Download Standard PDF - Wiley Online Library

Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 61, No. 10, October 15, 2009, pp 1447–1453
DOI 10.1002/art.24458
© 2009, American College of Rheumatology
REVIEW ARTICLE: EPIDEMIOLOGY OF THE RHEUMATIC DISEASES
Familial Mediterranean Fever in the World
ELDAD BEN-CHETRIT1
AND
ISABELLE TOUITOU2
Introduction
Prevalence of FMF in the world
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent episodes of fever
accompanied by peritonitis, pleuritis, arthritis, or erysipelas-like erythema (1,2). A typical FMF attack lasts approximately 3 days. The frequency of episodes varies from once
every week to several times a year. One of the devastating
complications of FMF is the development of serum amyloid A (SAA) amyloidosis, which mainly affects the kidneys but may involve other organs. Since 1972, colchicine
has been the treatment of choice for FMF (3). It controls the
acute attacks and prevents the development of amyloidosis.
The disease is prevalent among populations surrounding the Mediterranean Sea. However, in recent years, more
and more cases have been reported in countries not related
or close to this area, such as the US and Japan. This
observation raised the question as to the real prevalence of
FMF in countries other than those around the Mediterranean basin and to its clinical characteristics in these countries. Furthermore, it poses a challenge to find out the
ethnic origin of these patients and to study whether their
disease behaves similarly to that in the countries commonly associated with FMF. FMF may display a different
clinical picture among various populations, and these differences reflect the change in the repertoire of mutations
among the specific populations.
In this review, we will try to look for and explain the
origin of FMF in countries far from the Mediterranean and
Middle East regions. We will also compare the nature of
the disease in these countries and find out whether they
differ from the FMF manifestations, treatment, and prognosis in patients surrounding the Mediterranean Sea.
FMF is almost always restricted to Turks, Armenians, Arabs, and non-Ashkenazi Jews. It is quite a rare disease in
the rest of the world, although patients with FMF have
been reported in European countries such as France, Germany, Italy, and Spain, as well as in the US and Australia
(2,4). The exact frequency of FMF among the various populations is not always available because formal epidemiologic studies have not been done. Nevertheless, a rough
estimate regarding the prevalence of the disease can be
obtained by gathering details from different studies and
sources (Figure 1). Turkey is probably the country with the
highest number of FMF patients in the world. Since the
prevalence of FMF is approximately 1:400 to 1:1,000
(highest in the areas of Anatolia) and the population is
approximately 70 million, it is estimated that Turkey has
more than 100,000 patients with FMF (4 – 6). In Israel, the
prevalence is slightly more than 1:1,000 (depending on the
ethnic group), and since the population is approximately 7
million, it is estimated that there are approximately 10,000
patients (7). Armenia is probably the next country with
widespread FMF. It is estimated that the prevalence of
FMF is approximately 1:500 and with a population of 3
million, the total number of patients is approximately
6,000 (8). Other countries in the Middle East such as
Jordan, Syria, and Lebanon have many FMF patients, but
their exact number is not known (9,10).
In addition to the above countries, FMF is found in
significant numbers in North African countries, Greece,
Crete, France, Germany, Italy, and the US (11–14). In recent years, approximately 100 cases have been reported in
Japan (15, 16, and Tsuchiya-Suzuki A, et al: unpublished
observations). On the other hand, there are countries
where FMF has not been found or reported. These include
sub-Saharan African countries, Ethiopia, Yemen, and
Scandinavian states, as well as South Asian and Far Eastern countries such as India and Thailand.
The identification of the MEFV gene associated with
FMF and the prevalence of its mutations in the different
ethnic groups allowed some hypotheses on the phylogeny
of the disease (12).
Supported by the Canadian Friends of the Hebrew University.
1
Eldad Ben-Chetrit, MD: Familial Mediterranean Fever
Center, Hadassah-Hebrew University Medical Center,
Jerusalem, Israel; 2Isabelle Touitou, MD, PhD: Centre Hospitalier Universitaire de Montpellier, Unité Médicale des
Maladies Auto-Inflammatoires, Hôpital A de Villeneuve,
Montpellier, France.
Address correspondence to Eldad Ben-Chetrit, MD, Rheumatology Unit, Hadassah-Hebrew University Hospital, PO
Box 12000, Jerusalem 91120, Israel. E-mail: eldad@hadassah.
org.il.
Submitted for publication November 11, 2008; accepted in
revised form January 30, 2009.
Distribution of MEFV mutations in FMF patients
around the world
The 4 main mutations found in the studies that identified
the MEFV gene responsible for FMF were p.M680I,
1447
1448
Figure 1. World map showing the countries where familial Mediterranean fever (FMF) is relatively common. Circle size is proportional to the size of the FMF community in that country.
Arrows show the possible ways of spreading the disease. Red
arrows show the migration of the MEFV mutations in the ancient
world. The yellow arrow corresponds to the Silk Road, while
black arrows denote the migration of the disease in the new
world.
p.M694V, p.M694I, and p.V726A on exon 10 (17,18). Subsequently, the p.E148Q sequence alteration was identified
on exon 2 (19). These were found to be the most common
mutations among the populations of the countries where
FMF is prevalent. Several studies have pointed out that
these 5 mutations are responsible for more than 85% of
FMF patients in the Middle Eastern area (1).
Many other sequence alterations (more than 180) have
already been recorded in Infevers, an online database for
autoinflammatory mutations (online at http://fmf.igh.
cnrs.fr/ISSAID/infevers). However, most of them are relatively rare and do not have a clinical phenotype, and many
are found exclusively in populations where FMF is uncommon (20). For example, sequence alterations p.H478Y
and p.E163A are mainly found among Spanish patients
(21).
When the repertoire of mutations was analyzed in different populations (Table 1), an interesting picture was
drawn that could shed some light on the possible ways
these mutations spread. In Israel, Jews of Middle Eastern
origin (e.g., Iraq, Syria) carry many kinds of mutations
Table 1. Most frequent mutations according to various
ethnic groups and countries
Israel
North African Jews: p.M694V, p.E148Q
Iraqi Jews: p.V726A, p.M694V, p.E148Q, p.M680I
Ashkenazi Jews: p.E148Q, p.V726A
Middle East
Arabs: p.V726A, p.M680I, p.M694V, p.M694I, p.E148Q
Turkey
Turks: p.M694V, p.M680I, p.V726A, p.E148Q
Armenia
Armenians: p.M694V, p.M680I, p.V726A, p.E148Q
Japan
Japanese: p.M694I, p.[L110P; E148Q], p.R761H, p.E84
Ben-Chetrit and Touitou
similar to those in Arabs, Armenians, and Turks. However,
Jews of North African origin have only the mutations
p.M694V and p.E148Q, whereas Ashkenazi Jews carry
only the mutations p.E148Q and p.V726A. It seems that
these 3 mutations are very ancient and appeared in the
Middle East (Mesopotamia) more than 2,500 years ago
(22). Mutation p.M694V migrated to Spain and North Africa either in the early days via sailors (Phoenicians) who
crossed the Mediterranean Sea from the Middle East or
later (in the 8th century) via land migration westward
during the Muslim conquest of North Africa and Spain
(Figure 1). Mutation p.V726A migrated to Europe either by
sea or by land (1). In both cases, these reflect the consequences of the immigration of a few families carrying these
mutations and spreading them in their new location, leading to a founder effect. An interesting observation among
the “Chuetas” community in Palma de Mallorca can further support this hypothesis (21,23,24). The “Chuetas” are
descendants of converted Jews who were expelled from
Spain to Palma de Mallorca in the 11th century. They
comprise approximately 18 families in whom more than
60 FMF patients have been diagnosed. An analysis of their
FMF clinical manifestations and their haplotypes disclosed great similarity to FMF in North African Jews, who
are descendants of those expelled from Spain in the 16th
century. This suggests that the founder of both of these
populations lived in Spain, probably arriving with the Muslims who came from the Middle East in the 8th century.
Because Armenia has a direct land connection with
Turkey, it is most likely that neighboring interactions
brought FMF from Asia Minor to Armenia. A less plausible
explanation, although a more interesting one, would be the
migration of Jews from the Middle East to the Caspian Sea
in the 8th century to the kingdom of the Khazars, who
converted to Judaism. This interaction could have also
brought FMF to this area of Caucasia.
Most FMF patients in France are of North African origin,
and most of those who live in Germany are of Turkish
origin. Most FMF patients in Italy are located in the central
and southern parts of the peninsula. Their origin is probably composed of Greeks, Turks, and Phoenicians who
came by way of the sea (14). FMF migrated from the
Middle East (to Europe) in ancient times and reached the
“new world” (the US) in modern times. In the US, there are
FMF patients in communities originating from Armenia
(mainly in California) and from North African and Middle
Eastern countries (on the east coast). In South America,
most FMF patients are immigrants from the Middle East
and North Africa, although it has also been proposed that
Spanish ancestors brought the disease when Spain conquered this continent.
A recent case report described a Gypsy woman with
FMF in Hungary (25). Since the origin of the Gypsies is in
India, where the disease has not been reported, it is assumed that intermarriage with local Balkan or Turkish
citizens is responsible for this unexpected finding.
An interesting question is raised regarding the presence
of FMF in Japan. The possibility that the Silk Road was
also the route for spreading FMF, as is the case with
Behçet’s disease (BD), is quite plausible. Supporting this
FMF in the World
1449
Table 2. MEFV mutations associated at least once with
typical presentation of familial Mediterranean fever*
Exon 1
Exon 2
Exon 3
Exon 5
Exon 9
Exon 10
A89T
G111G
E125E
R143P
E148Q
R151S
E167D
T177I
S179I
G219G
E225D
S242R
T267I
A268V
P283L
A289V
T309M
R354W
V469L
H478Y
F479L
I506V
I591T
D661N
M680L
M680IGA
T681I
Y688X
I692DEL
M694V
M694L
M694DEL
M694I
K695R
V726A
F743L
A744S
R761H
* Note the numerous mutations, especially in exons 2 and 10
(adapted from Infevers). Only the usual names are shown.
view are the studies claiming that FMF is more prevalent
among patients with BD than in the control populations,
and that patients with BD carry MEFV mutations more
than controls (26,27). However, such a possibility would
predict a larger repertoire of mutations in Japan (similar to
that found among Turkish and Armenian patients). Furthermore, one would expect to find more FMF cases in
Japan resembling the high prevalence of BD. The fact that
the number of mutations in Japan is relatively restricted,
consisting mainly of p.M694I, p.E148Q, and p.[E148Q;
L110P] in cis, calls for the possibility of a founder effect.
Indeed, the presence of this complex allele was reported
for the first time in Turkish families where the p.M694I
mutation is also prevalent, further supporting the notion of
Turkish origin through the Silk Road (20). However, the
possibility of de novo appearance of the mutations cannot
be ruled out. This is supported by the fact that these
mutations are on exons 2 and 10, which contain a large
area of hot spots for sequence alterations (Table 2).
Clinical manifestations of FMF in various
populations
The typical manifestations of FMF include fever, peritonitis, pleuritis, arthritis, and erysipelas-like erythema. In
different individuals, the disease may present differently
or may change its course over the patient’s lifetime. Similarly, different manifestations of FMF have been observed
among populations of various ethnic origins. Comparison
of different populations showed that fever and peritonitis
were present in more than 90% of the patients (Table 3). In
the group of patients from Crete, the rates of these manifestations were somehow lower and no explanation was
offered (12). In most populations, joint involvement is the
next common symptom of FMF. However, in Armenians
and Japanese, pleuritis is more prevalent than arthritis.
The prevalence of skin rash (erysipelas-like erythema) is
much lower in all of the FMF populations studied (Table
3). Joint involvement (arthritis) was much more common
among non-Ashkenazi Jews than in Turks, Arabs, Armenians, or Japanese. The question is: what are the reasons
for these differences?
Following the isolation of the MEFV gene and mutations, numerous studies tested the genotype–phenotype
correlations in FMF patients in different countries. When
FMF was first discovered, it was shown that homozygosity
for p.M694V was associated with more severe disease,
including early onset, more frequent attacks, significantly
more joint disease, a higher dose of colchicine needed to
control attacks, and a higher rate of amyloidosis among
patients not adequately treated (28). These results were
confirmed in further studies performed in Israel, France
(with Armenian patients), and in Middle Eastern countries
(Jordan and Lebanon) (22–24). However, some studies
from Turkey were not in agreement with these results, but
many recent studies from this country do show similar
results (5,29 –31).
The various manifestations of FMF in different populations reflect the change in repertoire of mutations in the
specific populations. Usually, p.V726A causes a relatively
mild disease. When mutations are on exon 2 (such as
p.E148Q), the disease is milder with less arthritis and
there may be more pleuritis and almost no amyloidosis.
The p.E148Q mutation leads to FMF expression almost
exclusively when associated with other mutations. Fifty
percent of homozygotes for E148Q are asymptomatic, suggesting that this sequence variant is expressed only under
certain circumstances, genetic backgrounds, or environmental factors (32).
Patients carrying p.M694V, p.M694I, or p.M680I mutations are prone to have a more severe disease, more joint
Table 3. Main familial Mediterranean fever manifestations in various countries and
populations
No. of patients
Fever, %
Peritonitis, %
Pleuritis, %
Arthritis, %
Skin rash, %
References
Armenia
Turkey
Israel
Arabs
Italy
Crete
Japan
335
94
91
84
39
15
33,52,53
2,838
92
93
31
47
21
5
576
100
96
43
70
40
54,55
175
100
93
32
33
3
56
71
92
91
52
63
22
14
71
80
76
21
38
11
12
80
98
55
61
27
10
57
1450
involvement, and a greater chance of developing amyloidosis. If their prevalence is high in the studied population,
the overall clinical expression would be of a more severe
disease. If in a given population the frequency of the
p.M694V or p.M694I mutations is low, the disease would
on average run a milder course.
Thirty years ago it was observed that FMF patients of
North African origin in Israel had a much more severe
disease than those of Iraqi and Syrian origin (33). Following the isolation of the MEFV gene, a genetic analysis
revealed that the patients whose origins were in North
Africa mainly carried the p.M694V mutation, explaining
why they have a more severe disease, whereas Iraqi Jews
carried relatively more of the p.V726A and p.E148Q mutations.
Are there additional factors that may play a role in the
disease manifestations and complications? It seems quite
obvious that environmental factors may have an influence
on the disease. A typical example is the case of amyloidosis. Many years ago, it was shown that in Armenian FMF
patients living in Armenia, the prevalence of amyloidosis
was higher than in Armenian FMF patients living in the
US (34). Recently, similar results were reported in Turkish
patients. In FMF patients living in Turkey, the disease
score was much higher than that in Turkish FMF patients
living in Germany (35). The proposed explanation was the
lack of colchicine availability for treating FMF in Turkey
and Armenia compared with Germany and the US, respectively. This view is supported by the worldwide study of
2,482 FMF patients, in whom 260 developed amyloidosis
(36). It was found that the country of recruitment rather
than the MEFV genotype was the key risk for renal amyloidosis. This risk, which paralleled infant mortality rates,
indicates a possible environmental origin (availability of
health systems) for amyloidosis susceptibility.
In addition to the typical manifestations of FMF, some
less frequent presentations should also be mentioned. Protracted febrile myalgia is a rare form of vasculitic disease
that affects patients with FMF. Mutation analysis disclosed a high association with M694V homozygosity and
more severe disease. This syndrome may last 10 –14 days
and may require steroids in addition to colchicine treatment (37). A few FMF patients experience severe attacks of
FMF during their menstrual period (38). Estrogen can inhibit tubulin assembly using a binding site analogous to
colchicine sites. This effect may add to the colchicine
action in preventing FMF attacks. In menstruation, estrogen levels are sharply decreased and their protective effect
disappears, leading to the acute attack. The central nervous system and the meninges are spared in FMF. However, Mollaret meningitis was reported as part of FMF,
although in many cases the causative agent was identified
as herpesvirus 6 (39).
Diagnosis of FMF
The diagnosis of FMF in countries where the disease is
common is principally based on clinical grounds. Typical
periodic attacks of fever and serositis lasting 1– 4 days in a
patient from the appropriate ethnic origin confirm the
Ben-Chetrit and Touitou
diagnosis of FMF. Family history of FMF and a good
response to colchicine further support this diagnosis.
Blood levels of fibrinogen, SAA, and C-reactive protein
are nonspecific and do not contribute to the initial diagnosis of FMF. However, they may be of value in monitoring the course of the disease and the response of the
patient to treatment (40,41).
In cases where the patient does not present typical manifestations of FMF and the above components do not exist,
a genetic diagnosis is warranted. In countries where FMF
is widespread, the genetic test is contributory under 2
conditions: when the patient carries 2 mutations and
therefore certainly has FMF, or if the patient does not carry
any mutation and thus probably does not have FMF (in
almost all cases). However, because in populations with a
high prevalence of FMF the carrier rate is high as well, the
detection of a single mutation (heterozygosity) does not
help in making the diagnosis. In such cases, there is a
major role for a therapeutic trial where an FMF patient is
expected to respond to colchicine, whereas nonresponders
deserve further evaluation. Our practice in patients carrying a single mutation and who respond to colchicine is to
discontinue the medication. If the patient develops an
FMF attack within a few days following cessation of the
drug, this is an additional clue supporting the diagnosis of
FMF. This approach for making a diagnosis is also used in
patients highly suspected of having FMF but in whom no
mutation (among those tested in the particular laboratory)
could be detected.
In countries where FMF is rare, the mutations involved
in the disease may lead to a milder disease or to an atypical
presentation. Furthermore, a family history for the disease
would probably be negative. Therefore, a clinical diagnosis of FMF may be too difficult and the role of genetic
testing is much more crucial. In these populations, looking
for the 5 most common mutations for FMF (in Middle
Eastern countries) may not be sufficient and many potential FMF patients may be misdiagnosed.
Treatment of FMF
Since the report by Goldfinger in 1972, colchicine remains
the treatment of choice for FMF all over the world (3).
Colchicine can be given to children with the disease even
before the age of 1 year. It was shown that children
younger than 5 years of age might need colchicine dosages
ranging from 0.03 to 0.07 mg/kg/day (42). Children weighing more than 10 kg can take 1 mg of colchicine daily. In
most adults, 1 mg is the optimal dose for controlling the
disease and preventing amyloidosis. However, in the more
severe disease, the dosage can be increased to 2.5 mg daily
provided that the liver and kidney functions of the patient
are normal. Interestingly, many adult FMF patients in
Japan are asymptomatic even with a single tablet of colchicine (0.5 mg) daily. This may reflect their relatively
mild disease. In patients who cannot tolerate colchicine
due to its causing diarrhea, it is recommended that the
daily dose should be divided and taken 2 or 3 times in the
course of a day. In addition, there is the possibility of
taking medications such as tincture belladonna or tincture
FMF in the World
opii to counteract the tendency for diarrhea. As a matter of
fact, in France there is a formula called Colchimax that
contains 1 mg colchicine and 12.5 mg opium powder.
Colchicine is a relatively safe medication. It can be given
to FMF patients during pregnancy, and in contrast to our
previous policy, we no longer recommend amniocentesis
(Ben-Chetrit Eli, et al: unpublished observations). We also
recommend continuing colchicine while nursing, since
the dose to which the newborn or infant is exposed is very
low (43). Colchicine does not inhibit a child’s growth. On
the contrary, following treatment with colchicine and controlling the FMF attacks the children have a growth spurt
(44). In countries where FMF is common, there is a higher
incidence of severe disease as well as treatment-resistant
disease (45). In cases resistant to colchicine, several therapeutic options have been suggested over the years,
including thalidomide, interferon, anti–tumor necrosis
factor (anti-TNF) agents, and anakinra (46 – 48). When
thalidomide was tried in FMF patients nonresponsive to
colchicine, it showed good efficacy but the side effects
were almost intolerable. Studies evaluating the effect of
interferon injection in FMF were inconclusive because
some studies claimed that it is effective, whereas others
did not. The experience with anti-TNF agents and anakinra is very limited and comprises only a few case reports
(46 – 48). All of the treatment modalities other than colchicine have not been tested for their effect in preventing
amyloidosis. Nevertheless, some of them showed a beneficial effect in treating already established secondary amyloidosis developed in patients with chronic inflammatory
diseases such as rheumatoid arthritis (49,50). In some FMF
patients in Japan, treatment with prazosin, reserpine,
azelastine, and herbal medicines have also been reported
(51).
Prognosis of FMF
FMF prognosis primarily depends on the development of
amyloidosis. The development of amyloidosis is closely
related to the genotype of the patients and their treatment
with colchicine. If they have mutations associated with
mild disease, they will probably not develop amyloidosis
and will respond to colchicine.
However, as already mentioned, there are other genetic
modifiers such as sex and SAA polymorphisms and environmental factors that may affect the prognosis (amyloidosis), which should also be taken into account (35). Finally, it should be emphasized that the severity of FMF
attacks and their frequency usually decrease as the patient
gets older.
Summary
The above overview shows that FMF is not restricted to
Mediterranean countries, and the lack of diagnosis in other
areas of the world is probably due to a lack of awareness of
this fascinating disease. Based on the carrier states of
MEFV mutations, FMF is expected to be found in many
other countries and it may well be that such patients have
either mild disease according to the kind of mutations they
carry or the environmental factors, or that they were mis-
1451
takenly diagnosed as having another disease such as BD,
systemic lupus erythematosus, palindromic rheumatism,
or rheumatic fever, diseases whose clinical features resemble FMF.
We hope that the present review will raise the awareness
of physicians regarding this disease so that patients can
obtain the correct diagnosis and receive the appropriate
treatment.
AUTHOR CONTRIBUTIONS
All authors were involved in contributions to study conception
and design, acquisition of data, or analysis and interpretation of
data, and drafting the article or revising it critically for important
intellectual content, and all authors approved the final version to
be submitted for publication. Dr. Ben-Chetrit had full access to all
of the data in the study and takes responsibility for the integrity of
the data and the accuracy of the data analysis.
REFERENCES
1. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet
1998;351:659 – 64.
2. Eliakim M, Levy M, Ehrenfeld M. Recurrent polyserositis
(familial Mediterranean fever, periodic disease). New York:
Elsevier North-Holland; 1981. p. 5–14.
3. Goldfinger SE. Colchicine for familial Mediterranean fever
[letter]. N Engl J Med 1972;287:1302.
4. Touitou I. The spectrum of familial Mediterranean fever
(FMF) mutations. Eur J Hum Genet 2001;9:473– 83.
5. Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, et al, for the Turkish FMF Study Group. Familial
Mediterranean fever (FMF) in Turkey: results of a nationwide
multicenter study. Medicine (Baltimore) 2005;84:1–11.
6. Cobankara V, Fidan G, Turk T, Zencir M, Colakoglu M, Ozen
S. The prevalence of familial Mediterranean fever in the Turkish province of Denizli: a field study with a zero patient
design. Clin Exp Rheumatol 2004;22 Suppl 34:S27–30.
7. Daniels M, Shohat T, Brenner-Ullman A, Shohat M. Familial
Mediterranean fever: high gene frequency among the nonAshkenazic and Ashkenazic Jewish populations in Israel.
Am J Med Genet 2005;55:311– 4.
8. Sarkisian T, Ajrapetian H, Beglarian A, Shahsuvarian G, Egiazarian A. Familial Mediterranean fever in Armenian population. Georgian Med News 2008;156:105–11.
9. Medlej-Hashim M, Serre JL, Corbani S, Saab O, Jalkh N,
Delague V, et al. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of
three novel mutations. Eur J Med Genet 2005;48:412–20.
10. Mattit H, Joma M, Al-Cheikh S, El-Khateeb M, Medlej-Hashim
M, Salem N, 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– 6.
11. Belmahi L, Sefiani A, Fouveau C, Feingold J, Delpech M,
Grateau G, et al. Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from
familial Mediterranean fever. C R Biol 2006;329:71– 4.
12. Fragouli E, Eliopoulos E, Petraki E, Sidiropoulos P, Aksentijevich I, Galanakis E, et al. Familial Mediterranean fever in
Crete: a genetic and structural biological approach in a population of ‘intermediate risk.’ Clin Genet 2008;73:152–9.
13. Giaglis S, Papadopoulos V, Kambas K, Doumas M, Tsironidou
V, Rafail S, et al. MEFV alterations and population genetics
analysis in a large cohort of Greek patients with familial
Mediterranean fever. Clin Genet 2007;71:458 – 67.
14. La Regina M, Nucera G, Diaco M, Procopio A, Gasbarrini G,
Notarnicola C, et al. Familial Mediterranean fever is no longer
a rare disease in Italy. Eur J Hum Genet 2003;11:50 – 6.
15. Tomiyama N, Higashiuesato Y, Oda T, Baba E, Harada M,
1452
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
Azuma M, et al. MEFV mutation analysis of familial Mediterranean fever in Japan. Clin Exp Rheumatol 2008;26:3–7.
Sugiura T, Kawaguchi Y, Fujikawa S, Hirano Y, Igarashi T,
Kawamoto M, et al. Familial Mediterranean fever in three
Japanese patients, and a comparison of the frequency of
MEFV gene mutations in Japanese and Mediterranean populations. Mod Rheumatol 2008;18:1857–9.
French Familial Mediterranean Fever Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;
17:25–31.
The International Familial Mediterranean Fever Consortium.
Ancient missense mutations in a new member of the RoRet
gene family are likely to cause familial Mediterranean fever.
Cell 1997;90:797– 807.
Bernot A, da Silva C, Petit JL, Cruaud C, Caloustian C, Castet
V, et al. Non-founder mutations in the MEFV gene establish
this gene as the cause of familial Mediterranean fever (FMF).
Hum Mol Genet 1998;7:1317–25.
Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H,
Aksentijevich I, et al. The Infevers autoinflammatory mutation online registry: update with new genes and functions.
Hum Mutat 2008;29:803– 8.
Aldea A, Calafell F, Arostegui JI, Lao O, Rius J, Plaza S, et al.
The west side story: MEFV haplotype in Spanish FMF patients and controls, and evidence of high LD and a recombination “hot-spot” at the MEFV locus. Hum Mutat 2004;23:
399.
Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E,
Chae JJ, et al. Mutation and haplotype studies of familial
Mediterranean fever reveal new ancestral relationships and
evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet
1999;64:949 – 62.
Buades J, Ben-Chetrit E, Levy M. Familial Mediterranean fever in the “Chuetas” of Mallorca: origin in inquisition? Isr
J Med Sci 1995;31:497–9.
Domingo C, Touitou I, Bayou A, Ozen S, Notarnicola C, Dewalle M, et al. Familial Mediterranean fever in the ‘Chuetas’
of Mallorca: a question of Jewish origin or genetic heterogeneity. Eur J Hum Genet 2000;8:242– 6.
Kovacs G, Tarjan E, Magyar P, Nagy E, Muzes G, Ben-Chetrit
E. Identification of familial Mediterranean fever (FMF) in a
Gypsy woman: a case report. Clin Exp Rheumatol 2007;25(4
Suppl 45):S119.
Livneh A, Aksentijevich I, Langevitz P, Torosyan Y, G-Shoham N, Shinar Y, et al. A single mutated MEFV allele in
Israeli patients suffering from familial Mediterranean fever
and Behçet’s disease (FMF-BD). Eur J Hum Genet 2001;9:
191– 6.
Touitou I, Magne X, Molinari N, Navarro A, Quellec AL, Picco
P, et al. MEFV mutations in Behçet’s disease. Hum Mutat
2000;16:271–2.
Dewalle M, Domingo C, Rozenbaum M, Ben-Chetrit E, Cattan
D, Bernot A, et al. Phenotype-genotype correlation in Jewish
patients suffering from familial Mediterranean fever (FMF).
Eur J Hum Genet 1998;6:95–7.
Yalcinkaya F, Cakar N, Misirlioglu M, Tumer N, Akar N,
Tekin M, et al. Genotype-phenotype correlation in a large
group of Turkish patients with familial Mediterranean fever:
evidence for mutation-independent amyloidosis. Rheumatology (Oxford) 2000;39:67–72.
Olgun A, Akman S, Kurt I, Tuzun A, Kutluay T. MEFV mutations in familial Mediterranean fever: association of M694V
homozygosity with arthritis. Rheumatol Int 2005;25:255–9.
Dusunsel R, Dursun I, Gunduz Z, Poyrazoglu MH, Gurgoze
MK, Dundar M. Genotype-phenotype correlation in children
with familial Mediterranean fever in a Turkish population.
Pediatr Int 2008;50:208 –12.
Hershko AY, Ben-Chetrit E. The MEFV E148Q allele: a deleterious mutation or harmless variation? Clin Exp Rheumatol
2006;24(5 Suppl 42):S51–2.
Pras M, Bronshpigel N, Zemer D, Gafni J. Variable incidence
Ben-Chetrit and Touitou
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
of amyloidosis in familial Mediterranean fever among different ethnic groups. Johns Hopkins Med J 1982;150:22– 6.
Schwabe AD, Peters RS. Familial Mediterranean fever in
Armenians: analysis of 100 cases. Medicine (Baltimore) 1974;
53:453– 62.
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 – 8.
Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh
A, Cattan D, et al, for the International Study Group for
Phenotype–Genotype Correlation in Familial Mediterranean
Fever. Country as the primary risk factor for renal amyloidosis
in familial Mediterranean fever. Arthritis Rheum 2007;56:
1706 –12.
Sidi G, Shinar Y, Livneh A, Langevitz P, Pras M, Pras E.
Protracted febrile myalgia of familial Mediterranean fever:
mutation analysis and clinical correlations. Scand J Rheumatol 2000;29:174 – 6.
Ben-Chetrit E, Ben-Chetrit A. Familial Mediterranean fever
and menstruation. BJOG 2001;108:403–7.
Pearce JM. Mollaret’s meningitis. Eur Neurol 2008;60:316 –7.
Yalcinkaya F, Cakar N, Acar B, Tutar E, Guriz H, Elhan AH, et
al. The value of the levels of acute phase reactants for the
prediction of familial Mediterranean fever associated
amyloidosis: a case control study. Rheumatol Int 2007;27:
517–22.
Berkun Y, Padeh S, Reichman B, Zaks N, Rabinovich E, Lidar
M, et al. A single testing of serum amyloid A levels as a tool
for diagnosis and treatment dilemmas in familial Mediterranean fever. Semin Arthritis Rheum 2007;37:182– 8.
Kallinich T, Haffner D, Niehues T, Huss K, Lainka E, Neudorf
U, et al. Colchicine use in children and adolescents with
familial Mediterranean fever: literature review and consensus
statement. Pediatrics 2007;119:474 – 83.
Ben-Chetrit E, Scherrmann JM, Levy M. Colchicine in breast
milk of patients with familial Mediterranean fever. Arthritis
Rheum 1996;39:1213–7.
Savgan-Gurol E, Kasapcopur O, Hatemi S, Ercan O, Caliskan
S, Sever L, et al. Growth and IGF-1 levels of children with
familial Mediterranean fever on colchicine treatment. Clin
Exp Rheumatol 2001;19 Suppl 24:S72–5.
Ben-Chetrit E, Ozdogan H. Non-response to colchicine: definition, causes and suggested solutions. Clin Exp Rheumatol
2008;26 Suppl 50:S49 –51.
Seyahi E, Ozdogan H, Celik S, Ugurlu S, Yazici H. Treatment
options in colchicine resistant familial Mediterranean fever
patients: thalidomide and etanercept as adjunctive agents.
Clin Exp Rheumatol 2006;24 Suppl 42:S99 –103.
Roldan R, Ruiz AM, Miranda MD, Collantes E. Anakinra: new
therapeutic approach in children with familial Mediterranean
fever resistant to colchicine. Joint Bone Spine 2008;75:504 –5.
Calligaris L, Marchetti F, Tommasini A, Ventura A. The efficacy of anakinra in an adolescent with colchicine-resistant
familial Mediterranean fever. Eur J Pediatr 2008;167:695– 6.
Ortiz-Santamaria V, Valls-Roc M, Sanmarti M, Olive A. AntiTNF treatment in secondary amyloidosis [letter]. Rheumatology (Oxford) 2003;42:1425– 6.
Fernandez-Nebro A, Urena I, Irigoyen MV, Garcia-Vicuna R.
Anti-TNF-␣ for treatment of amyloidosis associated with
Crohn’s disease [letter]. Gut 2006;55:1666 –7.
Nakamura A, Yazaki M, Tokuda T, Hattori T, Ikeda S. A
Japanese patient with familial Mediterranean fever associated
with compound heterozygosity for pyrin variant E148Q/
M694I. Intern Med 2005;44:177– 8.
Oganesian LA, Farmanian AK, Avetisian VA. On the problem
of the so-called periodic disease. Klin Med (Mosk) 1969;43:
19 –23. In Russian.
Armenian HK, Khachadurian AK. Familial paroxysmal
polyserositis: clinical and laboratory findings of 120 cases.
J Med Liban 1973;26:605–14.
Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean
FMF in the World
fever: a survey of 470 cases and review of the literature. Am J
Med 1967;43:227–53.
55. Eliakim M, Rachmilewitz M, Rosenmann E, Niv A. Renal
manifestations in recurrent polyserositis (familial Mediterranean fever). Isr J Med Sci 1970;6:228 – 45.
56. Barakat MH, Karnik AM, Majeed HW, El Sobki NI, Fenech FF.
1453
Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs: a study of 175 patients and review of the
literature. Q J Med 1986;60:837– 47.
57. Tsuchiya-Suzuki A, Yazaki M, Nakamura A, Yamazaki K,
Agematsu K, Matsuda M, et al. Clinical and genetic features of
familial Mediterranean fever in Japan. J Rheumatol. In press.