PEDIATRICS Vol. 108 No. 1 July 2001, pp. 215

E148Q of the MEFV Gene Causes Amyloidosis in Familial Mediterranean Fever Patients

To the Editor.

We read the article entitled "Familial Mediterranean Fever: Effects of Genotype and Ethnicity on Inflammatory Attacks and Amyloidosis" by Mimouni et al with great interest.¹ They have reported the distribution of MEFV mutations causing amyloidosis. They analyzed 382 familial Mediterranean fever (FMF) patients from 4 ethnic groups including the Turks. In their series, they could not find a case of amyloidosis in 16 patients carrying the common mutation E148Q of the MEFV gene.¹ They mentioned a previously reported patient who was a compound heterozygote M694V/E148Q, suggesting that amyloidosis may develop rarely only when E148Q is combined with M694V. They concluded that continuing treatment seemed to be less indicated in the case of those patients where one or both mutations are E148Q.¹

Such a firm conclusion seems quite dangerous and should be discussed in the light of the previous reports.

We previously reported the distribution of the mutations in the carrier chromosomes of FMF-amyloidosis patients.^2-4 We have now completed the analysis of MEFV mutation analysis in 44 Turkish FMF-amyloid patients. Of these, 7 patients carried E148Q together with V726A and M694V in 2 patients each; and in 3 patients with M680I. Moreover, in 1 of these cases, we have reported E148Q that accompanies M680I/V726A.³ In light of this finding, we have screened all the amyloid patients for the E148Q mutation. The frequency of E148Q mutation in FMF-amyloidosis patients was found to be 0.79. None of the healthy controls without any family history of FMF (n = 46) had E148Q.

Furthermore, we have completed the analysis of 319 FMF patients, and the frequency of M694V mutation was found to be 39.6%.⁴ Our present data revealed that the frequency of M694V mutation in FMF-amyloidosis patients as 35.2%. The difference was not significant (P = .6).

In conclusion, E148Q seems to be a disease-causing mutation and colchicine treatment should be given to every patient with clinical symptoms of familial Mediterranean fever irrespective of the mutation type.

Nejat Akar, MD
E. Akar
F. Yalçinkaya
Pediatric Molecular Genetics and Nephrology Departments
Ankara University
Konutkent-2, Mudanya Sokak C-1 Blok B Giris Daire 2
06530 Cayyolu Ankara, Turkey

REFERENCES

1. Mimouni A, Magal N, Stoffman N, et al. Familial Mediterranean fever: effects of genotype and ethnicity on inflammatory attacks and amyloidosis. Pediatrics. 2000;105(5). URL: http://www.pediatrics.org/cgi/content/full/105/5/e70
2. Yalçinkaya F, Akar N, Misirlioglu M Familial Mediterranean feveramyloidosis and the Val726Ala mutation. N Engl J Med. 1998; 338:993-994 [Free Full Text]
3. Akar N, Yalçinkaya F, Akar E, Çakar N MEFV Mutation analysis in Turkish FMF patients with amyloidosis. Amyloid. 1999; 6:301-302 [Medline]
4. Akar N, Misirliolu M, Yalçinkaya F, MEFV mutations in Turkish patients suffering from familial mediterranean fever. Hum Mutation. 2000; 15:118-119

In Reply.

Thank you for forwarding to us the letter from Dr Akar et al in response to our recent article in Pediatrics.¹

In our article, we noted that the need for continuous (not continuing) treatment with colchicine seems to be less indicated in patients where 1 or both mutations are E148Q. By "continuous" we mean "lifelong." This was not a "firm conclusion," however, and we went on to recommend that this group should be followed closely in the clinic and tested every 6 months for the presence of proteinuria, and those who develop severe inflammatory episodes and/or proteinuria caused by amyloidosis should be treated as well.

As we reported in our article,¹ we found no cases of amyloidosis among 16 patients who carried the mutation E148Q. In this group, no E148Q homozygotes were found, but there were patients with E148Q/M694V and E148Q/V726A.

In addition, in another survey,² out of a total of 800 individuals in the healthy population group used for the carrier screening study, we found 53 alleles carrying the E148Q mutation, 29 alleles carrying the M694V mutation, 16 alleles carrying the V726 mutation, and only 2 alleles carrying the M680I mutation. Of these 800 normal healthy individuals, 6 were found to be either homozygotes (2 individuals) or compound heterozygotes (4 individuals) for mutation E148Q. The 4 compound heterozygotes comprised 3 with E148Q/M694V and 1 with E148Q/V726A. None of the 6 had any clinical symptoms of familial Mediterranean fever (FMF) attacks or amyloidosis.

Furthermore, based on these carrier frequencies,² we have calculated that in Israel there are approximately 52 000 individuals who carry the mutation E148Q, either as homozygotes or compound heterozygotes for this and another mutation. Of these, approximately 25 000 (48%) are homozygotes, 20 000 (38.5%) are compound heterozygotes for E148Q and any other mutation apart from M694V, and 7000 (13.5%) are compound heterozygotes E148Q/M694V. To date, we have not found any individuals at all in any of these 3 groups who have developed amyloidosis. Because most of them, including all the homozygotes, are clinically completely healthy and therefore have never received colchicine treatment, we have concluded that the risk to such individuals of developing amyloidosis must be extremely low, especially among the homozygotes. All patients with clinical signs and symptoms of FMF are under continuous follow-up in our clinic, and those with severe attacks, including those who carry the E148Q mutation, already receive colchicine. Of those who do not, they would immediately be commenced on this should they develop proteinuria.

There is 1 reported case from the United States³ of a patient who was a compound heterozygote E148Q/M694V who developed amyloidosis, and we were very interested to read that Dr Akar and his colleagues have identified 7 patients who are compound heterozygotes for the mutation E148Q and another mutation and who have also developed this complication. It would be important to know how many of these patients had clinical signs and symptoms of FMF and who should, therefore, have been receiving colchicine treatment anyway.

We would agree with Dr Akar's conclusion that E148Q does appear to be a disease-causing mutation, but with reduced penetrance, as suggested by several researchers and underscored by our finding of 6 healthy individuals who were either homozygotes or compound heterozygotes for this mutation.²

It is also interesting that all of Dr Akar's patients who carried the mutation E148Q and who developed amyloidosis were compound heterozygotes for this and another mutationone of them in fact carried 3 mutations (M680I/V726A/E148Q). This would further underscore the suggestion that there may be no or only a very small risk for E148Q homozygotes to develop amyloidosis.

Gabrielle J. Halpern
Aviva Mimouni
Mordechai Shohat
Department of Medical Genetics
Rabin Medical Center
Beilinson Campus
Petah Tikva, 49100, Israel

REFERENCES

[Medline]
1. Mimouni A, Magal N, Stoffman N, et al. Familial Mediterranean fever: effects of genotype and ethnicity on inflammatory attacks and amyloidosis. Pediatrics. 2000;105(5): URL: http://www.pediatrics.org/cgi/content/full/105/5/e70
2. Stoffman N, Magal N, Shohat T, Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. Eur J Hum Genet. 2000; 8:307-310 [CrossRef][Medline]
3. Samuels J, Aksentijevich I, Torosyan Y, Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine. 1998; 77:268-297 [CrossRef][Medline]