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- Evaluating Clinical Markers To Improve Selection Of Diabetes Patients For Genetic TestingPublication . Vaz, Margarida; Gaspar, Gisela; Dario, Paulo; Bourbon, MafaldaMaturity-Onset Diabetes of the Young (MODY) is a monogenic form of diabetes caused by variants in one of 14 genes, each affecting glucose metabolism differently and leading to heterogeneous clinical presentations. Because of this variability, MODY is frequently misdiagnosed as type 1 or type 2 diabetes. In this work, the aim was to characterize patients with and without pathogenic MODY variants among participants of the Molecular Study of Monogenic Diabetes. Clinical data—age at diagnosis, blood glucose, HbA1c, and C-peptide—were analyzed using statistical tests (Shapiro and Wilcoxon). Among these parameters, only age at diagnosis differed significantly, with MODY patients being diagnosed earlier, likely due to the high prevalence of GCK-MODY in the cohort. C-peptide levels were within normal ranges in both groups. The study concludes that these common clinical markers are insufficient to reliably identify MODY cases, emphasizing the need for additional biomarkers and highlighting genetic testing as the only definitive diagnostic tool
- Genetic Diagnosis of Familial Hypercholesterolaemia (FH) In Portugal: Insights from the Portuguese FH StudyPublication . Miranda, Beatriz; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, MafaldaThis work summarises the outcomes of FH genetic testing in the PFHS.
- Deciphering the genetic modifiers of sickle cell anemia in children: the role of CYB5R3 genePublication . Nascimento, Djanira; Lopes, Pedro; Kjollerstrom, Paula; Maia, Raquel; Faria, Teresa; Faustino, PaulaIntroduction: Sickle cell anemia (SCA) is an autosomal recessive disorder caused by the c.20A>T alteration in the beta-globin gene (HBB), leading the synthesis of abnormal hemoglobin S (HbS). Under hypoxic conditions, HbS polymerizes within red blood cells (RBCs), causing them to adopt the characteristic sickle shape. This results in a clinically heterogenous disease, characterized by chronic hemolytic anemia, vaso-occlusive crises, and multi-organ damage. The CYB5R3 gene encodes the enzyme NADH-cytochrome b5 reductase 3, which plays a crucial role in protecting hemoglobin (Hb) from oxidative damage to unfunctional methemoglobin. Patients with SCA may develop methemoglobinemia, particularly under conditions of oxidative stress. This study aimed to evaluate the potential modulatory effects of a CYB5R3 variant, along with other well-established genetic modifiers within the globin genes, on the phenotypic variability of SCA in pediatric age. Methodology: Eighty-one children with SCA were followed by pediatricians at two hospitals in the Greater Lisbon area, who characterized their clinical, hematological, and biochemical phenotypes. For this specific study, CYB5R3, HBG2, HBA1, and HBA2 genes were genotyped using PCR, Sanger sequencing, and Gap-PCR. Association analyses were performed using SPSS. Results and Discussion: Co-inheritance of α-thalassemia with SCA was observed in 43.2% of the children and proved to be beneficial, as it was associated with higher RBC counts, milder anemia, and a significant reduction in hemolysis biomarkers (bilirubin and reticulocyte counts). Similarly, elevated fetal Hb levels (HbF ≥10%) were also beneficial, leading to less severe hemolytic anemia. In the HBG2 gene, the rs7482144_T allele had a frequency of 15% and was associated with higher HbF, reduced hemolytic parameters, lower HbS level, milder anemia, and a lower frequency of clinical comorbidities, except for heart disease. In the CYB5R3 gene, the rs1800457_G allele showed a very high allelic frequency of 35% and appears to exert a deleterious effect because patients carrying this allele presented with more severe anemia, elevated hemolysis biomarkers, and a greater tendency toward hepatomegaly and cardiac comorbidities. This study contributes to understanding how genetic modifiers influence SCA severity, complication risk and eventually treatment response. Identifying these factors supports personalized medicine and may help uncover new therapeutic targets.
- Truncating APOB Variants Impair LDL Metabolism: Functional Evidence From Binding StudiesPublication . Ferreira, Maria Simões; Larrea-Sebal, Asier; Martín, César; Apellaniz-Ruiz, Maria; Ernaga-Lorea, Ander; Bourbon, Mafalda; Alves, Ana CatarinaFamilial hypercholesterolaemia ( is a condition caused by pathogenic variants in LDLR APOB or PCSK 9 genes, characterised by high levels of LDL cholesterol and premature cardiovascular disease ( APOB variants account for 5 10 of FH cases, most being due to missense variants however, this can be higher than initially estimated Although truncating variants are typically associated with hypocholesterolaemia phenotype, some have been reported in clinical FH patients and can be the cause of diseaseThis study is part of the PerMedFH project and aimed to functionally characterise four nonsense APOB variants in exon 29 identified in patients with a clinical diagnosis of FH, emphasising on their molecular consequences and possible contribution to the FH phenotype. This study is part of the PerMedFH project and aimed to functionally characterise four nonsense APOB variants in exon 29 identified in patients with a clinical diagnosis of FH, emphasising on their molecular consequences and possible contribution to the FH phenotype
- Generation of Cellular Models for Fabry Disease: Unlocking the Potential of iPSCs and Gene EditingPublication . Duarte, Ana Joana; Moreira, Luciana; Ribeiro, Diogo; Alves, Sandra; Gaspar, Paulo; Bragança, José; Amaral, OlgaIntroduction: Fabry Disease (FD) is a lysosomal storage disorder caused by mutations in the GLA gene, resulting in a defective α-GAL A enzyme. This deficiency leads to the accumulation of Gb3 and lyso-Gb3 within lysosomes, resulting in a multisystem disease. Through reprogramming, we obtained induced pluripotent stem cells (iPSCs) derived from fibroblasts of a patient with FD2 and from a wild-type (WT) control. We used CRISPR/Cas9 to correct the c.860G>A mutation present in the patient’s cells, as well as to generate a WT GLA knockout (KO). The resulting cells were then differentiated into cardiomyocytes, a cell type affected by this disease. Methods: We reprogrammed the fibroblasts into iPSCs using episomal vectors or Sendai virus. For gene editing, single-guide RNAs (sgRNAs) and Cas9 were nucleofected, and the editing was confirmed by Sanger sequencing. Following colony selection, isogenic cell lines were established. The FD iPSCs, the corrected FD iPSCs, and the WT iPSCs were then differentiated into iPSC-derived cardiomyocytes (iPSC-CMs). Results: Seven new cell models were generated. Functional studies of the FD iPSCs showed the maintenance of the molecular and biochemical characteristics and a normal karyotype. The KO cell line recapitulated the biological features observed in FD patient cells, with reduced GLA expression, lower α-Galactosidase A (α-Gal A) activity (1.5 nmol/h/mg protein), and Gb3 accumulation. The corrected cell line was generated with 75.8% efficiency and 69.6% on-target efficacy. Enzyme activity increased to 579 nmol/h/mg protein (vs. 0.78 nmol/h/mg protein in FD iPSCs), accompanied by a marked reduction in Gb3 levels. We successfully generated iPSC-CM lines, which were validated by qRT-PCR and immunofluorescence. Discussion: Cell modelling is essential for studying the pathophysiology of disease mechanisms. By retaining the characteristics of the original cells, iPSCs are a valuable biological resource for generating specific differentiated cell types affected by the disease, which would otherwise be difficult to access. This study also explored the therapeutic potential of gene editing as a promising approach to altering the course of rare diseases.
- Alle Frequency Distribution Of Clinicaly Relevant Pharmacogenetic Variants In Genes With CPIC Guidelines Across European Populations: A Scoping ReviewPublication . Simões, Raquel; Cardoso, Maria Luis; Martiniano, Hugo F. M. C.; Vicente, Astrid MouraIntroduction: Pharmacogenetics (PGx) is the study of how genetic variants affect drug response. PGx variants can affect either pharmacokinetics – the processes of drug absorption, distribution, metabolism, and elimination – or pharmacodynamics – the biochemical and physiological effects of drugs and their mechanisms of action. Pharmacokinetics gene variants often define haplotypes, which are described using the star (*) allele nomenclature for genes such as those in the Cytochrome P450 (CYP450) family. This results in phenotypes of normal, rapid, ultrarapid, or poor metabolisers, leading to various drug responses (1). In recognition of the importance of understanding the clinical impact of PGx variants, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed guidelines that translate PGx test results into clinical recommendations for drug selection and dosing (2). Reports in the literature on ancestry‑related differences in drug response highlight the need for a broader investigation of PGx variants, namely in CYP450 genes, across diverse groups(3).
- Porque saber o que comemos importa - A ciência por detrás das bases de dados da composição de alimentosPublication . Dias, Maria da GraçaSobre a importância dos dados na elaboração da Tabela da Composição de Alimentos (TCA) no âmbito da demonstração das novas funcionalidades da plataforma PortFIR, portal onde se encontra alojada a TCA e outras bases de dados sobre alimentação. A TCA é um documento de referência nacional para a composição de alimentos consumidos em Portugal. A informação sobre a composição nutricional dos alimentos disponível nesta tabela é determinante para a tomada de decisão na área das estratégias para a promoção da alimentação saudável. A atualização da TCA é um trabalho permanente e realizado em linha com os alimentos consumidos pela população portuguesa, com a evolução dos métodos analíticos e de acordo com critérios de qualidade estabelecidos internacionalmente. Desde 2017 que o INSA publica atualizações da TCA anuais, cujo acesso é livre.
- Mais abrangente, mais atual, a mesma qualidade científica | Nova versão da Tabela da Composição de AlimentosPublication . Ravasco, FranciscoA TCA é um documento de referência nacional para a composição de alimentos consumidos em Portugal. A informação sobre a composição nutricional dos alimentos disponível nesta tabela é determinante para a tomada de decisão na área das estratégias para a promoção da alimentação saudável. A atualização da TCA é um trabalho permanente e realizado em linha com os alimentos consumidos pela população portuguesa, com a evolução dos métodos analíticos e de acordo com critérios de qualidade estabelecidos internacionalmente. Desde 2017 que o INSA publica atualizações da TCA anuais, cujo acesso é livre.