DGH - Apresentações orais em encontros nacionais
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- Can an Antisense Oligonucleotide Exon Skipping Rewrite the Story of N-Acetylglucosamine-1-Phosphotransferase Deficiency?Publication . Gonçalves, M.; Moreira, L.; Encarnação, M.; Gaspar, P.; Duarte, A.J.; Santos, J.I.; Coutinho, M.F.; Prata, M.J.; Omidi, M.; Pohl, S.; Silva, F.; Oliveira, P.; Matos, L.; Alves, S.Mucolipidosis II (ML II) is a Lysosomal Storage Disorder caused by N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT) deficiency, which impairs the trafficking of lysosomal hydrolases. Of all ML II mutations, c.3503_3504delTC in GNPTAB exon 19 is the most frequent, making it a good target for a personalized therapy. Here, we explored an innovative therapeutic strategy based on the use of antisense oligonucleotides (ASOs). Previously, in ML II patients’ fibroblasts, we tested ASOs to induce exon 19 skipping in pre-mRNA, successfully generating an in-frame mRNA (Matos et al., 2020). Now, our aim is to determine whether this in-frame transcript leads to increased GlcNAc-PT levels improving ML II cellular phenotype.
- Can enzyme replacement therapy revert¨iNKT¨cell dysfunction in acid sphingomyelinase deficiency patients?Publication . Chaves, João; da Silva Gaspar, Paulo Jorge Miranda; Macedo, FatimaAcid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of the enzyme acid sphingomyelinase (ASM), resulting in an abnormal accumulation of sphingomyelin in lysosomes. The abnormal accumulation of sphingomyelin, a crucial cell membrane component, ultimately impairs pulmonary, hepatic, and sometimes neurological functions, with severe forms of the disease being fatal in the first years of life. Invariant Natural Killer T (iNKT) cells are lipid-reactive T cells that play a central role in a wide range of immune responses including cancer, infection and inflammation. iNKT cells are restricted to CD1d, depending on the presentation of lipids by this molecule for their function. Sphingomyelin is a lipid with affinity for CD1d and its accumulation in ASMD influences the role of iNKT cells by impairing normal lipid antigen presentation to these cells. Interestingly, ASM-/- mice have reduced number of iNKT cells and impaired iNKT cell activity, in ASMD patients a reduced frequency of iNKT cells is also observed (1). Noteworthy, enzyme replacement therapy (ERT) with recombinant ASM can prevent iNKT cell deficiency in ASM-/- mice (1). In the current study we are investigating the effect of ERT on iNKT cells in ASMD adult patients.
- An engineered U1 snRNA-based therapeutic approach can efficiently rescue a 5’ splice site mutation causing Mucolipidosis type IIIPublication . Peretto, L.; Gonçalves, M.; Santos, J.I.; Duarte, A.J.; Moreira, L.; Encarnação, M.; Coutinho, M.F.; Pinotti, M.; Balestra, D.; Alves, S.; Matos, L.A significant number of splicing mutations have been identified in Lysosomal Storage Disorders (LSDs). Mucolipidosis III (ML III) is a LSD caused by GlcNAc-1-phosphotransferase deficiency, which impairs the trafficking of lysosomal hydrolases. 10% of the genetic defects in ML III are splicing mutations, and around 45% affect 5' splice-sites (ss) thus constituting a good target for mutation specific therapies. The use of engineered U1 snRNA (either modified U1 snRNAs or exon-specific U1s - ExSpeU1s) has been applied as a potential therapeutic strategy to correct 5’ss defects. Here we used engineered U1 snRNAs to correct the GNPTAB exon 17 skipping caused by the 5’ss mutation (c.3335+6T>G) found in a ML III patient.
- Era bioquímica/genómica: critérios de inclusão e questões técnicasPublication . da Silva Gaspar, Paulo Jorge Miranda; GasparNewborn screening has evolved significantly in the biochemical and pilot studies of genomic, enabling the early detection of a broad range of congenital disorders. The shift from traditional biochemical assays to high-throughput tandem mass spectrometry and next-generation sequencing has broadened the spectrum of identifiable conditions, including metabolic, endocrine, hematological, and immunological diseases, as well as rare genetic syndromes. These technological advances enable presymptomatic diagnosis and prompt initiation of life-saving therapies, significantly improving long-term outcomes. However, the integration of genomic technologies introduces a host of technical challenges, including the standardization and validation assays, the interpretation and classification of genetic variants of unknown significance, and the management of incidental or secondary findings unrelated to the original screening purpose. Additional challenges involve the integration of large-scale data into healthcare systems, the need for robust data privacy protections, and the development of clear communication strategies for families. Addressing these technical, ethical, and logistical challenges is crucial to realizing the full potential of newborn screening in the modern era while ensuring responsible program expansion and equitable access.
- Find Project: Results of 8 YearsPublication . da Silva Gaspar, Paulo Jorge Miranda; Neiva, Raquel; Sousa e Silva, Lisbeth Elena; Guimarães, Fábio; Diogo, Luisa; Ferreia, Ana Cristina; Miranda, Ana; Antunes, Diana; Louro, Pedro; Ribeiro, Sara; Garcia, Paula; Rodrigues, Esmeralda; Campos, Teresa; Janeiro, Patrícia; Sousa, Sérgio; Ferreira, Sara; Silva, Carmen; Lopes, Altina; Pereira, Cristina; Nogueira, Célia; Alves, Sandra; Leão Teles, Elisa; Vilarinho, LauraIntrodução e Objectivos: 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 red flags of MPSs at pediatric age and to provide an useful tool for physicians to diagnose these pathologies, since most of them are amenable to enzyme replacement therapy.
- A new method for the identification of mucopolysaccharidosis and oligosaccharidosisPublication . da Silva Gaspar, Paulo Jorge Miranda; Neiva, Raquel; Sousa e Silva, Lisbeth Elena; Vilarinho, LauraIntrodução e Objectivos: Lysosomal storage disorders are a group of rare diseases that affect approximately 1 in 4,000 live births in Portugal (Pinto et al , 2004). They are characterized by multisystemic involvement and a wide range of phenotypical presentations, often overlapping with other diseases. As a result, many patients experience a lengthy process of seeking a correct diagnosis, known as the "diagnostic odyssey". To address this challenge, a new tandem mass spectrometry method has been developed for the urinary identification of both oligosaccharides and mucopolysaccharides(MPS).
- Rastreio neonatal da drepanocitose: prevalência ao nascimento de 1: 2 381 RNPublication . Rodrigues, Diogo; Marcão, Ana; Lopes, Maria de Lurdes soares; Guimarães, Fábio; Vilarinho, LauraIntrodução e Objetivos: A drepanocitose é uma das patologias monogénicas mais comuns e graves a nível mundial, sendo atualmente considerada um problema de saúde pública na Europa. Trata-se de uma doença hereditária, com transmissão autossómica recessiva, na qual os doentes apresentam uma variante estrutural anormal de hemoglobina – HbS. Com este trabalho pretendemos apresentar a prevalência ao nascimento da drepanocitose em Portugal. Metodologia: Foram rastreados para a drepanocitose 324 077 Recém-Nascidos (RN), em duas fases distintas: Fase I (05/2021 - 01/2022) 24 130 RN exclusivamente dos distritos de Lisboa e Setúbal; Fase II (02/2022 - 07/2025) 299 947 RN de todo o Português. O perfil de hemoglobinas foi estudado pelo método da eletroforese capilar, a partir de amostras de sangue seco colhidas em cartão de Guthrie, entre o 3.º e o 6.º dia de vida do RN. Resultados: No total foram identificados 152 casos de drepanocitose dos quais 135 eram homozigóticos (HbSS) e 17 heterozigóticos compostos (HbSC). Todos os doentes foram reportados a um Centro de Tratamento (CT) para confirmação e avaliação clínica. A prevalência ao nascimento de drepanocitose no nosso país é de 1:2 381 RN. Além do casos de drepanocitose, foram também identificados e reportados para CT mais 15 casos de outras hemoglobinopatias: 3 β-talassémia major, 8 HbEE, 3 HbCC e 1 HbDD. Conclusões: Estes resultados evidenciam a crescente prevalência da drepanocitose em Portugal, alinhando-se com o panorama europeu, e que parece dever-se aos fluxos migratórios mais recentes. A inclusão do rastreio neonatal da drepanocitose no painel de doenças do Programa Nacional de Rastreio Neonatal, em 2023, comprova a importância desta patologia no nosso país.