Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent attacks of inflammation of serosal membranes. Amyloidosis is the most severe complication of the disease. The aim of this study was to investigate the genotype-phenotype correlation and specifically the association between amyloidosis and the four common mutations in exon 10 of the gene causing FMF (MEFV) in a total of 83 FMF families from three ethnic groups: North African Jews, Armenians and Turks. A significant association was found between amyloidosis and the specific mutation at the MEFV gene: Met694Val (RR = 1.41, P = 0.02). Amyloidosis was present in 18 out of 87 homozygous FMF patients (20.7%) and in only two out of the 41 compound heterozygous FMF patients (4.9%). No patients carrying other mutations had amyloidosis. There was no significant association between the various mutations and the type or severity of the FMF symptoms. This finding underscores the importance of performing molecular studies on all suspect FMF patients. In addition to providing accurate diagnosis, these tests allow identification of presymptomatic genetically affected individuals, detection of carriers and assessment of the risk for amyloidosis in later life.

Allergen-specific leukocyte adherence inhibition (LAI) assay: sensitivity, specificity and mechanism.

An allergen-specific tube leukocyte adherence inhibition (LAI) assay has been developed in order to study the mechanism by which leukocytes lose their normal property of adherence to glass. Peripheral blood leukocytes (PBL) from 27 individuals allergic to Dermatophagoides farinae (DF), 10 with seasonal rhinitis not induced by DF and 49 non-allergic healthy volunteers were challenged in vitro with DF and a non-relevant allergen, Artemisia vulgaris (AV) and then assayed for the ability to adhere to glass tubes. Challenge by DF, but not by AV, resulted in loss of adherence by PBL from patients allergic to DF, but not in those of normal controls. The specific LAI response was dose-dependent and occurred only when a critical dose of 0.5 X 10(3) was employed. Following in vitro challenge with DF, radio-immunoassay using an antiserum to LTC4 detected immunoreactive material in supernatants of PBL from DF-allergic individuals. When highly enriched mononuclear cells from non-allergic individuals were armed with cytophilic allergen-specific IgE and challenged with the specific allergen, they lost the property of glass adherence and released a substance that was immunoreactive with LTC4. The results suggest that the chain of events leading to the LAI response in PBL from allergic individuals involves primary recognition of the allergen by specific IgE antibodies bound to receptors on mononuclear cells. The cells are thus triggered to synthesize cysteinyl-containing leukotrienes which mediate the LAI phenomenon. The results suggest that this assay may be used to study allergen-antibody interaction and the subsequent events leading to the clinical picture of atopic diseases.

The gene for familial Mediterranean fever in both Armenians and non-Ashkenazi Jews is linked to the alpha-globin complex on 16p: evidence for locus homogeneity.

Familial Mediterranean fever (FMF) is a recurrent inflammatory disorder characterized by short episodes of fever, peritonitis, pleuritis, and arthritis. While FMF has been shown to be inherited in an autosomal recessive fashion in both non-Ashkenazi Jews and Armenian families, clinical differences have raised the possibility of genetic heterogeneity. As its pathogenesis is unknown, mapping of the gene for FMF may provide the first objective method for early and accurate diagnosis of this disease. After excluding 45% of the entire human genome, we studied 14 Armenian and 9 non-Ashkenazi Jewish families with FMF and tested linkage with the alpha-globin locus on chromosome 16. Analysis of the PvuII length polymorphism of the 3' HVR (hypervariable region) probe showed significant linkage with the FMF gene (maximum lod score [lodmax] = 9.76 at maximum recombination fraction [theta] = .076). In the Armenians, the lodmax = 3.61 at theta = .10; and for the non-Ashkenazi Jews, lodmax = 6.28 at theta = .06. There was no evidence for genetic heterogeneity between the Armenians and the non-Ashkenazi Jews (chi 2 = 1.28; P = .26) or within either ethnic group (chi 2 = .00; P = .50). Thus, the gene for FMF is linked to the alpha-globin complex on chromosome 16p in both non-Ashkenazi Jews and Armenians.

Amyloidosis in familial mediterranean fever is associated with a specific ancestral haplotype in the MEFV locus.

Familial Mediterranean fever (FMF) is a recessive disease characterized by recurrent attacks of inflammation of serosal membranes, and the gene responsible, MEFV, has been recently identified. Amyloidosis is considered to be the most severe complication. Since colchicine is effective in preventing FMF amyloidosis and since this process can develop even prior to the FMF symptoms, lifelong colchicine treatment is recommended for all FMF patients. Identification of the factor which determines amyloidosis will allow treatment to be directed only to those at risk. In order to investigate the association between amyloidosis and MEFV haplotypes, we studied 56 families from three ethnic groups. We compared the haplotypes of FMF patients with and without amyloidosis in each ethnic group separately and identified 14 different MEFV core haplotypes. A significant association (P < 0.004) was found between amyloidosis and a specific core haplotype, 153bp:104bp at markers D16S3370 and D16S2617, respectively. Amyloidosis was present in 20 out of 70 homozygotes for this haplotype and in 6 out of 35 compound heterozygotes for this and other core haplotypes. None of the patients who did not carry this allele had amyloidosis. There was no association between the various haplotypes and severity of the FMF symptoms, age of onset, or age at commencement of colchicine. Further investigation of the MEFV haplotypes in additional patients is recommended as such an association may save many mildly affected or asymptomatic patients with non-amyloidotic genotypes from receiving unnecessary lifelong colchicine treatment.