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- Novos biomarcadores nas DLS´s: O que eles nos dizemPublication . Gaspar, Paulo; Rocha, Hugo; Alves, Sandra; Vilarinho, LauraComunicação sobre os novos biomarcadores nas Doenças Lisossomais de Sobrecarga, do diagnóstico ao follow-up.
- LIMP-2 deficiency-associated glycolipid abnormalities in micePublication . da Silva Gaspar, Paulo Jorge Miranda; Marques, André R.A.; Ferraz, Maria J.; Damme, Markus; Krame, Gertjan; Mirzaian, Mina; Gijbels, Marion; Ottenhoff, Roelef; van Roomen, Cindy; Overkleeft, Herman S.; Schwake, Michael; Heybrock, Saskia; Macário, Maria Carmo; Saftig, Paul; Aerts, Johannes M.Glucocerebrosidase (GCase) catalyzes the lysosomal degradation of glucosylceramide (GlcCer). GCase deficiency results in Gaucher disease (GD), a lysosomal storage disorder with characteristic hepatosplenomegaly. Transport of GCase to lysosomes is mediated by the lysosomal integral membrane protein type 2 (LIMP-2). Deficiency of LIMP-2 leads to reduced cellular GCase levels and manifests as Action Myoclonic Renal Failure Syndrome (AMRF). We investigated the cause for the markedly different symptomatology of GD and AMRF. In tissues of Limp2 − /− mice no prominent abnormalities in lysosomal enzymes were noted except for variable deficiency of GCase, as measured with enzymatic activity assay and detection of active GCase molecules with an activity-based probe. Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high in leukocytes. GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer. Isolated lysosomes from hepatocytes of Limp2 − /− mice revealed no prominent abnormalities in lysosomal matrix proteins except GCase. The Limp2 − /− tritosomes showed clear increases in GlcSph and GlcChol but not in GlcCer. In conclusion, our data imply a critical role of LIMP-2 in glycosphingolipid homeostasis. Despite low GCase levels striking GlcCer accumulation is avoided in tissues of LIMP-2 deficient mice.
- 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.
- 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.
- 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.
- Lyso-GB3: Usefulness and limitationsPublication . da Silva Gaspar, Paulo Jorge MirandaA lecture on Fabry Disease: A Rare Genetic Disorder.