The Spectrum of Familial Mediterranean Fever Gene Mutations in Arabs: Report of a Large Series

https://doi.org/10.1016/j.semarthrit.2005.01.010Get rights and content

Objectives

To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations in Arab patients.

Patients and methods

The study was performed in the pediatric FMF clinic of Jordan University Hospital over a period of 4 years. Patients were referred by their physicians for diagnosis, management, genetic study, and counseling. A diagnosis of FMF was made according to published criteria. Screening for 5 mutations, namely M694V, V726A, M694I, M680I, and E148Q, was performed by amplification refractory mutation system (ARMS) for the first 4 and by restriction endonuclease testing for E148Q.

Results

Of the 407 unrelated patients investigated, 239 (59%) had 1 or 2 mutations and 168 (41%) had none of the studied mutations detected. Of those with mutations, 92 were homozygous, 53 were compound heterozygotes, 3 had complex alleles, and 91 patients had only 1 identifiable mutation. Of the mutations, M694V, V726A, M694I, M680I, and E148Q accounted for 38, 26, 14, 10 and 13%, respectively. Twelve of our patients developed the protracted febrile myalgia syndrome (PFMS) of whom 5 (42%) were homozygous for M694V. Only 2 developed chronic renal failure, both of whom were homozygous for M694V and were not on colchicine prophylaxis. However, 43 patients had a family history of chronic renal failure, and 15 (35%) were homozygous for M694V.

Conclusions

Our data indicate that the 5 MEFV mutations are well distributed in Arabs. They also show that M694V is the most common mutation in Arab patients with FMF and seems to have an association with the development of amyloidosis and the PFMS. The high frequency of V726A, and the unique high frequency of M694I in Arabs compared with 3 other ethnic groups, are confirmed.

Section snippets

Patients and Methods

All patients were of Jordanian or Palestinian Arab origin and were referred by their physicians for diagnosis, management, genetic study, and counseling. The study was performed in the FMF clinic of Jordan University Hospital for 4 years (from September 1999 through August 2003). A clinical diagnosis of FMF was made according to published criteria. [Major criteria: attacks involving the abdomen, chest, joints, skin, and scrotum muscle and typical attacks of fever. Minor criteria: exertional

Results

Over the period of 4 years, 482 patients with a clinical diagnosis of FMF were referred to the FMF clinic of Jordan University Hospital, where they were tested for the 5 previously mentioned mutations. Of these, 407 unrelated index patients (probands) were entered in the study: 189 (46%) were male and 218 (54%) were female. The other 75 family members were excluded because of the nature of the study, addressing an unrelated group of index patients. A positive family history of FMF was present

Discussion

FMF is the prototype of a group of new disorders, known as hereditary periodic fever syndromes, as well as auto-inflammatory disorders (18). The other prominent members of this group are the hyper IgD and periodic fever syndrome (HIDS) (19, 20), the tumor necrosis factor receptor associated periodic fever syndrome (TRAPS) (21) (initially described as familial Hibernian fever (22, 23)), and the FMF-like syndrome with amyloidosis (24, 25).

The cloning of the MEFV proved to be of great help for

Acknowledgment

The authors are grateful to the families who participated in this study. Dr. H. El-Shanti is supported by “Chaire Internationale de Recherche, Blaise Pascal, de l’etat et de la Règion d’Ile-de-France,” which is managed with further support by the “Fondation de l’Ecole Normale Supèrieure.” Dr. M.S. El-Khateeb is supported by a grant from the University of Jordan.

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