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1.
Circulation ; 140(1): 16-26, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31109193

RESUMO

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and compare outcomes and quality of life among patients with acquired and hereditary forms of the disease. METHODS: We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V1221 variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients. RESULTS: There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9-27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of wild-type ATTR-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally ( P<0.001) and had worse measures of cardiac disease ( P<0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival ( P<0.001) in comparison with the other subgroups. CONCLUSIONS: ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/terapia , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/terapia , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/mortalidade , Cardiomiopatias/mortalidade , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida/tendências , Resultado do Tratamento
2.
Rheumatology (Oxford) ; 59(3): 554-558, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31384939

RESUMO

OBJECTIVES: Hereditary systemic autoinflammatory diseases are rare genetic disorders, which if untreated, can be complicated by AA amyloidosis leading to renal failure and premature death. Our objective was to find a genetic cause in a British family with a dominantly inherited autoinflammatory disease complicated by AA amyloidosis. METHODS: The index patient and his sister underwent comprehensive clinical and laboratory assessment including the next-generation sequencing panel targeting autoinflammatory genes. Subsequently, other relatives underwent clinical evaluation and genetic testing. Screening of the SAA1 gene was performed in all symptomatic cases. RESULTS: The index case and his sister presented with proteinuria due to AA amyloidosis. They have been suffering from episodes of fever accompanied by severe abdominal and chest pain, arthritis and erythema since childhood. Their father died aged 52 years from complications following a cadaveric renal transplantation. The post-mortem examination demonstrated AA amyloidosis. The index case's grandmother, two paternal cousins and two of their children described similar symptoms. All symptomatic individuals had excellent responses to colchicine. Next-generation sequencing analysis identified a single MEFV p.P373L variant in the index case, his sister and subsequently, in symptomatic family members. Sequencing of the SAA1 gene revealed all cases were heterozygous for the SAA1.1 allele. CONCLUSION: Typically FMF is an autosomal recessive disorder; nonetheless rare cases of dominantly inherited disease have previously been described. Here we report a novel MEFV variant p.P373L, causing dominant FMF complicated by AA amyloidosis in four generations of a British family.


Assuntos
Amiloidose/genética , Febre Familiar do Mediterrâneo/genética , Pirina/genética , Adulto , Amiloidose/tratamento farmacológico , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Resultado do Tratamento , Moduladores de Tubulina/uso terapêutico
3.
Blood ; 131(9): 974-981, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29284595

RESUMO

To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1ß (IL-1ß) production, although interest in the contribution of genetic factors has been fueled by detection of somatic NLRP3 mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) κ paraprotein was detected in 86%; the remainder had IgM λ or IgG κ. Patients underwent searches for germ line and somatic mutations using next-generation sequencing technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler syndrome. Genetic analysis revealed neither germ line nor somatic NLRP3, TNFRSF1A, NLRC4, or NOD2 mutations, apart from 1 patient with a germ line NLRP3 p.V198M substitution. The proinflammatory cytokines and extracellular apoptosis-associated speck-like protein with caspase recruitment domain (ASC) measured in the serum of Schnitzler syndrome patients during active disease were significantly higher than healthy controls. Ninety-five percent of our cohort achieved a complete response to recombinant IL-1 receptor antagonist (anakinra). Our findings do not support a role for somatic NLRP3 mosaicism in disease pathogenesis; although elevated levels of ASC, IL-6, and IL-18 in patients' serum, and the response to anakinra, suggest that Schnitzler syndrome is associated with upregulated inflammasome activation. Despite its rarity, Schnitzler syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves quality of life for patients.


Assuntos
Mutação em Linhagem Germinativa , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Síndrome de Schnitzler , Adulto , Idoso , Substituição de Aminoácidos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Feminino , Humanos , Interleucina-18/sangue , Interleucina-18/genética , Interleucina-6/sangue , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/genética
4.
Rheumatology (Oxford) ; 56(2): 209-213, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27150194

RESUMO

OBJECTIVE: This study was undertaken to characterize the phenotype and response to treatment in patients with autosomal dominant FMF caused by MEFV p.M694del mutation and to use haplotype reconstruction to investigate the possibility of common ancestry. METHODS: MEFV gene was analysed in 3500 subjects with suspected FMF referred to a single UK centre between 2002 and 2014. Patients with p.M694del underwent additional screening of the SAA1 gene as well as haplotype reconstruction of the MEFV locus. RESULTS: The p.M694del variant was identified in 21 patients, sharing an identical disease haplotype that appears to have arisen about 550 years ago. The SAA1.1 allele was found in four patients, including two with AA amyloidosis. The clinical features comprised typical FMF symptoms with median age at onset of 18 years; three patients presented with AA amyloidosis, of whom two had had symptoms of FMF in retrospect. Fifteen patients had received colchicine treatment, all with excellent responses. CONCLUSION: The p.M694del variant is associated with autosomal dominantly inherited FMF in Northern European Caucasians. Symptoms may develop later in life than in classical recessive FMF but are otherwise similar, as is the response to colchicine treatment. The 14% incidence of AA amyloidosis may reflect delay in diagnosis associated with extreme rarity of FMF in this population. The common haplotype suggests a single founder living in about 1460.


Assuntos
Febre Familiar do Mediterrâneo/genética , Pirina/genética , População Branca/genética , Adolescente , Adulto , Idoso , Amiloidose/genética , Criança , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Haplótipos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Proteína Amiloide A Sérica/genética , Proteína Amiloide A Sérica/metabolismo , Moduladores de Tubulina/uso terapêutico , Reino Unido , Adulto Jovem
5.
Rheumatology (Oxford) ; 56(12): 2102-2108, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28968868

RESUMO

Objective: To provide outcome data concerning pregnancies exposed to the Interleukin-1 (IL-1) inhibitors prior to conception in both men and women, during pregnancy and breast feeding. Methods: Retrospective data were collected from members of the International Society for Systemic Autoinflammatory diseases and collated in a single centre. A uniform data collection sheet was used to obtain standardized data including maternal age and diagnosis, type, duration of and response to IL-1 blockade, pregnancy duration, delivery, mode of feeding and neonatal development. Results: There were 31 maternal-exposed pregnancies from seven countries and we report the first data on paternal exposure: six to anakinra and five to canakinumab, with no negative outcomes. We also report the first data on canakinumab-exposed pregnancies: eight pregnancies that resulted in the delivery of seven healthy infants of normal gestational age and birthweight. There were 23 anakinra-exposed pregnancies resulting in the birth of 21 healthy infants, and one baby with unilateral renal agenesis and ectopic neurohypophysis. There were two first trimester miscarriages affecting a mother with active disease. There were no serious neonatal infections. Fourteen infants were breast fed with no complications. There were no reports of developmental delay, with follow-up of up to 10 years (median 18 months). Conclusion: This series substantially increases the published experience of IL-1 blockade and reproduction including the first data on canakinumab and on paternal exposure to these agents. Data are generally reassuring, although the case of renal agenesis is the second reported in an anakinra-exposed pregnancy.


Assuntos
Antirreumáticos/efeitos adversos , Doenças Autoimunes/tratamento farmacológico , Interleucina-1/antagonistas & inibidores , Exposição Materna/efeitos adversos , Exposição Paterna/efeitos adversos , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Doenças Autoimunes/complicações , Peso ao Nascer , Aleitamento Materno/efeitos adversos , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Masculino , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Adulto Jovem
6.
Hum Mutat ; 35(9): E2403-12, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25044787

RESUMO

Hereditary systemic amyloidosis comprises a group of rare monogenic diseases inherited in an autosomal dominant fashion. It is associated with mutations in genes encoding eight different proteins, including transthyretin, apolipoprotein AI, apolipoprotein AII, lysozyme, fibrinogen A α-chain, cystatin C, gelsolin and beta-2-microglobulin. With support from the EU FP6 EURAMY project we have designed an online registry of genes and mutations in hereditary amyloidosis including their associated clinical phenotypes, with a view to having a single free online portal for the collection and distribution of this information. Users can search the registry by either mutation, phenotype or authors who have published or submitted mutations. It provides a submission form for reporting newly identified mutations. We also wanted to introduce nomenclature which complies with recommendations set out by Human Genome Variation Society and HUGO Gene Nomenclature Committee for description of new and known genetic variants. We hope this registry would be a useful and convenient tool for the medical and scientific community.


Assuntos
Amiloidose Familiar/genética , Internet , Mutação , Sistema de Registros , Humanos , Ferramenta de Busca , Software , Terminologia como Assunto
7.
Arthritis Rheum ; 65(4): 1116-21, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23280696

RESUMO

OBJECTIVE: AA amyloidosis is a life-threatening complication of the hereditary periodic fever syndromes (HPFS), which are otherwise often compatible with normal life expectancy. This study was undertaken to determine the characteristics, presentation, natural history, and response to treatment in 46 patients who had been referred for evaluation at the UK National Amyloidosis Centre. METHODS: Disease activity was monitored by serial measurement of serum amyloid A. Renal function was assessed by measurement of serum creatinine and albumin levels, the estimated glomerular filtration rate, and proteinuria from 24-hour urine collections. The amyloid load was measured by serum amyloid P scintigraphy. RESULTS: Twenty-four patients had familial Mediterranean fever, 12 patients had tumor necrosis factor receptor-associated periodic syndrome, 6 patients had cryopyrin-associated periodic syndromes, and 4 patients had mevalonate kinase deficiency. The median age at onset of HPFS was 5 years; median age at presentation with AA amyloidosis was 38 years. Diagnosis of an HPFS had not been considered prior to presentation with AA amyloidosis in 23 patients (50%). Eleven patients (24%) had end-stage renal failure (ESRF) at presentation; of these, 3 had received transplants prior to referral. A further 13 patients developed ESRF over the followup period, with 10 undergoing renal transplantation. The median time to progression to ESRF from onset of AA amyloidosis was 3.3 years (interquartile range [IQR] 2-8), with a median time to transplant of 4 years (IQR 3-6). Eleven patients (24%) died. The median survival in the entire cohort was 19 years from diagnosis of AA amyloidosis. Of the 37 patients who were treated successfully, or in whom at least partial suppression of the underlying HPFS was achieved, 17 (46%) showed amyloid regression, 14 (38%) showed a stable amyloid load, and 2 (5%) showed increased amyloid deposition over the followup period. CONCLUSION: AA amyloidosis remains a challenging and serious late complication of HPFS; however, outcomes are excellent when HPFS is diagnosed early enough to allow effective treatment, thus preventing or retarding further amyloid deposition and organ damage.


Assuntos
Amiloidose/etiologia , Doenças Hereditárias Autoinflamatórias/complicações , Proteína Amiloide A Sérica/metabolismo , Adolescente , Adulto , Idoso , Amiloidose/mortalidade , Amiloidose/fisiopatologia , Criança , Estudos de Coortes , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/mortalidade , Síndromes Periódicas Associadas à Criopirina/fisiopatologia , Progressão da Doença , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/mortalidade , Febre Familiar do Mediterrâneo/fisiopatologia , Feminino , Doenças Hereditárias Autoinflamatórias/mortalidade , Doenças Hereditárias Autoinflamatórias/fisiopatologia , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/fisiopatologia , Masculino , Deficiência de Mevalonato Quinase/complicações , Deficiência de Mevalonato Quinase/mortalidade , Deficiência de Mevalonato Quinase/fisiopatologia , Pessoa de Meia-Idade , Adulto Jovem
8.
Haematologica ; 98(1): 136-40, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22983575

RESUMO

Weight loss is common in systemic immunoglobulin light chain amyloidosis but there are limited data on the impact of nutritional status on outcome. Using the Patient-Generated Subjective Global Assessment (PG-SGA) score, we prospectively examined nutritional status in 110 consecutive newly-diagnosed, treatment-naïve patients with immunoglobulin light chain amyloidosis attending the UK National Amyloidosis Centre. At study entry, 72 of 110 (66%) patients had a PG-SGA score of 4 or over, indicating malnutrition requiring specialist nutritional intervention. Number of amyloidotic organs, elevated alkaline phosphatase, presence of autonomic neuropathy and advanced Mayo disease stage were independently associated with poor nutritional status (P<0.05). Quality of life was substantially poorer among those with higher PG-SGA scores (P<0.001). Furthermore, PG-SGA score was a powerful independent predictor of patient survival (P=0.02). Malnutrition is prevalent and is associated with poor quality of life and reduced survival among patients with systemic immunoglobulin light chain amyloidosis. The PG-SGA score would be an appropriate tool to evaluate whether nutritional intervention could improve patient outcomes.


Assuntos
Amiloidose/genética , Amiloidose/mortalidade , Cadeias Leves de Imunoglobulina/genética , Estado Nutricional/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/imunologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
9.
Presse Med ; 48(1 Pt 2): e49-e59, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30665783

RESUMO

The systemic autoinflammatory disorders (SAIDs) are associated with dysregulation of the innate immune system, affecting pro-inflammatory cytokines and apoptosis pathways. The spectrum of SAIDs continues to grow with over 30 different disorders identified to date. The main indication for genetic referral is when a patient presents with clinical symptoms consistent with one or more of the SAIDs. Thus, in making a referral for DNA screening, clinical information that supports the choice for screening of one or more SAIDs genes is required. Many of the SAIDs can display overlapping, partial or atypical symptoms, which makes the differential diagnosis extremely difficult and thus heavily dependent on genetic testing. Various attempts have been aimed at improving the efficiency of SAIDs diagnosis by proposing a set of clinical criteria to guide the genetic analysis of the SAIDs. In the last decade, due to application of the next-generation sequencing (NGS) the genetic diagnosis in patients with SAIDs have greatly improved; novel diseases and disease-associated genes have been identified and remarkable progress has been made in the genetic characterization of the undiagnosed patients and the sporadic cases. To date more than 800 variants have been recorded on the Infevers database, an online repository for DNA changes in genes associated with SAIDs (http://fmf.igh.cnrs.fr/ISSAID/infevers/). Recently, it has been updated with the new guidelines for classification of genetic variants pathogenicity in the in four most recognised SAIDs genes: MEFV, TNFRSF1A, NLRP3 and MVK.


Assuntos
Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Bases de Dados Genéticas , Diagnóstico Diferencial , Previsões , Doenças Hereditárias Autoinflamatórias/classificação , Doenças Hereditárias Autoinflamatórias/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Técnicas de Diagnóstico Molecular
10.
Arthritis Rheumatol ; 71(12): 2121-2125, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31268627

RESUMO

OBJECTIVE: To assess the prevalence of the MYD88 L265P mutation and variants within NLRP3 and evaluate the status of oligoclonal hematopoiesis in 30 patients with Schnitzler syndrome (SchS). METHODS: Thirty patients with SchS were recruited from 3 clinical centers. Six patients with known acquired cryopyrin-associated periodic syndromes (aCAPS) were included as controls. Allele-specific oligonucleotide-polymerase chain reaction was used for the detection of the MYD88 L265P variant, next-generation sequencing was applied to analyze NLRP3 and 28 genes associated with myelodysplastic syndrome, and gene scanning was performed for the detection of X chromosome inactivation. RESULTS: Activating NLRP3 mutations were not present in 11 SchS patients who had not been sequenced for this gene previously. The MYD88 L265P variant was present in 9 of 30 SchS patients, and somatic mutations associated with clonal hematopoiesis were identified in 1 of 30 patients with SchS and 1 of 6 patients with aCAPS. Evidence of nonrandom X chromosome inactivation was detected in 1 female patient with SchS and 1 female patient with aCAPS. CONCLUSION: A shared molecular mechanism accounting for the pathogenesis of inflammation in SchS remains elusive. Clonal hematopoiesis is not associated with other somatic mutations found in individuals with SchS or aCAPS.


Assuntos
Hematopoese/genética , Mutação/genética , Fator 88 de Diferenciação Mieloide/análise , Proteína 3 que Contém Domínio de Pirina da Família NLR/análise , Síndrome de Schnitzler/genética , Síndromes Periódicas Associadas à Criopirina/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fator 88 de Diferenciação Mieloide/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Reação em Cadeia da Polimerase , Prevalência
11.
Amyloid ; 24(3): 162-166, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28686088

RESUMO

OBJECTIVE: Systemic AA amyloidosis is a serious complication of chronic inflammation; however, there are relatively few published data on its incidence. We investigated the changing epidemiology of AA amyloidosis over a 25-year period at a single national referral centre. METHODS: We conducted a retrospective study of all patients diagnosed with AA amyloidosis who had attended the centre between 1990 and 2014 inclusive. Six hundred and twenty-five patients were studied in three cohorts: C1: 1990-1997; C2: 1998-2006; C3: 2007-2014. RESULTS: Mean age at presentation increased from 46 in C1 to 56 in C3 (p < .0001). The proportion of South Asian patients increased from 4% in C1 to 17% in C3 (p = .0006). Comparison of underlying diseases between C1 and C3 revealed a reduction in patients with juvenile idiopathic arthritis from 25% to 2% (p < .0001), but an increase in patients with chronic infection due to intravenous recreational drug use from 1% to 13% (p < .0001), and uncharacterized inflammatory disorders from 10% to 27% (p <.0001). More patients were in end-stage renal failure at presentation in C3 (29%) than C1 (15%) (p = .0028). Median age at death was later in C3 (62 years) than C1 (54 years) (p = .0012). CONCLUSION: These data suggest both falling incidence and better outcome in AA amyloidosis over a quarter of a century, reflecting advances in therapeutics and overall management of complex chronic disease in an ageing population. AA amyloidosis of uncertain aetiology presents an emerging major problem. Newer techniques such as next-generation sequencing may aid diagnosis and effective treatment, thereby improving overall survival.


Assuntos
Amiloidose de Cadeia Leve de Imunoglobulina , Adulto , Idade de Início , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
12.
Front Immunol ; 8: 1410, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29163488

RESUMO

Cryopyrin-associated periodic syndrome (CAPS) is caused by gain-of-function NLRP3 mutations. Recently, somatic NLRP3 mosaicism has been reported in some CAPS patients who were previously classified as "mutation-negative." We describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood. All patients underwent comprehensive clinical and laboratory investigations, including analysis of the NLRP3 gene using Sanger and amplicon-based deep sequencing (ADS) along with measurements of extracellular apoptosis-associated speck-like protein with CARD domain (ASC) aggregates. The clinical phenotype in all subjects was consistent with mid-spectrum CAPS, except a median age at disease onset of 50 years. Sanger sequencing of NLRP3 was non-diagnostic but ADS detected a somatic NLRP3 mutation in each case. In one patient, DNA isolated from blood demonstrated an increase in the mutant allele from 5 to 45% over 12 years. ASC aggregates in patients' serum measured during active disease were significantly higher than healthy controls. This series represents 8% of CAPS patients diagnosed in a single center, suggesting that acquired NLRP3 mutations may not be an uncommon cause of the syndrome and should be sought in all patients with late-onset symptoms otherwise compatible with CAPS. Steadily worsening CAPS symptoms in one patient were associated with clonal expansion of the mutant allele predominantly affecting myeloid cells. Two patients developed AA amyloidosis, which previously has only been reported in CAPS in association with life-long germline NLRP3 mutations.

13.
Arthritis Rheumatol ; 68(8): 2044-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26992170

RESUMO

OBJECTIVE: To investigate the molecular cause of persistent fevers in a patient returning from working overseas, in whom investigations for tropical diseases yielded negative results. METHODS: DNA was extracted from the patient's whole blood, leukocyte subpopulations, saliva, hair root, and sperm. The TNFRSF1A gene was analyzed by polymerase chain reaction (PCR), allele-specific PCR, Sanger sequencing, and next-generation sequencing. In silico molecular modeling was performed to predict the structural and functional consequences of the tumor necrosis factor receptor (TNFR) type I protein mutation in the extracellular domain. RESULTS: Sanger sequencing corroborated by allele-specific PCR detected a novel in-frame deletion of 24 nucleotides (c.255_278del) in the TNFRSF1A gene, and this was subsequently confirmed using next-generation sequencing methods (targeted sequencing and amplicon-based deep sequencing). Results of amplicon-based deep sequencing revealed variable frequency of the mutant allele among different cell lines, including sperm, thus supporting the presence of gonosomal TNFRSF1A mosaicism. The patient had a complete response to treatment with interleukin-1 (IL-1) blockade, with resolution of symptoms and normalization of acute-phase protein levels. CONCLUSION: We describe the first case of gonosomal TNFRSF1A mosaicism in a patient with TNFR-associated periodic syndrome (TRAPS), which was attributable to a novel, somatic 24-nucleotide in-frame deletion. The clinical picture in this patient, including the complete response to IL-1 blockade, was typical of that found in TRAPS. This case adds TRAPS to the list of dominantly inherited autoinflammatory diseases reported to be caused by somatic (or postzygotic) mutation.


Assuntos
Febre/genética , Doenças Hereditárias Autoinflamatórias/genética , Mosaicismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Deleção de Sequência , Adulto , Humanos , Masculino
14.
Artigo em Inglês | MEDLINE | ID: mdl-27511979

RESUMO

BACKGROUND: Calcific aortic stenosis (cAS) affects 3% of individuals aged >75 years, leading to heart failure and death unless the valve is replaced. Wild-type transthyretin cardiac amyloid is also a disorder of ageing individuals. Prevalence and clinical significance of dual pathology are unknown. This study explored the prevalence of wild-type transthyretin amyloid in cAS by myocardial biopsy, its imaging phenotype and prognostic significance. METHODS AND RESULTS: A total of 146 patients with severe AS requiring surgical valve replacement underwent cardiovascular magnetic resonance and intraoperative biopsies; 112 had cAS (75±6 years; 57% men). Amyloid was sought histologically using Congo red staining and then typed using immunohistochemistry and mass spectrometry; patients with amyloid underwent clinical evaluation including genotyping and (99m)TC-3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) bone scintigraphy. Amyloid was identified in 6 of 146 patients, all with cAS and >65 years (prevalence 5.6% in cAS >65). All 6 patients had wild-type transthyretin amyloid (mean age 75 years; range, 69-85; 4 men), not suspected on echocardiography. Cardiovascular magnetic resonance findings were of definite cardiac amyloidosis in 2, but could be explained solely by AS in the other 4. Postoperative DPD scans demonstrated cardiac localization in all 4 patients who had this investigation (2 died prior). At follow-up (median, 2.3 years), 50% with amyloid had died (versus 7.5% in cAS; 6.9% in age >65 years). In univariable analyses, the presence of transthyretin amyloidosis amyloid had the highest hazard ratio for death (9.5 [95% confidence interval, 2.5-35.8]; P=0.001). CONCLUSIONS: Occult wild-type transthyretin cardiac amyloid had a prevalence of 6% among patients with AS aged >65 years undergoing surgical aortic valve replacement and was associated with a poor outcome.


Assuntos
Neuropatias Amiloides Familiares/epidemiologia , Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Cardiomiopatias/epidemiologia , Implante de Prótese de Valva Cardíaca , Idoso , Idoso de 80 Anos ou mais , Amiloide/análise , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/mortalidade , Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/mortalidade , Biópsia , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Cardiomiopatias/mortalidade , Ecocardiografia , Feminino , Predisposição Genética para Doença , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/mortalidade , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Londres , Imageamento por Ressonância Magnética , Masculino , Espectrometria de Massas , Mutação , Miocárdio/química , Miocárdio/patologia , Fenótipo , Pré-Albumina/genética , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de Risco , Índice de Gravidade de Doença , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento
15.
Amyloid ; 22(1): 26-30, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25430583

RESUMO

Hereditary transthyretin (ATTR) amyloidosis is caused by inheritance of an abnormal TTR gene in an autosomal dominant fashion. In its native state, TTR is a homotetramer consisting of four identical polypeptides. Mutations in the TTR gene contribute to destabilization and dissociation of the TTR tetramer, enabling abnormally folded monomers to self-assemble as amyloid fibrils. Currently, over 120 TTR variants have been described, with varying geographic distributions, degrees of amyloidogenicity and organ involvement. We report here a large Irish family with familial amyloid polyneuropathy (FAP), consisting of multiple affected generations, caused by a novel TTR mutation; p.H110D (H90D). The demonstration, by immunohistochemistry and laser micro dissection-mass spectrometry (LMD/MS) that the amyloid fibrils were composed of TTR, in conjunction with a typical FAP phenotype, indicates that the novel TTR mutation was the cause of amyloidosis. We used a molecular visualization tool PyMOL to analyze the effect of the p.H110D (H90D) replacement on the stability of the TTR molecule. Our data suggest that the loss of two hydrogen bonds and the presence of an additional negative charge in the core of a cluster of acidic residues significantly perturb the tetramer stability and likely contribute to the pathogenic role of this variant.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Pré-Albumina/genética , Idoso , Neuropatias Amiloides Familiares/genética , Análise Mutacional de DNA , Evolução Fatal , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Irlanda , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem
16.
Arthritis Rheumatol ; 66(1): 197-202, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24431285

RESUMO

OBJECTIVE: To identify the genetic cause of chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) using whole-exome sequencing in a child who had typical clinical features but who was NLRP3 mutation negative based on conventional Sanger sequencing. METHODS: We performed whole-exome sequencing on DNA from peripheral blood, using Illumina TruSeq Exome capture and the HiSeq sequencing platform. Exome data were analyzed in the Galaxy Web-based suite. Whole-exome sequencing findings were confirmed by massively parallel sequencing. RESULTS: Analysis of variants in known autoinflammatory genes led to the identification of the pathogenic p.F556L NLRP3 missense mutation in 17.7% of Illumina reads (25 of 141). No new candidate genes were identified. Massively parallel sequencing of DNA from peripheral blood (performed in duplicate) unequivocally confirmed the presence of this mutation in 14.5% of alleles. Reexamination of the original Sanger chromatograms revealed a small peak at nucleotide position c.1698 corresponding to the mutated allele. This had initially been regarded as background noise, but in retrospect is completely consistent with somatic mosaicism for the p.F556L NLRP3 mutation in this child with CINCA syndrome. CONCLUSION: This is the first description of somatic NLRP3 mosaicism detected using whole-exome sequencing in a "mutation-negative" patient with CINCA syndrome. Our findings suggest that whole-exome sequencing could be an important diagnostic tool for detecting somatic mosaicism, as well as for the discovery of novel causative gene mutations, in patients with clinical features of cryopyrin-associated periodic syndromes who are NLRP3 mutation negative by conventional sequencing. This approach could also be applicable to patients with other autosomal-dominant autoinflammatory diseases characterized by gain-of-function mutations who are mutation negative by conventional Sanger sequencing.


Assuntos
Proteínas de Transporte/genética , Síndromes Periódicas Associadas à Criopirina/genética , Mosaicismo , Criança , Exoma , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR , Análise de Sequência de DNA
17.
Retin Cases Brief Rep ; 7(3): 271-5, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-25391122

RESUMO

PURPOSE: To report a rare case of transthyretin (TTR) familial amyloid cardiomyopathy with retinal microangiopathy and vitreous amyloid as the initial manifestation. METHODS: A 54-year-old woman presented with bilateral retinal microangiopathy, presumed idiopathic retinal vasculitis. She subsequently developed retinal ischemia associated vitreous hemorrhage and was treated with panretinal laser photocoagulation. Clinical eye signs remained stable for 6 years with the absence of overt inflammation. However, the patient developed chest pain and atrial flutter and underwent echocardiography, cardiac magnetic resonance imaging, and Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy to investigate possible cardiac amyloidosis. Sequencing of the TTR gene was conducted and a rectal biopsy performed for tissue diagnosis. A full neurologic screen was also conducted. RESULTS: Cardiac investigations were highly suggestive of an amyloid cardiomyopathy. The rectal biopsy stained positive for Congo red with demonstration of apple green birefringence, confirming amyloid, and immunostaining confirmed the TTR subtype. Gene sequencing revealed heterozygous TTR mutation encoding E89K variant. No significant neuropathy could be detected. CONCLUSION: Amyloid should be considered as a masquerade diagnosis in cases of retinal microangiopathy, especially in the absence of inflammation. Liaising with physicians for systemic evaluation and TTR gene sequencing is essential for early diagnosis and management of this rare condition.

18.
Arthritis Res Ther ; 15(1): R30, 2013 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-23421920

RESUMO

INTRODUCTION: Mutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to characterize the clinical phenotypes and treatments in individuals with V198M assessed in a single UK center. METHODS: DNA samples from 830 subjects with fever syndromes or a family history of CAPS were screened for mutations in the NLRP3 gene with polymerase chain reaction (PCR) and sequencing. A detailed medical history was available in all cases. Inflammatory disease activity was monitored monthly with measurements of serum amyloid A protein (SAA) and C-reactive protein (CRP) in symptomatic individuals. RESULTS: NLRP3 V198M was identified in 19 subjects. It was found in association with CAPS in five cases, in one patient with Schnitzler syndrome, in three patients who also had a nucleotide alteration in another fever gene, and in three other patients with evidence of an autoinflammatory phenotype. Seven asymptomatic individuals were detected during screening of family members. CONCLUSIONS: The NLRP3 V198M variant shows variable expressivity and reduced penetrance. It may be associated with classical inherited or apparently sporadic CAPS and with atypical autoinflammatory disease of varying severity, intriguingly including Schnitzler syndrome. The factors that influence the pathogenic consequences of this variant remain unknown. However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.


Assuntos
Proteínas de Transporte/genética , Doenças Hereditárias Autoinflamatórias/genética , Adulto , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR , Linhagem , Penetrância , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Reino Unido , Adulto Jovem
19.
Arthritis Rheum ; 54(6): 2010-4, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16732551

RESUMO

AA amyloidosis is the most serious potential complication of the inherited autoinflammatory syndromes and frequently results in end-stage renal failure. Although this complication is well recognized in familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and Muckle-Wells syndrome, there is only 1 previous published report of its occurrence in hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). We report 2 further cases of patients with AA amyloidosis in HIDS, both of whom developed dialysis-dependent renal failure, and we describe the outcome of the first renal transplant in this setting.


Assuntos
Amiloidose/complicações , Febre Familiar do Mediterrâneo/complicações , Imunoglobulina D/sangue , Proteína Amiloide A Sérica , Adulto , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Masculino
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