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[PMID]: 29289886 [Au] Autor: Li HY; Lee JD; Chen CW; Sun YC; Cheng WC [Ad] Endereço: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, 155, Linong Street, Section 2, Taipei 112, Taiwan. [Ti] Título: Synthesis of (3S,4S,5S)-trihydroxylpiperidine derivatives as enzyme stabilizers to improve therapeutic enzyme activity in Fabry patient cell lines. [So] Source: Eur J Med Chem;144:626-634, 2018 Jan 20. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: A series of 3S,4S,5S-trihydroxylated piperidines bearing structural diversity at C-2 or C-6 positions has been synthesized and tested to determine their ability to stabilize the activity of recombinant human α-Galactosidase A (rh-α-Gal A). Hit molecules were identified by rapid inhibitory activity screening, and then further investigated for their ability to protect this enzyme from thermo-induced denaturation and enhance its activity in Fabry patient cell lines. Our study resulted in the identification of a new class of small molecules as enzyme stabilizers for the potential treatment of Fabry disease. Of these, stabilizer 21 was the most effective, showing a 12-fold increase in rh-α-Gal A activity in Fabry disease cell lines. [Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia Doença de Fabry/tratamento farmacológico Piperidinas/farmacologia alfa-Galactosidase/antagonistas & inibidores [Mh] Termos MeSH secundário: Linhagem Celular Relação Dose-Resposta a Droga Inibidores Enzimáticos/síntese química Inibidores Enzimáticos/química Estabilidade Enzimática Doença de Fabry/metabolismo Doença de Fabry/patologia Seres Humanos Estrutura Molecular Piperidinas/síntese química Piperidinas/química Proteínas Recombinantes/metabolismo Relação Estrutura-Atividade alfa-Galactosidase/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Enzyme Inhibitors); 0 (Piperidines); 0 (Recombinant Proteins); EC 3.2.1.22 (alpha-Galactosidase); EC 3.2.1.22 (alpha-galactosidase A, human) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180302 [Lr] Data última revisão: 180302 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180101 [St] Status: MEDLINE

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[PMID]: 27773586 [Au] Autor: Nowak A; Mechtler TP; Desnick RJ; Kasper DC [Ad] Endereço: Department of Internal Medicine, University Hospital Zurich and University of Zurich, Rämistrasse 100, 8091 Zürich, Switzerland. Electronic address: albina.nowak@usz.ch. [Ti] Título: Plasma LysoGb3: A useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes. [So] Source: Mol Genet Metab;120(1-2):57-61, 2017 Jan - Feb. [Is] ISSN: 1096-7206 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the α-galactosidase A gene (GLA) that result in absent or markedly reduce α-galactosidase A (α-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40-50% of GLA-mutation confirmed heterozygotes have normal or only slightly decreased leukocyte α-GalA activities. Recently, LysoGb3 has been appreciated as a novel FD biomarker, especially for therapeutic monitoring. METHODS: Among our GLA-mutation proven FD patients, we screened 18 heterozygotes whose leukocyte α-GalA activity was determined at initial diagnosis. For these females, we measured their serum LysoGb3 levels using highly-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. RESULTS: We identified three unrelated females in whom the accumulating LysoGb3 was increased, whereas their leukocyte α-GalA activities were in the normal range. CONCLUSION: LysoGb3 serves as an useful biomarker to improve the diagnosis of FD heterozygotes and for therapeutic evaluation and monitoring. [Mh] Termos MeSH primário: Biomarcadores/sangue Doença de Fabry/diagnóstico Glicolipídeos/sangue Esfingolipídeos/sangue alfa-Galactosidase/genética [Mh] Termos MeSH secundário: Adulto Criança Cromatografia Líquida Doença de Fabry/genética Doença de Fabry/metabolismo Feminino Heterozigoto Seres Humanos Meia-Idade Mutação Espectrometria de Massas por Ionização por Electrospray alfa-Galactosidase/sangue [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers); 0 (Glycolipids); 0 (Sphingolipids); 126550-86-5 (globotriaosyl lysosphingolipid); EC 3.2.1.22 (alpha-Galactosidase); EC 3.2.1.22 (alpha-galactosidase A, human) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171211 [Lr] Data última revisão: 171211 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161025 [St] Status: MEDLINE

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[PMID]: 29079200 [Au] Autor: Juchniewicz P; Kloska A; Tylki-Szymanska A; Jakóbkiewicz-Banecka J; Wegrzyn G; Moskot M; Gabig-Ciminska M; Piotrowska E [Ad] Endereço: Department of Medical Biology and Genetics, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland. [Ti] Título: Female Fabry disease patients and X-chromosome inactivation. [So] Source: Gene;641:259-264, 2018 Jan 30. [Is] ISSN: 1879-0038 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A (GLA). Once it was thought to affect only hemizygous males. Over the last fifteen years, research has shown that most females carrying mutated allele also develop symptoms, demonstrating a wide range of disease severity, from a virtually asymptomatic to more classical profile, with cardiac, renal, and cerebrovascular manifestations. This variable expression in females is thought to be influenced by the process of X-chromosome inactivation (XCI). The aim of this study was to assess severity of the clinical phenotype, to analyze XCI patterns, and to estimate their effect on disease manifestation in twelve female Fabry disease patients from five unrelated Polish families. Our analyses revealed that patients presented with the broad range of disease expression - from mild to severe, and their clinical involvement did not correlate with XCI profiles. Female carriers of the mutation in the GLA gene with the random XCI may present with the wide range of disease signs and symptoms. Thus, XCI is not a main factor in the phenotype variability of Fabry disease manifestation in heterozygous females. [Mh] Termos MeSH primário: Cromossomos Humanos X/genética Doença de Fabry/genética Inativação do Cromossomo X/genética [Mh] Termos MeSH secundário: Adolescente Adulto Idoso Alelos Criança Feminino Heterozigoto Seres Humanos Meia-Idade Mutação/genética Fenótipo Adulto Jovem alfa-Galactosidase/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 3.2.1.22 (alpha-Galactosidase) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171128 [Lr] Data última revisão: 171128 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171029 [St] Status: MEDLINE

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[PMID]: 28857617 [Au] Autor: Arenz C [Ad] Endereço: Institute for Chemistry, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany. [Ti] Título: Recent advances and novel treatments for sphingolipidoses. [So] Source: Future Med Chem;9(14):1685-1698, 2017 Sep. [Is] ISSN: 1756-8927 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Sphingolipidoses are genetically inherited diseases in which genetic mutations lead to functional deficiencies in the enzymes needed for lysosomal degradation of sphingolipid substrates. As a consequence, nondegradable lipids enrich in the lysosomes and lead to fatal pathological phenotypes in affected individuals. In this review, different drug-based treatment strategies including enzyme replacement therapy and substrate reduction therapy are discussed. A special focus is on the concept of pharmacological chaperones, one of which recently acquired clinical approval within the EU. On the basis of the different limitations for each approach, possible future directions of research are discussed. [Mh] Termos MeSH primário: Enzimas/uso terapêutico Esfingolipidoses/tratamento farmacológico [Mh] Termos MeSH secundário: Terapia de Reposição de Enzimas Enzimas/genética Enzimas/metabolismo Doença de Fabry/tratamento farmacológico Doença de Gaucher/tratamento farmacológico Glucosilceramidase/genética Glucosilceramidase/metabolismo Glucosilceramidase/uso terapêutico Seres Humanos Lisossomos/metabolismo Proteínas Recombinantes/biossíntese Proteínas Recombinantes/isolamento & purificação Proteínas Recombinantes/uso terapêutico Esfingolipidoses/genética Esfingolipidoses/patologia Esfingolipídeos/metabolismo alfa-Galactosidase/genética alfa-Galactosidase/metabolismo alfa-Galactosidase/uso terapêutico [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Enzymes); 0 (Recombinant Proteins); 0 (Sphingolipids); EC 3.2.1.22 (alpha-Galactosidase); EC 3.2.1.45 (Glucosylceramidase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171025 [Lr] Data última revisão: 171025 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170901 [St] Status: MEDLINE [do] DOI: 10.4155/fmc-2017-0065

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[PMID]: 28835396 [Au] Autor: Godel T; Bäumer P; Pham M; Köhn A; Muschol N; Kronlage M; Kollmer J; Heiland S; Bendszus M; Mautner VF [Ad] Endereço: From the Department of Neuroradiology (T.G., P.B., M.P., M.K., J.K., S.H., M.B.), Neurological University Clinic, Heidelberg University Hospital; Department of Radiology (P.B.), German Cancer Research Institute, Heidelberg; Department of Neuroradiology (M.P.), Würzburg University Hospital; Departmen [Ti] Título: Human dorsal root ganglion in vivo morphometry and perfusion in Fabry painful neuropathy. [So] Source: Neurology;89(12):1274-1282, 2017 Sep 19. [Is] ISSN: 1526-632X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVE: To evaluate functional and morphometric magnetic resonance neurography of the dorsal root ganglion and peripheral nerve segments in patients with Fabry painful neuropathy. METHODS: In this prospective study, the lumbosacral dorsal root ganglia and proximal peripheral nerve segments of the lower extremity were examined in 11 male patients with Fabry disease by a standardized 3T magnetic resonance neurography protocol. Volumes of L3 to S2 dorsal root ganglia, perfusion parameters of L5-S1 dorsal root ganglia and the spinal nerve L5, and the cross-sectional area of the proximal sciatic nerve were compared to healthy controls. RESULTS: Dorsal root ganglia of patients with Fabry disease were symmetrically enlarged by 78% (L3), 94% (L4), 122% (L5), 115% (S1), and 119% (S2) ( < 0.001). In addition, permeability of the blood-tissue interface was decreased by 53% ( < 0.001). This finding was most pronounced in the peripheral zone of the dorsal root ganglion containing the cell bodies of the primary sensory neurons ( < 0.001). Spinal nerve permeability showed no difference between patients with Fabry disease and controls ( = 0.7). The sciatic nerve of patients with Fabry disease at the thigh level showed an increase in cross-sectional area by 48% ( < 0.001). CONCLUSIONS: Patients with Fabry disease have severely enlarged dorsal root ganglia with dysfunctional perfusion. This may be due to glycolipid accumulation in the dorsal root ganglia mediating direct neurotoxic effects and decreased neuronal blood supply. These alterations were less pronounced in peripheral nerve segments. Thus, the dorsal root ganglion might play a key pathophysiologic role in the development of neuropathy and pain in Fabry disease. [Mh] Termos MeSH primário: Doença de Fabry/complicações Gânglios Espinais/patologia Imagem por Ressonância Magnética/métodos Dor/etiologia Dor/patologia Doenças do Sistema Nervoso Periférico/etiologia Doenças do Sistema Nervoso Periférico/patologia Nervo Isquiático/patologia [Mh] Termos MeSH secundário: Adulto Gânglios Espinais/diagnóstico por imagem Seres Humanos Vértebras Lombares/inervação Masculino Meia-Idade Dor/diagnóstico por imagem Dor/fisiopatologia Doenças do Sistema Nervoso Periférico/diagnóstico por imagem Doenças do Sistema Nervoso Periférico/fisiopatologia Estudos Prospectivos Sacro/inervação Nervo Isquiático/diagnóstico por imagem Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171004 [Lr] Data última revisão: 171004 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170825 [St] Status: MEDLINE [do] DOI: 10.1212/WNL.0000000000004396

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[PMID]: 28763515 [Au] Autor: Arends M; Biegstraaten M; Hughes DA; Mehta A; Elliott PM; Oder D; Watkinson OT; Vaz FM; van Kuilenburg ABP; Wanner C; Hollak CEM [Ad] Endereço: Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. [Ti] Título: Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors. [So] Source: PLoS One;12(8):e0182379, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR <90 ml/min/1.73m2 to 4 at eGFR <30, compared to patients with an eGFR >90. In addition, men with classical disease and a baseline eGFR <60 ml/min/1.73m2 had a faster yearly decline (-2.0 ml/min/1.73m2) than those with a baseline eGFR of >60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension. [Mh] Termos MeSH primário: Terapia de Reposição de Enzimas/efeitos adversos Doença de Fabry/tratamento farmacológico [Mh] Termos MeSH secundário: Adolescente Adulto Idoso Doenças Cardiovasculares/complicações Comorbidade Progressão da Doença Doença de Fabry/complicações Feminino Taxa de Filtração Glomerular Seres Humanos Rim/fisiopatologia Masculino Meia-Idade Análise Multivariada Fenótipo Prognóstico Modelos de Riscos Proporcionais Proteinúria/complicações Estudos Retrospectivos Fatores de Risco Resultado do Tratamento Triglicerídeos/sangue Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Triglycerides) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171010 [Lr] Data última revisão: 171010 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170802 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0182379

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[PMID]: 28749998 [Au] Autor: Pettazzoni M; Froissart R; Pagan C; Vanier MT; Ruet S; Latour P; Guffon N; Fouilhoux A; Germain DP; Levade T; Vianey-Saban C; Piraud M; Cheillan D [Ad] Endereço: Service de Biochimie et Biologie Moléculaire Grand Est, Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France. [Ti] Título: LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease. [So] Source: PLoS One;12(7):e0181700, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: The biological diagnosis of sphingolipidoses currently relies on the measurement of specific enzymatic activities and/or genetic studies. Lysosphingolipids have recently emerged as potential biomarkers of sphingolipidoses and Niemann-Pick type C in plasma. METHODOLOGY: We developed a sensitive and specific method enabling the simultaneous quantification of lysosphingolipids by LC-MS/MS: lysoglobotriaosylceramide for Fabry disease, lysohexosylceramide (i.e. lysoglucosylceramide and/or lysogalactosylceramide) for Gaucher and Krabbe diseases, lysosphingomyelin and its carboxylated analogue lysosphingomyelin-509 for Niemann-Pick type A or B, and C diseases, lysoGM1 ganglioside for GM1gangliosidosis and lysoGM2 ganglioside for GM2 gangliosidosis. FINDINGS: The diagnostic performances were validated in plasma samples analysing a large series of patients affected with sphingolipidoses and Niemann-Pick type C disease (n = 98), other inborn errors of metabolism (n = 23), and controls (n = 228). The multiplex measurement of lysosphingolipids allowed the screening of Fabry (including female patients and late-onset variants), Gaucher and infantile Krabbe, Niemann-Pick type A/B and C diseases with high sensitivity and specificity. LysoGM1 and LysoGM2 were elevated in most of the patients affected with GM1 and GM2 gangliosidosis respectively. In amniotic fluid supernatant from pregnancies presenting non-immune hydrops fetalis (n = 77, including previously diagnosed Gaucher (n = 5), GM1 gangliosidosis (n = 4) and galactosialidosis (n = 4) fetuses) and from normal pregnancies (n = 15), a specific and dramatic increase of lysohexosylceramide was observed only in the Gaucher amniotic fluid samples. INTERPRETATION: This multiplex assay which allows the simultaneous measurement of lysosphingolipids in plasma modifies the diagnostic strategy of sphingolipidoses and Niemann-Pick type C. Furthermore, in pregnancies presenting non-immune hydrops fetalis, lysohexosylceramide measurement in amniotic fluid offers a rapid screening of fetal Gaucher disease without waiting for glucocerebrosidase activity measurement in cultured amniocytes. [Mh] Termos MeSH primário: Doença de Niemann-Pick Tipo C/diagnóstico Esfingolipídeos/sangue [Mh] Termos MeSH secundário: Adulto Biomarcadores/sangue Cromatografia Líquida de Alta Pressão Doença de Fabry/sangue Feminino Seres Humanos Recém-Nascido Masculino Doença de Niemann-Pick Tipo C/sangue Diagnóstico Pré-Natal Sensibilidade e Especificidade Espectrometria de Massas em Tandem/normas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers); 0 (Sphingolipids) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170928 [Lr] Data última revisão: 170928 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170728 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0181700

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[PMID]: 28723748 [Au] Autor: Choi JH; Lee BH; Heo SH; Kim GH; Kim YM; Kim DS; Ko JM; Sohn YB; Hong YH; Lee DH; Kook H; Lim HH; Kim KH; Kim WS; Hong GR; Kim SH; Park SH; Kim CD; Kim SM; Seo JS; Yoo HW [Ad] Endereço: aDepartment of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine bAsan Institute for Life Sciences cMedical Genetics Center, Asan Medical Center Children's Hospital, Seoul dDepartment of Pediatrics, Pusan National University Children's Hospital eDepartment of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan fDepartment of Pediatrics, Seoul National University Children's Hospital, Seoul gDepartment of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon hDepartment of Pediatrics, College of Medicine, Soonchunhyang University, Bucheon Hospital, Bucheon iDepartment of Pediatrics, College of Medicine, Soonchunhyang University, Seoul Hospital, Seoul jDepartment of Pediatrics, Chonnam National University Hwasun Hospital, Hwasun kDepartment of Pediatrics, Chungnam National University Hospital, Daejeon lDepartment of Cardiology, Bucheon Sejong Hospital, Bucheon mDepartment of Cardiology, Kyung Hee University Hospital nDepartment of Cardiology, Yonsei University Severance Hospital oDepartment of Nephrology, Chung-Ang University Hospital pDepartment of Cardiology, Eulji University Hospital, Seoul qDepartment of Nephrology, Kyungpook National University Hospital, Daegu rDivision of Nephrology, Department of Internal Medicine, Dankook University Hospital, Dankook University, College of Medicine, Cheonan sDepartment of Cardiology, Inje University Busan Paik Hospital, Busan, Republic of Korea. [Ti] Título: Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: Underdiagnosis of late-onset phenotype. [So] Source: Medicine (Baltimore);96(29):e7387, 2017 Jul. [Is] ISSN: 1536-5964 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Fabry disease is a rare X-linked lysosomal storage disorder caused by an α-galactosidase A deficiency. The progressive accumulation of globotriaosylceramide (GL-3) results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. This study investigated the phenotypic and molecular spectra of GLA mutations in Korean patients with Fabry disease using a nationwide survey.This study included 94 patients from 46 independent pedigrees: 38 adult males, 46 symptomatic females, and 10 pediatric males. Each diagnosis was based on an enzyme assay and GLA gene mutation analysis.The mean age at presentation was 24 years (range, 5-65 years); however, the diagnoses were delayed by 21 ±â€Š19 years after the onset of symptoms. Those patients with late-onset Fabry disease were diagnosed by family screening or milder symptoms at a later age. Forty different mutations were identified: 20 missense (50%), 10 nonsense (25%), 8 frameshift (20%), and 2 splice site (5%) mutations. Five of them were novel. IVS4+919G>A (c.936+919 G>A) was not detected among the 6505 alleles via newborn screening using dried blood spots. Enzyme replacement therapy (ERT) was performed in all the males and pediatric patients, whereas 75% of the symptomatic females underwent ERT for 4.2 ±â€Š3.6 years.This study described the demographic data, wide clinical spectrum of phenotypes, and GLA mutation spectrum of Fabry disease in Korea. Most of the patients had classical Fabry disease, with a 4 times higher incidence than that of late-onset Fabry disease, indicating an underdiagnosis of mild, late-onset Fabry disease. [Mh] Termos MeSH primário: Doença de Fabry/epidemiologia Doença de Fabry/genética Mutação alfa-Galactosidase/genética [Mh] Termos MeSH secundário: Adolescente Idade de Início Idoso Criança Pré-Escolar Erros de Diagnóstico Terapia de Reposição de Enzimas Doença de Fabry/diagnóstico Doença de Fabry/tratamento farmacológico Feminino Estudos de Associação Genética Seres Humanos Incidência Recém-Nascido Masculino Meia-Idade Triagem Neonatal Fenótipo República da Coreia/epidemiologia Inquéritos e Questionários Resultado do Tratamento Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 3.2.1.22 (alpha-Galactosidase); EC 3.2.1.22 (alpha-galactosidase A, human) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170801 [Lr] Data última revisão: 170801 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170721 [St] Status: MEDLINE [do] DOI: 10.1097/MD.0000000000007387

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[PMID]: 28682471 [Au] Autor: Lenders M; Oder D; Nowak A; Canaan-Kühl S; Arash-Kaps L; Drechsler C; Schmitz B; Nordbeck P; Hennermann JB; Kampmann C; Reuter S; Brand SM; Wanner C; Brand E [Ad] Endereço: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany. [Ti] Título: Impact of immunosuppressive therapy on therapy-neutralizing antibodies in transplanted patients with Fabry disease. [So] Source: J Intern Med;282(3):241-253, 2017 Sep. [Is] ISSN: 1365-2796 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD. METHODS: In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation. RESULTS: No ERT-naïve transplanted patient (n = 8) developed antibodies within follow-up (80 ±72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition. CONCLUSION: We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males. [Mh] Termos MeSH primário: Anticorpos Neutralizantes/efeitos dos fármacos Terapia de Reposição de Enzimas Doença de Fabry/tratamento farmacológico Doença de Fabry/imunologia Transplante de Coração Imunossupressores/efeitos adversos Transplante de Rim [Mh] Termos MeSH secundário: Adolescente Adulto Anticorpos Neutralizantes/sangue Seres Humanos Imunossupressores/uso terapêutico Masculino Meia-Idade Estudos Retrospectivos Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antibodies, Neutralizing); 0 (Immunosuppressive Agents) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170911 [Lr] Data última revisão: 170911 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170707 [St] Status: MEDLINE [do] DOI: 10.1111/joim.12647

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[PMID]: 28682034 [Au] Autor: Villa G; Romagnoli S; Sharma A; Ronco C [Ad] Endereço: Dipartimento di Scienze della Salute, Sezione di Anestesia e Terapia Intensiva, Università degli studi di Firenze, AOU Careggi, Florence, Italy. [Ti] Título: [Fabry's disease: an example of cardiorenal syndrome type 5]. [So] Source: G Ital Nefrol;34(Suppl 69):131-141, 2017 Mar. [Is] ISSN: 1724-5990 [Cp] País de publicação: Italy [La] Idioma: ita [Ab] Resumo: Fabry's disease (FD) is a severe congenital metabolic disorder characterized by the deficient activity of lysosomal exoglycohydrolase alpha-galactosidase, characterized by glycosphingolipid deposition in several cells, such as capillary endothelial cells, renal, cardiac, and nerve cells. As a systemic disease leading to a contemporaneous myocardial and renal dysfunction, FD might be an example of cardiorenal syndrome type 5 (CRS-5). Kidney damage is commonly characterized by proteinuria, isosthenuria and altered tubular function when occurs at the second-third decade, azotemia and end-stage renal disease in third-fifth decade. Beyond the irreversible glomerular, tubular and vascular damages, the podocytes foot process effacement is the major cause of kidney dysfunction. Myocardial damage is usually observed with right and left ventricular hypertrophy, arrhythmias (due to sinus node and conduction system impairment), diastolic dysfunction, congestive heart failure, myocardial ischemia, fibrosis and cardiac death. The enzymatic replacement therapy is essential for the management of FD, as well as the control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors- and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statins to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias). [Mh] Termos MeSH primário: Síndrome Cardiorrenal/classificação Síndrome Cardiorrenal/etiologia Doença de Fabry/complicações [Mh] Termos MeSH secundário: Doença de Fabry/fisiopatologia Coração/fisiopatologia Seres Humanos Rim/fisiopatologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171024 [Lr] Data última revisão: 171024 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170707 [St] Status: MEDLINE

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