title: Familial Mediterranean fever: genotype-phenotype correlations in Japanese patients.
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.
authors.affiliation: From 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.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Migita
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
authors.forename: Masahide
authors.initials: M
authors.lastname: Yazaki
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Nonaka
authors.forename: Akinori
authors.initials: A
authors.lastname: Nakamura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toma
authors.forename: Dai
authors.initials: D
authors.lastname: Kishida
authors.forename: Ritei
authors.initials: R
authors.lastname: Uehara
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yuka
authors.initials: Y
authors.lastname: Jiuchi
authors.forename: Junya
authors.initials: J
authors.lastname: Masumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ida
authors.forename: Chihiro
authors.initials: C
authors.lastname: Terai
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawakami
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
authors.forename: Michio
authors.initials: M
authors.lastname: Yasunami
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D004252:DNA Mutational Analysis; D010505:Familial Mediterranean Fever / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006306:Health Surveys; D006801:Humans; D007564:Japan; D016015:Logistic Models; D008297:Male; D009154:Mutation; D010641:Phenotype; D015995:Prevalence; D055815:Young Adult