AA amyloidosis and pyrin gene mutations.

To the Editor: AA amyloidosis may develop in an otherwise asymptomatic case of familial mediterranean fever (FMF) as a presenting first symptom of the disease. This form of the disease is called phenotype II.1,2 This suggests that amyloidosis is rather a direct disease-associated condition rather than a complication of a more severe disease state. This hypothesis is further supported by observations of the role of the mutated protein in FMF in inflammatory processes and apoptosis. 3 Recently, Atagunduz et al reported an increased frequency of mutations of the MEFV gene both in FMF and non-FMF associated amyloidosis of AA type in Turkey.4 However, in their study they did not report any phenotype II FMF case despite a well-known high frequency of FMF in this country. An increased frequency of MEFV mutations in the population seems also to be the case in Italy5 and Cyprus6 Interestingly, neither of these two surveys encountered phenotype II cases in the populations of Italy5 and Cyprus (Deltas, respectively.

During the last years we tested in Athens for pyrin gene mutations, 4 cases were referred to us with an established diagnosis of AA amyloidosis without any evidence for a predisposing factor (e.g., inflammation). The molecular test applied and the findings indicating a diagnosis of AA amyloidosis have already been reported.7,8 Several parameters of these cases are shown in Table 1. It is evident that all four cases tested carry pyrin gene mutations with three compound heterozygotes and one heterozygote. Interestingly, we were recently referred one further case with a clinically ‘definite’ FMF diagnosis (according to the Tel-Hashomer diagnostic criteria) in whom only one FMF associated MEFV gene variation was found, namely M694V. This case is currently under investigation for a persisting proteinuria that points to some type of nephropathy. All amyloidosis cases without any evident predisposing factor turned to be either FMF cases (phenotype II) or disease carriers.

Table 1

AA amyloidosis cases tested for pyrin mutations.

Case no.	Origin	Sex	Age (y)	Mutation
1 (7)	Greek	M	50	V726A/M694V
2 (8)	Greek	F	65	M680I/M694V
3	Greek	F	45	E148Q/M694V
4	Greek	F	80	-/M680I

A recording system for all cases of AA amyloidosis seems necessary. Molecular study for MEFV gene point mutations in every amyloidosis case may shed further light on this putative predisposing factor.