Navegando por Palavras-chave "Doença De Fabry"

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    Alterações Funcionais Renais Em Pacientes Com Deficiência De Alfa-Galactosidase A
    (Universidade Federal de São Paulo (UNIFESP), 2017-08-31) Moreira, Silvia Regina Da Silva [UNIFESP]; Kirsztajn, Gianna Mastroianni [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Introduction: Fabry disease is caused by the deficiency of alpha-galactosidase A and affects different systems of human organism, presenting high morbidity and early mortality, particularly due to the involvement of renal, cardiac and cerebrovascular systems, usually aggravated by the delay in diagnosis of such disease. It is consequently necessary to better know its profile in the early phases of the disease. Objectives: In the patients with Fabry disease, it is our aim to define the frequency as well as clinical and laboratorial characteristics of the disease and of the renal involvement, by the time of diagnosis and during its course. Material and methods: This is an observational, transversal and retrospective study, in which data were collected from 68 medical records of the patients with Fabry disease followed at the “Centro de Erros Inatos do Metabolismo” (CREIM), Universidade Federal de São Paulo (UNIFESP)-Escola Paulista de Medicina (EPM). Results: We evaluated data of 68 patients (with and without specific enzimatic replacement therapy for Fabry disease treatment), 40 (44%) males, 43% Caucasians, with a mean age of 35.5 years by the time of diagnosis. In all patients mutation analysis of alpha-galactosidase gene had been performed, and mutation in exon 7 p.R356W (21%) was predominantly detected. Signs and symptoms more prevalent at diagnosis were acroparesthesias (63.24%), alterations in temperature sensitivity (19.12%) and fatigue (17.65%). During the course of the disease, the most prevalent manifestations were acroparesthesias (54.41%), proteinuria (30.88%) and cardiovascular disturbances (17.64%). Renal replacement therapy was necessary in seven patients, 3 (5%) were submitted to hemodialysis and 4 (7%) to renal transplantation. Overall 36 (53%) patients were in use of enzyme replacement therapy. The main reasons for initiating enzyme replacement therapy with algasidase were proteinuria (39%), followed by neuropathy (19%) and cardiac disease (17%). Conclusion: The renal changes were not common by the time of the disease presentation, but became frequent during the course of the disease. Proteinuria was the earliest renal abnormality, including even nephrotic levels; the frequency of proteinuria increased along the time of follow-up, involving 30.88% of the patients; a decreased glomerular filtration rate occurred in 13% of them; renal replacement therapy was necessary in 12% of the patients, and included dialysis as well as renal transplantation. The detection of renal involvement was the main indication of enzyme replacement therapy.
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    Mutações D313Y e R118C investigação da patogenicidade
    (Universidade Federal de São Paulo (UNIFESP), 2020-12-18) Goh, Cibele Keiko [UNIFESP]; Pesquero, Joao Bosco [UNIFESP]; Universidade Federal de São Paulo
    Fabry disease (FD) is an innate error in the metabolism of glycosphingolipids that causes the absence or deficiency of the enzyme α-galactosidase A (α-Gal A). This disease results in the accumulation of the glycosphingolipid globotriasylceramide (Gb3) in various tissues of the human body. Its worldwide distribution is quite varied, with incidences between 1: 470000 and 1: 117000 live births. Its diagnosis is made from clinical suspicion and, later, from complementary exams and genetic sequencing in search of evidence of injury resulting from sphingolipid deposition and genetic variants involved in its pathogenesis. The origin of FD is directly linked to pathogenic variants present in the GLA gene, most of which translate into a non-functional enzyme. Since the gene is located on the long arm of the X chromosome, male patients who have pathogenic variants will have the disease. The p.D313Y variant, missense type, results in the exchange of aspartic acid at position 313 in exon 6 for a tyrosine. There are studies showing that, although patients who have this variant have low activity of the enzyme α-Gal A, their symptoms do not determine DF, in addition to its presentation being very frequent in some populations, reaching 0.5%, which it is not equivalent to the prevalence of this condition. In the p.R118C mutation, there is an exchange of an arginine for a cysteine in exon 2, also of the missense type. Some studies show a relationship between this variant and late-onset FD. There are many controversies in the literature about the pathogenicity of both variants, the latest reviews claim that they are not disease-causing; however, they do not demonstrate why there are patients with characteristic clinical syndrome who benefit from enzyme replacement. The pathogenesis of FD in these patients could be related to some other mutation that secretes with p.D313Y and p.R118C, the presentation of microRNAs (miRNA), or even other changes in GLA RNA. In the present study, we evaluated the complete sequence of the GLA leukocyte RNA, through the study of its cDNA, of patients who have the p.D313Y and p.R118C mutations. It was not detected the presence of a possible new pathogenic variant or of modifications of alternative splicing.xiv These results suggest a possible presence in these patients of intronic vartiants in the GLA, as well as a role of epigenetics, influencing the phenotype of a disease considered of purely genetic etiology.
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    Prevalência de asma e avaliação da função pulmonar em pacientes com doença de Fabry
    (Universidade Federal de São Paulo (UNIFESP), 2021) Monteiro, Fernanda Pereira [UNIFESP]; Wandalsen, Gustavo Falbo [UNIFESP]; Universidade Federal de São Paulo
    Fabry disease (FD) is characterized by excessive accumulation of globotriaosylceramide inside the lysosome, affecting mainly the vascular endothelium with repercussion in multiple systems. Pulmonary complications in FD are still not well established. The objectives of our study were to assess lung function in patients with a confirmed diagnosis of DF who were followed up at a Brazilian referral center and to repeat the evaluations after 12 months to monitor the evolutionary patterns. Methods: The study included patients with a confirmed diagnosis of FD. Lung function was evaluated by spirometry and impulse oscillometry (IOS). Symptoms and medical history were obtained by questionnaire and review of medical records. The reassessment followed the interval of 12 months ± 2 months. Results: In the first moment, forty-seven patients were evaluated. Spirometry was abnormal in 32% of the patients and IOS in 47%. Restrictive pattern of pulmonary dysfunction was found in 60% (spirometry) and in 50% (IOS) of patients with abnormal results. Positive bronchodilator response was observed in 17% of the patients. Worse values of pulmonary function were observed in patients with proteinuria (FEV1: 80% vs 93%, p=0.02; R5: 152% vs 116%, p<0.01), fatigue (FEV1: 83% vs 97%, p=0.02), wheezing in the last year (R5: 164% vs 125%, p=0.02), renal insufficiency (FEV1: 65% vs 89%, p<0.01), and with classical phenotype (X5: 1.7cmH2O/L/s vs 2.6 cmH2O/L/s, p=0.04). Forty-one of these patients were reassessed. Spirometry was abnormal in 48% after one year with a mixed pattern (restrictive and obstructive) predominating. Altered IOS were found in 39% after reassessment. Worse evolution of pulmonary function values was observed in patients with classic phenotype (p = 0.04) and there was a trend towards worse evolution of pulmonary function in male patients. Conclusions: Pulmonary involvement is a relevant manifestation of FD, especially observed with disease progression and in the classical phenotype. IOS seems to be a sensitive test that may play a complementary role to spirometry in the evaluation of the pulmonary function of these patients, but a year is a relatively short period to monitor the evolution of the disease and progression in the deterioration of lung function.
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    Variantes no gene GLA e o perfil enzimático da alfagalactosidase a em pacientes com suspeita de Doença de Fabry
    (Universidade Federal de São Paulo (UNIFESP), 2019-03-28) Teixeira, Patricia Varela Lima [UNIFESP]; Pesquero, Joao Bosco [UNIFESP]; http://lattes.cnpq.br/0856630824759511; http://lattes.cnpq.br/1816388063402796; Universidade Federal de São Paulo (UNIFESP)
    Objective: To analyze a database with molecular and biochemical results of patients with suspected Fabry disease. From these results, to evaluate the pathogenicity of the variants, as well as to carry out the in vitro characterization of novel mutations, and finally to trace the enzymatic profile of the genotypes in order to evaluate the impact of these variants on the enzyme. Methods: Bioinformatics tools were used to analyze the variants found in the GLA gene of patients with Fabry disease suspected. Patients were divided according to the genotype they carried in order to trace the enzymatic profile and correlation with the pathogenicity. For in vitrocharacterization, experiments were conducted on HeLa cells transfected with wild-type GLA or with mutants plasmids, finally, gene expression as well as the enzymatic activity of α-Gal A were evaluated. Results: 215 men and 48 women presented 103 variants in GLA exons; 57 variants were previously described as pathogenic, eleven described as unknown effect and the other 35 are family-specific mutations. The other patients presented variants in non-coding regions or had no alterations inGLA. In vitro analysis confirmed pathogenicity in mutations classified as pathogenic and possibly pathogenic; in the new mutations classified as with unknown effect, pathogenicity was confirmed in three mutations, the other four did not cause DF. The enzymatic profile revealed a possible non-pathogenicity of variants of unknown effect, as well as variants found in non-coding regions. Finally, the study of haplotypes formed by variants in non-coding regions revealed a high frequency in the control population, similar to that found in patients. Conclusion: The DBS enzymatic activity was markedly reduced in patients with mutations described as pathogenic, as well as in novel variants classified as pathogenic or possibly pathogenic (with in vitro confirmation) when compared with individuals presenting VUS, variants in non-coding regions or without variants, indicating non-pathogenic potential of these latter genotypes.