INCREASED FREQUENCY OF MEFV GENES IN
PATIENTS WITH EPIGASTRIC PAIN SYNDROME
Coskun BD1, Kiraz A2, Sevinc E1, Baspinar O3, Cakmak E4
*Corresponding Author: Banu D. Coskun, M.D., Kicikapı Mahallesi Hoca Ahmet Yesevi Cad Hidayet Eraslan sitesi B Blok
No: 12, Talas/Kayseri Turkey. Tel: +90-506-323-24-86. Fax: +90-352-437-52-73. E-mail: demetcoskun2@gmail.com
page: 51
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DISCUSSION
Our study aimed to determined the frequency of
MEFV gene mutations and FMF clinical findings in patients
who were followed with a diagnosis of EPS. Familial
Mediterranean fever is an autoinflammatuar disease characterized
by recurrent and self-limited episodes of fever,
abdominal pain and serositis with a duration of 1-3 days.
The prevelance of FMF is 1/1000 and the carrier rate is
15.0-34.0% in Turkey [3,4]. It is caused by mutations in
the MEFV gene. More than 300 mutations of the MEFV
gene have been reported [11]. A diagnosis of FMF was
established according to clinical criteria (Tel Hashomer
criteria), rather than genetic analysis [12,13]. However,
genetic analyses are helpful in detecting atypical FMF
presentations, presymptomatic patient’s relatives and confirmation
of the FMF diagnosis [14]. There are also many
studies indicating that there are FMF patients who do not
carry MEFV gene mutations (10.0-20.0%) [15,16]. In the
present study, EPS patients were evaluated according to
both the Tel Hashomer criteria and genetic analysis for
the diagnosis of FMF. The FMF diagnosis has not been
established in EPS patients who do not carry MEFV gene
mutations.
The most commonly seen mutations in FMF patients
are M694V, M680I (G/C), E148Q, V726A, and frequency
of the mutations change according to ethnicity [17,18].
Erden et al. [19] reported that 68.6% of FMF patients had
at least one of the several mentioned mutations: M694V;
46.2%, E148Q; 16.4%, V726A; 13.4% and M680I; 5.9%.
In our study population, 43 EPS patients (57.3%) had
MEFV gene mutations and the carrier rate was 30.0%.
The most common mutation was R202Q (55.0%), followed
by E148Q (16.2%), R761H (16.2%), V726A (9.3%),
M680I (9.3%) and M694V (4.6%). While the frequency
of M694V, which is the most commonly observed MEFV
gene in Turks, was quite low, the frequencies of other
genes were approximately consistent with previous studies
[20,21]. The different frequency distribution of mutations
may be related to the small sample size, the geographical
region, genetic heterogeneities, patients’ inclusion criteria,
and the use of different genetic analytical techniques.
The R202Q was another common mutation in the
Turkish population. Some studies have also recently reported
that frequency of R202Q was higher than the frequency
of the M694V mutation in FMF patients [22,23]. In
a study by Yigit et al. [24] conducted on 191 FMF patients
and 150 control patients; the frequency of the R2O2Q
mutation was higher than that found for the M694V mutation.
The frequency of heterozygous R202Q was similar
between FMF patients and controls (59.7 vs. 44.7%; p
>0.05), while the frequency of homozygous R202Q mutations
was higher than that in the controls (14.7 vs. 0.0%; p
<0.05) [24]. Giaglis et al. [25] reported that homozygous
R202Q was detected in 14/152 (9.2%) FMF patients and
in 1/140 (0.7%) in a Greek study population. They also
reported that the heterozygous state of R202Q produced
no symptoms and only the homozygous and compound
heterozygous states were associated with the development
of symptoms [25]. In present study, the most common
MEFV gene mutation in EPS patients was R202Q. In our
geographic region, MEFV genetic analysis showed that
R202Q gene mutations in FMF patients and healthy controls
were not found.
However, contrary to the above data, Comak et al.
[26] found that some patients with a heterozygous R202Q
mutation had typical episodes of FMF. In addition, Cankaya
et al. [27] compared the clinical symptoms between
R202Q/– and non-R202Q/– in FMF patients. It was shown
that there were no differences in the frequencies of symptoms
and definitive diagnosis of FMF in either group. In
our study of 24 EPS patients with the R202Q gene mutation,
15 were heterozygotes, three were homozygotes,
two were compound heterozygotes, and four carried the
compound heterozygotes for three mutations [27]. We
did not find a homozygous R202Q in the control group,
which was in agreement with results from previous studies.
In our study, one patient with the heterozygous R202Q
mutation had arthralgia, fever, and a familial history of
FMF. While only one of the patients with the homozygous
R202Q mutation had FMF clinical findings, the remainder
were silent carriers. We also observed that there were no
clinical symptoms in either R202Q/– or non-R202Q/– in
EPS patients.
E148Q and V726A are other commonly observed
mutations in Turkish FMF patients. The carrier frequencies
of E148Q and V726A have been reported as 12.0
and 3.0-14.0%, respectively. The frequency of E148Q in
Turks is similar with other ethnicities [25,28,29], while
V726A is especially common in Arabs [30]. Ben-Chetrit
et al. [31] found a similar frequency of E148Q mutations
between patients and controls and suggested that E148Q
is a benign polymorphism. However, some authors accepted
that E148Q was a pathogenic mutation because of
substitution of the glutamine for glutamic acid at codon
148 in exon 2 [32]. Familial Mediterranean fever patients
with homozygous and compound heterozygous mutations have moderate/severe disease. In addition, several studies
reported that E148Q was also associated with vasculitis
(Henosch-Schonlein purpura, polyarteritis nodosa) and
rheumatic diseases [33]. In the present study, E148Q was
the second most common mutation with a frequency of
16.2%. While one patient who was a compound heterozygote
for three mutations (R202Q/E148Q/R408Q) had
FMF symptoms, five patients heterozygous for E148Q/–,
and one patient with a compound heterozygosity for two
mutations (L110P/E148Q) had no FMF symptoms.
V726A is associated with a mild form of the disease.
However, V726A homozygotes and compound heterozygotes
for the V726A/E148Q variants are associated with
severe disease, and patients can develop renal amyloidosis.
Hence, the authors proposed that patients carrying this
complex allele should have been given colchicine prophylaxis
[9,34]. In the present study, V726A is the third
most common mutation with a frequency of 9.3%. While
two patients who had compound heterozygosities for two
or three mutations (V726A/K695R and V726A/M694V/
R202Q), presented with FMF symptoms, one patient with
heterozygous V726A/– and one patient with a compound
heterozygosity for V726A/M680I, did not.
In this study, the rare MEFV gene mutations were also
identified as K695R (2.3%), L110P (2.3%) and G304R
(2.3%). Dogan et al. [35] reported that the frequency of
rare mutations were identified as L110P (0.2%) and K695R
(0.1%) in 731 participants. In another study, Gunesacar et
al. [36] found that the frequency of rare mutations were
as follows: K695R (0.20%), L110P (0.10%) and G304R
(0.05%). Moreover, they also detected the G304R mutation
for the first time in Turkey. To date, it has been detected
in a total of 33 patients carrying K695R in Turkey. It has
been reported in the literature that some patients carrying
K695R (compound heterozygotes) have severe FMF
sypmtoms [37]. L110P is a more common MEFV gene
mutation in Japan and is associated with a milder form
of the disease [38]. In the present study, two patients carrying
rare MEFV gene mutations were diagnosed with
FMF (K695R/V726A and G304R/–), and another patient
(L110P) was asymptomatic. We also detected a second
case carrying the G304R mutation in Turkey.
Familial Mediterranean fever can be divided into
three clinical phenotypes: type 1 or typical FMF phenotype
(attacks of abdominal pain, arthritis, fever); type 2 characterized
by the presence of amyloidosis in asymptomatic
subjects and (incidence of 7.0-25.0%); type 3 ‘silent type’
homozygous or compound heterozygous state and is estimated
to occur in 1:300 Ashkenazi and 1:25 Iraqi Jews.
In recent years, it has been observed that heterozygous
mutation carriers can suffer also from a mild or incomplete
form of FMF, named ‘FMF-like’ disease (a new phenotype)
[9]. In recent years, a new phenotype termed ‛FMF-like
disease,’ which is characterized as a mild or incomplete
form of FMF in patients with heterozygous mutations
has been defined. The reason why some carriers experience
FMF clinical symptoms, while others present with
only mild or no symptoms, is largely unknown, but it is
assumed that the MEFV gene mutations combined with
other potential modifier genes and environmental factors
determine the FMF phenotype [9,14].
Thus, we also speculated that the heterozygous state
of the MEFV gene may be associated with the atypical
inflammatory forms of FMF. Epigastric pain might be an
incomplete FMF attack, and physicians should keep this
in mind in high-risk populations.
Treatment for asymptomatic individuals with heterozygous
mutations is unknown. Guidelines recommend
that they should be followed with urine analyses [39].
Familial Mediterranean fever-like disease may initiate
periodic follow-up, and administering colchicine should
be considered. The patients with the ‘silent’ carrier status
of two mutations (homozygous or compound heterozygous)
could predispose to developing renal amyloidosis,
and particularly patients with a family history of FMF
should be administered colchicine prophylaxis [40]. In our
study, we started colchicine therapy for FMF patients and
patients who have an asymptomatic homozygous R202Q
mutation and family history of FMF for increased risk of
developing amyloidosis.
Conclusions. Our results demonstrated a high carrier
rate of MEFV gene mutations in the EPS patients.
The EPS patients showed only homozygous or compound
heterozygous MEFV gene mutations. Eight patients with
EPS were diagnosed with FMF and colchicine therapy was
started. Thus, therapy-resistant EPS patients should also be
examined for FMF, especially in high risk populations such
as the Turks. However, additional and larger studies are
needed to identify the association between EPS and FMF.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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