime; Clinical Research Center (HF), Sagamihara National Hospital, National Hospital Organization, Sagamihara, Kanagawa; Department of Rheumatology (HI), Kurume University School of Medicine, Kurume; Department of Rheumatology (CT), Saitama Medical Center, Jichi Medical University, Saitama-City; First Department of Internal Medicine (Y. Nakashima, AK), Nagasaki University School of Medicine, Nagasaki; Department of Rheumatology (TN), Kumamoto Shinto General Hospita, Kumamoto; and Institute of Tropical Medicine (NEKKEN) (M. Yasunami), Nagasaki University, Nagasaki; Japan.
Abstract:
Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by MEditerranean FeVer gene (MEFV) mutations. In Japan, patients with FMF have been previously reported, including a mild or incomplete form. Several factors are presumed to contribute to the variable penetrance and to the phenotypic variability of FMF. We conducted the current study to investigate the correlation of variable clinical presentations and MEFV genotypic distributions in Japanese FMF patients.We analyzed demographic, clinical, and genetic data for 311 FMF patients enrolled in the study. Clinically, we classified FMF into 2 phenotypes: 1) the "typical" form of FMF, and 2) the "atypical" form of FMF according to the Tel Hashomer criteria. Patients with the typical FMF phenotype had a higher frequency of febrile episodes, a shorter duration of febrile attacks, more frequent thoracic pain, abdominal pain, a family history of FMF, and MEFV exon 10 mutations. Conversely, patients with the atypical FMF phenotype had a lower frequency of fever episodes and more frequent arthritis in atypical distribution, myalgia, and MEFV exon 3 mutations. Multivariate analysis showed that the variable associated with typical FMF presentation was the presence of MEFV exon 10 mutations. Typical FMF phenotype frequencies were decreased in patients carrying 2 or a single low-penetrance mutations compared with those carrying 2 or a single high-penetrance mutations (M694I), with an opposite trend for the atypical FMF phenotype. In addition, patients having more than 2 MEFV mutations had a younger disease onset and a higher prevalence of thoracic pain than those carrying a single or no mutations. Thus, MEFV exon 10 mutations are associated with the more typical FMF phenotype. In contrast, more than half of the Japanese FMF patients without MEFV exon 10 mutations presented with an atypical FMF phenotype, indicating that Japanese FMF patients tend to be divided into 2 phenotypes by a variation of MEFV mutations.
Insights
Familial Mediterranean fever (FMF) is an autoinflammatory disease. MEFV gene mutations influence FMF presentation, with exon 10 mutations linked to typical FMF and other variations to atypical forms in Japanese patients.
Area of Science:
- Genetics
- Immunology
- Rheumatology
Background:
- Familial Mediterranean fever (FMF) is a genetic autoinflammatory disorder.
- MEFV gene mutations are the known cause of FMF.
- Phenotypic variability and incomplete penetrance are characteristic of FMF.
Purpose of the Study:
- To investigate the correlation between clinical presentations and MEFV genotypic distributions in Japanese FMF patients.
- To understand the genetic basis of variable FMF phenotypes in Japan.
Main Methods:
- Analysis of demographic, clinical, and genetic data from 311 Japanese FMF patients.
- Classification of FMF into typical and atypical phenotypes using Tel Hashomer criteria.
- Multivariate analysis to identify associations between MEFV mutations and clinical features.
Main Results:
- MEFV exon 10 mutations were significantly associated with the typical FMF phenotype (fever, thoracic pain, abdominal pain).
- Atypical FMF phenotypes (arthritis, myalgia) were more frequent with MEFV exon 3 mutations and in patients lacking exon 10 mutations.
- Patients with multiple MEFV mutations exhibited earlier disease onset and increased thoracic pain.
Conclusions:
- MEFV exon 10 mutations are key determinants of the typical FMF phenotype in Japanese patients.
- Atypical FMF presentations are common in Japanese patients without MEFV exon 10 mutations, highlighting genotype-phenotype correlations.
- Genetic variations in MEFV significantly contribute to the diverse clinical spectrum of FMF in Japan.
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