Browsing by Author "Tavares, Isabel"
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- Cardiac Amyloidosis Associated with Apolipoprotein A-IV Deposition Diagnosed by Mass Spectrometry-Based Proteomic AnalysisPublication . Martins, Elisabete; Urbano, Joana; Leite, Sérgio; Pinto, Adriana; Garcia, Raquel; Bergantim, Rui; Rodrigues-Pereira, Pedro; Costa, Paulo Pinho; Osório, Hugo; Tavares, IsabelAmyloidosis is a group of disorders characterised by the accumulation of extracellular deposits of insoluble protein aggregates. Clinical management depends on the accurate identification of the amyloid precursor and underlying cause. We describe a rare case of apolipoprotein A-IV cardiac amyloidosis, the diagnosis of which required mass spectrometry-based proteomic analysis.
- CTNS Molecular Genetics Profile in a Portuguese Cystinosis PopulationPublication . Ferreira, Filipa; Leal, Inês; Sousa, David; Costa, Teresa; Mota, Conceição; Gomes, Ana Marta; Lopes, Daniela; Carmo Macário, Maria do; Tavares, Isabel; Pinto, Helena; Oliveira, João Paulo; Magriço, Rita; Carmona, Célia; Ramos, Sónia; Neiva, Raquel; Marcão, Ana; Vilarinho, LauraBackground: Cystinosis is a multisystemic autosomal recessive deficiency of the lysosomal membrane transporter protein (cystinosin) caused by mutations in CTNS gene. Objective : This study summarizes the Portuguese experience in the diagnosis and management of patients with this rare disease over the past few years and reports recurrent mutations in the CTNS gene . Methods : Unrelated patients from different pediatric and adult hospitals all over Portugal with non-nephrotic proteinuria, hypercalciuria, hypokalemia impaired proximal reabsorption of amino acids, glycosuria and hypophosphatemia, suggestive of a Fanconi syndrome and ocular problems, were studied. Intra-leukocyte cystine levels were determined and molecular analysis was performed, to determine the presence or absence of the 57-kb deletion in CTNS , followed by direct sequencing of the coding exons of CTNS . Results : From 1998 to 2017, twenty-one cystinotic patients were biochemically diagnosed. From the remaining seventeen (four deceased), eleven were studied for CTNS gene. Five out of eleven patients were homozygous for the 57-kb deletion (10/22; 45.5%), and other five were compound heterozygous for this variant (15/22; 68.2%). The other mutations found were p.Q128X (c.721 C>T; 2/22), p.S139F (c.755 C>T; 4/22) and c.18-21delGACT (p.T7FfsX7; 1/22). All of these seventeen cystinotic patients are in treatment. Approximately 84% are adults, 16% are young children, and 54.5% are kidney transplant recipient. Conclusions: The authors would like to emphasize the importance of first screening for the 57-kb deletion since it is very common in our population. This genetic study is the first in our country and it could be the basis for future genetic counseling in Portuguese population.
- Espectro mutacional da cistinose em Portugal, 1998-2017Publication . Ferreira, Filipa; Leal, Inês; Sousa, David; Costa, Teresa; Mota, Conceição; Gomes, Ana Marta; Lopes, Daniela; Macário, Maria do Carmo; Tavares, Isabel; Pinto, Helena; Oliveira, João Paulo; Magriço, Rita; Carmona, Célia; Ramos, Sónia; Neiva, Raquel,; Marcão, Ana; Vilarinho, LauraA cistinose é uma doença metabólica multisistémica, autossómica recessiva caracterizada por uma acumulação de cistina em diferentes órgãos e tecidos devido a uma deficiência no transporte de cistina para o exterior dos lisossomas. O gene responsável pela doença, CTNS, está localizado no cromossoma 17 e codifica para uma proteína de membrana lisossomal, a cistinosina. Neste trabalho foram estudados doentes não relacionados provenientes das consultas de adultos e pediatria de diferentes hospitais de Portugal continental e ilhas, que apresentavam proteinuria não-nefrótica, hipercalciúria, hipocaliemia, hiperaminoacidúria, glicosúria e hipofosfatemia, sugestivo de síndroma de Fanconi e queixas oculares. Bioquimicamente, a cistina intraleucocitária foi quantificada, tendo-se igualmente efetuado a caracterização molecular do gene CTNS, inicialmente apenas direcionado para a pesquisa da deleção de 57-kb, seguida da sequenciação de todos os exões codificantes do gene CTNS. Desde 1998 a 2017, 21 doentes cistinóticos foram bioquimicamente caracterizados. Entretanto, 4 destes doentes faleceram e dos restantes 17, apenas 11 foram estudados para o gene CTNS. Verificouse que 5 destes 11 doentes foram homozigóticos para a deleção de 57-kb (10/22; 45,5%), e outros 5 foram compostos heterozigóticos para esta mutação (15/22; 68,2%). As outras mutações identificadas foram: p.Q128X (c.721 C>T; 2/22), p.S139F (c.755 C>T; 4/22) e c.18-21delGACT (p.T7FfsX7; 1/22). Todos estes 17 doentes cistinóticos estão em tratamento, sendo que 84% são adultos, 16% são crianças jovens e 54,5% são transplantados renais. Este estudo efetuado ao longo de vários anos, reflete a experiência no diagnóstico e monitorização dos doentes cistinóticos. Além disso, a caracterização das mutações encontradas no gene CTNS, ressalta a importância para um screening inicial da deleção de 57-kb e permite um futuro aconselhamento genético aos casais de risco.
- Evidence for an ancient origin of the FGA p.Glu545Val (E526V) amyloidosis-causing mutation endemic in Northern PortugalPublication . Costa, P.P.; Lacerda, P.C.; Oliveira, M.E.; Maia, N.; Lobato, Luísa; Santos, Rosário; Tavares, IsabelFibrinogen alpha chain amyloidosis is widely spread throughout the world, and is most frequently associated with the FGA p.Glu545Val (E526V) mutation, particularly in European countries, with endemic foci of the disease identified in the UK and in northern Portugal. All identified Portuguese patients are from the same region, and a preliminary attempt to characterize the disease-associated haplotype hinted at a common ancestor, but whether this is true and how far back in time the founding event would have taken place is still much an open question. In order to address these questions we studied all available Portuguese patients and relatives, 56 individuals in total, 33 of which were mutation carriers, belonging to 12 extended families. Thirteen polymorphic short tandem-repeats spanning 5.8Mbps over the FGA gene in chromosome 4 were genotyped. A control population of 67 unrelated individuals was also genotyped for the same polymorphisms. Haplotype phasing was carried out using an empirical linkage disequilibrium-based method implemented in the Beagle 4.1 computer program, with some manual adjustments to take into account pedigree constraints and to preserve parsimony. In total 7 different but closely related disease-associated haplotypes were identified, the most frequent of which (I), represented in 5 families, was presumed to be the ancestral haplotype. The age of the E526V mutation in this population was estimated by fitting a multipoint LD model, as implemented in the DMLE+ program. While this model is somewhat sensitive to estimates of population growth and other parameters, it consistently predicted a mutation age above 100 generations (2500 years). These results point to a relatively ancient mutation, which could explain, at least in part, its wide dissemination throughout the world. It would be interesting to extend this study to other populations, to see if there is evidence for a common ancestor, and to try to establish a pattern of mutation dissemination.
- Fibrinogen A alpha-chain amyloidosis: a non-negligible cause of chronic kidney disease in dialysis patientsPublication . Tavares, Isabel; Moreira, Luciana; Costa, Paulo Pinho; Lobato, LuísaBackground: Fibrinogen A alpha-chain (AFib) amyloidosis is a rare and late-onset disease, that result from amyloidogenic autosomal dominant mutations in the gene-encoding AFib (FGA). Patients invariably develop chronic kidney disease (CKD), typically progressing to end-stage renal failure within 5 years of recognition of renal involvement [1]. In Portugal, four apparently unrelated patients with AFib amyloidosis were identified in the district of Braga, Northern Portugal. They all carried the FGA p.Glu545Val mutation, three were heterozygous and one homozygous [2,3]. This observation led us to assess the prevalence of AFibE526V (p.Glu545Val) amyloidosis among Portuguese patients undergoing hemodialysis in the same district, through genetic screening for the FGA p.Glu545Val mutation.
- Haplotype analysis of newly diagnosed Portuguese and Brazilian families with fibrinogen amyloidosis caused by the FGA p.Glu545Val variantPublication . Tavares, Isabel; Oliveira, Márcia E.; Maia, Nuno; Moreira, Luciana; Castro Lacerda, Pedro; Santos, Josefina; Santos, Rosário; Pinho Costa, Paulo; Lobato, LuísaBackground: Fibrinogen A alpha-chain (AFib) amyloidosis is an autosomal dominant disease with an endemic foci in the district of Braga, northern Portugal [1]. Among the 16 amyloidogenic mutations identified in the fibrinogen A alpha-chain gene (FGA) [2,3], the c.1634A > T (p.Glu545Val) mutation (rs121909612) is the most common and, so far, the only one identified in Portugal. A first study using three common polymorphisms showed a single haplotype, associated with the FGA p.Glu545Val mutation in Irish–American and Polish–Canadian kindreds [4]. However, the origin of this amyloidogenic variant in diverse regions and its migration in the different populations are still unclear. Therefore, we proceeded to a preliminary study using two FGA haplotype markers in newly identified Portuguese and Brazilian carriers to investigate the possibility of a common ancestor.
- Short-term complications after renal transplantation in AFibE526V (p.Glu545Val) amyloidosisPublication . Tavares, Isabel; Silvano, José; Moreira, Luciana; Oliveira, Márcia E.; Silva, Roberto; Sampaio, Susana; Costa, Paulo Pinho; Lobato, LuísaIntroduction: Fibrinogen Aa chain (AFib) amyloidosis is an autosomal dominant disease that typically presents with predominant renal involvement and has a predictable progressive clinical course [1]. The p.Glu545Val AFib gene (FGA) mutation is at the origin of all AFib amyloidosis cases (AFibE526V [p.Glu545Val]) that have been identified in Portugal so far, and accounts for the disease in 17 families. Current treatment of AFib amyloidosis comprises both supportive measures and disease-modifying approaches, such as liver transplantation [2,3]. Renal transplantation (RTx) is a supportive therapy with risk of premature graft loss due to amyloid recurrence or other unexpected complications related to progression of extrarenal amyloid deposition. The aim of this study was to evaluate the outcome of Portuguese patients with AFibE526V (p.Glu545Val) amyloidosis after RTx.
- Unrecognized Fibrinogen A α-Chain Amyloidosis: Results From Targeted Genetic TestingPublication . Tavares, Isabel; Oliveira, João Paulo; Pinho, Ana; Moreira, Luciana; Rocha, Liliana; Santos, Josefina; Pinheiro, Joaquim; Costa, Paulo Pinho; Lobato, LuísaFibrinogen A α-chain (AFib) amyloidosis results from autosomal-dominant mutations in the gene encoding AFib (FGA). Patients with this disorder typically present with proteinuria. Isolated cases of AFib amyloidosis, carrying the FGA p.Glu545Val variant, were identified in the district of Braga, in northwest Portugal. This observation led us to hypothesize that this disorder might be an unrecognized cause of kidney disease in that region and prompted us to carry out targeted genetic testing for the p.Glu545Val variant in the local hemodialysis population and family members of identified cases.