Introduction
Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent, self-limiting episodes of fever accompanied by peritonitis, pleuritis, synovitis, and erysipelas-like skin lesions [
1]. The patients having severe FMF attacks sometimes develop lethal renal amyloid A (AA) amyloidosis. Typical FMF attacks usually last for approximately 3 days, and they vary in frequency from once a week to several times per year. Oral colchicine therapy is quite effective for preventing attacks and the development of reactive AA amyloidosis. The gene responsible,
MEFV, maps to the short arm of chromosome 16 and encodes a protein of 781 amino acids called pyrin [
2],[
3]. Though the mechanism of pyrin action is still debated, it is considered to be a negative regulator of inflammation [
4].
FMF affects more than 100,000 people around the world, and is particularly prevalent in the Mediterranean basin, occurring most commonly in Turks, Arabs, Armenians, and Jews. Five mutations, M694V, V726A, M680I, M694I (in exon 10), and E148Q (in exon 2), account for 74% of FMF mutations [
5]. However, increasing numbers of cases have been reported in different ethnic groups and countries [
6]. In Japan, cases of FMF with
MEFV mutations were first reported in 2002 [
7], and large numbers of FMF patients have been reported since even in Japan [
8]-[
13]. In addition, we described the clinical manifestations of FMF in 80 Japanese patients [
14]. This study indicated that the severity of FMF is milder in Japanese than Mediterranean patients, with a lower frequency of AA amyloidosis, and the mutations are also different between Japanese and Mediterranean patients. However, FMF is still thought of as an uncommon disease in Japan, and the detailed clinical features associated with each type of
MEFV mutation in Japanese patients have not been elucidated. To date, a number of clinical diagnostic criteria have been used to make a diagnosis of FMF [
15]-[
18]. However, it is possible that some Japanese patients would not meet these diagnostic criteria as they are based on the symptoms seen in Mediterranean patients. Therefore, many patients may remain undiagnosed and a comprehensive diagnosis, including genetic analysis, may be necessary especially in countries outside the Mediterranean area, such as Japan. The present study was performed to examine the precise relationships between each type of
MEFV mutation and clinical manifestations in a large cohort of Japanese FMF patients. Moreover, we reconsidered the validity of the existing diagnostic criteria based on the genotype-phenotype correlation seen in Japanese FMF.
Discussion
In this study, we examined the frequency of
MEFV mutation, clinical manifestations, and the genotype-phenotype correlations in 116 Japanese patients with FMF. The clinical features of the Japanese patients were different from those seen in Mediterranean populations. Compared to Mediterranean patients, Japanese patients had late onset of symptoms, relatively low frequency of peritonitis, rarity of reactive AA amyloidosis, and low dosage of colchicine [
14]. The results of the present study suggest that the differences in mutations between Japanese and Mediterranean populations are associated with differences in genotype. Over 280 sequence variants in the
MEFV gene have been recorded in the Infevers database [
29], the most common of which are M694V, M694I, V726A, M680I, and E148Q [
5],[
19],[
30]. These five mutations account for approximately 90% of sequence variants in classically affected ethnic groups (Turks, Arabs, Armenians, and Jews) (Figure
1). However, only 61.2% of Japanese FMF patients in the present study had E148Q and/or M694I, and none of our patients had M694V, V726A, or M680I. Especially, M694V, which is related to the most severe clinical course [
19],[
30], has not been detected in Japanese patients. On the other hand, the largest number of Japanese patients with the E148Q mutation had a mild clinical course [
5]. It has been suggested that FMF, along with Behçet’s disease, may have been transmitted to Japan via travel along the Silk Road [
6]. However, this hypothesis cannot explain the differences in mutation types between Japan and Mediterranean regions and the low prevalence of FMF, compared to Behçet’s disease, which is a common disease in Japan. As an island nation, Japan has a number of intrinsic disease features and Japanese patients have specific clinical presentations and mutation types.
As shown in Tables
1 and
2, the majority of Japanese FMF patients had some combination of M694I, E148Q, L110P, P369S/R408Q, and R202Q mutations. The presence of M694I in exon 10 is thought to be important for diagnosis and treatment. Patients with this mutation show a typical and severe clinical course, with early onset, high frequency and short duration of attacks, and high percentages of fever and serositis. However, their therapeutic response to colchicine is very good. Hence, identification of the M694I mutation is a useful diagnostic foundation for Japanese patients with suspected FMF.
E148Q has been considered to be a polymorphism because its allele frequency is high in healthy controls [
31]. In Japan, it has been reported that allele frequency of E148Q, L110P, and M694I are 0.26, 0.039, and 0.0, respectively [
14]. Nevertheless, several studies have indicated that most homozygous or compound heterozygous patients associated with other
MEFV mutations are symptomatic and their clinical course is relatively mild [
5],[
32]. In the present study, the clinical manifestations of patients with E148Q were later onset, lower frequency, and slightly longer duration of attacks, compared to patients with M694I. Moreover, some patients heterozygous only for E148Q presented with typical FMF manifestations. Generally, it is difficult to make a definite diagnosis in patients heterozygous for only E148Q. In such cases, a comprehensive diagnosis including not only the clinical course but also the efficacy of colchicine may be required.
The L110P mutation was always compound heterozygous with E148Q mutation, and there were no patients heterozygous for L110P alone. This mutation was identified commonly in our study and several cases of FMF with this mutation have been reported in Japan [
33],[
34]. Although L110P may be a frequent mutation, especially in Japanese patients, there were no marked differences in the clinical picture between L110P/E148Q and E148Q alone.
In addition, it may be necessary to pay special attention to the diagnosis in patients with P369S/R408Q mutations in exon 3. P369S and R408Q are always identified in
cis[
35], as observed in our study. In the present study, 12 patients with P369S/R408Q (alone or with additional mutations) were identified, and their clinical features were characterized by a high frequency of attacks, variable phenotype, and incomplete efficacy of colchicine therapy. The mean frequency of attacks in these 12 patients was 22.5 times per year. Their clinical symptoms were highly variable: four were variable in frequency or duration of attacks, two experienced frequent abdominal attacks without high fever and elevation of serum C-reactive protein (CRP) level, and other findings. Eight patients received colchicine therapy, but four had only a partial response, and the others showed no response. Ryan
et al. report that patients with P369S/R408S mutations have clinical diversity, atypical clinical presentation, and relative lack of response to colchicine treatment [
35]. This report is comparable to the phenotype in our patients with P369S/R408S. Therefore, it will be necessary to establish other more effective therapies, including biological treatment, for such cases.
As indicated in the present study, there were differences in clinical characteristics between the various MEFV mutations. As the majority of patients with M694I have typical FMF symptoms, identification of this mutation can lead to a definite diagnosis. When other mutations, such as E148Q and/or L110P, P369S/R408Q, R202Q, E84K, S503C, or G304R are identified, a comprehensive diagnosis including the efficacy of colchicine treatment may be required. Therefore, it is important to perform MEFV gene analysis for diagnosis of patients with suspected FMF (recurrent febrile episodes and/or serositis, and exclude diagnosis of other diseases). After treatment with colchicine, it is important to examine the diagnostic validity. The possibility of FMF cannot be excluded even in the absence of detectable MEFV mutations, but a careful colchicine trial is required.
Authors' contributions
DK: conception and design, data collection and analysis, drafting of the manuscript and final approval of the manuscript. AN: conception and design, data collection and analysis, help in drafting the manuscript, critical revision and final approval of the manuscript. MY: conception and design, data collection and analysis, help in drafting the manuscript, critical revision and final approval of the manuscript. AT: data collection and analysis, critical revision and final approval of the manuscript. MM: data collection and analysis, critical revision and final approval of the manuscript. SI: data collection and analysis, critical revision and final approval of the manuscript. All authors read and approved the final manuscript
Acknowledgements
This study was supported by a grant-in-aid for research on intractable diseases from the Ministry of Health, Labour and Welfare of Japan and a grant-in-aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan to Akinori Nakamura (213001857) and Promotion Project of Education, Research, and Medical Care from Shinshu University Hospital to Dai Kishida. We would like to thank the following contributors for their effective and dedicated participation: Hiroyuki Yahikozawa, MD; Mihoko Yotsumoto, MD (Nagano Red Cross Hospital); Naoki Oomiya, MD; Osamu Watanabe, MD (Nagoya University Hospital); Yutaka Tsuchiya, MD; Shotaro Hanamura, MD; Yoshinori Sato, MD; Fumihiro Yamaguchi, MD (Showa University Fujigaoka Hospital); Naho Aikawa, MD (Tokyo Medical University Hospital); Shigeko Hara, MD; Tatsuya Suwabe, MD; Hideki Araoka, MD; Aya Imahuku, MD (Toranomon Hospital); Tomoko Tamaoki, MD (Hyogo Medical University Hospital); Yoshinobu Suzuki, MD (Shinonoi Suzuki Clinic); Kazuhiko Sekiguchi, MD (Sekiguchi Ladies Clinic); Keisuke Izumi, MD (Keio University Hospital); Shogo Itano, MD; Yoshihito Hayami, MD (Nagoya City University Hospital); Takafumi Tezuka, MD; Masaru Yamazoe, MD (Niigata City General Hospital); Tomoki Yonaha, MD (Japanese Red Cross Medical Center); Kumiko Ishida, MD (Kasugai Municipal Hospital); Ayumu Yamagami, MD (Fussa Hospital); Hiroe Sato, MD (Niigata Rheumatic Center); Tomohiko Sasaki, MD; Noriko Nara, MD (Yokohama City University Medical Center); Kiminori Hasegawa, MD; Takao Katsuragawa, MD; Ryutaro Morizono, MD (Kin-ikyo Chuo Hospital); Kenya Oguchi, MD (Chushin Matsumoto Hospital); Chisho Hoshino, MD (Saka General Hospital); Eri Kawatani, MD; Yoshiaki Aomi, MD (Fukuoka University Chikushi Hospital); Yoko Wada, MD (Niigata University Hospital); Yuichiro Haba, MD (Juntendo University Hospital); Junichi Mise, MD; Takeshi Tanabe, MD (Jichi Medical University Hospital); Naohito Fujishima, MD (Akita University Hospital); Yuki Yasuda, MD (Tokyo Women's Medical University Medical Center East); Ryuichi Chiba, MD (Iida Hospital), Yukihiro Ootaka, MD (Takasaki General Medical Center), Fumiaki Aoki, MD (Gunma University Hospital); Hiroshi Kasahara, MD (Suwa Red Cross Hospital); Takehisa Ogura, MD (Toho University Medical Center Ohashi Hospital); Michinori Yoshimi, MD (Kyoritsu General Hospital); Tomohisa Baba, MD (Kanagawa Cardiovascular and Respiratory Center); Ryosuke Hara, MD (Shinonoi General Hospital); Takamasa Tanaka, MD (Sakai City Hospital); Mito Daisuke, MD, Junwa Kunimatsu, MD (National Center for Global Health and Medicine); Tomomi, Abe, MD (Kawakita General Hospital); Kyoichi Nakajima, MD (East Saitama National Hospital); Kunihiro Yoshida, MD; Hiroshi Morita, MD; Wataru Ishii, MD; Akiyo Hineno, MD; Tomomi Kinoshita, MD; and Kenji Oka, MD (Shinshu University Hospital).
Competing interests
The authors declare that they have no competing interests.