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Familial Mediterranean fever, Inflammation and Nephrotic Syndrome: Fibrillary Glomerulopathy and the M680I Missense Mutation

Patrick W Fisher*, L Tammy Ho, Robert Goldschmidt, Ronald J Semerdjian and Gregory W Rutecki

BMC Nephrology 2003, 4:6  doi:10.1186/1471-2369-4-6

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Response to COMMENT: MEFV mutations and renal pathology

Patrick Fisher   (2004-01-05 01:00)  Virginia Commonwealth University Medical Center, Richmond, VA USA email

I would like to thank Konstantopoulos, et al. for their interest in our paper and their respective comments. Furthermore, I would like to respond to the comments made by Konstantopoulos regarding our paper entitled:

Familial Mediterranean fever, Inflammation and Nephrotic Syndrome: Fibrillary Glomerulopathy and the M680I Missense Mutation [1].

A. The clinical diagnosis in our patient was made based on the highly recognized Tel-Hashomer criteria [2], which was the same criteria used by Tunca,et al. in the article which was referenced by Konstantopoulos [3]. Furthermore, no evidence was provided by Konstantopoulos to support the comment that "resistance to colchicine treatment ...can make [the] diagnosis [of] [FMF] doubtful". Again the reference which was cited [3], does not support their aforementioned statement.

B. Regarding the comment on the genetic analysis utilized in identifying the MEFV genotype in our patient:

Our paper clearly states that only nine mutations were tested for out of more than 40 mutations identified to-date. We obviously agree that this test, performed at the time by the UCLA Medical Center in Los Angeles, CA USA,"cannot exclude additional mutation(s) of the MEFV gene".

C. Regarding the comment that "detection of a single mutation in people of Armenian ancestry does not per se support FMF diagnosis strongly":

In our patient, only one out of nine mutations tested for was detected. However,the diagnosis of FMF in our patient is strongly supported by the Tel-Hashomer criteria [2], irrespective of the genotype. Futhermore, we cannot be certain that this patient has another missense mutation that has since been identified and which he was not originally tested for. [1]

References

1. Fisher PW, Ho LT, Goldschmidt R, Semerdjian RJ & Rutecki GW. Familial Mediterranean fever, Inflammation and Nephrotic Syndrome: Fibrillary Glomerulopathy and the M680I Missense Mutation. BMC Nephrol. 2003 Aug 11;4(1):6.

2. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M: Criteria for the diagnosis of familial Mediterranean fever.

Arthritis Rheum 1997, 40:1879-1885.

3. Tunca M, Tankurt E, Akbaylar Akpinar H, Akar S, Hizli N & Gonen O.The efficacy of interferon alpha on colchicine-resistant familial Mediterranean fever attacks: a pilot study. Br J Rheumatol. 1997, 36:1005-1008.

Competing interests

NONE

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MEFV mutations and renal pathology

Kostas Konstantopoulos   (2003-11-27 21:16)  Athens University Medical School, Athens-11527, Greece email

We like to comment on the work by Fisher et al on glomerulopathy complicating a case of clinical Familial Mediterranean Fever (FMF) carrying also a single MEFV mutation [1].

A. Although the clinical diagnosis of FMF sounds clear, the final resistance to colchicine treatment in the certain patient, observed in 25% of all true cases [2] can make diagnosis doubtful.

B. Mutation screening according to the method applied by the authors is limited to the few mutations tested for [3]. This method does not exclude additional mutation(s) of the MEFV gene.

C. The MEFV mutation frequency in Armenians may approximate 1:5; therefore, detection of a single mutation in people of Armenian ancestry does not per se support FMF diagnosis strongly.

D. We have in the past published two cases of the so-called phenotype II of FMF (renal amyloidosis as a presenting symptom in homozygotes). Interestingly, the one case carried M694V/V726A and the other carried the M680I/M694V mutations [4,5]. Although in our cases no indication for a glomerulopathy was evident, in the one of them, diagnosis was based on histochemical detection of amyloid A component only, the Congo red staining being negative and renal size being normal. Therefore, an un-detectable by light microscopy glomerular pathology cannot be excluded. On the other hand, one should not ignore that glomerulonephritis, parenchymous nephritis and lipoid nephrosis occur with an increased frequency in FMF and their inter-relation and relation with amyloidosis remains a classical dispute [6]

It seems that the biological effects of MEFV mutations as far as renal pathology is concerned needs further clarification in various categories of patients. This effect must also be considered in the context of the prevalence of these mutations in several populations.

Kostas Konstantopoulos (kkonstan@med.uoa.gr)

Alexandra Kanta

Department of Medicine I, Athens University Medical School, Athens-11527 Greece

References

1. Fisher PW, Ho LT, Goldschmidt R, Semerdjian RJ & Rutecki GW. Familial Mediterranean fever, Inflammation and Nephrotic Syndrome: Fibrillary Glomerulopathy and the M680I Missense Mutation. BMC Nephrol. 2003 Aug 11;4(1):6.

2. Tunca M, Tankurt E, Akbaylar Akpinar H, Akar S, Hizli N & Gonen O.The efficacy of interferon alpha on colchicine-resistant familial Mediterranean fever attacks: a pilot study. Br J Rheumatol. 1997, 36:1005-1008

3. Eisenberg S, Aksentijevich I, Deng Z, Kastner DL, Matzner Y. Diagnosis of familial Mediterranean fever by a molecular genetics method. Ann Intern Med. 1998, 129(7):539-542.

4. Konstantopoulos K, Michael S, Kanta A, Pecheux C, Grateau J, Helioti H & Stathakis C. Renal amyloidosis as a first manifestation of Familial Mediterranean Fever. Scand J Rheumatol. 2000, 29:129-130

5. Konstantopoulos K, Kanta A, Tzoulianos M, Dimou S, Sotsiou F, Politou M & Loukopoulos D. Familial Mediterranean fever phenotype II in Greece. Isr Med Assoc J. 2001, 3:862-863.

6. Heller H, Sohar E, Gafni J & Heller J. Amyloidosis in familial mediterranean fever. An independent genetically determined characteristic. Arch Intern Med 1961, 107: 539-590

Competing interests

None declared

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