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1.
Clin Exp Rheumatol ; 37 Suppl 121(6): 93-97, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31603074

RESUMO

OBJECTIVES: To evaluate differences between the patients with familial Mediterranean fever (FMF) with homozygous (Hom), heterozygous (Het) and compound heterozygous (cHet) MEFV mutations in terms of clinical features and severity of the disease, as well as frequency of concomitant disorders, without focusing on Exon 10 mutations. METHODS: The patients with FMF were diagnosed using the Tel-Hashomer diagnostic criteria. The presence of MEFV mutations was investigated in exons 2,3,5 and 10 by multiplex-PCR reverse hybridisation method. All the patients were questioned for the presence of concurrent disorders, and the medical records of these patients were revised retrospectively. RESULTS: 259 unrelated patients (female: 143, male: 116; mean age: 33.5±12 years) were included in this study. Hom and Het mutations were found in 79 (31.9%) and 88 (35.6%) patients with FMF, respectively. cHet mutations were found in 68 (27.5%) FMF patients. Early onset and early diagnosis of FMF were found in Hom group compared to Het and compound Het groups. The number of the patients with a higher severity score was significantly higher in Hom group (n=40, 50.6%) than Het (n=12, 13.6%) and cHet groups (n=10, 14.7%), (p<0.0001). No significant differences were found between the groups in terms of clinical features, except for erysipelas like erythema (ELE) (Hom group: 69.6% vs. Het group 37.5%, p<0.0001). Amyloidosis and concomitant disorders were found in 22 FMF patients with Hom MEFV mutations, 16 FMF patients with heterozygous mutations, 7 FMF patients with cHet mutations. CONCLUSIONS: While the presence of homozygous mutations creates tendency for a severe disease phenotype, the development of concomitant disorders seems to be independent of homozygous mutations.


Assuntos
Febre Familiar do Mediterrâneo , Adulto , Febre Familiar do Mediterrâneo/genética , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fenótipo , Pirina , Estudos Retrospectivos , Adulto Jovem
3.
Isr Med Assoc J ; 21(7): 487-490, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507126

RESUMO

BACKGROUND: Recurrent pericarditis is a state of repetitive inflammation of the pericardium with intervals of remission. The etiology of recurrent pericarditis is still largely unknown, yet most causes are presumed to be immune mediated. Genetic factors, including human leukocyte antigen (HLA) haplotypes, can be involved in dysregulation of the immune system and as a predisposition to several autoimmune conditions, including recurrent pericarditis. Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. However, idiopathic recurrent pericarditis remains the most frequently observed clinical condition and the conundrum of this disease still needs to be solved.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Pericardite/fisiopatologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Antígenos HLA/genética , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Pericardite/genética , Pericardite/imunologia , Recidiva
4.
Clin Exp Rheumatol ; 37 Suppl 121(6): 89-92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31376265

RESUMO

OBJECTIVES: We investigated a Turkish family with multiple patients presenting with familial Mediterranean fever (FMF) and Behçet's disease (BD)-like manifestations. The index case and the two daughters with Behçet-like disease, were previously found to have a TNFAIP3 frameshift mutation. The high number of affected cases in this expanded family could be consistent with a dominantly inherited inflammatory disease, although some individuals had clinical features more consistent with recessively inherited FMF. We sequenced DNA from members of this family to determine whether the TNFAIP3 frameshift mutation and/or MEFV variants could explain this autoinflammatory disease pedigree. METHODS: Patients were clinically diagnosed to have FMF or BD. Sanger sequence targeting TNFAIP3 exon 5 and MEFV exon 10 was carried out. RESULTS: The symptomatic mother of the index case and her affected maternal uncle had compound heterozygous FMF-associated MEFV mutations, p.Met680Ile and p.Arg761His. Two affected daughters of the maternal uncle also had compound heterozygous FMF-associated mutations, p.Met680Ile and p.Val726Ala. The index case and her two affected daughters had a TNFAIP3 frameshift mutation (c.799delG; p.Pro268Leufs*19), which is consistent with their HA20 diagnosis, and also carried a heterozygous MEFV p.Arg761His mutation. CONCLUSIONS: Autoinflammatory disease manifestations in a Turkish family with multiple affected cases could be explained by co-inheritance of pathogenic MEFV variants and a heterozygous HA20-associated mutation. FMF-associated p.Arg761His allele carried with the loss of function TNFAIP3 mutation by all three HA20 patients may contribute to their autoinflammatory phenotype and could also be responsible for their favourable response to colchicine.


Assuntos
Síndrome de Behçet , Febre Familiar do Mediterrâneo , Mutação/genética , Síndrome de Behçet/genética , Febre Familiar do Mediterrâneo/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haploinsuficiência , Heterozigoto , Humanos , Pirina , Turquia
5.
Intern Med ; 58(14): 2025-2028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308342

RESUMO

A 37-year-old man developed abdominal pain and the frequency of severe abdominal pain steadily increased to once a month. He was therefore admitted to our hospital. Abdominal CT showed bowel obstruction. It revealed transient stenosis in the small intestine. There were no symptoms such as fever or weight loss, it seemed unlikely that the patient had inflammatory bowel disease. Considering the history of recurrent abdominal pain, Familial Mediterranean Fever (FMF) was considered. As a result, a genetic analysis revealed mutations in exons 3 and 8 of the MEFV gene. We herein report the first known case of FMF with transient small bowel stenosis in Japan.


Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Pirina/genética , Dor Abdominal/etiologia , Adulto , Constrição Patológica , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/complicações , Febre/genética , Humanos , Obstrução Intestinal , Intestino Delgado , Japão , Masculino , Mutação
6.
Reumatismo ; 71(2): 85-87, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31309779

RESUMO

Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation.


Assuntos
Febre Familiar do Mediterrâneo/genética , Mutação , Pirina/genética , Criança , Humanos , Irã (Geográfico) , Masculino
7.
BMJ Case Rep ; 12(7)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266757

RESUMO

A 51-year-old South African female of Ashkenazi Jewish descent was admitted with acute pleuritic chest pain, shortness of breath, fatigue and fever. She experienced vague abdominal and calf pains for 30 years. Her monozygotic twin was investigated independently for recurrent abdominal pain. Despite initially responding to antibiotics, treating suspected pneumonia, she developed recurrent fevers and pleuritic chest pain. After thorough investigation without significant findings, she re-attended days after discharge with similar symptoms. Familial Mediterranean fever (FMF) was suggested as she met diagnostic criteria and responded to colchicine, though FMF normally presents before 20 years old. Genetic testing showed no pathogenic mutations but heterozygous P369S and R408Q mutations. The significance of these mutations remains unclear, as they are found in asymptomatic patients, suggesting incomplete penetrance. She remains well, with full symptom resolution, but mixed auto-inflammatory syndrome may be a more appropriate diagnosis in symptomatic patients with both P369S and R408Q mutations.


Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Mutação/genética , Colchicina/uso terapêutico , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/genética , Feminino , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Síndrome , Moduladores de Tubulina/uso terapêutico
8.
Clin Chim Acta ; 495: 562-569, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173732

RESUMO

BACKGROUND: Long-range PCR (LR-PCR) is used to enrich the target regions of the genome. This study aimed to establish the pipeline of targeted gene sequencing using LR-PCR and massively parallel sequencing (MPS). METHODS: The 14-kb-long MEFV gene, including the entire coding exons, was selected as a target gene and amplified using LR-PCR. The evaluated analytical factors were as follows: LR-PCR conditions, three types of post-PCR cleanup methods, and two types of MPS library preparation methods. RESULTS: With regard to LR-PCR conditions, Tks Gflex DNA polymerase at 7-min (30-s/kb) annealing/extension with 100-ng genomic DNA input had the highest yield. Regarding post-PCR purification methods, the magnetic beads-based method had high recovery and purity. In the MPS library preparation methods, the ligation-based method had a higher base coverage in the target (94.58%), uniformity of base coverage (99.95%), and target bases with no strand bias (97.40%). The exonic variants determined by Sanger sequencing were detected by both ligation- and transposon-based methods. CONCLUSIONS: Various analytical factors were evaluated, and the pipeline of targeted gene sequencing using LR-PCR and MPS was established. These data can enable the optimization of targeted gene sequencing using LR-PCR and MPS in the clinical laboratory.


Assuntos
DNA/sangue , DNA/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas de Diagnóstico Molecular/métodos , Pirina/genética , Sequência de Bases , Febre Familiar do Mediterrâneo/sangue , Biblioteca Gênica , Humanos , Reação em Cadeia da Polimerase em Tempo Real
9.
Zhonghua Er Ke Za Zhi ; 57(6): 477-482, 2019 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-31216807

RESUMO

Objective: To analyze the clinical manifestations and gene variations of tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Methods: Clinical data and gene testing of four children and three adult relatives in a family from Puning, Guangdong were retrospectively analyzed. CD4(+)T cells, CD8(+)T cells, B cells, monocytes and NK cells were assessed by flow cytometry. Plasma level of TNFR receptors were assessed by enzyme linked immunosorbent assay (ELISA). TNFRSF1A gene variation was identified by second generation sequencing. Swiss-Model was used to analyze the potential impact of TNFRSF1A gene variation on its protein tertiary structure. Results: For all the patients,periodic fever was the main clinical feature,combined with arthralgia,myalgia,multiple serositis,periorbital edema and migratory cutaneous rash,accompanied with elevated level of acute-phase reactants and increased white blood cell counts during each episode. This disease was found in both gender and every generation in this family. The median age of onset was 2 years, ranging from 6 months to 30 years. The plasma level of TNFR1 of the patients range from 0 to 12.4 ng/L,which was lower than that of the normal controls range from 18.0~22.2 ng/L,while the level of TNFR2 was normal. Also, the numbers of T cells, B cells and monocytes were within normal range; however,number of NK cells in the patients (0.070±0.034) was lower than that in the normal controls (0.152±0.122). The TNFRSF1A variation,located in exon 3: c.295T>A (p.C99S),was found in the proband as well as the other 6 family members,which could induce change of the side chain of amino acid according to the prediction of the three-dimensional structure,subsequently affecting the binding to the receptor. Conclusions: TRAPS is characterized by periodic fever,arthralgia,myalgia,multiple serositis,periorbital edema and migratory cutaneous rash,with a significant decrease in plasma level of TNFR1 and NK cells. The gene sequencing analysis revealed a pathogenic variation in TNFRSF1A gene.


Assuntos
Análise Mutacional de DNA/métodos , Febre Familiar do Mediterrâneo/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/genética , Adulto , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Éxons , Febre Familiar do Mediterrâneo/diagnóstico , Febre , Citometria de Fluxo , Doenças Hereditárias Autoinflamatórias , Humanos , Mutação , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Estudos Retrospectivos , Análise de Sequência de DNA
10.
Int J Immunogenet ; 46(4): 232-240, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31135083

RESUMO

Periodic fever syndromes (PFSs) are a family of clinical disorders, which are characterized by recurrent episodes of fever in the absence of microbial, autoimmune or malign conditions. Most common types of PFSs are associated with four genes: MEFV, MVK, TNFRSF1A and NLRP3. This paper aims to add new data to the genotype-phenotype association of MVK-, TNFRSF-1A- and NLRP3-associated PFSs. A total number of 211 patients were evaluated. Two different approaches were used for the molecular genetic evaluation of MVK-, TNFRSF-1A- and NLRP3-associated PFSs. For the first 147 patients, Sanger sequence analysis of selected exons of MVK, TNFRSF1A and NLRP3 genes was done. For subsequent 64 patients, targeted NGS panel analysis, covering all exons of MVK, TNFRSF1A and NLRP3 genes, was used. A total number of 48 variants were detected. The "variant detection rate in index patients" was higher in the NGS group than Sanger sequencing group (19% vs. 15,1%). For the variant positive patients, a detailed genotype-phenotype table was built. In PFSs, lack of correlation exists between genotype and phenotype in the general population and even within the families. In some cases, mutations behave differently and yield unexpected phenotypes. In this study, we discussed the clinical effects of eight different variants we have detected in the MVK, TNFRSF1A and NLRP3 genes. Four of them were previously identified in patients with PFS. The remaining four were not reported in patients with PFS. Thus, we had to interpret their clinical effects by analysing their frequencies and in silico analysis predictions. We suggest that new studies are needed to evaluate the effects of these variants more clearly. To be able to demonstrate a clearer genotype-phenotype relationship, all PFS-related genes should be analysed together and the possibility of polygenic inheritance should be considered.


Assuntos
Febre Familiar do Mediterrâneo/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Éxons , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/patologia , Feminino , Febre/genética , Febre/imunologia , Febre/patologia , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Mutação , Pirina/genética
11.
Med Arch ; 73(1): 55-57, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31097862

RESUMO

Introduction: The auto-inflammatory diseases (AID) are a heterogeneous group of multi-system disorders of innate immunity dysregulation. MEFV gene has major role in AID. Aim: The aim of this study is to investigate the frequency of MEFV variant alleles in gout patients as an AID and their genotype-phenotype relationship. Methods: Total amount of 224 of the healthy people as a control group (113 male and 111 female) and 24 gouty arthritis patients (20 male and 4 female) entered this study. Blood samples screened for the 12 common pathogenic mutations according to manufacturer's instructions. Results: The mean age of patients was 54 years. MTP joint was the most involved joint (91.66%). Mutations were shown in 5 patients (20.83%) that were not different from healthy population (25%). Five patients carry one mutated MEFV allele, E148Q in 4 patients and V726A in 1 patient. Control group showed 25% mutations as E148Q (18.3%), P369S (3.1%), V726A (2.2%), A744S (1.3%) respectively. The most common mutation detected in patients was E148Q (16.66%) and all of them were males. No significant and meaningful associations were detected between the MEFV gene mutations and gouty arthritis patients. Conclusion: There was not any correlation between MEFV gene mutations carriage with age, sex, the number of joint involvement and the course of disease in gouty arthritis. MEFV gene mutations were more frequent in men than women, but this is not statistically significant.


Assuntos
Febre Familiar do Mediterrâneo/genética , Gota/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Artrite Gotosa/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estudos Retrospectivos
12.
Pediatr Rheumatol Online J ; 17(1): 22, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088470

RESUMO

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease in Canada and is characterized by a clinical syndrome of episodic inflammatory symptoms. Traditionally, the disease is defined by autosomal recessive inheritance of MEFV gene variants, yet FMF also not uncommonly manifests in individuals with only one identified disease-associated allele. Increasing availability and affordability of gene sequencing has led to the identification of multiple MEFV variants; however, they are often of unknown clinical significance. Variants in other genes affecting overlapping or distinct inflammatory signaling pathways - together with gene-environment interactions including epigenetic modulation - likely underlie the significant genetic and phenotypic heterogeneity seen among patients with this disease. We review recent evidence of the expanding spectrum of FMF genotype and phenotype and suggest that current drug funding schemes restricting biologic agents to patients with homozygous mutations have not kept pace with our biological understanding of the disease.


Assuntos
Febre Familiar do Mediterrâneo/genética , Terapia Biológica/métodos , Criança , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/terapia , Genótipo , Humanos , Mutação/genética , Pirina/genética , Pirina/metabolismo
14.
PLoS Genet ; 15(4): e1008038, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946743

RESUMO

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1ß, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1ß, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1ß and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1ß function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.


Assuntos
Febre Familiar do Mediterrâneo/genética , Pirina/genética , Espondilite Anquilosante/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Febre Familiar do Mediterrâneo/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígeno HLA-B27/genética , Antígeno HLA-B51/genética , Humanos , Interleucina-1beta/sangue , Interleucina-23/sangue , Irã (Geográfico) , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/imunologia , Turquia
15.
Turk J Med Sci ; 49(2): 472-477, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30887796

RESUMO

Background/aim: The distribution of Mediterranean fever (MEFV) gene mutations in Turkish familial Mediterranean fever (FMF) patients varies according to geographic area of Turkey. There is a need for highly representative data for Turkish FMF patients. The aim of our study was to investigate the distribution of the common MEFV mutations in Turkish FMF patients in a nationwide, multicenter study. Materials and methods: Data of the 2246 FMF patients, from 15 adult rheumatology clinics located in different parts of the country, were evaluated retrospectively. The following mutations have been tested in all patients: M694V, M680I, M694I, V726A, and E148Q. Results: There were 1719 FMF patients with available genetic testing. According to the genotyping, homozygous M694V, present in 413 patients (24%), was the most common mutation . One hundred and fifty-four (9%) of patients had no detectable mutations. Allele frequencies of common mutations were: M694V (n = 1529, 44.5%), M680I (n = 423, 12.3%), V726A (n = 315, 9.2%), E148Q (n = 214, 1%), and M694I (n = 12, <1%). Conclusion: In this large-scale multicenter study, we provided information about the frequencies of common MEFV gene mutations obtained from adult Turkish FMF patients. Nearly half of the patients were carrying at least one M694V mutations in their alleles.


Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/genética , Genética Populacional , Mutação/genética , Pirina/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Testes Genéticos , Genética Populacional/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Estudos Retrospectivos , Turquia/epidemiologia , Adulto Jovem
16.
Clin Rheumatol ; 38(7): 1947-1952, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30826945

RESUMO

OBJECTIVE: To explore the frequency of MEFV gene mutations in children with Henoch-Schönlein purpura who had no prior familial Mediterranean fever diagnosis and to evaluate the association of MEFV mutations with the clinical and laboratory features of Henoch-Schönlein purpura. METHODS: Data of 1120 patients diagnosed with Henoch-Schönlein purpura were reviewed retrospectively. The spectrum and degree of organ involvement and acute phase reactant levels were documented for each patient. Blood for MEFV gene mutation analysis was obtained either at the time of the Henoch-Schönlein purpura diagnosis or during follow-up visits. Pathological specimens of patients who underwent biopsy (renal/skin) were evaluated with special consideration for immunofluorescent examinations. RESULTS: Two hundred and thirty-eight (21.3%) patients were found to have one of the MEFV mutations in which exon 10 mutations were the most common (16.7%). Abdominal pain, joint involvement, scrotal involvement, and relapse were more frequent, and acute-phase reactant levels were significantly high in patients with MEFV mutations. More severe characteristics were observed in the presence of homozygous exon 10 mutations. There was no significant association between exon 2 variants and clinical course of Henoch-Schönlein purpura. Patients carrying MEFV mutations did not have significantly higher levels of IgA deposits in the biopsy materials. CONCLUSION: Henoch-Schönlein purpura in patients with homozygous exon 10 MEFV mutations seems to be more severe than that in patients carrying other mutations. In patients with exon 10 MEFV mutations, Henoch-Schönlein purpura might be considered as an associated presentation of familial Mediterranean fever rather than a separate clinical entity. Key points • p.M694V mutation is more common in Henoch-Schönlein purpura than in the general population. • p.E148Q variants have no impact on clinical symptoms and laboratory findings in Henoch-Schönlein purpura patients. • The majority of Henoch-Schönlein purpura patients with familial Mediterranean fever have no IgA deposits. • Henoch-Schönlein purpura in familial Mediterranean fever patients may be considered as an integral clinical feature of familial Mediterranean fever.


Assuntos
Mutação , Púrpura de Schoenlein-Henoch/genética , Púrpura de Schoenlein-Henoch/patologia , Pirina/genética , Adolescente , Proteína C-Reativa/análise , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/genética , Feminino , Homozigoto , Humanos , Masculino , Estudos Retrospectivos
17.
Rheumatol Int ; 39(5): 911-919, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30783801

RESUMO

Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle-Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.


Assuntos
Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Adolescente , Adulto , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/genética , Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Feminino , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/genética , Pessoa de Meia-Idade , Proteínas de Transporte de Nucleosídeos/genética , Osteomielite/diagnóstico , Osteomielite/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Pirina/genética , Análise de Sequência de DNA , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Adulto Jovem
18.
J Clin Lab Anal ; 33(4): e22852, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30714637

RESUMO

BACKGROUND: Familial Mediterranean fever (FMF) is the most common hereditary monogenic autoinflammatory disease caused by mutations in the MEFV gene. It is controversial whether E148Q alteration is an insignificant variant or a disease-causing mutation. The aim of this study was to evaluate the clinical features and disease severity of FMF patients carrying E148Q mutation. METHODS: Files of FMF patients were retrospectively evaluated. Patients with at least one E148Q mutation were included to the study. The clinical characteristics and disease severity of the patients who were carrying only E148Q mutation were compared with the patients who were compound heterozygous for E148Q and homozygous for M694V mutation. RESULTS: The study group comprised 33 patients who were homozygous or heterozygous for E148Q; 34 with compound heterozygous E148Q mutations and 86 patients who had homozygous M694V mutation. Patients who had only E148Q mutation were found to have the oldest mean age of disease onset and lowest mean disease severity score. Attack frequency and colchicine doses were lower in patients with only E148Q mutation as compared with the other two groups. The frequency of clinical findings such as fever, abdominal pain, arthralgia, and arthritis among the three groups was similar. CONCLUSION: Familial Mediterranean fever patients with only E148Q mutation are presenting with late-onset and milder disease course despite having similar clinical findings as compared with patients who had other mutations. Finally, we imply that E148Q is a mutation and colchicine treatment should be given.


Assuntos
Febre Familiar do Mediterrâneo/etiologia , Mutação , Pirina/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Colchicina/uso terapêutico , Éxons , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Estudos Retrospectivos , Adulto Jovem
19.
Presse Med ; 48(1 Pt 2): e61-e76, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30686512

RESUMO

Familial Mediterranean Fever (FMF) is the oldest and the most frequent of all described hereditary periodic fever syndromes. The populations originating from Mediterranean basin carry the highest risk for FMF however it is being increasingly recognized in many parts of the world. It is an autoinflammatory disease with an autosomal recessive transmission. In the majority of the patients it is related with mutations in the MEFV gene that encodes a protein named pyrin. This protein has been shown to act as a regulator of inflammation mediated by IL-1ß, which plays a major role in the pathogenesis of FMF. Approximately one-third of the patients have either a single or no mutation which raise questions about its mode of inheritance. FMF is a clinical diagnosis and characterized by self-limited bouts of fever and serositis. The main long-term complication of the disease is AA amyloidosis. The mainstay of treatment is life-long colchicine given daily to prevent the recurrence of febrile attacks and the development of amyloidosis. Patients with insufficient response to colchicine may be treated with anti IL-1 agents.


Assuntos
Febre Familiar do Mediterrâneo , Idade de Início , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Feminino , Estudos de Associação Genética , Humanos , Imunidade Inata , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Masculino , Gravidez , Complicações na Gravidez/genética , Pirina/deficiência , Pirina/genética , Pirina/fisiologia
20.
Int J Lab Hematol ; 41(2): 293-297, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30624866

RESUMO

INTRODUCTION: Few data are available on the clinical utility of new red cell parameters for detecting anemia in children with inflammatory diseases. The aim was to investigate the utility of three new red cell parameters for distinguishing functional iron deficiency (FID) from absolute iron deficiency (AID) in children with familial Mediterranean fever (FMF). METHODS: The study involved 198 children with genetically confirmed FMF and 18 healthy-age and sex-matched controls. Complete blood counts with the new red cell parameters of low hemoglobin (Hb) density (LHD), microcytic anemia factor (MAF), and red blood cell size factor (RSF) were measured in a Unicel® DxH800, along with conventional iron parameters. The FMF patients' medical records were retrospectively reviewed to assess inflammation status and genetic results. RESULTS: The frequencies of FID and AID among the 198 FMF patients were 35% and 65%, respectively. Among patients with homozygous MEFV mutation, FID was more common than AID (P < 0.05). Mean LHD was significantly higher and mean Hb, MCV, MAF, and RSF were significantly lower among the FMF patients with FID compared to those with AID and controls (P < 0.05). Specificity for distinguishing FID from AID in children with FMF was greatest for MAF (92%; 95% confidence interval [CI] 85%-96%), followed by LHD (85%; 95% CI 76%-91%) and RSF (81%; 95% CI 72%-88%). CONCLUSION: The new red cell parameters measured by the Unicel® DxH800 may be useful for guiding physicians in distinguishing FID from AID in children with FMF.


Assuntos
Eritrócitos/metabolismo , Febre Familiar do Mediterrâneo/sangue , Ferro/deficiência , Adolescente , Criança , Pré-Escolar , Contagem de Eritrócitos/instrumentação , Contagem de Eritrócitos/métodos , Eritrócitos/patologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/patologia , Feminino , Humanos , Lactente , Ferro/sangue , Masculino
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