RESUMO
OBJECTIVE: Cryopyrin-associated periodic syndromes (CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1ß (IL-1ß) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti-IL-1 treatment in patients with low-penetrance NLRP3 variants. METHODS: A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1ß release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed. RESULTS: The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients. CONCLUSION: Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1ß and non-IL-1ß-mediated inflammatory pathway activation.
Assuntos
Síndromes Periódicas Associadas à Criopirina/genética , Febre/genética , Gastroenteropatias/genética , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Adolescente , Adulto , Idoso , Antirreumáticos/uso terapêutico , Estudos de Casos e Controles , Caspase 1/metabolismo , Morte Celular/genética , Morte Celular/imunologia , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/imunologia , Síndromes Periódicas Associadas à Criopirina/metabolismo , Oftalmopatias/tratamento farmacológico , Oftalmopatias/genética , Oftalmopatias/imunologia , Oftalmopatias/metabolismo , Feminino , Febre/tratamento farmacológico , Febre/imunologia , Febre/metabolismo , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/imunologia , Gastroenteropatias/metabolismo , Variação Genética , Perda Auditiva/tratamento farmacológico , Perda Auditiva/genética , Perda Auditiva/imunologia , Perda Auditiva/metabolismo , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/imunologia , Nefropatias/tratamento farmacológico , Nefropatias/genética , Nefropatias/imunologia , Nefropatias/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Penetrância , Fenótipo , Resultado do Tratamento , Adulto JovemRESUMO
Pyogenic arthritis, pyoderma gangrenosum and acne syndrome was diagnosed in a 42-year-old patient, after an unusual persistency of high synovial cell counts had been noticed. Clinical peculiarities and problems with diagnosing septic versus non-septic arthritis are discussed.
Assuntos
Acne Vulgar/diagnóstico , Artrite Infecciosa/diagnóstico , Pioderma Gangrenoso/diagnóstico , Membrana Sinovial/citologia , Contagem de Células , Diagnóstico Diferencial , HumanosRESUMO
Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological, cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease (CINCA/NOMID) were originally described as three distinct diseases. After the identification of their common genetic origin in 2001 and 2002, they are now perceived as a continuum of one disease entity and labelled cryopyrin-associated periodic syndromes (CAPS). Mutations in the NLRP3 gene on chromosome 1q44 can be detected in many affected patients. These lead to the synthesis of an altered gene product named cryopyrin. This is part of the NLRP3 inflammasome and causes the activation of caspase 1 and an excess production of IL-1ß, which is the driving force behind the inflammatory reactions observed in CAPS patients. In symptomatic patients, confirmation of a mutation using traditional methods of genetic analysis may not always be successful (up to 40% in the case of CINCA/NOMID phenotypes); however, in many cases somatic mutations can be found using modern methods, such as next generation sequencing (NGS) technologies. In contrast, low-penetrance NLRP3 variants may also be identified in healthy family members and are present in low frequencies in the general population. Some of the mutation carriers nevertheless present with typical signs of autoinflammation; however, their phenotype is different compared to the classical CAPS presentation. These patients display unspecific systemic inflammatory signs more frequently but show an organ involvement less often. While the detection of NLRP3 gene mutations may be viewed as confirmatory, CAPS is still predominantly a clinical diagnosis; therefore, recently published diagnostic criteria do not require the demonstration of a mutation.
Assuntos
Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/genética , Citocinas/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Medicina Baseada em Evidências , Predisposição Genética para Doença/genética , Humanos , Inflamassomos/genética , Mutação/genéticaRESUMO
BACKGROUND: The group of autoinflammatory syndromes associated with Pyoderma gangrenosum, Acne, and Suppurative Hidradenitis are poorly defined and difficult to control with currently available treatment modalities. OBJECTIVES: We describe a patient with PASH syndrome and report about the successful multimodal treatment with infliximab, cyclosporine, and dapsone. METHODS: A review of the available literature to date about this group of autoinflammatory diseases was performed. We performed genetic analysis for PSTPIP1 mutations associated with PAPA syndrome. RESULTS: A 22-year-old woman presented to our department with pyoderma gangrenosum, concomitant acne, and suppurative hidradenitis. She had previously been treated unsuccessfully with etanercept, adalimumab, fumaric acid and the IL-1 receptor antagonist (IL-1RA) anakinra without prolonged remission. Treatment with intravenous infliximab in combination with cyclosporine and dapsone lead to sudden and prolonged improvement of the clinical symptoms that we classified as PASH syndrome. We review the literature about this group of diseases and report the third case of PASH syndrome to date. CONCLUSION: PASH syndrome and associated diseases should be considered whenever hidradenitis suppurativa is found in association with pyoderma gangrenosum. We provide a systematic overview about PASH syndrome and suggest a novel multimodal therapeutic regimen beyond isolated inhibition of TNF or IL-1.
Assuntos
Acne Vulgar/tratamento farmacológico , Ciclosporina/uso terapêutico , Dapsona/uso terapêutico , Hidradenite Supurativa/tratamento farmacológico , Infliximab/uso terapêutico , Pioderma Gangrenoso/tratamento farmacológico , Anti-Infecciosos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/uso terapêutico , Síndrome , Adulto JovemRESUMO
Iron overload in MR-imaging with decreased signal intensity in T2 weighting of liver, spleen, adrenal gland and pituitary gland in combination with an extremely elevated ferritin level of 9859â ng/mL and a positive family history of hyperferritinaemia led to the diagnosis of the rare hemochromatosis type 4 (synonym: ferroportin disease) in the case of a 62-year-old patient. The autosomal dominant disease was confirmed by analysis of the SLC40A1-gene. Histologically, a liver cirrhosis was detected. This was neither detectable in the case of the two similarly aged cousins (ferritin about 4750â ng/mL, transferrin saturation normal), nor in the case of the 82-year-old mother (ferritin 7860â ng/dL, transferrin saturation 58â%). Hemochromatosis type 4 with worldwide less than 200 described cases is caused by a disorder of the hepcidin ferroportin metabolism, which regulates the iron export from the cells. A hepatocellular carcinoma may occur even without cirrhosis. Therefore, surveillance of these patients is necessary. Treatment options are therapeutic phlebotomies and alternatively iron-chelating drugs (Deferoxamin, Deferasirox) if the patient develops anaemia.
Assuntos
Catarata/congênito , Hemocromatose/congênito , Hemocromatose/patologia , Distúrbios do Metabolismo do Ferro/congênito , Idoso de 80 Anos ou mais , Catarata/patologia , Diagnóstico Diferencial , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-IdadeAssuntos
Angioedemas Hereditários/genética , Proteína Inibidora do Complemento C1/metabolismo , Fator XII/genética , Deleção de Sequência , Adulto , Angioedemas Hereditários/metabolismo , Povo Asiático/genética , Éxons , Fator XII/metabolismo , Feminino , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de DNA , Turquia , Adulto JovemRESUMO
Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children.
Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Genótipo , Fenótipo , Adolescente , Alelos , Substituição de Aminoácidos/genética , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Proteínas do Citoesqueleto/genética , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/etnologia , Feminino , Frequência do Gene/genética , Alemanha , Homozigoto , Humanos , Lactente , Líbano/etnologia , Masculino , Metionina/genética , Pirina , Sistema de Registros , Turquia/etnologia , Valina/genéticaRESUMO
Cholesteryl ester storage disease (CESD) is a rare, autosomal recessively inherited disorder resulting from deficient activity of lysosomal acid lipase (LAL). LAL is the key enzyme hydrolyzing cholesteryl esters and triglycerides stored in lysosomes after LDL receptor-mediated endocytosis. Mutations within the LIPA gene locus on chromosome 10q23.2-q23.3 may result either in the always fatal Wolman disease, where no LAL activity is found, or in the more benign disorder CESD with a reduced enzymatic activity, leading to massive accumulation of cholesteryl esters and triglycerides in many body tissues. CESD affects mostly the liver, the spectrum is ranging from isolated hepatomegaly to liver cirrhosis. Chronic diarrhea has been reported in some pediatric cases, while calcifications of the adrenal glands, the hallmark of Wolman disease, are rarely observed. Hypercholesterolemia and premature atherosclerosis are other typical disease manifestations. Hepatomegaly as a key finding has been reported in all 71 pediatric patients and in 134 of 135 adult cases in the literature. We present a 13-year-old boy with mildly elevated liver enzymes in the absence of hepatomegaly, finally diagnosed with CESD. Under pravastatine treatment, the patient has normal laboratory findings and is clinically unremarkable since 5 years of follow-up. To our knowledge, this is the first pediatric case of genetically and biopsy confirmed CESD without hepatomegaly, suggesting that this diagnosis can be easily missed. It further raises the question about the natural course and the therapy required for this oligosymptomatic form.
Assuntos
Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/genética , Erros de Diagnóstico/prevenção & controle , Predisposição Genética para Doença/genética , Esterol Esterase/genética , Adolescente , Diagnóstico Diferencial , Reações Falso-Negativas , Humanos , Masculino , Avaliação de Sintomas/métodosRESUMO
SFTPC (surfactant protein C) mutations resulting in SP-C deficiency causing ongoing respiratory failure in the neonatal period represent a rare entity. We report a full-term female infant who developed respiratory distress and respiratory failure shortly after birth. From the first day of life the infant was mechanically ventilated. Application of exogenous surfactant or cortisone did not lead to any clinical improvement. Genetic analysis identified a novel SFTPC mutation as the cause of her lung disease. The patient was diagnosed as heterozygous for a p.Cys121Gly/C121G substitution encoded by exon 4, which could not be detected in both parents. Experimental therapy with hydroxychloroquine resulted in a significant clinical improvement within 2 weeks time. Mechanical ventilation was no longer needed, and the patient was discharged without additional oxygen demand. The patient remained well under therapy till the age of 6 months. After that time, the therapy was successfully discontinued.
Assuntos
Substituição de Aminoácidos/genética , Análise Mutacional de DNA , Éxons/genética , Hidroxicloroquina/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Insuficiência Respiratória/genética , Insuficiência Respiratória/terapia , Cesárea , Cisteína/genética , Feminino , Seguimentos , Triagem de Portadores Genéticos , Glicina/genética , Humanos , Lactente , Recém-Nascido , Proteína C Associada a Surfactante Pulmonar/deficiência , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Insuficiência Respiratória/diagnósticoRESUMO
OBJECTIVE: To characterize patients with familial Mediterranean fever (FMF) with and without AA amyloidosis living in Germany. METHOD: Clinical and genetic data from 64 FMF patients were analysed for amyloidosis risk factors. RESULTS: Fifty-five patients (85%) were of Turkish or Armenian origin. Thirty-one patients (48%) developed FMF symptoms before the age of 16 years. Sixteen patients (26%) became symptomatic after age 20. Symptoms reported were peritonitis (95%), fever (78%), pleuritis (59%), arthralgia (60%), arthritis (32%), erysipelas-like erythema (23%), and vasculitis (8%). FMF diagnosis was delayed for a median of 8.0 years. Genetic analysis confirmed M694V as the most prevalent Mediterranean fever (MEFV) gene mutation in 46 out of 59 patients (78%). M694V homozygosity was associated with an earlier FMF onset (median age 5.5 years, p = 0.0001) and a higher prevalence of peritonitis (p = 0.007) and pleuritis (p = 0.0007) compared to patients without an M694V mutation. AA amyloidosis was detected in 16 patients (25%) at a median age of 36.5 years and tended to be associated with a higher age at disease onset (p = 0.062) and a higher FMF activity score (p = 0.093). AA amyloidosis was significantly associated with a higher age at FMF diagnosis (p = 0.0022). CONCLUSIONS: Clinical symptoms of FMF-affected migrants living in Germany resemble those observed in their home country. In particular, patients with an onset of FMF symptoms after age 20 and a later FMF diagnosis have a high risk of AA amyloidosis. Symptomatic patients who originate from countries with a higher FMF prevalence should be screened for FMF and proteinuria.
Assuntos
Amiloidose/etnologia , Amiloidose/genética , Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/etnologia , Febre Familiar do Mediterrâneo/genética , Migrantes/estatística & dados numéricos , Adolescente , Adulto , Idade de Início , Idoso , Amiloidose/diagnóstico , Febre Familiar do Mediterrâneo/diagnóstico , Alemanha/epidemiologia , Humanos , Pessoa de Meia-Idade , Peritonite/diagnóstico , Peritonite/etnologia , Peritonite/genética , Mutação Puntual/genética , Prevalência , Pirina , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
UNLABELLED: Familial Mediterranean fever (FMF) is an autoinflammatory disease and belongs to the heterogeneous group of hereditary recurrent fever syndromes (HRFs). AIMS: The aims of the study were to determine the incidence of FMF in Germany and to describe the spectrum of pyrin mutations and the clinical characteristics in children. A prospective surveillance of children with HRF including FMF was conducted in Germany during a time period of 3 years by the German paediatric surveillance unit for rare paediatric diseases (ESPED). Monthly inquiries were sent to 370 children's hospitals (Clinic-ESPED, n1) and to 23 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤ 16 years of age, disease-associated pyrin mutations, and more than three self-limiting episodes of fever >38.5 °C with increased inflammation markers. In n1, 122 patients with FMF and 225 pyrin mutations were identified. Ninety-two of 122 (75 %) children were of Turkish origin. The minimum incidence of FMF was estimated to be 3 (95 % CI: 2.48-3.54) per 10(6) person-years in the whole children population and 55 (95 % CI: 46-66) per 10(6) person-years in Turkish children living in Germany. N1 U n2 amounted to 593 asymptomatic and symptomatic carriers of 895 mutations (overlap of 73 cases with 134 mutations). p.Met694Val (45 %), p.Met680Ile (14 %), p.Val726Ala (12 %), and p.Glu148Gln (11.5 %) were the most common pyrin mutations. CONCLUSIONS: Despite FMF being the most frequent of the HRFs, its incidence in Germany is low. Twenty-five to 50 FMF patients ≤ 16 years are newly diagnosed per year. The disease is most commonly observed in individuals of Turkish ancestry.
Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/etnologia , Mutação , Biomarcadores/sangue , Febre Familiar do Mediterrâneo/genética , Alemanha/epidemiologia , Humanos , Incidência , Polimorfismo Genético , Vigilância da População , Estudos Prospectivos , Pirina , Turquia/etnologiaRESUMO
BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent febrile polyserositis. A possible association of FMF and multiple sclerosis (MS) has been suggested in cohorts from Turkey and Israel. OBJECTIVE: The objective of this study was to investigate the prevalence of MEFV mutations in subjects with MS and in controls in Germany. METHODS: One-hundred and fifty seven MS patients with at least one symptom or without symptoms suggestive of FMF from our outpatient clinic were investigated for mutations in exons 2, 3, and 10 of the MEFV gene (group 1). 260 independent MS patients (group 2) and 400 unrelated Caucasian controls (group 3) were screened selectively for the low-penetrance pyrin mutations E148Q and K695R RESULTS: In group 1, 19 MS patients (12.1%) tested positive for a mutation in the MEFV gene, mainly the E148Q (n=7) substitution. Fifteen of the 19 mutation-positive individuals reported at least one symptom suggestive of FMF. In three cases, we could identify additional family members with MS. In these pedigrees, the E148Q exchange co-segregated with MS (p=0.026). Frequencies of the pyrin E148Q and K695R mutations were not statistically different between MS group 2 and controls but they occurred with a surprisingly high frequency in the German population. CONCLUSION: The MEFV gene appears to be another immunologically relevant gene locus which contributes to MS susceptibility. In particular, the pyrin E148Q mutation, which co-segregated with disease in three MS families, is a promising candidate risk factor for MS that should be further explored in larger studies.
Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/genética , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA , Avaliação da Deficiência , Éxons , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Alemanha , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/imunologia , Fenótipo , Estudos Prospectivos , Pirina , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
Autoinflammatory diseases (AIDs) are characterized by recurrent, self-limiting systemic inflammation. Disorders include hereditary recurrent fever (HRF) syndromes such as hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). To determine the incidence of HIDS and report clinical and genetic characteristics together with the underlying MVK genotypes in German children, a prospective active surveillance was conducted in Germany during a period of 3 years. Monthly inquiries were sent to 370 children's hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to two laboratories (Laboratory-ESPED, n2) performing genetic analyses. Inclusion criteria were a MVK mutation-positive patient ≤16 years of age with more than three self-limiting episodes of fever >38.5°C associated with increased inflammation markers. Clinical, epidemiological, and genetic data were assessed via questionnaires. Eight out of 16 patients were identified in Clinic-ESPED (n1) and 15 of 16 in Laboratory-ESPED (n2). Clinical and laboratory surveys overlapped in 7 of 16 cases. Incidence of HIDS was estimated to be 0.39 (95% CI: 0.22, 0.64) per 10(6) person-years. HIDS symptoms generally started in infancy with recurrent fever episodes lasting 3-12 (median, 4.5) days and recurring every 1-12 weeks. Fever was accompanied by abdominal pain, vomiting, diarrhea, cervical lymphadenopathy, and sometimes by headache, skin and joint symptoms. The patients carried 11 different MVK mutations mostly in compound heterozygosity (75%, 12 out of 16). The most frequent mutation was p.Val377Ile (81%, 13 out of 16). In Germany, the incidence of HIDS is very low with 0.39 per 10(6) person-years.
Assuntos
Deficiência de Mevalonato Quinase/genética , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Alemanha/epidemiologia , Heterozigoto , Humanos , Incidência , Lactente , Masculino , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/enzimologia , Deficiência de Mevalonato Quinase/epidemiologia , Deficiência de Mevalonato Quinase/terapia , Fenótipo , Prognóstico , Estudos Prospectivos , Inquéritos e Questionários , Fatores de TempoRESUMO
AGel amyloidosis is an autosomal dominantly inherited systemic amyloidosis which is most commonly observed in Finland. The clinical manifestation is characterised by lattice corneal dystrophy, bilateral facial palsy with myokymias, and cutis laxa. We report on a German family with an AGel amyloidosis due to a gelsolin p.Asp214Asn/D187N mutation encoded by exon 4 of the GSN gene on chromosome 9q34.
Assuntos
Amiloidose Familiar/fisiopatologia , Gelsolina/genética , Doenças do Sistema Nervoso/fisiopatologia , Idoso , Amiloidose/complicações , Amiloidose/fisiopatologia , Amiloidose Familiar/complicações , Cromossomos Humanos Par 9/genética , Distrofias Hereditárias da Córnea/complicações , Distrofias Hereditárias da Córnea/etiologia , Distrofias Hereditárias da Córnea/fisiopatologia , Cútis Laxa/etiologia , Eletrodiagnóstico , Éxons/genética , Paralisia Facial/etiologia , Paralisia Facial/fisiopatologia , Família , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/etiologia , Mutação/genética , Doenças do Sistema Nervoso/etiologiaRESUMO
INTRODUCTION: Progression of coronary artery disease (CAD) after primary coronary artery bypass grafting (CABG) is frequent and may lead to recurrent symptoms. Various data indicate that apoptosis is the main event occurring during development and progression of atherosclerotic plaque. Plaque vascular smooth muscle cells (VSMCs) are more sensitive than regular VSMCs to TP53-mediated apoptosis. METHODS: We investigated EDTA blood of 192 patients (18% female, age 60.9 ± 7.4 years) who had primary CABG more than 5 years ago. CAD progression was defined as clinical endpoints: re-operation (n = 88; 46%), catheter re-intervention (n = 58; 30%), or angina at follow-up (n = 89; 46%). Apoptotic gene polymorphisms (Toll-like receptor 2 A753G, FAS ligand C-844T, FAS promoter G-670A, TP53 Arg72Pro, and CD14 C-260T) were investigated by PCR-RFLP and compared to healthy controls (n = 200, 24% female, age 63.4 ± 5.4). Gender-specific analysis was carried out. RESULTS: Heterozygous, homozygous and wild-type expression of all five genetic polymorphisms showed almost identical distribution between patients with CAD and healthy controls. Looking at clinical endpoints, with GG expression of Toll-like receptor 2 polymorphism and GG expression of FAS promoter polymorphism, results showed a relative increased risk (p = 0.09) for recurrent symptoms and re-intervention. Patients with FAS promoter polymorphism with AA expression had an increased risk of suffering from recurrent symptoms (n = 28, p = 0.04). We found that patients with homozygous expression of TP53 polymorphisms (n = 3, all male) were prone to needing re-intervention after prior CABG (p = 0.03), but not re-operation. Over a period up to 15 years, the re-intervention rate was significantly different in homozygous genotypes of FAS LG, FAS promoter and TP53. CONCLUSIONS: Patients presenting with polymorphisms of FAS LG, FAS promoter and TP53 have an increased risk of CAD progression, as they have a higher rate of re-interventions.
Assuntos
Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana/genética , Proteína Ligante Fas/genética , Genes p53 , Regiões Promotoras Genéticas , Proteína Supressora de Tumor p53/genética , Receptor fas/genética , Idoso , Apoptose , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Análise de Sequência de DNA , Resultado do TratamentoRESUMO
The authors report, for the first time in the literature, a case of respiratory distress syndrome in a term baby due to homozygosity for a p.Trp308Arg/W308R substitution in the ATP-binding cassette transporter 3. The sequence was confirmed by genetic analysis of the baby and both parents. Management and long-term outcome of a patient carrying this novel genetic defect have not been reported in the literature before. Currently, lung transplant appears to be the only long-term survival option available, for which, our patient is being evaluated.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mutação , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Feminino , Homozigoto , Humanos , Recém-Nascido , Nascimento a TermoRESUMO
BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) are rare disorders belonging to the group of hereditary periodic fever (HPF)syndromes. These auto-inflammatory diseases(AID) are characterized by recurrent episodes of inflammation with attacks of fever variably associated with serosal, synovial and / or cutaneous inflammation, usually in a self-limiting manner, and with a mostly monogenic origin. The aims were to determine the incidence of CAPS and the spectrum of mutations in the NLRP3 (formerly= CIAS1) gene and to describe the clinical manifestations. PATIENTS AND METHODS: A prospective surveillance of children with CAPS was conducted in Germany during a time period of 3 years(2003-2006). Monthly inquiries were sent to 370 children's hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to 2 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤ 16 years of age, disease-associated NLRP3 mutation, more than 3 self-limiting episodes of fever > 38.5 ° C, and increased inflammation markers. Clinical, epidemiological and genetic data were evaluated via questionnaires. FINDINGS: 6 out of 14 patients were identified in Clinic-ESPED (n1) and 13 / 14 in Laboratory-ESPED(n2). Clinical and laboratory surveys overlapped in 5 of 14 cases. The incidence of CAPS in German children was estimated to be 3.43 per 107 person-years. The patients carried 11 different NLRP3 mutations and were classified as MWS(n = 6), CINCA (n = 4), FCAS (n = 1) and undefined CAPS (n = 3). INTERPRETATION: The incidence of CAPS in Germany is very low and corresponds to 2-7 newly diagnosed patients ≤ 16 years per year.
Assuntos
Síndromes Periódicas Associadas à Criopirina/epidemiologia , Síndromes Periódicas Associadas à Criopirina/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Estudos Transversais , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Análise Mutacional de DNA , Feminino , Triagem de Portadores Genéticos , Alemanha , Humanos , Incidência , Lactente , Masculino , Vigilância da População , Estudos ProspectivosRESUMO
We report a 16-year-old female patient with a severe course of multiple sclerosis and concomitant symptoms suggestive of a hereditary autoinflammatory disease. Genetic analyses revealed that she inherited a TNFRSF1A R92Q mutation from her mother and a pyrin E230K mutation from her father. To our knowledge, this is the first report of a patient with severe childhood multiple sclerosis and mutations in two genes which predispose to hereditary autoinflammatory disorders. We speculate that these mutations contribute to early multiple sclerosis manifestation and enhance the inflammatory damage inflicted by the autoimmune response.
Assuntos
Proteínas do Citoesqueleto/genética , Esclerose Múltipla/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Adolescente , Feminino , Humanos , Masculino , Mutação , Linhagem , PirinaRESUMO
We present the case of a patient with suspected congenital hypopituitarism first diagnosed at the age of 38 years. Despite partial insufficiency of all pituitary-regulated hormonal axes, the patient never suffered from severe health problems. However, the patient was disfigured, and his intellectual and physical capacities were clearly impaired. The initiation of a hormone replacement therapy with hydrocortisone and thyroid hormones is essential in such a patient, but the substitution of sex hormones can create ethical problems.