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OBJECTIVE: Immunoglobulin-A vasculitis (IgAV) is an inflammatory disease that affects small blood vessels. This study was performed to identify an association between protein tyrosine phosphatase non-receptor type 22 (PTPN22) + 788G > A (rs33996649), transforming growth factor-beta (TGF-ß) -509C > T (rs18004069), interleukin 1-beta (IL-1ß) -511C > T (rs16944), interleukin 5 (IL-5) -746C/T (rs2069812), and angiotensin-converting enzyme (ACE) I/D (rs4646994) gene polymorphisms, susceptibility to IgAV, as well as the mRNA levels of IL-1ß, IL-1ß, and TGF-ß. METHOD: A total of 53 patients with IgAV and 50 healthy controls were enrolled. PTPN22, TGF-ß, IL-1ß, ACE gene polymorphisms, ACE gene I/D polymorphisms, and mRNA expression levels were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, allele-specific PCR, and real-time PCR with TaqMan kits, respectively. RESULTS: PTPN22, TGF-ß, IL-1ß, IL-5, and ACE variants showed no genotype or allele differences between patients with IgAV and controls. Increased levels of IL-1ß and TGF-ß mRNA expressions were observed in patients with IgAV (p < 0.001). Patients with the IL-1ß AG genotype showed significantly increased amounts of arthritis than patients with non-AG (p = 0.004). Age at disease onset was found to be significantly different in patients with IgAV according to the presence of TGF-ß TT genotype (p = 0.047). CONCLUSION: Polymorphisms in PTPN22, TGF-ß, IL-5, IL-1ß, and ACE genes are unlikely to confer susceptibility to IgAV. However, the presence of the AG genotype of IL-1ß is associated with susceptibility to IgAV-related arthritis. This is the first study to report a significant increase in serum mRNA levels of IL-1ß and TGF-ß in IgAV patients, supporting a susceptibility to IgAV in childhood.
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Artritis , Vasculitis por IgA , Niño , Humanos , Interleucina-5/genética , Vasculitis por IgA/genética , Factor de Crecimiento Transformador beta/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético/genética , Genotipo , Reacción en Cadena en Tiempo Real de la Polimerasa , ARN Mensajero/genética , Expresión Génica , Predisposición Genética a la Enfermedad , Frecuencia de los Genes/genética , Estudios de Casos y Controles , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
OBJECTIVES: Alkaptonuria is a rare autosomal recessive genetic disorder resulting from the deficiency of homogentisate 1,2 dioxygenase (HGD), the third enzyme in the tyrosine degradation pathway. Homogentisic acid produced in excess oxidizes into ochronotic pigment polymer. Accumulation of this pigment in various tissues leads to systemic disease. METHODS: Clinical, laboratory, molecular findings and treatment characteristics of 35 patients followed up in Ege University Pediatric Nutrition, and Metabolism Department with the diagnosis of alkaptonuria were evaluated retrospectively. RESULTS: Twenty-four males (68.57%) and 11 females (31.42%) with a confirmed diagnosis of alkaptonuria from 32 different families were included in the study. We identified 11 different genetic variants; six of these were novel. c.1033C>T, c.676G>A, c.664G>A, c.731_734del, c.1009G>T, c.859_862delins ATAC were not previously reported in the literature. 24 (68.57%) patients only adhered to a low-protein diet in our study group. Seven (20%) patients initiated a low protein diet and NTBC therapy. Mean urinary HGA decreased by 88.7% with nitisinone. No statistical changes were detected in urinary HGA excretion with the low protein diet group. CONCLUSIONS: In our study, alkaptonuria patients were diagnosed at different ages, from infancy to adulthood, and progressed with other systemic involvement in the follow-up. Since the initial period is asymptomatic, giving potentially effective treatment from an early age is under discussion. Raising disease awareness is very important in reducing disease mortality and morbidity rates.
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Alcaptonuria , Adulto , Alcaptonuria/diagnóstico , Alcaptonuria/epidemiología , Alcaptonuria/genética , Niño , Femenino , Estudios de Seguimiento , Homogentisato 1,2-Dioxigenasa/genética , Homogentisato 1,2-Dioxigenasa/metabolismo , Ácido Homogentísico/metabolismo , Humanos , Masculino , Estudios Retrospectivos , TirosinaRESUMEN
Objective: In this study, we aimed to evaluate other interleukin-1b-mediated monogenic autoinflam- matory diseases (AIDs) (tumor necrosis factor receptor-1-associated periodic syndrome, hyperimmuno- globulin D syndrome, cryopyrin-associated periodic syndrome (CAPS), pyogenic arthritis, pyoderma gangrenosum, and acne syndrome) by the next-generation sequencing method (NGS) in cases with clinical Familial Mediterranean Fever symptoms, and no variant detected in the MEFV gene. Methods: The cases included in this study and their parents were interviewed and filled in a survey form. The targeted genetic panel for interleukin-1b-mediated AIDs covering four genes (MVK, NLRP3,TNFRSF1A, and PSTPIP1) was studied for cases with a negative result from the MEFV gene analysis. The genetic analysis was conducted using the targeted NGS method. Results: Variants were found in 16 out of the 40 patients in the study sample. These variants were pri- orly reported in variant databases, and three of them were identified as definitely pathogenic (V377I of the MVK gene, C52Y of the TNFRSF1A gene, and I313V of the NLRP3 gene), four as a variant of uncer- tain significance (VUS) (R92Q of the TNFRSF1A, A372V of the PSTPIP1, and V198M and Q703K of the NLRP3), and one as benign polymorphism (S52N of the MVK gene). The median age of onset among variant-positive cases was 10.5 (3.5-18) years. The most common clinical findings in the variant-positive group were arthralgia, fever, and abdominal pain. While three out of 40 patients met the classification criteria before genetic analysis, only one patient was diagnosed with CAPS as a result of genetic analy- sis, and other patients were considered as nonspecific phenotype. Conclusion: The use of NGS gene panels seems beneficial in diseases with heterogeneous clinical manifestations such as systemic AIDs. Although the number of variants detected is high, clinical diag- nosis rates remain low. The genotypephenotype relationship in these diseases is still unclear.
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BACKGROUND: OTULIN-related autoinflammatory syndrome (ORAS) is an autosomal recessive disease characterized by systemic inflammation, recurrent fever. Due to limited knowledge about the OTULIN DNA variants that cause ORAS, the diagnosis and treatment of this disease is difficult. In this study, we aim to identify OTULIN DNA variants responsible for the genetic pathology of ORAS and observe the effects of these variants on the OTULIN protein structure and the function with different bioinformatics approaches. METHODS: The present study included 3230 individuals with the suspicion of an autoinflammatory disease who were referred to Ege University Children's Hospital Molecular Medicine Laboratory. OTULIN variants were detected using a panel consisting of 37 different autoinflammatory diseases (AID) genes via targeted Next-Generation Sequencing. RESULTS: As a result of the study, DNA variants associated with various AID were detected in 65% of the individuals to whom the panel was applied. Among these variants, only three different OTULIN variants (p.Val82Ile, p.Gln115His and p.Leu131_Arg132insLeuCysThrGlu) were detected. The pathogenic effects of the variants detected in the OTULIN gene were determined by using Polyphen2 as "Probably Pathogenic" for the p.Val82Ile and "benign" for the p.Gln115His. At the same time, the effects of these variants on the structure and function of the OTULIN protein were investigated by in silico approaches. Both variants reduce protein stability and binding affinity. CONCLUSION: The results of the current study suggest that the evaluation of OTULIN variants with in silico approaches will contribute to the development of personalized treatments by diagnosing the disease specific to the variant.
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Secuenciación de Nucleótidos de Alto Rendimiento , Inflamación , Niño , Endopeptidasas , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Inflamación/genética , Mutación/genéticaRESUMEN
Familial Mediterranean Fever (FMF, OMIM ID: 249100) is the most common autoinflammatory, autosomal recessive disease caused by mutations in the MEFV gene. It is widespread in the Mediterranean, primarily among Turkish, Armenian, Arab and Jewish. This study aims to examine genotype distributions of common MEFV variants in the Turkish population using targeted NGS and to evaluate all rare mutations. It included 3230 people applying to Ege University Children's Hospital Molecular Medicine Laboratory with the suspicion of autoinflammatory disease between 2017 and 2021. MEFV missense variant was detected in 1839 (56.9%) individuals. One or more mutations were found in them. 1063 patients were heterozygous (57.8%), 410 were compound heterozygous (22.3%), 238 were complex genotype (12.9%), and 128 were homozygous (7%). 56 different mutations and 141 genotypes were detected, two of which were novel (p.His87Arg, c.260A > G and p.Leu396Phe, c.1186C > T). These were determined as 6benign, 40 uncertain significant, 3 likely pathogenic and 7 pathogenic according to the ACMG classification. The most common ones were R202Q (n = 1097, 37.48%), E148Q (n = 512, 17.49%), M694V (n = 493, 16.84%), V726A (n = 155, 5.30%), M680I (n = 150, 5.12%), P369S (n = 108, 3.69%), R408Q (n = 95, 3.25%) respectively. They constitute 89.17 % of the entire patient population. In conclusion, DNA variants/mutations in the MEFV gene were evaluated in 3230 patients. To date, no mutation screening has been encountered in such a large population using NGS. Genotype distributions of both common and rare mutations were revealed. The obtained data will hopefully contribute to the future genotype-phenotype studies of FMF disease.
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Fiebre Mediterránea Familiar , Secuenciación de Nucleótidos de Alto Rendimiento , Fiebre Mediterránea Familiar/genética , Frecuencia de los Genes , Genotipo , Humanos , Mutación , Pirina/genéticaRESUMEN
15-lipoxygenase (15-LOX) is a critical enzyme that allows the direction of arachidonic acid metabolism to change from inflammation into the resolution. This study aims to reveal how the immunomodulation properties of mesenchymal stem cells (MSC) alter by the 15-LOX overexpression. For this purpose, peripheral blood mononuclear cells (PBMCs) isolated from seven healthy volunteers, and both MSCs and 15-LOX overexpressing MSCs (15-LOXMSCs) were co-cultured at different cell ratios (1/1, 1/5 and 1/10). Alterations of CD4+Tbet+, CD4+Gata3+, CD4+RoRC2+, and CD4+FoxP3+ lymphocyte frequencies were detected by flow cytometry, and IFN-γ, IL-4, IL-6, IL-10, IL-17a, TGF-ß and LXA4 levels of medium supernatants were measured by ELISA method. According to our findings, MSC and 15-LOXMSCs have a suppressive effect on PHA activated PBMCs. However, as the ratio of PBMCs increased, the effects of 15-LOXMSCs increased significantly, while the effects of MSCs decreased. The most notable effect of the 15-LOX modification was the significant reduction in IL-6, IL-10 and IL-17a expression and the accompanying increase in TGF-ß and LXA4 levels. We also observed a similar situation between CD4+RoRC2+ and CD4+FoxP3+ cell frequencies. These data suggested that the effects of MSCs on the balance of Th17 / Treg could change by the 15-LOX overexpression, and this might be in favor of the Treg cells.
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Células Madre Mesenquimatosas , Linfocitos T Reguladores , Tejido Adiposo/metabolismo , Araquidonato 15-Lipooxigenasa/metabolismo , Factores de Transcripción Forkhead/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Leucocitos Mononucleares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Factor de Crecimiento Transformador beta/metabolismoAsunto(s)
Pérdida Auditiva Sensorineural/patología , Mutación , Cadenas Pesadas de Miosina/genética , Púrpura Trombocitopénica Idiopática/complicaciones , Trombocitopenia/congénito , Niño , Femenino , Pérdida Auditiva Sensorineural/etiología , Pérdida Auditiva Sensorineural/metabolismo , Humanos , Pronóstico , Trombocitopenia/etiología , Trombocitopenia/metabolismo , Trombocitopenia/patologíaRESUMEN
We suggest PLAID, APLAID, and FCAS3 have to be considered as different aspects of the same underlying condition, because of our long-term clinical and genetical experiences. Some CVID patients have the same disease-causing mutations in PLCG2 gene, so it may be better to define all of them as "PLCG2deficiency."
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Background/aim: In children with autosomal dominant polycystic kidney disease (ADPKD), clinical manifestations range from severe neonatal presentation to renal cysts found by chance. We aimed to evaluate demographic, clinical, laboratory findings, and genetic analysis of children with ADPKD. Materials and methods: We evaluated children diagnosed with ADPKD between January 2006 and January 2019. The diagnosis was established by family history, ultrasound findings, and/or genetic analysis. The demographic, clinical, and laboratory findings were evaluated retrospectively. Patients <10 years and ≥10 years at the time of diagnosis were divided into 2 groups and parameters were compared between the groups. Results: There were 41 children (M/F: 18/23) diagnosed with ADPKD. The mean age at diagnosis was 7.2 ± 5.1 (0.616.9) years and the follow-up duration was 59.34 ± 40.56 (8198) months. Five patients (12%) were diagnosed as very early onset ADPKD. All patients had a positive family history. Genetic analysis was performed in 29 patients (PKD1 mutations in 21, PKD2 mutations in 1, no mutation in 3). Cysts were bilateral in 35 (85%) of the patients. Only one patient had hepatic cysts. No valvular defect was defined in 12 patients detected. Only 1 patient had hypertension. None of them had chronic kidney disease. No difference could be demonstrated in sex, laterality of the cysts, maximum cyst diameter, cyst or kidney enlargement, follow-up duration, or GFR at last visit between Groups 1 and 2. Conclusion: The majority of children with ADPKD had preserved renal functions and slight cyst enlargement during their follow-up. However, they may have different renal problems deserving closed follow-up.
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Quistes/patología , Riñón/patología , Imagen por Resonancia Magnética/métodos , Riñón Poliquístico Autosómico Dominante/genética , Canales Catiónicos TRPP/genética , Niño , Preescolar , Quistes/diagnóstico por imagen , Quistes/epidemiología , Quistes/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Riñón/diagnóstico por imagen , Masculino , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Riñón Poliquístico Autosómico Dominante/epidemiología , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios RetrospectivosRESUMEN
OBJECTIVES: This study aims to discuss the clinical, laboratory and genetic findings, and treatment options for six patients who were diagnosed with Blau syndrome (BS)/early-onset sarcoidosis (EOS). PATIENTS AND METHODS: The study included four patients (2 males,2 females; mean age 7 years; range 4 to 10 years) with EOS and two siblings (1 male, 1 female; mean age 10 years; range, 9 to 11 years) with BS. Age, age of initial symptoms, age of diagnosis; articular involvement, presence of uveitis, dermatitis, or fever, other organ involvement, laboratory findings, results of metabolic tests for mucopolysaccharidosis and mucolipidosis, results of genetic, pathologic, and immunologic tests, radiologic findings to evaluate skeletal dysplasia, and treatment options were collected. RESULTS: The median age at diagnosis of all patients was 6 years (range, 1 to 10 years). Five patients had camptodactyly and bilateral boggy synovitis in the wrists and ankles, one had granulomatous inflammatory changes in the liver and kidney biopsy, and one had attacks of fever and granulomatous dermatitis. None had uveitis. The detected mutations in nucleotide-binding oligomerization domain containing 2 (NOD2) were P268S (rs2066842), M513T (rs104895473), R702W (rs2066844), V955I (rs5743291), H343Y (rs199858111), and M491L (16:50745293). The treatments of patients included corticosteroids, non-steroid anti-inflammatory drugs, methotrexate, infliximab, adalimumab, anakinra, and canacinumab. CONCLUSION: Camptodactyly and boggy synovitis are important signs of BS/EOS. Methotrexate and tumor necrosis factor blockers are more effective in patients with predominantly articular symptoms. In patients 5 and 6 and their mother, we determined a novel M491L mutation in the NOD2 gene. Currently, this work is in progress towards identifying the pathogenesis and treatment options for this disease.
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Nephrotic syndrome (NS) is characterized by proteinuria in children. Steroid- resistant NS (SRNS) is defined by resistance to standard steroid therapy, and it continues to be one of the most common causes of chronic renal failure. Molecular studies have revealed specialized molecules in different regions of the podocytes that play a role in proteinuria. Mutations in NPHS2 that encode for podocin constitute a frequent cause of SRNS worldwide. This study aimed to screen for podocin mutations in Azerbaijani patients with SRNS. Our study included 21 pediatric patients with SRNS aged between 0 and 18 years and the same number of healthy control groups. Mutational analysis of the NPHS2 gene was performed using direct sequencing methods. Disease-causing mutations in the NPHS2 gene were detected in eight patients (38%). Thirteen patients (62%) had NPHS2 mutations without causing the disease. Two patients had p.Val290Met homozygous mutation; two had p.Arg229Gln homozygous mutations; and one each had p.Pro20Leu homozygote, p.Leu169Pro homozygote, p.Arg138Gln homozygote, and p.Arg168His homozygous mutations. When we correlated the NPHS2 mutation status with disease progression, there was a statistically significant increase in serum creatinine, proteinuria, and serum albumin values in patients with NPHS2 gene mutations compared to the group without mutation (P <0.05). Our study concludes that mutations of the NPHS2 gene (38%) are heterogeneous in Azerbaijani SRNS patients. Based on our results, we support a model in which ethnicity plays an important role in certain NPHS2 mutations. NPHS2 mutation analysis may help to better predict the course of the disease, remove unnecessary long-term immunosuppressive therapy, and develop specific treatment.
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Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Mutación/genética , Síndrome Nefrótico/genética , Adolescente , Azerbaiyán , Estudios de Casos y Controles , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Proteinuria/genéticaRESUMEN
Interleukin-1ß (IL-1ß), which is secreted by host tissues leading to periodontal tissue inflammation, is a major pro-inflammatory cytokine in the pathogenesis of periodontal disease. The conversion of pro-IL-1ß into its biologically active form is controlled by multiprotein complexes named as inflammasomes, which are key regulator of host defense mechanisms and inflammasome involved diseases, including the periodontal diseases. Inflammasomes are regulated by different proteins and processes, including pyrin domain (PYD)-only proteins (POPs), CARD-only proteins (COPs), tripartite motif family proteins (TRIMs), autophagy, and interferons. A review of in vitro, in vivo, and clinical data from these publications revealed that several inflammasomes including (NOD)-like receptor (NLR) pyrin domain-containing 3 (NLRP3) and absent in melanoma 2 (AIM2) have been found to be involved in periodontal disease pathogenesis. To the best of our knowledge, the current article provides the first review of the literature focusing on studies that evaluated both inflammasomes and their regulators in periodontal disease. An upregulation for inflammasomes and a downregulation of inflammasome regulator proteins including POPs, COPs, and TRIMs have been reported in periodontal disease. Although interferons (types I and II) and autophagy have been found to be involved in periodontal disease, their possible role in inflammasome activation has not evaluated yet. Modulating the excessive inflammatory response by the use of inflammasome regulators may have potential in the management of periodontal disease.
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Inflamasomas , Enfermedades Periodontales , Proteínas Portadoras , Humanos , Inflamación , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLRRESUMEN
BACKGROUND: The inflammasome modulates the release of key proinflammatory cytokines associated with periodontal disease pathogenesis. The aim of this study was to evaluate the expression of proteins that regulate the inflammasome, namely pyrin domain-only proteins (POPs), caspase activation recruitment domain (CARD)-only proteins, and tripartite motif-containing (TRIM) proteins, in periodontal diseases. METHODS: A total of 68 participants (34 males and 34 females) were divided into four groups, including periodontal health (H), gingivitis (G), chronic periodontitis (CP), and aggressive periodontitis (AgP) based on clinical parameters. Gingival tissue samples were obtained from all participants for reverse transcription polymerase chain reaction (RT-PCR)-based gene expression analyses of molecules that regulate the inflammasome, including apoptosis-associated speck-like protein (ASC) containing CARD, caspase-1, interleukin-1ß (IL-1ß), interleukin-18 (IL-18), nucleotide-binding domain, leucine rich family (NLR) pyrin domain containing 3 (NLRP3), NLR family pyrin domain containing 2 (NLRP2), AIM2 (absent in melanoma 2), POP1, POP2, CARD16, CARD18, TRIM16, and TRIM20 by RT-PCR. RESULTS: NLRP3 and IL-1ß were upregulated in the G, CP, and AgP groups compared with group H (P < 0.05). AIM2 was downregulated in the CP group compared with the H, G, and AgP groups (P < 0.05). TRIM20, TRIM16, and CARD18 were downregulated in the G, CP, and AgP groups compared with the H group (P < 0.05). POP1 and POP2 were downregulated in the CP and AgP, and AgP and G groups, respectively (P < 0.05). CONCLUSION: Active periodontal disease may result in downregulation of inflammasome regulators that may increase the activity of NLRP3 and IL-1ß in periodontal disease.
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Periodontitis Agresiva , Periodontitis Crónica , Caspasa 1 , Proteínas de Unión al ADN , Femenino , Humanos , Inflamasomas , Interleucina-1beta , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR , Factores de Transcripción , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína LigasasRESUMEN
BACKGROUND: Mutations in about 50 genes have been identified as monogenic causes of nephrotic syndrome, a frequent cause of CKD. These genes delineated the pathogenetic pathways and rendered significant insight into podocyte biology. METHODS: We used whole-exome sequencing to identify novel monogenic causes of steroid-resistant nephrotic syndrome (SRNS). We analyzed the functional significance of an SRNS-associated gene in vitro and in podocyte-like Drosophila nephrocytes. RESULTS: We identified hemizygous missense mutations in the gene TBC1D8B in five families with nephrotic syndrome. Coimmunoprecipitation assays indicated interactions between TBC1D8B and active forms of RAB11. Silencing TBC1D8B in HEK293T cells increased basal autophagy and exocytosis, two cellular functions that are independently regulated by RAB11. This suggests that TBC1D8B plays a regulatory role by inhibiting endogenous RAB11. Coimmunoprecipitation assays showed TBC1D8B also interacts with the slit diaphragm protein nephrin, and colocalizes with it in immortalized cell lines. Overexpressed murine Tbc1d8b with patient-derived mutations had lower affinity for endogenous RAB11 and nephrin compared with wild-type Tbc1d8b protein. Knockdown of Tbc1d8b in Drosophila impaired function of the podocyte-like nephrocytes, and caused mistrafficking of Sns, the Drosophila ortholog of nephrin. Expression of Rab11 RNAi in nephrocytes entailed defective delivery of slit diaphragm protein to the membrane, whereas RAB11 overexpression revealed a partial phenotypic overlap to Tbc1d8b loss of function. CONCLUSIONS: Novel mutations in TBC1D8B are monogenic causes of SRNS. This gene inhibits RAB11. Our findings suggest that RAB11-dependent vesicular nephrin trafficking plays a role in the pathogenesis of nephrotic syndrome.
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Proteínas de Unión al Calcio/genética , Mutación Missense , Síndrome Nefrótico/genética , Podocitos/metabolismo , Vesículas Transportadoras/fisiología , Proteínas de Transporte Vesicular/genética , Proteínas de Unión al GTP rab/metabolismo , Animales , Autofagia , Línea Celular Transformada , Perros , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Exocitosis , Silenciador del Gen , Células HEK293 , Humanos , Inmunoglobulinas/metabolismo , Células de Riñón Canino Madin Darby , Proteínas de la Membrana/metabolismo , Síndrome Nefrótico/metabolismo , Fenotipo , Mapeo de Interacción de Proteínas , Interferencia de ARN , ARN Interferente Pequeño/farmacología , Secuenciación del ExomaRESUMEN
INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is associated with mutations or antibodies that affect the regulation of the alternative complement pathway. In the recent years several studies have been published describing these mutations. In this study, the initial clinical findings, treatments and long-term follow-up results of 19 patients who were hospitalized with the diagnosis of aHUS were presented. MATERIALS AND METHODS: Nineteen patients who were diagnosed as aHUS were enrolled from January 2010 to March 2017. Initial clinical signs and clinical follow-up of patients with aHUS were evaluated. Disease causing complement factor H (CFH) mutations were determined. Results. CFH mutations were detected in 5 of 19 aHUS cases. Of these, one was novel and 4 were previously reported. We reported here the clinical course of aHUS patients with CFH mutations (p.Glu936Asp, Val 1197Ala) and a novel mutation (Glu927Lys) which caused previously defined aHUS. Two of the CFH mutation cases developed end stage kidney disease that required hemodialysis, 1 case developed chronic kidney disease. Two cases were in remission, one of them with supportive therapy and the other case was in remission with eculizumab treatment. CONCLUSIONS: Morbidity rate is higher in children with aHUS. The renal prognosis and morbidity rate is higher in children with CFH mutations than other children with aHUS. Poor prognosis in aHUS children with CFH mutation depends on the genetic background.
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Síndrome Hemolítico Urémico Atípico/genética , Adolescente , Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico Urémico Atípico/etnología , Síndrome Hemolítico Urémico Atípico/terapia , Niño , Preescolar , Factor H de Complemento/genética , Inactivadores del Complemento/uso terapéutico , Femenino , Humanos , Lactante , Fallo Renal Crónico/etnología , Fallo Renal Crónico/genética , Fallo Renal Crónico/terapia , Masculino , Diálisis Renal , Estudios Retrospectivos , Resultado del Tratamiento , Turquía/etnologíaRESUMEN
OBJECTIVE: Familial Mediterranean fever (FMF) is the most common inherited monogenic autoinflammatory disease worldwide. It is caused by loss-of-function mutations in the MEFV gene, mostly affecting Eastern Mediterranean population. It is discussed if it should be considered an autosomal-dominant disease with variable penetrance, because heterozygosis mutations are associated with clinical autoinflammatory manifestations. Colchicine constitutes that the mainstay of FMF treatment should be preventing acute attacks and amyloidosis, and decreasing the chronic inflammation. In colchicine-resistant or intolerant patients, recent insights into the pathogenesis of FMF have made the anti-IL1 treatments important. We aimed to search for the retrospective results of canakinumab treatment in patients with FMF who are unresponsive to colchicine. METHODS: In this study, 22 (13 males and nine females) patients with FMF with colchicine resistance/intolerance, age ranging from 6 to 18 years, were included in Ege University Department of Pediatric Rheumatology. After clinical and genetic diagnosis, colchicine treatment with standard doses was started. After treatment with canakinumab, complete response to treatment was determined as no acute episodes and normal level of acute phase reactants. RESULTS: After canakinumab treatment, 22 patients with FMF who were colchicine-resistant were evaluated. After the treatment, no attack was observed in 19 patients, and the values of acute phase reactants were normal in 22 patients. In three patients, disease attack was observed 16 months after the first dose treatment. In all patients, the values of acute phase reactants were found at normal level during treatment. No drug-related side effects were observed in any patient. CONCLUSION: Canakinumab is an effective and safe anti-IL1 agent to reduce attacks in patients with FMF with no response to colchicine and to reduce the level of high-level laboratory findings associated with FMF.
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BACKGROUND/AIMS: Gastric cancers vary across countries and ethnic groups. They are the second most common type of cancer worldwide. Dietary and non-dietary factors as well as genetic and epigenetic alterations of many mechanisms are implicated in the development of gastric cancer. We aimed to determine the sequence of possible nucleotide changes, polymorphisms, and mutations, and to establish genotype and phenotype relation by performing whole DNA sequence analysis of the XRCC1 and ERCC1 genes belonging to base excision repair (BER) and nucleotide excision repair (NER) family of DNA repair genes in patients with gastric cancer. MATERIALS AND METHODS: We included 50 patients of both sexes who had received diagnosis of gastric cancer and 50 healthy people who showed same demographic traits that forms the control group. We analyzed the ERCC1 and XRCC1 genes by DNA sequence analysis on both groups. After the analysis, we compared the genotype-phenotype relation. RESULTS: Neither patients nor the control group has any nucleotide replacement in any exon of ERCC1 genes. We could not detect significant difference between patients and healthy groups when we correlated genotype contribution of mutations Arg194Trp, Arg208His, Arg399Gln detected in the XRCC1 gene and allele frequency. CONCLUSION: According to our study, the ERCC1 gene in Turkish population is not getting mutation in patients with gastric cancer and healthy individuals. Three mutations were detected in the XRCC1 gene, and these mutations were not associated with gastric cancer.