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1.
High Blood Press Cardiovasc Prev ; 27(6): 539-546, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33047250

RESUMEN

Fabry disease is a progressive, X-linked inherited lysosomal storage disorder where accumulation of glycosphingolipids increases the risk for early cardiovascular complications, including heart failure, stroke, and end stage renal disease. Besides disease-specific therapy, blood pressure (BP) control is of central importance in Fabry disease to reduce disease progression and improve prognosis. Both Fabry disease and hypertension are characterized by the activation of the innate component of the immune system, with Toll-like receptor 4 (TLR4) as a common trigger to the inflammatory cascade. The renin-angiotensin system (RAS) participates in the establishment of low-grade chronic inflammation and redox unbalance that contribute to organ damage in the long term. Besides exploiting the anti-inflammatory effects of RAS blockade and enzyme replacement therapy, targeted therapies acting on the immune system represent an appealing field of research in these conditions. The aim of this narrative review is to examine the issue of hypertension in the setting of Fabry disease, focusing on the possible determinants of their reciprocal relationship, as well as on the related clinical and therapeutic implications.


Asunto(s)
Presión Sanguínea , Enfermedad de Fabry/inmunología , Hipertensión/inmunología , Inmunidad Innata , Inflamación/inmunología , Animales , Antiinflamatorios/uso terapéutico , Antihipertensivos/uso terapéutico , Antioxidantes/uso terapéutico , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/metabolismo , Enfermedad de Fabry/fisiopatología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Inmunidad Innata/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/fisiopatología , Mediadores de Inflamación/metabolismo , Estrés Oxidativo , Sistema Renina-Angiotensina , Transducción de Señal , Receptor Toll-Like 4/metabolismo
2.
J Biol Regul Homeost Agents ; 34(4 Suppl. 2): 107-119, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33000609

RESUMEN

Lysosomal storage diseases (LSDs) include a heterogeneous group of rare, inborn, metabolic diseases characterized by deficiency of lysosomal enzymes or of other proteins involved in lysosomal function, leading to multi organ system substrates accumulation, with consequent multi systemic clinical presentation. Cardiac disease is particularly important in some group of LSDs as glycogen storage diseases (Pompe), mucopolysaccharidoses and in glycosphingolipidoses (Anderson-Fabry disease and less frequently Gaucher disease). Various cardiac manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular disease. The availability of enzyme replacement therapy (ERT) has changed the natural history of some LSDs such as Pompe disease, thanks to the significant effects on cardiological involvement. In other LSDs such as MPSs or Fabry disease, ERT has been shown to stabilize or slow the progression of heart damage. This imposes the need for a timely diagnosis that allows a rapid onset of ERT.


Asunto(s)
Enfermedad de Fabry , Cardiopatías , Enfermedades por Almacenamiento Lisosomal , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/tratamiento farmacológico , Cardiopatías/etiología , Humanos , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Enfermedades por Almacenamiento Lisosomal/tratamiento farmacológico
3.
Brasília; CONITEC; out. 2020.
No convencional en Portugués | BRISA/RedTESA | ID: biblio-1141493

RESUMEN

CONTEXTO: Doença de Fabry (DF) é uma condição genética rara em que a ausência ou atividade reduzida da enzima αgalactosidase A (αGal-A) provoca acúmulo do seu substrato, globotriaosilceramida (Gb3), nas células do organismo, afetando principalmente os sistemas nervoso, renal e cardíaco. Pacientes com DF, em especial homens com o tipo clássico, apresentam impacto negativo em qualidade e expectativa de vida. O SUS oferece tratamento sintomático e paliativo para a DF. Há disponíveis comercialmente terapias específicas para a doença, como terapia de reposição enzimática (TRE) (alfa e beta-agalsidase) e chaperonas (migalastate). TECNOLOGIA: Alfagalsidase (Replagal®) 0,2mg/kg intravenosa a cada duas semanas e Beta-agalsidase (Fabrazyme®) 1mg/kg intravenosa a cada duas semanas. PERGUNTA: O uso da alfagalsidase ou beta-agalsidase é eficaz, seguro e custo-efetivo em pacientes com doença de Fabry? EVIDÊNCIAS CIENTÍFICAS: A melhor evidência de eficácia da alfagalsidase é baseada em dois ensaios clínicos randomizados, controlados por placebo e inclusão de 41 pacientes adultos do sexo masculino e fenótipo clássico da DF, acompanhados por 6 meses. Foi observada redução significativa dos níveis de dor, massa ventricular esquerda e concentração plasmática de Gb3 (certeza moderada da evidência). Não foram localizados estudos comparativos com pacientes pediátricos ou adultos do sexo feminino com DF tratados com alfagalsidase. A melhor evidência de eficácia da beta-agalsidase é baseada em dois ensaios clínicos randomizados, controlados por placebo e inclusão de 140 pacientes com idade superior a 16 anos, de ambos os sexos, e acompanhamento por até 35 meses. Não foram identificados benefícios nos desfechos de qualidade de vida, dor e desfechos composto incluindo função renal, doenças cardíacas e doenças cerebrovasculares em análise por intenção de tratar (certeza moderada da evidência). Foi observada redução significativa da concentração plasmática de Gb3 (certeza moderada da evidência). Ambas as enzimas apresentaram perfil de segurança semelhante a placebo (certeza moderada da evidência). AVALIAÇÃO ECONÔMICA: Os dois demandantes apresentaram avaliações de custo-utilidade distintas, mas ambas baseadas em modelos de Markov já publicados e utilizando os mesmos parâmetros de efetividade, utilidade e utilização de recursos dos estudos internacionais originais. Com custo unitário proposto de R$3.802,22 (ICMS 18%) e custo anual por paciente de R$395.430,88, o demandante da alfagalsidase estimou que o tratamento representaria ganho de 14,74 anos de vida ajustados pela qualidade (QALY) em horizonte lifetime e custo incremental de R$5.684.051, composto quase inteiramente pelo custo do medicamento. A razão de custo efetividade incremental (RCEI) foi estimada em R$385.689/QALY. O demandante da beta-agalsidase apresentou proposta de preço de R$7.275,86 por frasco (ICMS 18%), com custo anual por paciente de R$378.344,72. Foi estimado ganho de 1,43 QALY e custo incremental de R$6.706.163, resultando numa RCEI de R$4.699.570/QALY. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O demandante da alfagalsidase estimou um impacto orçamentário incremental de cerca de R$250 milhões ao ano para atender aproximadamente 500 pacientes com fenótipo clássico da DF, resultando em R$1,3 bilhão acumulado em 5 anos. Para a beta-agalsidase, o demandante estimou impacto orçamentário incremental de cerca de R$230 milhões ao ano para atender em torno de 600 pacientes adultos com DF, com impacto total de R$1,1 bilhão em 5 anos. Como cenário alternativo, propõe-se uma estimativa de impacto orçamentário incluindo todos os pacientes com DF (cerca de 1.000 ao ano), distribuídos equitativamente entre as duas enzimas. O impacto orçamentário proposto resultou em cerca de R$380 milhões ao ano e R$1,9 bilhão acumulado em 5 anos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas três tecnologias para o tratamento de pacientes adultos de ambos os sexos com doença de Fabry: lucerastate alfa (oral) e pegnigalsidase alfa (intravenosa), ambas sem registros na Anvisa, FDA ou EMA; e migalastate (oral), com registro nas três agências. Para a população pediátrica, foram identificados estudos fase 3 em andamento com migalastate e com beta-agalsidase. CONSIDERAÇÕES FINAIS: O benefício da alfagalsidase ou beta-agalsidase para DF foi observado apenas em desfechos pouco importantes para a tomada de decisão, sem evidências de modificação no curso natural da doença. O impacto orçamentário ao SUS é potencialmente superior à sua capacidade de pagamento. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O Plenário da Conitec considerou que as melhores evidências científicas disponíveis são limitadas em número de pacientes incluídos e tempo de acompanhamento, e não demonstram benefício em desfechos clínicos importantes ou modificação do curso natural da doença. Soma-se a isso o grande impacto orçamentário que a incorporação representaria ao SUS. Assim, a Conitec, em sua 89ª reunião ordinária, realizada no dia 05 de agosto de 2020, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar não favorável à incorporação no SUS do medicamento alfagalsidase para pacientes acima de sete anos com diagnóstico confirmado de doença de Fabry e do medicamento beta-agalsidase para pacientes acima de 16 anos com diagnóstico confirmado de Doença de Fabry. CONSULTA PÚBLICA: A consulta pública ficou vigente no período entre 24 de agosto e 14 de setembro de 2020. Foram recebidas 1.939 contribuições, sendo 90 por meio do formulário técnico-científico e 1.849 por meio do formulário de experiência ou opinião. As contribuições versaram principalmente sobre: 1) inclusão de estudos com menor qualidade metodológica diante da raridade da doença; 2) indicação de uma subpopulação de pacientes para os quais a TRE seria indicada; 3) inconsistência com recomendações anteriores da Conitec para outras doenças raras; 4) necessidade de avaliação do medicamento migalastate; 5) relatos de experiência com as enzimas, indicando melhora especialmente em qualidade de vida, incluindo componentes físicos e emocionais. O Plenário da Conitec considerou, entretanto, que as evidências científicas disponíveis não comprovam uma interrupção da progressão da doença de Fabry pelas enzimas analisadas e entendeu que não houve argumentação suficiente para alterar a recomendação inicial. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 91ª reunião ordinária, no dia 08 de outubro de 2020, deliberaram por unanimidade recomendar a não incorporação no SUS do medicamento alfagalsidase para terapia crônica de reposição enzimática em pacientes acima de 7 anos com diagnóstico confirmado de doença de Fabry e do medicamento beta-agalsidase para tratamento de longo prazo da reposição enzimática em pacientes acima de 16 anos com diagnóstico confirmado de Doença de Fabry, devido a: 1) não comprovação de interrupção da progressão da doença, 2) evidências limitadas quanto ao número de pacientes incluídos nos estudos clínicos comparativos, 3) evidências limitadas quanto ao tempo de acompanhamento dos pacientes nos estudos comparativos, 4) elevado impacto orçamentário que a incorporação representaria ao SUS. Foram assinados os Registros de Deliberação nº 568/2020 e 569/2020, respectivamente. DECISÃO: Não incorporar a alfagalsidase e a beta-agalsidase para o tratamento da doença de Fabry, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 56, publicada no Diário Oficial da União nº 224, seção 1, página 65, em 24 de novembro de 2020.


Asunto(s)
Humanos , Enfermedad de Fabry/tratamiento farmacológico , beta-Galactosidasa/uso terapéutico , alfa-Galactosidasa/uso terapéutico , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economía
4.
Medicine (Baltimore) ; 99(39): e22326, 2020 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-32991443

RESUMEN

RATIONALE: The most common cardiac involvement of Fabry disease (FD) is left ventricular hypertrophy (LVH), which usually occurs in male patients over the age of 30. In rare cases, it can progress to ventricular dilation in the late stage of the disease. PATIENT CONCERNS: A 16-year-old boy presenting with recurrent extremity pain and chest distress was admitted to our hospital. Imaging examinations revealed ventricular dilation. DIAGNOSIS: α-Galactosidase A enzyme assay and GLA gene sequencing confirmed the diagnosis of FD and revealed a novel mutation c.76_77insT. INTERVENTIONS: The patient was treated using metoprolol (23.75 mg qd) and angiotensin-converting enzyme inhibitor (fosinopril sodium 5 mg qd). He refused enzyme replacement therapy for financial reasons. OUTCOMES: The echocardiography, electrocardiography, renal function, and routine blood and urine tests performed 20 months after the patients discharge from hospital showed no significant changes. The patient reported a slow and gradual decrease in the frequency and degree of pain and chest distress, starting approximately 24 months after discharge. LESSONS: Cardiac involvement of FD can progress rapidly in some cases. Screening for FD should be considered in patients with unexplained ventricular dilation, especially in those with a history of typical FD manifestations.


Asunto(s)
Dilatación Patológica/diagnóstico por imagen , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/genética , Hipertrofia Ventricular Izquierda/etiología , alfa-Galactosidasa/genética , Adolescente , Cuidados Posteriores , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Ecocardiografía/métodos , Electrocardiografía/métodos , Terapia de Reemplazo Enzimático/economía , Enfermedad de Fabry/tratamiento farmacológico , Fosinopril/uso terapéutico , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Masculino , Metoprolol/uso terapéutico , Mutación , Simpaticolíticos/uso terapéutico , Resultado del Tratamiento
5.
Intern Med ; 59(7): 971-976, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32238663

RESUMEN

Mulberry cells are often present in the urinary sediments of patients with Fabry disease (FD). We herein report two patients with FD undergoing enzyme replacement therapy (ERT). A 41-year-old man was diagnosed based on lack of α-galactosidase A activity. ERT was subsequently administered. A 40-year-old woman was diagnosed based on urinary Mulberry cells and genetic testing, and ERT was initiated. While the renal function of the male patient deteriorated, the Mulberry cells disappeared in the female patient after ERT was administered. The detection of urinary Mulberry cells can contribute to the diagnosis as well as serve as a biomarker for the response to treatment.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Podocitos/patología , Orina/citología , Adulto , Biomarcadores , Enfermedad de Fabry/genética , Enfermedad de Fabry/patología , Femenino , Pruebas Genéticas , Humanos , Masculino , Microscopía Electrónica , Podocitos/ultraestructura , alfa-Galactosidasa/metabolismo , alfa-Galactosidasa/uso terapéutico
6.
Eur J Med Chem ; 192: 112173, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32146376

RESUMEN

The synthesis of a chemical library of multimeric pyrrolidine-based iminosugars by incorporation of three pairs of epimeric pyrrolidine-azides into different alkyne scaffolds via CuAAC is presented. The new multimers were evaluated as inhibitors of two important therapeutic enzymes, human α-galactosidase A (α-Gal A) and lysosomal ß-glucocerebrosidase (GCase). Structure-activity relationships were established focusing on the iminosugar inhitope, the valency of the dendron and the linker between the inhitope and the central scaffold. Remarkable is the result obtained in the inhibition of α-Gal A, where one of the nonavalent compounds showed potent inhibition (0.20 µM, competitive inhibition), being a 375-fold more potent inhibitor than the monovalent reference. The potential of the best α-Gal A inhibitors to act as pharmacological chaperones was analyzed by evaluating their ability to increase the activity of this enzyme in R301G fibroblasts from patients with Fabry disease, a genetic disorder related with a reduced activity of α-Gal A. The best enzyme activity enhancement was obtained for the same nonavalent compound, which increased 5.2-fold the activity of the misfolded enzyme at 2.5 µM, what constitutes the first example of a multivalent α-Gal A activity enhancer of potential interest in the treatment of Fabry disease.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Enfermedad de Fabry/tratamiento farmacológico , Glucosilceramidasa/antagonistas & inhibidores , Iminoazúcares/farmacología , Pirrolidinas/farmacología , alfa-Galactosidasa/antagonistas & inhibidores , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Enfermedad de Fabry/metabolismo , Glucosilceramidasa/metabolismo , Humanos , Iminoazúcares/síntesis química , Iminoazúcares/química , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Relación Estructura-Actividad , alfa-Galactosidasa/metabolismo
7.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-32023956

RESUMEN

Fabry disease is one of the most common lysosomal storage disorders caused by mutations in the gene encoding lysosomal α-galactosidase A (α-Gal A) and resultant accumulation of glycosphingolipids. The sugar mimetic 1-deoxygalactonojirimycin (DGJ), an orally available pharmacological chaperone, was clinically approved as an alternative to intravenous enzyme replacement therapy. The decision as to whether a patient should be treated with DGJ depends on the genetic variant within the α-galactosidase A encoding gene (GLA). A good laboratory practice (GLP)-validated cell culture-based assay to investigate the biochemical responsiveness of the variants is currently the only source available to obtain pivotal information about susceptibility to treatment. Herein, variants were defined amenable when an absolute increase in enzyme activity of ≥3% of wild type enzyme activity and a relative increase in enzyme activity of ≥1.2-fold was achieved following DGJ treatment. Efficacy testing was carried out for over 1000 identified GLA variants in cell culture. Recent data suggest that about one-third of the variants comply with the amenability criteria. A recent study highlighted the impact of inter-assay variability on DGJ amenability, thereby reducing the power of the assay to predict eligible patients. This prompted us to compare our own α-galactosidase A enzyme activity data in a very similar in-house developed assay with those from the GLP assay. In an essentially retrospective approach, we reviewed 148 GLA gene variants from our former studies for which enzyme data from the GLP study were available and added novel data for 30 variants. We also present data for 18 GLA gene variants for which no data from the GLP assay are currently available. We found that both differences in experimental biochemical data and the criteria for the classification of amenability cause inter-assay discrepancy. We conclude that low baseline activity, borderline biochemical responsiveness, and inter-assay discrepancy are alarm signals for misclassifying a variant that must not be ignored. Furthermore, there is no solid basis for setting a minimum response threshold on which a clinical indication with DGJ can be justified.


Asunto(s)
Sustitución de Aminoácidos , Enfermedad de Fabry/genética , alfa-Galactosidasa/metabolismo , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapéutico , Bioensayo , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/metabolismo , Células HEK293 , Humanos , Medicina de Precisión , Reproducibilidad de los Resultados , Estudios Retrospectivos , alfa-Galactosidasa/genética
8.
Int J Mol Sci ; 21(2)2020 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-31940970

RESUMEN

The term "pharmacological chaperone" was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.


Asunto(s)
Enfermedad de Fabry , Chaperonas Moleculares/uso terapéutico , Mutación Missense , alfa-Galactosidasa , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/enzimología , Enfermedad de Fabry/genética , Humanos , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo
9.
Biochem J ; 477(2): 359-380, 2020 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-31899485

RESUMEN

The lysosomal storage disorder Fabry disease is characterized by a deficiency of the lysosomal enzyme α-Galactosidase A. The observation that missense variants in the encoding GLA gene often lead to structural destabilization, endoplasmic reticulum retention and proteasomal degradation of the misfolded, but otherwise catalytically functional enzyme has resulted in the exploration of alternative therapeutic approaches. In this context, we have investigated proteostasis regulators (PRs) for their potential to increase cellular enzyme activity, and to reduce the disease-specific accumulation of the biomarker globotriaosylsphingosine in patient-derived cell culture. The PRs also acted synergistically with the clinically approved 1-deoxygalactonojirimycine, demonstrating the potential of combination treatment in a therapeutic application. Extensive characterization of the effective PRs revealed inhibition of the proteasome and elevation of GLA gene expression as paramount effects. Further analysis of transcriptional patterns of the PRs exposed a variety of genes involved in proteostasis as potential modulators. We propose that addressing proteostasis is an effective approach to discover new therapeutic targets for diseases involving folding and trafficking-deficient protein mutants.


Asunto(s)
Enfermedad de Fabry/genética , Enfermedades por Almacenamiento Lisosomal/genética , Proteostasis/genética , alfa-Galactosidasa/genética , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapéutico , Biomarcadores/metabolismo , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/enzimología , Enfermedad de Fabry/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Enfermedades por Almacenamiento Lisosomal/tratamiento farmacológico , Enfermedades por Almacenamiento Lisosomal/enzimología , Enfermedades por Almacenamiento Lisosomal/patología , Lisosomas/enzimología , Lisosomas/genética , Lisosomas/metabolismo , Mutación Missense/genética , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Transporte de Proteínas/efectos de los fármacos , Esfingosina/análogos & derivados , Esfingosina/metabolismo
10.
Clin Exp Nephrol ; 24(2): 157-166, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31889231

RESUMEN

BACKGROUND: Fabry disease is a progressive X-linked lysosomal disorder. In this subgroup analysis of the global phase III ATTRACT study, the efficacy and safety of oral migalastat, a pharmacologic chaperone, were investigated in Japanese patients with Fabry disease. METHODS: Patients were randomly assigned to receive migalastat (150 mg every other day) or to continue biweekly enzyme replacement therapy infusions (ERT; agalsidase alfa 0.2 mg/kg or agalsidase beta 1.0 mg/kg) for 18 months followed by a 12-month open-label extension during which all patients received migalastat. End points included glomerular filtration rate (estimated and measured), left ventricular mass index (LVMi), composite clinical outcomes, leukocyte alpha-galactosidase A activity, plasma globotriaosylsphingosine (lyso-Gb3), and safety. RESULTS: Data from 7 Japanese patients (migalastat, 5; ERT, 2), mean age 55 years, with high disease burden, were analyzed. All patients in the migalastat group completed the open-label comparison and extension periods. At 18 months, efficacy in the Japanese patient population was similar to that in the overall ATTRACT population. Migalastat treatment increased leukocyte alpha-galactosidase A activity, stabilized renal function, and decreased LVMi. Plasma lyso-Gb3 levels remained low and stable. Additionally, the long-term extension study showed that efficacy of migalastat was maintained for up to 48 months. Migalastat was safe and well tolerated in the Japanese patients, as in the overall ATTRACT population. CONCLUSION: Migalastat can be used to treat Japanese patients with Fabry disease with GLA mutations amenable to migalastat according to the dosage and administration approved in other countries. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov, NCT01218659 and NCT02194985.


Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Enfermedad de Fabry/tratamiento farmacológico , 1-Desoxinojirimicina/administración & dosificación , 1-Desoxinojirimicina/efectos adversos , Administración Oral , Adulto , Enfermedad de Fabry/enzimología , Enfermedad de Fabry/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Japón , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo
11.
Exp Neurol ; 324: 113134, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31778662

RESUMEN

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder that leads to cellular globotriaosylceramide (Gb3) accumulation due to mutations in the gene encoding α-galactosidase A. Trigger-induced acral burning pain is an early FD symptom of unknown pathophysiology. We aimed at investigating the potential role of skin fibroblasts in nociceptor sensitization. PATIENTS AND METHODS: We enrolled 40 adult FD patients and ten healthy controls, who underwent a 6-mm skin punch biopsy at the lower leg. Dermal fibroblasts were cultivated and analyzed for Gb3 load. Fibroblast electrical activity was assessed using patch-clamp analysis at baseline and upon incubation with agalsidase-α for 24 h. We investigated gene expression of CC motif chemokine ligand 2 (CCL2), Ca2+activated K+-channel 1.1 (KCa1.1), interferone-γ (IFN-γ), transforming growth factor-ß1 (TGF-ß1), and transmembrane receptor notch homolog 1 (Notch1) using quantitative real-time-PCR, and protein levels of KCa1.1 by ELISA. Gene expression was determined at baseline and after fibroblast stimulation with tumor necrosis factor-α (TNF), modeling inflammation as a common pain trigger in FD. RESULTS: Total Gb3 load was higher in FD fibroblasts than in control fibroblasts (p < .01). Upon increase of intracellular Ca2+ concentrations, we detected differential electrical activity of KCa1.1 in fibroblasts obtained from patients with FD. Gene expression (p < .05) and protein levels of KCa1.1 (p < .05) were higher in fibroblasts from FD patients compared to control fibroblasts, whereas electric channel activity was lower in FD fibroblasts. After incubation with agalsidase-α, we observed an over-proportionate increase of KCa1.1 activity in FD fibroblasts reaching 7-fold the currents of control cells (p < .01). Gene expression studies revealed higher mRNA levels of CCL2, INF-γ, and Notch1 in FD fibroblasts compared to controls at baseline and after TNF incubation (p < .05 each), while TGF-ß1 was higher in FD fibroblasts only after incubation with TNF (p < .05). CONCLUSIONS: Gb3 deposition in skin fibroblasts may impair KCa1.1 activity and activate the Notch1 signaling pathway. The resulting increase in pro-inflammatory mediator expression may contribute to cutaneous nociceptor sensitization as a potential mechanism of FD-associated pain.


Asunto(s)
Enfermedad de Fabry/tratamiento farmacológico , Fibroblastos/efectos de los fármacos , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/farmacología , Receptor Notch1/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Trihexosilceramidas/metabolismo , Adolescente , Adulto , Anciano , Animales , Quimiocina CCL2/metabolismo , Enfermedad de Fabry/metabolismo , Enfermedad de Fabry/patología , Femenino , Fibroblastos/patología , Expresión Génica/efectos de los fármacos , Humanos , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/genética , Ratones , Persona de Mediana Edad , Dolor , Cultivo Primario de Células , Piel/patología , Factor de Transcripción ReIA/metabolismo , Trihexosilceramidas/antagonistas & inhibidores , Trihexosilceramidas/genética , Adulto Joven
12.
Mol Genet Metab ; 129(2): 142-149, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31879214

RESUMEN

BACKGROUND: Two established scores, the Mainz Severity Score Index (MSSI) and Fabry Disease Severity Scoring System (DS3), quantify the disease burden in Fabry disease (FD), while the recent developed FAbry STabilization indEX (FASTEX) aims to detect disease progression. OBJECTIVE: MSSI, DS3 and FASTEX were compared to evaluate disease stability or progression in a prospective cohort of Fabry patients under enzyme replacement therapy (ERT). METHODS: Disease load of 62 patients (28 [45%] females) treated with ERT (26 [42%] under agalsidase-alfa) was assessed using the current scores and re-assessed after 12 months of treatment. Fifteen (24%) patients were ERT-naïve at baseline. RESULTS: All scores showed a correlation with each other, while MSSI and DS3 showed the strongest (Pearson r: 0.81, p < .0001). Plasma lyso-Gb3 levels in naïve patients correlated with increasing DS3 and MSSI scores (Pearson r: 0.60, p < .05; Pearson r: 0.64, p < .01; respectively), but not with the total weighted FASTEX score. Longitudinal analysis suggested a stable disease course using DS3 and MSSI. Only males long-term-treated with agalsidase-alfa presented with a slight increase of the general MSSI score (p = .0084). By contrast, the FASTEX score demonstrates that only 21 patients (33.9%) were stable, all other patients presented a disease progression. Patients with an unstable FASTEX mainly suffered from a significant loss of renal function (eGFRcreat: -2.7 ± 7.3 ml/min/1.73 m2, p = .0298). CONCLUSION: We conclude that the FASTEX seems to be a simple and user friendly, valuable tool to assess early changes in disease progression even in smaller patient cohorts and short term surveillance.


Asunto(s)
Costo de Enfermedad , Enfermedad de Fabry/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Anciano , Progresión de la Enfermedad , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/patología , Femenino , Humanos , Isoenzimas/uso terapéutico , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , alfa-Galactosidasa/uso terapéutico
13.
Circ Cardiovasc Imaging ; 12(12): e009430, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31826677

RESUMEN

BACKGROUND: Cardiac response to enzyme replacement therapy (ERT) in Fabry disease is typically assessed by measuring left ventricular mass index using echocardiography or cardiovascular magnetic resonance, but neither quantifies myocardial biology. Low native T1 in Fabry disease represents sphingolipid accumulation; late gadolinium enhancement with high T2 and troponin elevation reflects inflammation. We evaluated the effect of ERT on myocardial storage, inflammation, and hypertrophy. METHODS: Twenty patients starting ERT (60% left ventricular hypertrophy-positive) were compared with 18 patients with early disease and 18 with advanced disease over 1 year at 3 centers. Cardiovascular magnetic resonance (left ventricular mass index, T1, T2, global longitudinal strain, and late gadolinium enhancement) and biomarkers (high-sensitive troponin-T and NT-proBNP [N-terminal Pro-B-type natriuretic peptide]) at baseline (pre-ERT) and 12 months were performed. Early disease controls were stable, treatment-naïve patients (mainly left ventricular hypertrophy-negative); advanced disease controls were stable, established ERT patients (mainly left ventricular hypertrophy-positive). RESULTS: Over 1 year, early disease controls increased maximum wall thickness and left ventricular mass index (9.8±2.7 versus 10.2±2.6 mm; P=0.010; 65±15 versus 67±16 g/m2; P=0.005) and native T1 fell (981±58 versus 959±61 ms; P=0.002). Advanced disease controls increased T2 in the late gadolinium enhancement area (57±6 versus 60±7 ms; P=0.023) with worsening global longitudinal strain (-13.2±3.4 versus -12.1±4.8; P=0.039). Newly treated patients had a small reduction in maximum wall thickness (14.8±5.9 versus 14.4±5.7 mm; P=0.028), stable left ventricular mass index (93±42 versus 92±40 g/m2; P=0.186) and a reduction in T1 lowering (917±49 versus 931±54 ms; P=0.017). CONCLUSIONS: Fabry myocardial phenotype development is different at different disease stages. After 1 year of ERT initiation, left ventricular hypertrophy-positive patients have a detectable, small reduction in left ventricular mass and storage.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Isoenzimas/uso terapéutico , Miocardio/metabolismo , Proteínas Recombinantes/uso terapéutico , Esfingolípidos/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , alfa-Galactosidasa/uso terapéutico , Adulto , Anciano , Progresión de la Enfermedad , Enfermedad de Fabry/diagnóstico por imagen , Enfermedad de Fabry/enzimología , Enfermedad de Fabry/fisiopatología , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/enzimología , Hipertrofia Ventricular Izquierda/fisiopatología , Londres , Imagen por Resonancia Magnética , Persona de Mediana Edad , Miocardio/patología , Nueva Gales del Sur , Fenotipo , Estudios Prospectivos , Recuperación de la Función , Factores de Tiempo , Resultado del Tratamiento
14.
BMC Nephrol ; 20(1): 469, 2019 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-31847900

RESUMEN

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene, followed by deficiency in α-galactosidase A (α-gal) activity. Nephrotic syndrome, as the renal phenotype of FD, is unusual. Here, we report the rare case of a patient with FD with nephrotic syndrome whose proteinuria disappeared by immunotherapy. CASE PRESENTATION: A 67-year-old Japanese man was admitted to our hospital because of emesis, abdominal pain, and facial edema due to nephrotic syndrome. The patient was diagnosed with focal segmental glomerulosclerosis (FSGS) by renal biopsy before being diagnosed with FD, and immunotherapy was initiated. After treatment, the kidney biopsy results showed typical glycosphingolipid accumulation in the podocytes of this patient. The white blood cell α-gal activity was very low, and genetic analysis revealed a GLA gene variant (M296I), which is known as a late-onset genetic mutation of FD. Immunotherapy (steroids and cyclosporine A) dramatically improved the massive proteinuria. Currently, he has been undergoing enzyme replacement therapy, and his proteinuria has further decreased. There is the possibility that other nephrotic syndromes, such as minimal change nephrotic syndrome or FSGS, may co-exist in this patient. CONCLUSIONS: We experienced the rare case of a FD patient whose nephrotic syndrome disappeared by immunotherapy. These findings suggest that immunosuppressive treatment may be considered if nephrotic syndrome develops, even in patients with FD.


Asunto(s)
Enfermedad de Fabry/sangre , Enfermedad de Fabry/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Síndrome Nefrótico/sangre , Síndrome Nefrótico/tratamiento farmacológico , Anciano , Enfermedad de Fabry/complicaciones , Humanos , Masculino , Síndrome Nefrótico/complicaciones , Resultado del Tratamiento
15.
G Ital Nefrol ; 36(4)2019 Jul 24.
Artículo en Italiano | MEDLINE | ID: mdl-31373466

RESUMEN

Fabry disease is a rare inborn error of the enzyme α-galactosidase (Α-Gal) and results in lysosomal substrate accumulation in tissues with a wide range of clinical presentations. The disease has attracted a lot of interest over the last years and several issues has been discovered up to now leading to increasing knowledge and awareness of the disease. However, several aspects are still unclear and under investigation. Thus, the new challenges that physicians encounter are the discovering of the pathogenic mechanisms, the neutralising antibodies to ERT, the long-term efficacy of therapies. In this article, we summarise and review the latest developments in the science community regarding diagnosis, management and monitoring of Fabry disease concerning in particular its physiopathology, novel biomarkers, antibodies development and novel treatment options.


Asunto(s)
Enfermedad de Fabry/complicaciones , Enfermedades Renales/etiología , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapéutico , Progresión de la Enfermedad , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/genética , Femenino , Glomeruloesclerosis Focal y Segmentaria/etiología , Glucolípidos/metabolismo , Heterocigoto , Humanos , Isoenzimas/inmunología , Isoenzimas/uso terapéutico , Enfermedades Renales/diagnóstico , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Masculino , Estrés Oxidativo , Podocitos/metabolismo , Podocitos/patología , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéutico , Factores Sexuales , Esfingolípidos/metabolismo , Trihexosilceramidas/metabolismo , alfa-Galactosidasa/inmunología , alfa-Galactosidasa/uso terapéutico
16.
Mol Genet Genomic Med ; 7(9): e894, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31393666

RESUMEN

BACKGROUND: Fabry disease (OMIM 301500) is an X-linked disorder caused by alpha-galactosidase A (α-Gal A) deficiency. The administration of a pharmacologic chaperone (migalastat) in Fabry patients with amenable mutations has been reported to improve or stabilize organ damages and reduce lyso-Gb3 plasma level. An increase of α-Gal A activity has been observed in vitro in cells expressing amenable GLA mutations when incubated with migalastat. The impact of the drug on α-Gal A in vivo activity has been poorly studied. METHODS: We conducted a retrospective analysis of two unrelated male Fabry patients with p.Asn215Ser (p.N215S) variant. RESULTS: We report the important increase of α-Gal A activity in blood leukocytes reaching normal ranges of activity after about 1 year of treatment with migalastat. Cardiac parameters improved or stabilized with the treatment. CONCLUSION: We confirm in vivo the effects of migalastat that have been observed in N215S carriers in vitro. The increase of α-Gal A activity may be the strongest marker for biochemical efficacy. The normalization of enzyme activity could become the new therapeutic target to achieve.


Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Enfermedad de Fabry , Leucocitos/enzimología , Mutación Missense , 1-Desoxinojirimicina/administración & dosificación , Administración Oral , Sustitución de Aminoácidos , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/enzimología , Enfermedad de Fabry/genética , Humanos , Masculino , Estudios Retrospectivos , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo
17.
Transplant Proc ; 51(9): 3171-3173, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31371217

RESUMEN

Fabry's disease is a X-linked hereditary disease that causes the accumulation of glycosphingolipids in tissues and organs, including the kidneys and heart. This can result in both chronic kidney disease and cardiac dysfunction, including arrhythmias and heart failure. We describe a case of a 62-year-old male with Fabry's disease undergoing successful combined heart and kidney transplantation for chronic renal failure and low-output systolic heart failure. The patient has normal cardiac function and normal renal function 7 years after transplantation, while being maintained on enzyme replacement therapy with recombinant human alpha-galactosidase A. Fabry's disease is not a contraindication for organ transplantation, even in patients presenting with both renal failure and heart failure.


Asunto(s)
Enfermedad de Fabry/complicaciones , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón/métodos , Fallo Renal Crónico/cirugía , Trasplante de Riñón/métodos , Enfermedad de Fabry/tratamiento farmacológico , Insuficiencia Cardíaca/genética , Humanos , Fallo Renal Crónico/genética , Masculino , Persona de Mediana Edad , alfa-Galactosidasa/uso terapéutico
18.
Adv Ther ; 36(10): 2866-2880, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31435831

RESUMEN

INTRODUCTION: Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A. Symptoms include neuropathic pain and gastrointestinal problems, such as diarrhoea. To inform and support the design of a Phase III clinical trial for a new oral treatment for Fabry disease, this study evaluated patients' experiences of Fabry disease symptoms, the impact of symptoms on their quality of life, and their views on participating in clinical trials. METHODS: An online survey questionnaire was distributed to patients with Fabry disease, through relevant patient organisations. The questionnaire consisted mainly of quantitative, closed questions with pre-defined response options. Fabry-specific pain intensity and its impact on quality of life were rated on a scale from 0 to 10. RESULTS: In total, 367 patients completed the survey, of whom half reported frequent pain, moderate to severe pain, and pain in their hands and feet. Pain frequency, intensity and location were similar for males and females. There was no clear association between Fabry-specific pain and the use of enzyme replacement therapy (ERT), with moderate to severe pain reported by 80.4% of participants receiving ERT and by 75.0% of participants not receiving ERT. Of participants who were receiving ERT, 35.7% said they were willing to discontinue it to take part in a clinical trial testing a new oral drug for treating Fabry disease. Gastrointestinal symptoms were more heterogeneous in nature and frequency than Fabry-specific pain, but still affected a significant proportion of participants. CONCLUSIONS: Both male and female patients with Fabry disease experience significant Fabry-specific pain, which affects their quality of life. Furthermore, frequent diarrhoea affects many patients. The symptoms occur independently of the use of ERT. This suggests the healthcare needs of patients with Fabry disease are not being fully met, and additional treatments are required to improve symptoms and quality of life. FUNDING: This study was sponsored by Actelion Pharmaceuticals Ltd. Study sponsorship was transferred to Idorsia Pharmaceuticals Ltd in July 2018.


Asunto(s)
Terapia de Reemplazo Enzimático/métodos , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/psicología , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/psicología , Calidad de Vida/psicología , alfa-Galactosidasa/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios
19.
JACC Cardiovasc Imaging ; 12(7 Pt 1): 1230-1242, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31272606

RESUMEN

Anderson-Fabry disease (AFD) is a rare X-linked inherited metabolic disorder which results in a deficiency or absence of the enzyme α-galactosidase A, leading to the accumulation of glycosphingolipids in various cells and organs including the heart. Cardiac involvement is common and results in increased myocardial inflammation, left ventricular hypertrophy (LVH), and myocardial fibrosis. Echocardiography and cardiovascular magnetic resonance (CMR) offer distinctive and often complementary use to assist in the diagnosis and monitoring pharmacologic therapy in AFD, including detection of the AFD cardiac phenotype, differentiation from other forms of LVH, and patient selection for therapeutic intervention. Advanced cardiac imaging holds promise in subclinical detection of AFD-related abnormalities as well as disease staging and prognostication.


Asunto(s)
Ecocardiografía , Enfermedad de Fabry/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Imagen por Resonancia Magnética , Diagnóstico Diferencial , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/fisiopatología , Femenino , Fibrosis , Humanos , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Miocardio/patología , Selección de Paciente , Valor Predictivo de las Pruebas , Pronóstico , Función Ventricular Izquierda , Remodelación Ventricular
20.
Medicine (Baltimore) ; 98(28): e16256, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31305407

RESUMEN

RATIONALE: Fabry's disease is an X-linked inherited syndrome. Herein, we presented an unusual case of Fabry disease coexisting with immunoglobulin A nephropathy (IgAN) presenting with Alport syndrome-like pathological findings. PATIENT CONCERNS: We report a 30-year-old male who presented with proteinuria and elevated serum creatinine and for whom the initial pathologic diagnosis supported Alport syndrome. DIAGNOSES: A diagnosis of Fabry disease with immunoglobulin A nephropathy (IgAN) was finally made after further examination. INTERVENTIONS: After the initial diagnosis the patient was treated with herbal medications and mecobalamin. OUTCOMES: The patient was discharged 1 week later. He was maintained on these treatments and received regular follow-up in our hospital. LESSONS SUBSECTIONS AS PER STYLE: FD coexisting with IgAN is rare and may have nonspecific clinical presentations. Laboratory examination and genetic diagnosis is needed for confirmation. Timely diagnosis and reproductive intervention is needed for therapy.


Asunto(s)
Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/diagnóstico , Nefritis/complicaciones , Nefritis/diagnóstico , Adulto , Diagnóstico Diferencial , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/inmunología , Humanos , Inmunoglobulina A/metabolismo , Riñón/patología , Masculino , Nefritis/tratamiento farmacológico , Nefritis/inmunología
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