Phenotypic characterization of Familial Mediterranean Fever patients harboring variants of uncertain significance

Background/aim: Familial Mediterranean Fever (FMF) is the prototype of hereditary autoinflammatory disorders and caused by mutations on the MEFV gene located on the short arm of chromosome 16. Although some MEFV variants are clearly associated with disease phenotype, there are numerous variants with unknown clinical association which are termed as variants of uncertain significance (VUS). Here, we present clinical correlations of VUS in a large cohort of adult FMF patients from three tertiary centers located in Central Anatolia. Materials and methods: All patients were recruited from FMF in Central Anatolia (FiCA) cohort. Demographic (sex, age at disease onset) and clinical features (disease characteristics, attack frequency, mean colchicine dose, colchicine nonresponsiveness, amyloidosis, and persistent inflammation) of patients with VUS were compared with those harboring pathogenic variants. Disease severity and damage were also evaluated using international severity score for FMF (ISSF) and autoinflammatory disease damage index (ADDI), respectively. Results: Among 971 participants included, MEFV gene analysis results were available for 814 patients. Twenty-six (3.2%) patients had single heterozygous VUS and 54 (6.6%) had pathogenic/VUS complex heterozygous variants. Patients with single heterozygous VUS had similar demographic/clinical features, ISSF and ADDI scores compared to those with single heterozygous pathogenic variant (p > 0.05 for all). No difference was observed in the demographic and clinical features of patients with single heterozygous pathogenic mutation and pathogenic/VUS complex heterozygous variant (p > 0.05 for all). ISSF and ADDI scores were lower in pathogenic/VUS complex heterozygous patients than those harboring single pathogenic mutation (p = 0.006 and 0.004, respectively). Conclusion: Our findings suggest that patients with single heterozygous VUS has mild FMF phenotype similar to those with single pathogenic mutation. Pathogenic/VUS complex heterozygosity does not lead to a more severe clinical phenotype than having a single pathogenic variant.

Familial Mediterranean fever in Chinese adult patients.

Objectives: FMF is the most frequent monogenic auto-inflammatory disease worldwide. There have been hardly any cases reported in the Chinese population. We aimed to describe the first cohort of adult FMF patients in China. Methods: We evaluated all the adult patients suffering from FMF referred to our centre from April 2015 through March 2017. Patients were diagnosed clinically according to the Tel Hashomer criteria. Whole exome sequencing was performed in each patient. Results: A total of 11 adult patients were diagnosed as FMF in our centre. The mean age of onset was 29.4 years (s.d. 18.2). All patients were of Chinese Han ethnicity with no positive family history. All patients had intermittent febrile episodes. During attacks, seven patients had generalized abdominal pain, three experienced chest pain, four developed arthritis and none reported erysipelas-like skin changes. No patient had evidence of AA amyloidosis. Every patient carried at least one variant in the MEFV gene. All patients had good response to colchicine. Conclusion: Our study is the first to suggest the presence of FMF in the Chinese adult population. The late onset, often atypical and mild clinical manifestations and absence of AA amyloidosis in our patients might be related to low-penetrance and heterozygous MEFV variants. Our results await to be confirmed on larger Chinese populations.

A retrospective study comparing the phenotype and outcomes of patients with polyarteritis nodosa between UK and Turkish cohorts.

There is a need for better definition of polyarteritis nodosa (PAN) subphenotypes and the influence of ethnicity and geography. This study is aimed to study the demographic and clinical features of PAN cohorts from the UK and Turkey (TR) and to compare and contrast disease characteristics. A retrospective survey of databases from two vasculitis centres between 1990 and 2016 for PAN patients fulfilling the EMEA Vasculitis Classification algorithm. All paediatric-onset adult patients met the Ankara 2008 (EULAR/PReS endorsed) criteria for childhood PAN. Those with typical angiographic and/or histopathologic findings consistent with PAN were included. 93 (M/F: 51/42) patients (UK: 47, TR: 46) were included. Three were HBV-related, 20 (21.5%) had paediatric onset and 16 (16.5%), cutaneous PAN. TR patients had younger age of disease onset 44 (28.5-59.0) vs. 24.5 (11.8-40.5), p = 0.002. Twelve (26%) of TR patients had monogenic disease (Familial Mediterranean Fever association (n = 7), deficiency of adenosine deaminase 2, DADA2, (n = 5). No difference was found in phenotype between paediatric and adult onset patients except for frequency of cutaneous lesions (p = 0.002). During a median 67.5 (32-126) months follow-up, 13 patients died (12.7% in UK vs. 15.2% in Turkish cohorts). No difference was found between two cohorts in relation to relapse rate, death and vasculitis damage index. This study defined a diagnosis of PAN according to the EMEA algorithm. The TR group had a younger age of disease onset and more cases of monogenic disease; however, disease extent, relapse rate, damage index and death rates were similar between groups.

Boundaries between familial Mediterranean fever and juvenile spondyloarthritis: Analysis of three French retrospective cohorts.

OBJECTIVES: Children with Familial Mediterranean fever may suffer from musculoskeletal involvement, somewhat difficult to distinguish from juvenile spondyloarthritis. The association of these two diseases has been scarcely reported in children. Objective of this work was to define the association of familial Mediterranean fever and juvenile spondyloarthritis in France. METHODS: Three cohorts of children with familial Mediterranean fever, juvenile spondyloarthritis, familial Mediterranean fever related juvenile spondyloarthritis, were retrospectively identified in the French reference center of auto-inflammatory diseases. Familial Mediterranean fever was defined according to Tel-Hashomer or Turkish pediatric criteria with at least one exon-10 MEFV-gene mutation. Juvenile spondyloarthritis was defined according to ILAR criteria. Patients with familial Mediterranean fever or juvenile spondyloarthritis were respectively compared to familial Mediterranean fever related juvenile spondyloarthritis patients. RESULTS: Sixteen children were identified as having familial Mediterranean fever related juvenile spondyloarthritis. The male/female-ratio was 0.6, with median age at spondyloarthritis onset of 7.5years (3-16years). All carried at least one M694V variant in MEFV gene; 16.7% were HLA-B27-carriers. Compared to 83 familial Mediterranean fever patients, familial Mediterranean fever related juvenile spondyloarthritis patients had less frequently fever (P<0.01) and more frequently arthritis (P<0.05), enthesitis (P<0.001), inflammatory back pain (P<0.001), inadequate response to colchicine (P<0.05). Compared to 20 juvenile spondyloarthritis patients, familial Mediterranean fever related juvenile spondyloarthritis patients less often received non-steroidal anti-inflammatory drugs (P<0.01) and anti-tumor necrosis factor drugs (P<0.001). CONCLUSIONS: Familial Mediterranean fever may be associated with typical pattern of juvenile spondyloarthritis. These patients, with less response to colchicine, should be diagnosed earlier and treated as for jSpA.

Mutational Spectrum of the MEFV Gene in AA Amyloidosis Associated With Familial Mediterranean Fever.

INTRODUCTION: Familial Mediterranean fever (FMF) is a recessively inherited disease which is characterized by recurrent episodic fever, abdominal pain, and polyserositis. It is caused by mutations in the MEFV gene, encoding the pyrin protein. The most important complication of FMF is secondary (AA) amyloidosis that leads to kidney failure. This study aimed to identify the frequency and distribution of MEFV mutations in Turkish patients with FMF-associated AA amyloidosis. MATERIALS AND METHODS: A total of 57 patients with FMF-associated AA amyloidosis and 60 healthy controls were included in this study. We analyzed the MEFV gene for E148Q, M694V, M680I, and V726A mutations and R202Q variant by polymerase chain reaction and restriction fragment length polymorphism methods.  Results. The male-female ratio was 0.72. The mean age of the patients was 29.8 ± 12.8 years. Among the patients, the rate of the MEFV mutations was found to be 77.2%. The most frequently observed genotype was homozygous M694V mutation, which was present in 17 patients (29.8%, P < .001), followed by compound heterozygous M680I/M694V (14.3%, P = .01). The R202Q allele frequencies were significantly different between patients and control group (P = .02; odds ratio, 0.53; 95% confidence interval, 0.30 to 0.94). CONCLUSIONS: In this study, mutation analysis of MEFV gene confirmed that the most frequent mutation was homozygous M694V genotype. R202Q may be important in patients with FMF-associated AA amyloidosis. Thus, it is suggested that investigation of R202Q should be considered as a genetic test for Turkish FMF patients.

Familial Mediterranean fever in Germany: clinical presentation and amyloidosis risk.

OBJECTIVE: To characterize patients with familial Mediterranean fever (FMF) with and without AA amyloidosis living in Germany. METHOD: Clinical and genetic data from 64 FMF patients were analysed for amyloidosis risk factors. RESULTS: Fifty-five patients (85%) were of Turkish or Armenian origin. Thirty-one patients (48%) developed FMF symptoms before the age of 16 years. Sixteen patients (26%) became symptomatic after age 20. Symptoms reported were peritonitis (95%), fever (78%), pleuritis (59%), arthralgia (60%), arthritis (32%), erysipelas-like erythema (23%), and vasculitis (8%). FMF diagnosis was delayed for a median of 8.0 years. Genetic analysis confirmed M694V as the most prevalent Mediterranean fever (MEFV) gene mutation in 46 out of 59 patients (78%). M694V homozygosity was associated with an earlier FMF onset (median age 5.5 years, p = 0.0001) and a higher prevalence of peritonitis (p = 0.007) and pleuritis (p = 0.0007) compared to patients without an M694V mutation. AA amyloidosis was detected in 16 patients (25%) at a median age of 36.5 years and tended to be associated with a higher age at disease onset (p = 0.062) and a higher FMF activity score (p = 0.093). AA amyloidosis was significantly associated with a higher age at FMF diagnosis (p = 0.0022). CONCLUSIONS: Clinical symptoms of FMF-affected migrants living in Germany resemble those observed in their home country. In particular, patients with an onset of FMF symptoms after age 20 and a later FMF diagnosis have a high risk of AA amyloidosis. Symptomatic patients who originate from countries with a higher FMF prevalence should be screened for FMF and proteinuria.

The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA.

Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.

Tumor necrosis factor-α gene polymorphisms in FMF and their association with amyloidosis.

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by periodic provocative attacks of fever with peritonitis, pleuritis, arthritis, or eriseplemya. Tumor necrosis factor-α (TNF-α) plays an important role in the regulation of the immune response as a part of the cytokine network, including activation of macrophages and apoptosis. We investigated the possible association of TNF-α promoter -1031T/C and -308G/A polymorphisms in 86 FMF patients carrying M694 V homozygous mutation and 100 matched healthy controls both from Iranian Azeri Turks. Our data showed that patients with TNF-α -308 GG are more susceptible to the development of amyloidosis and arthritis (P value <.05). These data also showed that the frequency of TNF-α -308 A allele is considerably low among patients with amyloidosis, and it may have protective role among them (odds ratio [OR] = 0.083, χ(2) = 5.46, P value = .003). Further evaluation of this polymorphism may be important and need further studies.

Role of the R92Q TNFRSF1A mutation in patients with familial Mediterranean fever.

OBJECTIVE: To define the frequency of the R92Q tumor necrosis factor receptor-associated periodic syndrome (TRAPS) mutation in patients with familial Mediterranean fever (FMF) and to study the role of this mutation in FMF. METHODS: Ninety-two FMF patients and 250 controls were genotyped for the R92Q mutation. The frequency of R92Q was assessed among 5 groups of FMF patients. RESULTS: R92Q was found in 6% of the controls, with an especially high carrier rate among Moroccan Jews (8%). R92Q was found in 3 (3.2%) of the 92 FMF patients, 1 homozygous for the MEFV M694V mutation and 2 heterozygous for M694V. All 3 patients showed partial response to colchicine. R92Q was not found in patients unresponsive to colchicine, nor was it found in patients with amyloidosis or in patients with FMF-like disease without MEFV mutations. CONCLUSION: The frequency of the R92Q mutation in FMF patients is comparable with that of controls. Despite the fact that TRAPS and FMF share common biochemical pathways, we found no evidence for an interaction between these two genes.

MEFV gene compound heterozygous mutations in familial Mediterranean fever phenotype: a retrospective clinical and molecular study.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal-recessive inherited inflammatory disease caused by mutations in the MEFV gene that encodes pyrin/marenostrin. It is characterized by recurrent short episodes of fever, abdominal pain and serositis affecting mainly Mediterranean and Middle Eastern populations. We determined the frequency of the compound heterozygous mutations which has been rarely reported. The present study not only investigated clinical features of child-onset FMF patients with compound heterozygous mutations but also determined whether there is a phenotype-genotype correlation in the same patient population. METHODS: The medical records of 66 heterozygous patients with FMF were retrospectively reviewed and assessed. Patients were investigated regarding the mutation type, clinical characteristics at the time of inflammatory attacks such as fever, abdominal pain, arthritis, chest pain, erysipelas-like erythema and oedema, epidemiological data, consanguinity, severity score and family history of FMF and amyloidosis. RESULTS: The most frequent mutation was M694V, identified in 32% of the alleles examined, followed by E148Q in 20.6%, V726A in 17% and M680I in 14.5%, respectively. Consequently, we determined that P369S (n = 10; 8%) was the most frequent rare mutation in Turkish FMF patients. Frequency of the other rare mutations were R761H (3%), F479L (3%), A744S (1.5%) and K695R (0.7%). Fever was seen in 96.5%, abdominal pain in 98.5%, arthralgia in 85%, chest pain in 45.5% and erysipelas-like lesions in 23%. None of these patients had amyloidosis, but 16 had a family history of chronic renal failure, 44% had vomiting and 35% had diarrhoea during the attack. Although regular colchicine treatment was effective in 83% of the patients, the percentage of patients that did not start colchicine therapy was 18%. In addition, the patients were divided into four groups according to the presence of the mutation types and we compared genotype-phenotype correlations. CONCLUSIONS: We suggest that regular colchicine therapy may be administered to symptomatic patients with MEVF gene compound heterozygous mutations, regardless of the mutation type.

Clinical and genetic features of familial Mediterranean fever in Japan.

OBJECTIVE: Familial Mediterranean fever (FMF) is thought to be a rare disorder in Japan, and the clinical features of Japanese patients with FMF remain unclear. Our aim was to elucidate the clinical characteristics of FMF in Japanese patients. METHODS: We analyzed clinical and genetic data of 80 patients based on the results of a nationwide questionnaire survey and review of the literature. RESULTS: From clinical findings of 80 Japanese patients, high-grade fever was observed in 98.8%, chest attacks (pleuritis symptoms) in 61.2%, abdominal attacks (peritonitis symptoms) in 55.0%, and arthritis in 27.5%. Twenty-four percent of patients experienced their first attacks before 10 years of age, 40% in their teens, and 36% after age 20 years. Colchicine was effective in many patients at a relatively low dose (< 1.0 mg/day). AA amyloidosis was seen in only 1 patient. Common MEFV mutation patterns were E148Q/M694I (25.0%), M694I alone (17.5%), and L110P/E148Q/M694I (17.5%), and no patient carried the M694V mutation, the most common mutation in Mediterranean patients with FMF. CONCLUSION: A larger than expected number of patients with FMF exist in Japan, and the clinical presentation of Japanese FMF patients seems to be relatively milder than those of Mediterranean FMF patients. AA amyloidosis rarely occurs in Japanese patients, probably due to difference in patterns of the MEFV genotype between Japanese and Mediterranean patients.

Disease severity in children and adolescents with familial Mediterranean fever: a comparative study to explore environmental effects on a monogenic disease.

BACKGROUND: Worldwide, familial Mediterranean fever (FMF) is the most common autoinflammatory disease. It has been suggested that environmental factors affect the phenotype as some patients do not develop the complication of secondary amyloidosis. OBJECTIVE: To analyse whether disease severity in Turkish children with FMF, living in Turkey and Germany is different. PATIENTS AND METHODS: A total of 55 Turkish children living in Turkey were compared with 45 Turkish children born and raised in Germany. Mean age among the group from Turkey and Germany was 42.2 and 44.29 months, respectively. M694V was the leading mutation in both groups. The severity scores were compared with two scoring systems, modified according to published paediatric data for dosage. RESULTS: There was no significant difference between the mean C-reactive protein and erythrocyte sedimentation rate levels of the two groups. According to the modified Sheba Center score, 78.2% of patients from the group living in Turkey had a severe course compared with 34.1% from the group living in Germany. The modified score of Pras et al also showed more severe disease in the patients from Turkey. The difference between the two groups for both scoring systems were significant (both p<0.05). CONCLUSIONS: We believe the modified scores that we introduce can be widely used for children. Our results suggest that the environment affects the phenotype of a monogenic disease of the innate inflammatory pathway.

Prevalence of known mutations in the familial Mediterranean fever gene (MEFV) in various carrier screening populations.

PURPOSE: To determine the carrier frequency of familial Mediterranean fever (FMF) mutations of individuals in three different US testing populations: Cystic fibrosis, Factor V Leiden, and Ashkenazi Jews. METHODS: DNA samples from 1234 anonymous samples were screened for 12 FMF mutations using a laboratory-developed test. RESULTS: Genotyping revealed carrier frequencies of 1:16, 1:46, and 1:8, respectively. CONCLUSION: MEFV mutation frequency seems to correlate positively with Mediterranean influence of the tested population and the high overall carrier rate for MEFV mutations in the Factor V Leiden testing population (1:46) suggests that the disease may be under-diagnosed in the US population or that the mutant alleles have a low penetrance.

Genotype-phenotype correlation in children with familial Mediterranean fever in a Turkish population.

BACKGROUND: The aim of the present study was not only to review clinical and demographic features of child-onset familial Mediterranean fever (FMF) patients but also to investigate whether there is a phenotype-genotype correlation in the same patient population. METHODS: The medical records of 102 patients with FMF were retrospectively reviewed. Patients were classified into three groups according to mutations: group 1, Met694Val-Met694Val (homozygote); group 2, Met694Val-other; and group 3, other-other. These groups were compared with regard to gender, age of onset, age of diagnosis, time interval between disease onset and diagnosis, fever, abdominal pain, arthritis, chest pain, erysipelas-like erythema, edema, amyloidosis, number of attacks per year before and after treatment, consanguinity, severity score, response of colchicines treatment, and family history of FMF and amyloidosis. RESULTS: The presence of M694V homozygote was found to be associated with amyloidosis. Homozygosity for M694V was found in 46 patients (45%). CONCLUSIONS: M694V homozygosity is associated with phenotype II and amyloidosis compared to other common genotypes in patients with FMF. Despite current knowledge on FMF, prospective clinical studies with large numbers of patients and different ethnic groups will help us to clarify this considerable disease.

MEFV mutations in Japanese rheumatoid arthritis patients.

OBJECTIVE: Familiar Mediterranean Fever (FMF) is common among Mediterranean populations, while other populations are rarely affected. The aim of this study was to assess the involvement of MEFV gene mutations among Japanese rheumatoid arthritis patients with or without amyloid A (AA) amyloidosis. METHODS: The frequency of the MEFV mutations, which were identified in Japanese FMF patients, was determined in 126 Japanese RA patients and 76 Japanese healthy subjects. RESULTS: The M694I mutation was not observed among RA patients and healthy subjects. Allele frequency of R408Q, P369S, E148Q, L110P mutations account respectively for 3.3%, 3.9%, 23.7%, 9.2% in healthy subjects and 5.6%, 6.7%, 24.2%, 9.5% in RA patients. The overall mutation rate was comparable between the RA patients and healthy subjects, as well as between the RA patients with and without amyloidosis. CONCLUSION: This study shows the high prevalence of mutations of the MEFV genes in Japanese RA patients. However, our data suggest that the MEFV gene mutations may not be a genetic factor affecting the susceptibility of RA or the development of amyloidosis in a Japanese population.

Analysis of SAA1 gene polymorphisms in the Greek population: rheumatoid arthritis and FMF patients relative to normal controls. Homogeneous distribution and low incidence of AA amyloidosis.

OBJECTIVE: To address whether or not the rarity of amyloidosis in Greek patients with rheumatoid arthritis (RA) is related to specific alleles of single nucleotide polymorphisms (SNPs) in the 5'-flanking region and the exon 3 of the SSA1 gene. METHODS: The genotypes of the -13T/C SNP in the 5'-flanking region of the SAA1 gene and the two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined in 88 Greek patients with RA, 14 patients with familial Mediterranean fever (FMF) and 110 healthy controls. Linkage disequilibrium and haplotype frequencies involving -13T/C, 2995C/T and 3010C/T in these populations were tested and estimated, respectively. RESULTS: The genotypic distribution and allelic frequencies were similar in all groups tested. SNPs 2995 and 3010 were in linkage disequilibrium for all study populations (p < 0.05), whereas SNP -13 was not in linkage disequilibrium with either 2995 or 3010 (p > or = 0.05). Two major haplotypes presented in all patients with RA and FMF and controls: -13C; 2995T; 3010C (-13C; alpha) and -13C; 2995C; 3010T (-13C; beta). The -13T allele was linked with the gamma haplotype in Greek patients with RA and controls. The frequency of the -13T allele was found to be very rare in all groups tested. CONCLUSIONS: In conclusion, the rarity of the putative amyloidogenic -13T allele in Greek populations may be related to low prevalence of AA amyloidosis development in Greek RA patients.

Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF), the prototype of autoinflammatory disorders, is caused by recessive mutations in the MEFV gene. Some FMF patients develop renal amyloidosis, a potentially fatal condition. This complication has mainly been associated with the M694V mutation, although the different study designs, small numbers of patients, and/or evaluation of few or no covariables calls this association into question. The aim of this study was to examine the controversial issue of amyloidosis susceptibility in FMF by determining the relative contributions of MEFV and numerous epidemiologic factors to the risk of renal amyloidosis. METHODS: Online questionnaires were completed at the MetaFMF database by patients at 35 centers in 14 countries. Using a standardized mode of data collection, we retrieved crude initial data from over half of the genetically confirmed FMF patients referred worldwide until May 2003 (2,482 cases, including 260 patients who developed renal amyloidosis). RESULTS: Amyloid nephropathy was present in 11.4% of the cases. In the total study population, country of recruitment was the leading risk factor for this manifestation (odds ratio 3.2 [95% confidence interval 1.8-5.9]), followed by M694V homozygosity, proband status, and disease duration. Differing results were found when countries were stratified. CONCLUSION: Country of recruitment, rather than MEFV genotype, is the key risk factor for renal amyloidosis in FMF. This risk, which parallels infant mortality rates, indicates a possible environmental origin of amyloidosis susceptibility. The patient's country should be considered in addition to MEFV genotype as an indication for prophylactic colchicine, a treatment suggested for asymptomatic individuals who are incidentally discovered to be M694V homozygous.

SAA1 alpha/alpha alleles in amyloidosis.

BACKGROUND: Amyloidosis, mainly AA type, is one of the common diseases in nephrology clinics in Turkey. AA type amyloidosis is a complication of various chronic infections or inflammatory diseases such as familial Mediterranean fever (FMF), rheumatoid arthritis (RA), tuberculosis and bronchiectasis. A controversy exists in the literature regarding the relationship between SAA1 genotypes and AA type amyloidosis. This study aimed to investigate SAA1 gene polymorphism in different patient groups: 1) amyloidosis, 2) FMF and 3) healthy controls. METHODS: Eighty-two patients from the three groups were included in the study: 1) amyloidosis, 2) FMF without amyloidosis, and 3) healthy controls. SAA1 genotypes were studied by the polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The homozygous alpha/alpha genotype is the most common SAA1 genotype among patient groups with amyloidosis, and the alpha/alpha genotype frequency is significantly higher than in healthy controls (68 vs. 38%, p<0.05). CONCLUSIONS: The SAA1 alpha/alpha genotype is a risk factor for AA type amyloidosis in Caucasoid populations and more studies are needed to investigate why the gamma/gamma genotype is associated with AA type amyloidosis in Japan.

A decision tree for genetic diagnosis of hereditary periodic fever in unselected patients.

BACKGROUND: The diagnostic value of molecular analysis of the familial Mediterranean fever (FMF) gene (Mediterranean fever (MEFV)) has been well established only in patients selected on the basis of ethnic background or clinical criteria. Genetic diagnosis for other hereditary periodic fever syndromes has been poorly evaluated. OBJECTIVE: To determine the diagnostic contribution of genetic tests for hereditary periodic syndromes in a large, unselected series of patients. METHODS: A retrospective study was conducted on 1941 patients referred to us for FMF genetic tests between 1997 and 2005. MEFV genotypes were compared with clinical data to appraise criteria for FMF diagnosis. Genetic tests for tumour necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinaemia D syndrome (HIDS) and cryopyrin-associated periodic syndromes (CAPS) were also reviewed. RESULTS: 71% of the 1574 patients with enough data had a clinical diagnosis of FMF according to the widely used Israeli criteria. Two MEFV mutations were found in only 409 patients of this subgroup (sensitivity = 37%) and in 15 (3.3%) of the patients with an improbable clinical diagnosis of FMF (specificity = 97%). Molecular diagnosis for alternate hereditary periodic syndromes was carried out in 456 of the patients having a non-conclusive FMF genetic test. A positive diagnosis was obtained in 31 of these patients (TRAPS (n = 19), HIDS (n = 4) and CAPS (n = 8)). CONCLUSIONS: First-line MEFV mutation screening in patients with clinically typical FMF may be appropriate only in particular areas. To optimise genetic diagnosis, we propose a decision tree, which, with the advice of an expert practitioner, could help redirect test indications towards non-FMF hereditary periodic syndromes.