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- Hazard characterisation of bisphenol A alternatives to improve risk assessment for human health: genotoxic and carcinogenic effects in mammalian cellsPublication . Pereira, Maria João Rodrigues; Silva, Maria João; Farinha, CarlosBisphenol A (BPA) is a compound used in the production of epoxy resins, polycarbonate plastics and as an additive (e.g. in thermal paper). It is present in several different products and has been detected both in the environment and in human matrices. BPA is a known endocrine disruptor, with several studies linking it to multiple harmful health effects. Therefore, there is an effort to phase out its use, but also to replace it with alternative substances. Various alternatives are already being used and have been detected in the environment and human matrices. Furthermore, some harmful health effects have also been reported for those substances (albeit not as many as BPA), justifying the need for more research on these alternatives. This thesis is part of the Partnership for the Assessment of Risks from Chemicals (PARC), that prioritized alternatives based on the lack of data on their effects on human health and due to human exposure to them occurring or being likely to occur. This thesis focused on BPS-MAE and BPAP, aiming to contribute to their hazard assessment, through the characterisation of their in vitro genotoxic and carcinogenic potential. The former was assessed for BPS-MAE and BPAP with the Cytokinesis-Block Micronucleus assay, in human peripheral blood lymphocytes. The results suggest that BPS-MAE and BPAP do not have a genotoxic effect at the concentrations and exposure times tested. Genotoxic and non-genotoxic carcinogenicity of BPAP and BPA was ascertained with the Cell Transformation assay, in Bhas 42 cells. BPA was tested to allow inter-laboratory comparison of results and assay optimisation. The results indicate that neither BPAP nor BPA have potential carcinogenic activity at the concentrations and treatment durations tested. The data obtained will help eliminating existing data gaps, aid to improve these alternatives’ risk assessment and contribute to the formulation of legislation, if necessary.
- Early Diagnosis of Mucopolysaccharidoses in PediatricsPublication . da Silva Gaspar, Paulo Jorge Miranda; Neiva, Raquel; Sousa e Silva, Lisbeth Elena; Diogo, Luisa; Ferreira, A.; Miranda, A.; Ribeiro, S.; Antunes, D.; Garcia, P.; Rodrigues, E.; Campos, T.; Janeiro, P.; Lopes, Altina; Pereira, Cristina; Nogueira, Célia; Sousa, S.; Ferreira, S.; Alves, Sandra; Leão Teles, Elisa; Vilarinho, LauraIntroduction: Mucopolysaccharidoses (MPSs) are a group of Lysosomal Storage Disorders with multisystem involvement, presenting different degrees of severity and evolution. At early disease stages and late onset forms, diagnosis can be postponed for years or even missed. The FIND PROJECT was designed to claim awareness to the redflags of MPSs at pediatric age and to provide a useful tool for physicians to diagnose these pathologies, since most of them are amenable to enzyme replacement therapy.
- Differential Diagnosis of Alpha-Mannosidosis in MPSsPublication . da Silva Gaspar, Paulo Jorge Miranda; Gonçalves, Diana; Neiva, Raquel; Sousa e Silva, Lisbeth Elena; Vilarinho, LauraIntroduction: Mucopolysaccharidosis (MPSs) and oligosaccharidosis, two subgroups of lysosomal storage disorders (LSDs), face diagnostic challenges due to their wide spectrum of clinical presentations and overlapping symptoms. One of the oligosaccharidose is α-mannosidosis, an extremely rare and often undiagnosed disorder. It is characterized by a deficiency in the enzymatic activity of α-mannosidase, which is responsible for cleaving mannose from N-linked oligosaccharides. This study aimed to investigate the activity of α-mannosidase in dried blood spot (DBS) samples that had undergone screening for MPSs.
- Olipudase alfa enzyme replacement therapy. One-year outcomes in an adult patient with acid sphingomyelinase deficiency type BPublication . Cardoso, M.; Chaves, P.C.; Pintalhão, M.; da Silva Gaspar, Paulo Jorge Miranda; Castro, R.; Bastos, J.; Silva, A.; Campos, T.; Macedo, Fatima; Rodrigues, E.; Leão Teles, ElisaIntroduction: Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive lysosomal storage disorder caused by variants in the SMPD1 gene, leading to a deficiency in the activity of sphingomyelinase (ASM) that catabolizes sphingomyelin (SPM). ASMD Type B is a late-onset, severe disease characterized by progressive hepatosplenomegaly, gradual deterioration of liver and pulmonary function, osteopenia and an atherogenic lipid profile. Olipudase alfa is a recombinant human ASM enzyme replacement therapy indicated for the treatment of non-C-NS manifestations of ASMD.
- Early diagnosis of acid sphingomyelinase deficiency (ASMD) through biomarkers analysisPublication . Neiva, Raquel; da Silva Gaspar, Paulo Jorge Miranda; Sousa e Silva, Lisbeth Elena; Gonçalves, I.; Ferreira, S.; Diogo, Luisa; Vilarinho, LauraIntroduction: Acid sphingomyelinase deficiency (ASMD), historically known as Niemann–Pick disease (NPD) types A, A/B, and B, is a rare, progressive, potentially fatal lysosomal storage disease caused by pathogenic variants in SMPD1 gene. It presents a wide spectrum of symptoms, age of onset, and degree and type of organ effected. The disease manifestations frequently involve hepatosplenomegaly with progressive organ dysfunction, interstitial lung disease, and bleeding. In this work, we will present a patient whose lysosomal biomarkers study allowed the diagnosis of ASMD. Methods: This patient had hepatosplenomegaly, elevated transaminases in which the primary clinical suspicion was an acid lipase deficiency. By the analysis of our multiplex biomarker panel by LC-MS/MS analysis, we were able to do a differential diagnosis. Results/Case report: The lysosphingomyelin (lysoSM) and lysosphingomyelin-509 (lysoSm-509) were approximately 100 a 150x than normal, suggestive of Niemann–Pick disease. The diagnosis of ASMD was confirmed by reduced acid sphingomyelinase enzyme activity measured in peripheral blood leukocytes and the presence of a pathogenic variant in both alleles in the SMPD1 gene. Conclusion: ASMD can be underestimate and the diagnostic odissey arise from an overlap in symptomology with other diseases, including primary hepatic disease, Gaucher disease, Niemann–Pick disease, and lysosomal acid lipase deficiency. The multiplex biomarker panel, with different lysolipids, allows simultaneously diagnosis of different LSDs, in a timely manner, leading to an early intervention, before the appearance of more deleterious symtpoms.
- Forty-four years of newborn screening in Portugal: new challenges, the same commitment to the communityPublication . Marcão, Ana; Sousa, Carmen; Pinho, Conceição; Ribeiro, Diogo; Rodrigues, Diogo; Guimarães, Fábio; Fonseca, Helena; Rocha, Hugo; Carvalho, Ivone; Lopes, Lurdes; Vilarinho, LauraIntrodução: O Programa Nacional de Rastreio Neonatal (PNRN) é um programa sistemático destinado a todos os recém-nascidos (RN) com nascimento em Portugal, e que atualmente inclui 28 patologias, das quais uma em estudo piloto. O aumento do número de patologias rastreadas, a implementação de novas e mais complexas técnicas de rastreio, o aumento da diversidade genética da população Portuguesa, os novos hábitos dietéticos e a exigência crescente da sociedade atual, trouxeram desafios que exigiram uma adaptação permanente do programa ao longo destes anos. Material e métodos: Mais de 4, 200 000 RN foram rastreados desde 1979. Diferentes métodos e estratégias de rastreio foram utilizados ao longo destes 44 anos. Atualmente, utilizam-se técnicas imunológicas (HC e CF), espectrometria de massa em tandem (IEM), eletroforese capilar (SCD) e estudo genético (FQ e SMA). Resultados: A antecipação da data de colheita (3º-6º dia), e a publicação de resultados na internet foram importantes mudanças organizacionais do programa. A alteração do protocolo de colheitas nos RN grandes prematuros veio responder à necessidade de evitar resultados falsos negativos no rastreio do CH. A performance do rastreio das 24 IEM foi claramente melhorada com a introdução de vários testes de segunda linha na estratégia de rastreio. A alteração recente da estratégia de rastreio da CF (2023), passando a incluir o estudo genético, trouxe uma melhoria extraordinária na performance deste rastreio, esperando-se ainda uma melhoria acrescida com uma nova alteração introduzida em 2024. As alterações efetuadas permitiram aumentar a sensibilidade e especificidade de deteção das várias patologias rastreadas e melhorar a resposta do PNRN à comunidade. Conclusão: O PNRN é um programa dinâmico que se mantém em constante atualização, quer em termos organizacionais e comunicacionais, quer em termos de patologias rastreadas e estratégias de rastreio. Desde 1979, mais de 2,700 casos positivos foram identificados e referenciados para CR, permitindo uma intervenção terapêutica adequada, com benefício dos RN e das famílias. A atualização permanente dos programas de rastreio, com adaptação constante aos novos desafios tecnológicos e às mudanças emergentes na comunidade a que se dirigem é fundamental para o seu sucesso.
- Reverse phenotyping after ngs panel of x-linked intellectual disability unravels creatine transporter (SLC6A8) deficiencyPublication . Padeira, Gonçalo; Jacinto, Sandra; Venâncio, Margarida; Marcão, Ana; Conceição, Carla; Ferreira, Ana CristinaX-linked intellectual disability (XLID) is characterized by extensive genetic heterogeneity. Next-generation sequencing (NGS) have been used in these cases as a cost-effective diagnosis approach. Genetic findings often reveal variants unforeseen during clinical investigation, prompting the need for reevaluation of specific features designated as reverse phenotyping (RP). X-linked creatine transporter deficiency (CTD) is a potentially treatable intellectual disability caused by pathogenic variants in the SLC6A8 gene leading to impaired creatine transport into the brain. A 7-year-old boy with intellectual disability, speech delay, hyperactivity and epilepsy was referred to Metabolic and Neuropediatric Clinic. Family history identified a mother with learning difficulties and a maternal uncle with intellectual disability, indicating a possible X-linked inheritance. NGS intellectual disability panel identified a variant classified as probably pathogenic (c.880_881del (p(Lys294Alafs*2)) in the SLC6A8 gene, in hemizygosity which prompted referral to Metabolic and Neuropediatric Clinic. Reverse phenotyping was carried out with biochemical and imaging assessment that showed: high urinary Creatine-Creatinine ratio (2.17; RV 0.04-1.07) with normal guanidinoacetate acid and absence of creatine peak in brain MRI spectroscopy, confirming the diagnosis. Genetic studies on female family members are ongoing. He started treatment with creatine, arginine and glycine in the last appointment. CTD is a rare disease that has been reported in more than 150 individuals worldwide. We present a case in which the diagnostic approach was reverse phenotyping, through biochemical and imaging studies, after the identification of pathogenic variants in SLC6A8 by NGS panel. The efficacy of its treatment remains controversial with variable results, and a close evaluation will be needed.
- Twenty Years of Newborn Screening for MCADD in Portugal: genetic dataPublication . Fonseca, Helena; Marcão, Ana; Sousa, Carmen; Rocha, Hugo; Vilarinho, LauraIntroduction: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive inherited metabolic disorder that affects fatty acid oxidation metabolism. Most cases present the most common c.985G>A mutation in ACADM gene, while a few patients carry other rare mutations. In Portugal, MCADD has been included in the newborn screening program since 2004 and is the most frequently diagnosed inborn error of metabolism detected through this program, with an incidence of 1 in 6,433. Materials and Methods: Approximately 1,762,713 newborns were screened for MCAD deficiency between October 2004 and January 2025, using tandem mass spectrometry (MS/MS) to detect elevated octanoylcarnitine (C8) levels and an increased C8/C10 ratio. Tandem mass spectrometry (MS/MS) results and genetic testing data were analyzed. Results: Over the 20 years period, a total of 274 newborns were identified with high values of C8 and C8/C10 ratios from dried blood spots. Biochemical and molecular follow up confirmed the MCADD diagnosis in 273 cases. Molecular characterization was not available for 90 cases. Of the remaining 183 cases, which were studied at our Newborn Screening, Metabolism and Genetics Unit, 162 (88%) were homozygous for the c.985G>A mutation, while 22 were compound heterozygotes. Of these, 13 carried the c.985G>A mutation along with a another mutation, whereas 8 had two distinct mutations. Additionally, seven novel mutations were identified in this cohort: c.94G>C, c.113G>C, c.214G>T, c.532A>T, c.974A>G, c.1133G>A, and c.708+1G>A. Conclusion: Newborn screening has been crucial for identifying and managing of MCADD in Portugal. Our study confirms the c.985G>A mutation as the most frequent pathogenic variant, consistent with previous reports. The identification of seven novel mutations expands the spectrum of known variants, underscoring the importance of comprehensive genetic analysis. These findings reinforce the importance of newborn screening in early diagnosis and intervention, while also contributing to a deeper understanding of the genetic diversity of MCADD, with implications for genetic counseling and long-term management.