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1.
Medicina (Kaunas) ; 57(2)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525390

RESUMO

Uncertainty analysis is the process of identifying limitations in knowledge and evaluating their implications for scientific conclusions. Uncertainty analysis is a stable component of risk assessment and is increasingly used in decision making on complex health issues. Uncertainties should be identified in a structured way and prioritized according to their likely impact on the outcome of scientific conclusions. Uncertainty is inherent to the rare diseases (RD) area, where research and healthcare have to cope with knowledge gaps due to the rarity of the conditions; yet a systematic approach toward uncertainties is not usually undertaken. The uncertainty issue is particularly relevant to multifactorial RD, whose etiopathogenesis involves environmental factors and genetic predisposition. Three case studies are presented: the newly recognized acute multisystem inflammatory syndrome in children and adolescents associated with SARS-CoV-2 infection; the assessment of risk factors for neural tube defects; and the genotype-phenotype correlation in familial Mediterranean fever. Each case study proposes the initial identification of the main epistemic and sampling uncertainties and their impacts. Uncertainty analysis in RD may present aspects similar to those encountered when conducting risk assessment in data-poor scenarios; therefore, approaches such as expert knowledge elicitation may be considered. The RD community has a main strength in managing uncertainty, as it proactively develops stakeholder involvement, data sharing and open science. The open science approaches can be profitably integrated by structured uncertainty analysis, especially when dealing with multifactorial RD involving environmental and genetic risk factors.


Assuntos
/epidemiologia , Febre Familiar do Mediterrâneo/epidemiologia , Defeitos do Tubo Neural/epidemiologia , Doenças Raras/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Incerteza , Causalidade , Febre Familiar do Mediterrâneo/genética , Genótipo , Humanos , Conhecimento , Fenótipo , Doenças Raras/etiologia , Medição de Risco , Fatores de Risco
2.
Clin Exp Rheumatol ; 38 Suppl 127(5): 49-52, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33331265

RESUMO

OBJECTIVES: The modification and pathogenesis of MEFV exon 2 or 3 variants in familial Mediterranean fever (FMF) remains unclear. We compared the clinical and laboratory characteristics between the coexistence and noncoexistence of MEFV exon 2 or 3 variants in patients with FMF that had a heterozygous MEFV exon 10 mutation. METHODS: We excluded patients with FMF that had two MEFV exon 10 mutations in one or more alleles and/or MEFV mutations in exons other than in exons 2, 3, or 10. Finally, we reviewed 131 Japanese patients with FMF that had a heterozygous MEFV exon 10 mutation, and they were divided into the groups with and without MEFV exon 2 or 3 variants of 97 and 34, respectively. RESULTS: All patients with MEFV exon 2 variants had either E148Q and/or L110P variants, none of patients had exon 3 variants. In the univariate analysis, the group with variants had significantly earlier onset, a higher percentage of thoracic pain with febrile attacks, a higher frequency of attack, and a higher IL-18 level at remission compared to the group without variants (all, p<0.05). Importantly, multivariate analyses showed that the coexistence of MEFV exon 2 variants was independently and significantly associated with earlier onset of FMF and thoracic pain (both, p<0.05). CONCLUSIONS: Our results suggested that coexistence of MEFV exon 2 variants have additional effects on manifestations of FMF with MEFV exon 10 mutations. Our findings highlighted the modifications and pathogenesis of such MEFV variants in FMF.


Assuntos
Febre Familiar do Mediterrâneo , Inflamassomos , Éxons , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Humanos , Japão , Mutação , Pirina/genética
4.
Nihon Shokakibyo Gakkai Zasshi ; 117(11): 978-984, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33177260

RESUMO

A 69-year-old man had been intermittently experiencing abdominal pain from his 30s and was diagnosed with colonic diverticulitis. He further experienced right lower abdominal pain and received treatment. However, his condition did not improve, and he was referred to the National Defense Medical College Hospital. His abdominal pain episodes continued even after treatment for few weeks;subsequently, familial Mediterranean fever (FMF) was suspected based on the clinical course because of elevated inflammatory responses, although his body temperature was ≤38°C. After administrating colchicine as a diagnostic treatment, the repeated abdominal pain disappeared. Considering the other findings and genetic examination that showed the representative gene mutation of MEFV (M694I), he was diagnosed with FMF. This case indicates that high body temperature, one of the primary diagnostic criteria of FMF, is sometimes not evident in elderly patients, thereby causing potential misdiagnosis in some elderly patients with FMF.


Assuntos
Doença Diverticular do Colo , Febre Familiar do Mediterrâneo , Dor Abdominal/etiologia , Idoso , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Febre , Humanos , Masculino , Mutação , Pirina/genética
5.
Front Immunol ; 11: 574593, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072117

RESUMO

Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein - whose mutations cause FMF- in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.


Assuntos
Betacoronavirus , Colchicina/uso terapêutico , Infecções por Coronavirus , Febre Familiar do Mediterrâneo , Mutação , Pandemias , Pneumonia Viral , Pirina , Animais , Betacoronavirus/genética , Betacoronavirus/imunologia , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pirina/genética , Pirina/imunologia
8.
Nat Immunol ; 21(8): 857-867, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601469

RESUMO

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.


Assuntos
Resistência à Doença/genética , Febre Familiar do Mediterrâneo/genética , Peste , Pirina/genética , Seleção Genética/genética , Animais , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Resistência à Doença/imunologia , Haplótipos , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Peste/imunologia , Peste/metabolismo , Pirina/imunologia , Pirina/metabolismo , Turquia , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo , Yersinia pestis
9.
Intern Med ; 59(11): 1373-1378, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32475906

RESUMO

Objective Familial Mediterranean Fever (FMF) is the most frequent autoinflammatory syndrome, and its frequency is reported to be increasing in Japan. We studied the clinical features and genetic background of patients with FMF in our hospital. Methods We analyzed the clinical features and genomic variants of MEFV, as well as 10 genes related to other autoinflammatory syndromes, in 22 Japanese patients with FMF. A genetic analysis was performed with a next generation sequencer. Results The patients were classified into the typical FMF (n=16) and atypical FMF (n=6) groups. Fever, abdominal pain, thoracic pain, and arthralgia were observed in 22, 12, 8, and 10 patients, respectively. MEFV variants were found in 19 patients (86.4%). Two cases had no MEFV variants and one case only had a variant in the 3' untranslated region (3'-UTR) of MEFV. Genomic variants were found in genes other than MEFV in 7 patients (31.8%); however, none met the diagnostic criteria for autoinflammatory syndromes with disease-related gene variants, and all were classified as typical FMF. Moreover, none of the 6 patients with atypical FMF had any variants among the 10 disease-related genes. All cases in which the onset occurred before 20 years of age were classified as typical FMF. Conclusion The clinical features of FMF recorded in our hospital coincided with those from the Japanese national epidemiological survey of FMF in Japan. More than 30% of the patients with FMF had non-MEFV genes, related to other autoinflammatory syndromes, thereby suggesting that variants of these genes may act as a disease-modifier in FMF.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/fisiopatologia , Predisposição Genética para Doença , Pirina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Testes Diagnósticos de Rotina , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Ann Rheum Dis ; 79(7): 960-968, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32312770

RESUMO

BACKGROUND AND OBJECTIVE: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype-phenotype association for most of the 340 reported MEFV variants. In this study, the authors designed a functional assay and evaluated its potential in supporting FMF diagnosis. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Pyrin-associated autoinflammation with an FMF phenotype (n=43) or with autoinflammatory features not compatible with FMF (n=8), 10 asymptomatic carriers and 48 healthy donors. Sera were obtained from patients with distinct AIDs (n=10), and whole blood from a subset of patients and controls. The clinical, demographic, molecular genetic factors and other characteristics of the patient population were assessed for their impact on the diagnostic test read-out. Interleukin (IL)-1ß and IL-18 levels were measured by Luminex assay. RESULTS: The ex vivo colchicine assay may be performed on whole blood or PBMC. The functional assay robustly segregated patients with FMF from healthy controls and patients with related clinical disorders. The diagnostic test distinguished patients with classical FMF mutations (M694V, M694I, M680I, R761H) from patients with other MEFV mutations and variants (K695R, P369S, R202Q, E148Q) that are considered benign or of uncertain clinical significance. CONCLUSION: The ex vivo colchicine assay may support diagnosis of FMF and functional subtyping of Pyrin-associated autoinflammation.


Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Imunofenotipagem/métodos , Pirina/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Colchicina/análise , Febre Familiar do Mediterrâneo/genética , Feminino , Estudos de Associação Genética , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Pirina/genética , Adulto Jovem
11.
Z Rheumatol ; 79(7): 649-659, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32253511

RESUMO

Autoinflammatory syndromes (AIS) are characterized by uniform attacks often with febrile episodes, exanthema, abdominal pain, muscle and joint pain. Patients show markedly elevated levels of the inflammatory serum parameters C­reactive protein (CRP) and systemic amyloid A (SAA) during an attack. The origin of the family of the patient and the duration of the attacks are helpful to find the appropriate diagnosis. Molecular genetic tests are used to confirm the clinical diagnosis of an AIS. Colchicine can prevent attacks of familial Mediterranean fever but not the other forms of AIS. In refractory cases anakinra or canakinumab can be used to control the inflammatory exacerbations. Systemic AA amyloidosis can develop secondary to any insufficiently treated chronic inflammatory disease. Renal involvement is the predominant initial organ dysfunction, which can be detected early on by the evaluation of proteinuria. If AA amyloidosis can be diagnosed early and successfully treated, the renal function and the function of other organs can be preserved for many years. In patients with advanced AA amyloidosis renal failure with the subsequent necessity for dialysis can often no longer be prevented. These patients should be treated to prevent involvement of the stomach, intestines and heart.


Assuntos
Amiloidose , Febre Familiar do Mediterrâneo , Amiloidose/diagnóstico , Amiloidose/terapia , Colchicina , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Síndrome
12.
Intern Med ; 59(10): 1267-1270, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32051376

RESUMO

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease commonly observed around the Mediterranean basin presenting as recurrent febrile episodes. We herein describe a Japanese case of genetically-confirmed FMF, in which fever was lacking during attacks. An otherwise healthy 34-year-old man presented with frequent episodes of abdominal pain, which resolved spontaneously. During the attacks, the patient was afebrile, but the inflammatory marker levels in his blood were increased. Abdominal CT demonstrated enhancement of the jejunal membrane. After the initiation of colchicine therapy, the patient experienced no attacks for more than one year. The diagnosis of FMF was confirmed by a genetic analysis.


Assuntos
Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Dor Abdominal/etiologia , Adulto , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Testes Genéticos , Humanos , Mediadores da Inflamação , Masculino
13.
Postgrad Med ; 132(2): 220-224, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31903829

RESUMO

Objectives: Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent, self limited attacks of fever with serositis. The aim of this study was to describe the frequency of musculoskeletal complaints in children with FMF and to investigate the effect of genotype on these findings.Methods: Files of patients who had been seen in our department (during routine follow-up visits) were retrospectively evaluated. Comparisons regarding musculoskeletal findings were performed between patients with homozygous/compound heterozygous and heterozygous mutations. Thereafter, patients with two mutations were divided into three groups; M694V/M694V, M694V/other mutation, and patients carrying two mutations other than M694V. Patients with single mutation were divided into two groups; M694V and non M694V carriers.Results: The study group comprised 317 FMF patients (170 females) with a mean age of 12.2 ± 5.7 years. Arthralgia (42.6%), leg pain (42.9%), and heel pain (35.6%) were the most common musculoskeletal complaints in children with FMF. Frequency of musculoskeletal findings of the patients who had two mutations did not differ from the patients with single mutations (p > 0.05). Leg and heel pain were more frequently detected in patients with homozygous M694V mutation (p = 0.001). Among patients with heterozygous mutations; children with M694V mutation had more frequently arthralgia, leg, and heel pain (p < 0.05).Conclusions: Musculoskeletal problems were commonly encountered in patients with FMF. Genotype seems to affect the frequency of these problems and M694V mutation is a predisposing factor for musculoskeletal complaints.


Assuntos
Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/genética , Doenças Musculoesqueléticas/etiologia , Adolescente , Criança , Feminino , Genótipo , Humanos , Masculino , Estudos Retrospectivos
14.
Mol Biol Rep ; 47(3): 1835-1843, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31989427

RESUMO

Familial Mediterranean fever is an auto inflammatory genetic disease involving especially Turks, Armenians, Arabs and non-Ashkenazi Jews and caused by variants in the MEFV gene. In this study, we aimed to evaluate the distribution and frequency of clinical, MEFV gene variants in FMF patients and the relationship between mutations in different exons and phenotype-genotype and clinical findings. 1028 patients diagnosed as FMF were included. The most common genotypes were M694V / R202Q heterozygous (10.4%), M694V homozygous (7.5%), M694V / E148Q / R202Q heterozygous (4.6%), V726A heterozygous (4.5%), M680I heterozygous (4.2%). c.1611-1 G > C, G152R, S104C, R116S, E336K, R461Q mutations were detected in the literature for the first time in FMF patients. We also divided the patients into 4 groups according to whether the MEFV mutations were exon 10 or non-exon 10. The first group consisted of non-exon 10 homozygous or compound heterozygous (n = 180) patients, Group 2 consisted of exon 10- non-exon 10 compound heterozygous (n = 318) patients, Group 3 consisted of exon 10 homozygous or compound heterozygous (n = 256) patients, while Group 4 consisted of heterozygous (n = 227) patients at any exon. There was no significant difference between the groups in terms of abdominal pain, arthritis, arthralgia, vomiting diarrhea, erysipelas like rash, amyloidosis, renal failure family history. There was no difference in fever between Group 1 (55.6%) and 2 (62.3%); however, these two groups were different from Group 3 (75.8%) and 4 (76.7%). Group 3 (18.8%) had the highest rate of appendectomy. In addition, allele frequencies of all mutations detected in the analyses were compared with allele frequencies of healthy people in the gnomad database. It is useful to analyse all exons in the MEFV gene with the next generation sequence analysis in the detection of FMF disease. S104C, R116S, G152R, E336K, R461Q, L508Q and c.1611-1 G > C mutations are also new variants in literature. c.1611-1 G > C is a possible pathogenic variant.


Assuntos
Febre Familiar do Mediterrâneo/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Pirina/genética , Adolescente , Adulto , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Análise de Sequência de DNA/métodos , Adulto Jovem
15.
Ital J Pediatr ; 46(1): 7, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941537

RESUMO

Familial Mediterranean Fever, a monogenic autoinflammatory disease secondary to MEFV gene mutations in the chromosome 16p13, is characterized by recurrent self-limiting attacks of fever, arthritis, aphthous changes in lips and/or oral mucosa, erythema, serositis. It is caused by dysregulation of the inflammasome, a complex intracellular multiprotein structure, commanding the overproduction of interleukin 1. Familial Mediterranean Fever can be associated with other multifactorial autoinflammatory diseases, as vasculitis and Behçet disease.Symptoms frequently start before 20 years of age and are characterized by a more severe phenotype in patients who begin earlier.Attacks consist of fever, serositis, arthritis and high levels of inflammatory reactants: C-reactive protein, erythrocyte sedimentation rate, serum amyloid A associated with leucocytosis and neutrophilia. The symptom-free intervals are of different length.The attacks of Familial Mediterranean Fever can have a trigger, as infections, stress, menses, exposure to cold, fat-rich food, drugs.The diagnosis needs a clinical definition of the disease and a genetic confirmation. An accurate differential diagnosis is mandatory to exclude infective agents, autoimmune diseases, etc.In many patients there is no genetic confirmation of the disease; furthermore, some subjects with the relieve of MEFV mutations, show a phenotype not in line with the diagnosis of Familial Mediterranean Fever. For these reasons, diagnostic criteria were developed, as Tel Hashomer Hospital criteria, the "Turkish FMF Paediatric criteria", the "clinical classification criteria for autoinflammatory periodic fevers" formulated by PRINTO.The goals of the treatment are: prevention of attacks recurrence, normalization of inflammatory markers, control of subclinical inflammation in attacks-free intervals and prevention of medium and long-term complications, as amyloidosis. Colchicine is the first step in the treatment; biological drugs are effective in non-responder patients.The goal of this paper is to give a wide and broad review to general paediatricians on Familial Mediterranean Fever, with the relative diagnostic, clinical and therapeutic aspects.


Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/terapia , Biomarcadores/sangue , Criança , Colchicina/uso terapêutico , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/genética , Humanos , Fenótipo , Moduladores de Tubulina/uso terapêutico
16.
Eur J Med Genet ; 63(4): 103780, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31586650

RESUMO

Tumor necrosis factor receptor associated periodic fever syndrome (TRAPS) is caused by heterozygote mutations in TNFRSF1A, characterized by recurrent inflammatory attacks. In this report, we described two patients with different heterozygote mutations in TNFRSF1A. Patient 1, a 15-year-old male, had suffered from recurrent fever attacks accompanied by abdominal pain, eye manifestations, and myalgia with increased acute phase reactants since the age of 6-month. He had been unsuccessfully treated with colchicine for having familial Mediterranean fever without an identifiable MEFV mutation since the age of 4-year. At the age of 15 years, he was diagnosed with immunoglobulin (Ig) A nephropathy due to massive proteinuria and renal biopsy findings. Next generation sequencing revealed NM_001065.3: c.236C>T; p. (Thr79Met); T50M heterozygote mutation in TNFRFS1A. He was treated with methylprednisolone and cyclosporine for IgA nephropathy, thereafter with canakinumab for TRAPS. Patient 2, a 17-year-old female, had recurrent arthritis attacks accompanied by increased acute phase reactants for the last two months. She had neither fever attacks nor rashes or myalgia. Her physical examination was normal between attacks. Magnetic resonance imaging of both knees and ankles showed no signs of chronic arthritis. MEFV analyzes showed no mutation. Next generation sequencing revealed NM_001065.3: c.362G>A; p.(Arg121Gln); R92Q heterozygote mutation in TNFRFS1A. Arthritis attacks were treated successfully with ibuprofen thereafter. In conclusion, we wish to emphasize the diversity of the clinical manifestations between these two patients with distinct sequence variants in TNFRSF1A. Moreover, we presented a rare manifestation of TRAPS, IgA nephropathy.


Assuntos
Variação Biológica da População , Febre Familiar do Mediterrâneo/genética , Predisposição Genética para Doença , Glomerulonefrite por IGA/patologia , Mutação , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Adolescente , Febre Familiar do Mediterrâneo/patologia , Feminino , Glomerulonefrite por IGA/genética , Humanos , Masculino , Prognóstico , Síndrome
17.
Rheumatology (Oxford) ; 59(6): 1372-1380, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31598713

RESUMO

OBJECTIVES: FMF is the most common periodic fever syndrome, characterized by recurrent episodes of fever and serosal inflammation accompanied with high acute phase reactants. The analysis of possible comorbidities is important to understand the impact of these conditions on clinical care and whether they share a common aetiological pathway. In this study, we aimed to evaluate the comorbidities associated with FMF patients in a large genetically diagnosed cohort. METHODS: We retrospectively evaluated the medical and genetic records of FMF patients who were followed up by rheumatologists in Hacettepe University for 15 years. The FMF patients who had homozygous or compound heterozygous mutations were included in the study. Comorbidities associated with FMF were divided into three groups: (i) comorbidities directly related to FMF, (ii) comorbidities due to increased innate inflammation, and (iii) comorbidities that were regarded as being incidental. RESULTS: A total of 2000 patients with a diagnosis of FMF were enrolled in the study. Among them 636 were children (31.8%) and M694V was the most common mutation in patients with associated inflammatory conditions. The frequency of AS, Iga Vasculitis (Henoch-Schönlein purpura), juvenile idiopathic arthritis, polyarteritis nodosa, multiple sclerosis and Behçet's disease were increased in patients with FMF when compared with those in the literature. CONCLUSION: This study represents the largest genetically confirmed cohort and compares the frequencies with existing national and international figures for each disease. The increased innate immune system inflammation seen in FMF may be considered as a susceptibility factor since it predisposes to certain inflammatory conditions.


Assuntos
Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Pirina/genética , Adolescente , Adulto , Amiloidose/epidemiologia , Amiloidose/genética , Artrite Juvenil/epidemiologia , Artrite Juvenil/genética , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/genética , Criança , Comorbidade , Feminino , Humanos , Masculino , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Mutação , Poliarterite Nodosa/epidemiologia , Poliarterite Nodosa/genética , Púrpura de Schoenlein-Henoch/epidemiologia , Púrpura de Schoenlein-Henoch/genética , Estudos Retrospectivos , Adulto Jovem
18.
Clin Rheumatol ; 39(1): 255-261, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31502094

RESUMO

INTRODUCTION/OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever, serositis, and arthritis, but some patients may experience long-term complications of disease such as infertility/subfertility. The published data about FMF-associated infertility is still limited. The aim of this study is to investigate the frequency and to determine potential factors for FMF-associated infertility/subfertility. METHODS: We enrolled 971 adult patients with FMF. We defined infertility as the failure to conceive after 12 months of regular, unprotected intercourse. All patients fulfilled Tel Hashomer criteria. Demographic data, FMF disease characteristics and genotype data (if available), disease complications, laboratory parameters, and treatment features were recorded. RESULTS: There were 582 subjects eligible for the present study (mean age 41.05 ± 10.6 years, 65.8% female). MEFV mutations were available in 482 subjects, and 74.9% of subjects were harboring M694 V mutation (25.1% homozygous for M694 V). Infertility was present in 64 patients (14.6% of females and 4% of males). Multivariate analysis showed female sex [odds ratio (OR), 4.47; 95% confidence interval (CI95%) 1.75-11.42; p = 0.002], FMF disease onset < 20 years [OR, 2.99; (CI95% 1.04-8.61);p = 0.04], disease severity (ISSF) [OR, 4.81; (CI95% 2.28-10.17); p < 0.001], and colchicine nonresponse [OR, 2.80; (CI95% 1.17-6.74) p = 0.021] were the independent predictors of infertility. We also observed reversal of infertility in five patients who were treated with IL-1 ß antagonists. CONCLUSION: Disease severity, FMF disease onset < 20 years, colchicine nonresponse, and female sex were found to be the independent predictors of infertility. The value of effective therapeutic interventions must be determined to treat infertility in these patients.Key Points•The prevalence of infertility increased in female patients with FMF.• Female sex, FMF disease onset < 20 years, disease severity, and colchicine nonresponse were risk factors for FMF-associated infertility.• With effective treatment of FMF, reversal of infertility was observed in five patients.


Assuntos
Febre Familiar do Mediterrâneo/complicações , Infertilidade/etiologia , Adulto , Colchicina/uso terapêutico , Progressão da Doença , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Feminino , Genótipo , Homozigoto , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mutação , Pirina/genética , Fatores de Risco , Índice de Gravidade de Doença , Turquia/epidemiologia
19.
Intern Med ; 59(1): 125-128, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31511485

RESUMO

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by a recurrent fever and multiple serositis. In the present report, we discuss the case of a 42-year-old man diagnosed with FMF accompanied by recurrent aseptic meningitis (RAM). The patient experienced RAM at intervals of several years without any serositis or synovitis. We detected Mediterranean fever (MEFV) gene mutations (E148Q homozygotes) and diagnosed FMF in perfect accordance with clinical diagnostic criteria. FMF, in which RAM is a major symptom, has also been described in previous reports. Therefore, FMF should be considered in the differential diagnosis of causative diseases for RAM.


Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Meningite Asséptica/diagnóstico , Adulto , Colchicina/uso terapêutico , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Homozigoto , Humanos , Japão , Masculino , Meningite Asséptica/etiologia , Mutação , Pirina/genética , Recidiva , Moduladores de Tubulina/uso terapêutico
20.
Clin Rheumatol ; 39(2): 585-594, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31401792

RESUMO

An 86-year-old Caucasian man had prior episodes of fever (up to 38 °C), mild abdominal pain, tachycardia, and malaise in the last 3 months, lasting 2-3 days. He never suffered from abdominal or chest pain, rash, or arthralgia. Major causes of fever were excluded (pulmonary, urinary, abdomen, skin infections, neoplasms, and major rheumatologic disorders). The patient was native of Altamura with a family history of familial Mediterranean fever (FMF). The genetic testing confirmed the presence of MEFV gene variants c.442G>C (E148Q) on exon 2 and c.2282G>A (R761H) on exon 10, all in heterozygosity. Mildly elevated serum transaminases suggested an ongoing form of FMF hepatitis on nonalcoholic liver steatosis. The patient started colchicine 1 mg/day that induced symptom control and normalization of inflammatory markers, hyperbilirubinemia, and markers of cholestasis. Symptoms of FMF can appear at any age in life and our patient represents a very late-onset clinical case. The Apulian region has a consistent clustering of MEFV variants and FMF families with affected individuals in multiple consecutive generations. Families show unique clinical features and rare signs of secondary amyloidosis without kidney damage. Genetic and environmental bases of this phenotypic variant are under scrutiny. Colchicine lifetime remains the mainstay of treatment in FMF patients. KEY POINTS: • Familial Mediterranean fever (FMF) is the most frequent hereditary monogenic recurrent fever syndrome, and symptoms can appear at any age in life. • Late-onset FMF approaches 30% in late adulthood, but in general, onset of FMF after the age of 40 (late onset FMF) is rare, usually associated with M694V heterozygosity. • In a local cluster of FMF families (Altamura, Puglia, Southern Italy), we report a very late-onset FMF (variants E148Q, R761H) in an 86-year-old patient with a positive family history of FMF in two generations of descendants. • While lifetime colchicine remains the mainstay of treatment in FMF patients, prospective studies need to identify the characteristics of several phenotypic variants accounting for (very)-late onset FMF.


Assuntos
Febre Familiar do Mediterrâneo/genética , Pirina/genética , Idade de Início , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Linhagem
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