Q J Med 2000; 93: 681-684
© 2000 Association of Physicians
Familial Mediterranean fever and systemic amyloidosis in untreated Turkish patients
nFrom the Department of Pediatrics, Ankara University School of Medicine, and 1 Ankara Social Security Children's Hospital, Ankara, Turkey
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We compared the frequencies of seven MEFV mutations (M694V, M680I, V726A, M694I, K695R, R761H, E148Q) and the clinical findings in 20 Turkish FMF patients who had not developed amyloidosis by the age of 40 years in the absence of colchicine therapy, with those in 27 Turkish amyloidosis patients. No mutation frequency, including that of M694V, was different between the two groups. Family history of amyloidosis and parental consanguinity were noted to be higher in the amyloidosis group. The seven mutations do not appear to be sufficient to explain the development of amyloidosis in Turkish FMF patients. Other genetic factors may be important for this association.
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Introduction |
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Familial Mediterranean fever (FMF) is an autosomal recessive disease with episodic fever, abdominal pain, pleuritis and arthritis. The most devastating clinical consequence of FMF is systemic amyloidosis, clinically manifested as progressive nephropathy leading to end-stage renal disease.1 The discovery of the gene (MEFV) responsible for FMF in 1997.2,3 has gone a long way towards understanding its molecular basis. Nevertheless, we are still struggling with the puzzle of how amyloidosis develops during the disease course. Most of the previous reports covering north African Jewish FMF patients found that M694V is the leading mutation among patients who developed amloidosis.4–7 Some investigators however, indicated that patients with mutations other than M694V were also prone to amyloidosis.8–10 Interpreting these data is very complicated, since using regular colchicine therapy prevents amyloidosis in all cases, regardless of the mutation type. Therefore, evaluation of a patient population that has never received regular colchicine therapy would be very helpful in studying this genotype-phenotype correlation.
To find such a population, we searched for patients who were older than 40 years of age but had not developed amyloidosis, although they were not on colchicine therapy. Our search yielded 20 patients who have been experiencing the classical manifestations of FMF for many years without amyloidosis. As they had not been diagnosed as having FMF, none of them had received colchicine. Thus, we considered these patients as having very low or no risk for amyloidosis, as it is well accepted that amyloidosis usually develops by 40 years of age1 in the absence of therapy.
We compared the MEFV mutations and some other phenotypic and demographic findings in this group with those in another group of patients who developed amyloidosis in the absence of therapy.
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Methods |
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We studied 20 FMF patients without amyloidosis who had not received colchicine therapy until 40 years of age, selected from our original panel. The diagnosis of FMF was made according to accepted criteria.1,11 All had their first FMF attack before 40 years of age and none had proteinuria. All were started on colchicine following the diagnosis of FMF (after 40 years of age). Twenty-seven Turkish FMF patients with FMF-related amyloidosis were selected as the control group. These patients had typical clinical manifestations of FMF prior to the diagnosis of amyloidosis and were considered as phenotype 1 (some FMF patients presenting with amyloidosis without other manifestations of the disease were referred to as phenotype 2). Amyloidosis was diagnosed by either renal or rectal biopsy in all cases. Similarly, none of the patients in this group had been diagnosed or started on colchicine therapy prior to the development of amyloidosis. All patients in both groups were evaluated for their demographic findings, clinical manifestations, family history of FMF and amyloidosis, and mutation analysis.
The seven MEFV mutations (M694V, M680I, V726A, M694I, K695R, R761H, E148Q) were systematically investigated in the patients. DNA was extracted from peripheral blood lymphocytes according to standard procedures. Mutation identification was performed according to previously-described PCR and restriction-enzyme digestion or amplification refractory mutation system techniques.2, 3, 13–15
The statistical significance of differences between two groups was calculated by either the 
2 test or Fisher's exact test.
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Results |
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Table 1
represents the demographic aspects and clinical manifestations of the patients with and without amyloidosis. The age at onset and age at diagnosis were both later in the patients without amyloidosis than in those with amyloidosis. The delay in diagnosis was three times longer in the patients without amyloidosis than in those with amyloidosis. In addition, although patients in both groups had similar frequencies of a family history of FMF, family history of amyloidosis was lower in the patients without amyloidosis. No statistically significant differences were found between the two groups for most of the phenotypic features, including fever, abdominal and chest pain. However, the frequency of arthritis was slightly lower in the patients without amyloidosis compared to those with amyloidosis.
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Table 2 shows the genotypes of the patients. The studied seven mutations were detected in 89 (95%) of the 94 alleles. Only six alleles could not be detected with our panel. The most frequent mutation was the M694V in both groups. Thirteen patients were homozygous for a given mutation and 27 were compound heterozygous for two mutations. Six patients were found to be heterozygous, and one patient had a complex allele with M680I/V726A-E148Q mutations. There was no difference in the frequency of any particular genotype between the two groups.
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Discussion |
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Most of the earlier reports and the results of some recent studies suggested a relation between the M694V mutation and development of renal amyloidosis and even severity of the disease.4–7,16 Based on these publications, a clinical approach assuming that the M694V mutation bears the worst prognosis for an FMF patient has been suggested, although most studies included several FMF patients with amyloidosis bearing mutations other than M694V.5,8,10,17,18 Our recent analysis, including 167 index FMF patients12 and seven multiplex FMF families,19 as well as the 27 FMF patients including nine with amyloidosis of Booth et al. did not demonstrate this association at all. However, all the previous studies included patients who were on regular colchicine therapy, and regular colchicine treatment prevents amyloidosis in all cases. This may obviously produce a ‘false-positive amyloid-negative patient’ phenotype bearing any type of mutation regardless of the M694V.
Our results in this study are surprising. Only one of 20 patients without amyloidosis lacked the M694V mutation, and five were found to be homozygous for it. More perplexing, 8/27 patients with amyloidosis did not have the M694V mutation (Table 2
). These results strongly suggest that the development of amyloidosis is not due to only the presence or homozygosity of the M694V mutation, at least in our study population. Our findings contradict with those of Cazeneuve et al.16 a recent similar study performed in untreated Armenian FMF patients showing that the M694V homozygous genotype was associated with a higher prevalence of amyloidosis. Importantly, the authors of that study failed to demonstrate the presence of the same association in their general FMF population, raising questions about the generalization of their results, especially in the light of our results.
Some other results of our study deserve attention: the patients without amyloidosis had a considerable delay in their diagnosis and treatment but still had not developed amyloidosis. The genetic and/or environmental factors preventing amyloidosis in these individuals remain to be elucidated. Further, consistent with the results of a previous study from Turkey,20 the family history of amyloidosis was significantly lower in patients without amyloidosis than in that with amyloidosis. However, the family history of FMF was found to be similar in both groups. Lastly, the higher consanguinity rate in patients with amyloidosis, when considered with the higher frequency of family history of amyloidosis, may be indicating the presence of autosomal-recessive inherited amyloidosis-facilitating factors.
There are no striking differences in other clinical findings between the two groups. Patients without amyloidosis appear to have all the clinical findings that the patients with amyloidosis have, perhaps in slightly milder form. Our results indicate that mutation analysis does not help us to predict whether one patient will develop amyloidosis later on his life, even when the colchicine effect is eliminated.
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Notes |
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Address correspondence to Dr F. Yalcinkaya, Çinar Sitesi 5. Blok No 62, Ümitköy 06530, Ankara, Turkey. e-mail: yalcinkaya{at}tr-net.net.tr
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References |
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