Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.
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Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was cloned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3. Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF. The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region. (+info)
MEFV-Gene analysis in armenian patients with Familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications.
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Familial Mediterranean fever (FMF) is a recessively inherited disorder that is common in patients of Armenian ancestry. To date, its diagnosis, which can be made only retrospectively, is one of exclusion, based entirely on nonspecific clinical signs that result from serosal inflammation and that may lead to unnecessary surgery. Renal amyloidosis, prevented by colchicine, is the most severe complication of FMF, a disorder associated with mutations in the MEFV gene. To evaluate the diagnostic and prognostic value of MEFV-gene analysis, we investigated 90 Armenian FMF patients from 77 unrelated families that were not selected through genetic-linkage analysis. Eight mutations, one of which (R408Q) is new, were found to account for 93% of the 163 independent FMF alleles, with both FMF alleles identified in 89% of the patients. In several instances, family studies provided molecular evidence for pseudodominant transmission and incomplete penetrance of the disease phenotype. The M694V homozygous genotype was found to be associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes (P=.0002 and P=.006, respectively). The demonstration of both the diagnostic and prognostic value of MEFV analysis and particular modes of inheritance should lead to new ways for management of FMF-including genetic counseling and therapeutic decisions in affected families. (+info)
Epidemic investigation of diphtheria in the Republic of Armenia, 1990-1996.
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While incidence rates of diphtheria steadily declined in Armenia after World War II, reemergence of the disease in 1990 brought about changes in public health practices and identified resource needs. The Armenian Ministry of Health (MOH) routinely collected diphtheria case reports, as a reportable health outcome. Diphtheria incidence rates increased from 0.02/100,000 in 1993 to 1/100,000 (36 cases) in 1994. The distribution of cases showed that the greatest number of illnesses and deaths occurred among persons 5-14 years old, yet incidence rates among persons 1-4 and 5-14 years old were similar (4. 4 cases/ and 4.3 cases/100,000, respectively). During 1990-1996, 9 (75%) of 12 cases who died and 18 (21%) of 84 cases who survived had not been vaccinated. The diphtheria epidemic in Armenia was an important, serious, and signal public health event. The Armenian MOH responded by revising immunization practices (1994), improving epidemic control measures (1995), and soliciting international resources (1992-1996). (+info)
Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever.
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Familial Mediterranean fever (FMF) is a recessively inherited disorder predisposing to renal amyloidosis and associated with mutations in MEFV, a gene encoding a protein of unknown function. Differences in clinical expression have been attributed to MEFV-allelic heterogeneity, with the M694V/M694V genotype associated with a high prevalence of renal amyloidosis. However, the variable risk for patients with identical MEFV mutations to develop this severe complication, prevented by lifelong administration of colchicine, strongly suggests a role for other genetic and/or environmental factors. To overcome the well-known difficulties in the identification of modifying genetic factors, we investigated a relatively homogeneous population sample consisting of 137 Armenian patients with FMF from 127 independent families living in Armenia. We selected the SAA1, SAA2, and APOE genes-encoding serum amyloid proteins and apolipoprotein E, respectively-as well as the patients' sex, as candidate modifiers for renal amyloidosis. A stepwise logistic-regression analysis showed that the SAA1alpha/alpha genotype was associated with a sevenfold increased risk for renal amyloidosis, compared with other SAA1 genotypes (odds ratio [OR] 6. 9; 95% confidence interval [CI] 2.5-19.0). This association, which was present whatever the MEFV genotype, was extremely marked in patients homozygous for M694V (11/11). The risk for male patients of developing renal amyloidosis was fourfold higher than that for female patients (OR=4.0; 95% CI=1.5-10.8). This association, particularly marked in patients who were not homozygous for M694V (34.0% vs. 11.6%), was independent of SAA1-allelic variations. Polymorphisms in the SAA2 or APOE gene did not appear to influence susceptibility to renal amyloidosis. Overall, these data, which provide new insights into the pathophysiology of FMF, demonstrate that susceptibility to renal amyloidosis in this Mendelian disorder is influenced by at least two MEFV-independent factors of genetic origin-SAA1 and sex-that act independently of each other. (+info)
Phenotype-genotype correlation in 91 patients with familial Mediterranean fever reveals a high frequency of cutaneomucous features.
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OBJECTIVES: To describe the clinical manifestations of familial Mediterranean fever (FMF) in 91 patients from 47 families and provide data from the genetic study. P:atients and methods. We conducted a retrospective chart review of 91 patients (including 83 children aged <15 yr) from 47 families through a questionnaire and a specific database. The genetic analysis included complete screening of known mutations of the MEFV gene on chromosome 16p13.3. A positive diagnosis required at least two mutations, one on each chromosome. RESULTS: Our panel included 52 females and 39 males, with a mean age of 7.27 yr. Of the 47 families, 31 were non-Ashkenazi Jews, 10 were Armenians and six were from other ethnic groups. Clinical features included fever (100%), peritonitis (86%), pleuritis (56%), arthritis (34%) and myalgias (27%). We observed a high rate of cutaneous manifestations (47%); erythema, oedema and recurrent oral ulcers were the most frequent. Phenotype-genotype correlations showed a significant association of M694V homozygosity with earlier age of onset (P: = 0.044), fever >39 degrees C (P: = 0. 002), pleural crisis (P: = 0.0044), splenomegaly (P: = 0.0005) and arthritis (P: = 0.001). Associations with mucocutaneous features were as follows: erysipelas-like erythema (P: = 0.012), oedema (P: = 0.61, not significant) and oral ulcers (P: = 0.45, not significant). CONCLUSION: New phenotype-genotype correlations emerged from our study: homozygosity for the M694V mutation was associated with intensity of fever, splenomegaly and with erysipelas-like erythema. Apart from erysipelas-like erythema, no significant association was found between other cutaneous features and the genotype. (+info)
Republican Scientific-Medical Library, The Republic of Armenia: progress and programs.
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In 1990, the Republican Scientific-Medical Library (RSML) of the Ministry of Health of Armenia in collaboration with the Fund for Armenian Relief created a vision of a national library network supported by information technology. This vision incorporated four goals: (1) to develop a national resource collection of biomedical literature accessible to all health professionals, (2) to develop a national network for access to bibliographic information, (3) to develop a systematic mechanism for sharing resources, and (4) to develop a national network of health sciences libraries. During the last decade, the RSML has achieved significant progress toward all four goals and has realized its vision of becoming a fully functional national library. The RSML now provides access to the literature of the health sciences including access to the Armenian medical literature, provides education and training to health professionals and health sciences librarians, and manages a national network of libraries of the major health care institutions in Armenia. The RSML is now able to provide rapid access to the biomedical literature and train health professionals and health sciences librarians in Armenia in information system use. This paper describes the evolution of the RSML and how it was accomplished. (+info)
Chromosome aberrations in lymphocytes of persons exposed to an earthquake in Armenia.
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OBJECTIVE: This study attempted to determine the level of chromosome aberrations in lymphocytes of victims of the 1988 earthquake in Armenia. METHODS: Chromosome aberrations were measured in blood samples taken from 41 victims of the earthquake that hit Armenia in 1988 and in samples of 47 reference blood donors. The victims suffered from severe psychoemotional stress but were otherwise healthy. All the samples were taken 2 to 3 weeks after the earthquake. All the subjects were lifetime nonsmokers. The cells were scored blind as to the exposure status. RESULTS: The subjects exposed to the earthquake had a higher proportion of cells with chromosome aberrations [3.1 (SD 2.1)%] than the referents [1.7 (SD 1.3)%, P-value for the difference 0.0009]. The difference persisted when the values were adjusted for age and gender [relative risk (RR) 1.9, 95% confidence interval (95% CI) 1.4-2.5]. The difference was present for double breaks (RR 4.1, 95% CI 2.6-6.4), but not for single breaks (RR 1.1, 95% CI 0.8-1.7). The exposed subjects also had a lower percentage of cells with 46 chromosomes (P=0.03) than the referents. CONCLUSIONS: This study suggests an increase in chromosome aberrations in the lymphocytes of victims of a severe earthquake as compared with the levels of referents. If not due to bias or confounding, the difference may reflect the effect of either environmental exposures related to the earthquake or severe psychogenic stress. The levels of chromosome aberrations found among the earthquake victims in this study are comparable with those found in prospective studies of long-term cancer risk. (+info)
MEFV mutations and phenotype-genotype correlations in North African Jews and Armenians with familial Mediterranean fever.
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BACKGROUND: Familial Mediterranean fever is a genetic disease in which some characteristic gene mutations have been found. OBJECTIVES: To analyze the phenotype-genotype correlations in North African Jews and Armenians with FMF. METHODS: We studied MEFV gene mutations and phenotype-genotype correlations in North African Jews and Armenians with Familial Mediterranean Fever living in France. RESULTS: M694V mutation was the most common mutation in Jews and in Armenians. Patients with M680I homozygosity or M680I/M694V compound heterozygosity had a phenotype as severe as patients with M694V homozygosity. CONCLUSIONS: This study characterizes the phenotype-genotype in specific ethnic groups of patients with FMF. (+info)