Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry , Humanos , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/complicaciones , Terapia de Reemplazo Enzimático/métodos , alfa-Galactosidasa/uso terapéutico , Masculino , Resultado del Tratamiento , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/diagnósticoRESUMEN
INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder affecting glycosphingolipid metabolism. Most FD patients have cardiac involvement, mainly manifested as left ventricular hypertrophy (LVH), leading to early death due to complications (arrhythmias, valvular disease, vascular involvement). Early initiation of enzyme replacement therapy (ERT) before fibrosis development has been associated with better cardiac outcomes in terms of left ventricular mass index (LVMI) and functional parameters. METHODS: A retrospective observational study was conducted in patients with FD treated with agalsidase alfa for at least 2 years. The primary objectives were: [a] to assess the annual rate of change in LVMI; [b] to define the overall incidence of stability, regression or progression of LVMI. RESULTS: Forty-nine patients were included in the final analysis, with a median follow-up of 7 years. The overall change in LVMI was 0.38 g/m2.73/year, without significant influence of baseline LVH, gender, age at ERT initiation, LV ejection fraction, body mass index, renal disease, and classical cardiovascular risk factors. Long-term ERT with agalsidase alfa was associated with stabilization of LVMI in 98% of patients with FD and was independent of the same covariables. CONCLUSION: Our results are in line with previous literature of comparable FD populations and probably represent the first study of its kind in Argentina. We here highlight the importance of cardiac morphometric stability as a positive outcome of ERT.
Introducción: La enfermedad de Fabry (EF) es una enfermedad de almacenamiento lisosomal ligada al cromosoma X que afecta el metabolismo de glicoesfingolípidos. La mayoría de pacientes EF tienen afectación cardíaca, manifestada principalmente como hipertrofia ventricular izquierda (HVI), que conduce a muerte prematura secundaria a complicaciones (arritmias, valvulopatías, afectación vascular). El tratamiento de reemplazo enzimático (TRE) precoz, iniciado antes del desarrollo de la fibrosis, se relaciona con mejores resultados cardíacos en términos del índice de masa ventricular izquierda (IMVI) y parámetros funcionales. Métodos: Se realizó un estudio retrospectivo observacional en que se incluyeron pacientes con EF tratados con agalsidasa alfa por al menos 2 años. Los objetivos primarios fueron: [a] evaluar el cambio anual del IMVI; [b] definir la incidencia global de estabilidad, regresión o progresión del IMVI. Resultados: Se incluyeron 49 pacientes, con seguimiento (mediana) de 7 años. El cambio global en el IMVI fue 0.38 g/m2.73/año, sin influencia significativa de HVI basal, sexo, edad de inicio de TRE, fracción de eyección del VI, índice de masa corporal, insuficiencia renal y factores de riesgo cardiovascular clásicos. La TRE a largo plazo con agalsidasa alfa se relacionó con la estabilización del IMVI en el 98% de los pacientes con EF, independientemente de las mismas covariables. Conclusión: Nuestros resultados están en línea con la bibliografía previa de poblaciones comparables y, probablemente, representan el primer estudio de este tipo en Argentina. Se destaca la importancia de la estabilidad morfométrica cardíaca como resultado positivo de la TRE.
Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry , Hipertrofia Ventricular Izquierda , Isoenzimas , Proteínas Recombinantes , alfa-Galactosidasa , Humanos , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/complicaciones , Masculino , Femenino , Estudios Retrospectivos , alfa-Galactosidasa/uso terapéutico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Adulto , Terapia de Reemplazo Enzimático/métodos , Persona de Mediana Edad , Isoenzimas/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Estudios de Seguimiento , Factores de TiempoRESUMEN
Fabry Update.
Asunto(s)
Biomarcadores , Progresión de la Enfermedad , Enfermedad de Fabry , Enfermedad de Fabry/terapia , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Humanos , Terapia de Reemplazo Enzimático , alfa-Galactosidasa/genética , alfa-Galactosidasa/uso terapéuticoRESUMEN
BACKGROUND: Enzyme replacement therapy (ERT) may halt or attenuate disease progression in patients with Anderson-Fabry disease (AFD). However, whether left ventricular hypertrophy (LVH) can be prevented by early therapy or may still progress despite ERT over a long-term follow-up is still unclear. METHODS: Consecutive patients with AFD from the Independent Swiss-Fabry Cohort receiving ERT who were at least followed up for 5 years were included. Cardiac progression was defined as an increase of >10 g/m2 in left ventricular mass index (LVMI) between the first and the last available follow-up transthoracic echocardiography. RESULTS: 60 patients (35 (23-48) years, 39 (65%) men) were followed up for 10.5 (7.2-12.2) years. 22 had LVH at ERT start (LVMI of 150±38 g/m2). During follow-up, 22 (36%, 34±15 years) had LVMI progression of 12.1 (7-17.6) g/m2 per 100 patient-years, of these 7 (11%, 29±13 years) with no LVH at baseline. Three of them progressed to LVH. LVMI progression occurred mostly in men (17 of 39 (43%) vs 5 of 21 (24%), p<0.01) and after the age of 30 years (17 of 22 (77%)). LVH at ERT start was associated with LVMI progression (OR 1.3, 95% CI 1.1 to 2.6; p=0.02). A total of 19 (31%) patients experienced a major AFD-related event. They were predominantly men (17 of 19, 89%), older (45±11 vs 32±9 years) with baseline LVH (12 of 19, 63%), and 10 of 19 (52%) presented with LVMI progression. CONCLUSIONS: Over a median follow-up of >10 years under ERT, 36% of the patients still had LVMI cardiac progression, and 32%, predominantly older men, experienced major AFD-related events. LVH at treatment initiation was a strong predictor of LVMI progression and adverse events on ERT.
Asunto(s)
Progresión de la Enfermedad , Terapia de Reemplazo Enzimático , Enfermedad de Fabry , Hipertrofia Ventricular Izquierda , Humanos , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/complicaciones , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Masculino , Terapia de Reemplazo Enzimático/métodos , Adulto , Femenino , Persona de Mediana Edad , Adulto Joven , Ecocardiografía , Suiza/epidemiología , Factores de Tiempo , alfa-Galactosidasa/uso terapéutico , Estudios de Seguimiento , Resultado del Tratamiento , Factores de RiesgoRESUMEN
INTRODUCTION: Fabry's disease (FD) is a genetic lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) lost/reduced activity. We aim to systematically assess the safety and efficacy of Migalastat, an oral pharmacological chaperone, that has been approved for the treatment of FD in patients with amenable mutations. METHODS: We conducted literature search following the PRISMA guidelines in major databases up to 4 February 2024, for studies that assessed the clinical outcomes of migalastat in patients with FD. The New Castle Ottawa Scale was used to evaluate the quality of the included studies. RESULTS: A total of 2141 records were identified through database searches and register searches, amongst which 26 records were screened, and 12 of these were excluded. The remaining 14 reports were sought for retrieval. The 12 retrieved articles were assessed for eligibility and their quality was assessed after their inclusion. Amongst the included studies, 5 were of high quality, 6 were of medium quality, and 1 was of low quality. CONCLUSION: Migalastat showed varied effects on enzyme activity and substrate levels, with gender-specific differences noted in GL-3 substrate activity and eGFR. Overall, it improved cardiac and renal outcomes similarly to enzyme replacement therapy, with a comparable safety profile.
Asunto(s)
1-Desoxinojirimicina , Enfermedad de Fabry , alfa-Galactosidasa , Enfermedad de Fabry/tratamiento farmacológico , Humanos , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapéutico , 1-Desoxinojirimicina/efectos adversos , alfa-Galactosidasa/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/administración & dosificación , Resultado del TratamientoRESUMEN
The clinical use of agalsidase alfa as enzyme replacement therapy (ERT) for Fabry disease (FD) has spread since 2001, and a large body of evidence of its effectiveness has been collected. This review presents the clinical and laboratory results achieved with agalsidase alfa, which has been published in the literature. Agalsidase alfa infusion slows down or stops the progression of renal damage, expressed by reduction or stabilization of the annual decline of the glomerular filtration rate; yearly decrease of glomerular filtration rate (slope) sometimes is reduced until its stabilization. ERT prevents or reduces the occurrence of hypertrophic cardiomyopathy or slows the increase over time if it is already present. Moreover, regarding neurological manifestations, ERT improves neuropathic pain and quality of life, and recent data indicated that it may also prevent the burden of cerebrovascular disease. In addition to ERT's clinical benefits, crucial topics like the most appropriate time to start therapy and the role of anti-drug antibodies (ADA) are analyzed. Treatment with agalsidase alfa in patients with FD substantially improves their outcomes and enhances their quality of life in patients with FD.
Asunto(s)
Enfermedad de Fabry , Isoenzimas , Humanos , Enfermedad de Fabry/tratamiento farmacológico , Terapia de Reemplazo Enzimático/métodos , Calidad de Vida , Resultado del Tratamiento , alfa-Galactosidasa/uso terapéutico , Anticuerpos , Proteínas Recombinantes/uso terapéuticoAsunto(s)
Enfermedad de Fabry , Isoenzimas , Proteínas Recombinantes , alfa-Galactosidasa , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/genética , Enfermedad de Fabry/inmunología , Humanos , alfa-Galactosidasa/uso terapéutico , alfa-Galactosidasa/inmunología , alfa-Galactosidasa/genética , Isoenzimas/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Terapia de Reemplazo Enzimático , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a heterogeneous clinical presentation. Patients with FD may exhibit early signs/symptoms including neuropathic pain, gastrointestinal complaints, and dermatologic manifestations. FD may ultimately progress to renal, neurologic, and cardiac dysfunction. Current treatments for FD have significantly improved the management and outcomes for patients with FD, but important clinical and convenience limitations still exist. METHODS: To illuminate the impact of FD on daily life from the patient's perspective, we asked adult patients (≥ 18 years old) with FD in the United States and Canada to complete a 33-question online survey to assess patient-reported disease severity, management, and treatment outcomes. RESULTS: A total of 280 respondents with FD completed the survey; they had a mean age of 47 years, and 68% (191/280) were women. Most were currently receiving FD treatment (84%, 234/280) with enzyme replacement therapy (ERT) (89%, 208/234) or chaperone therapy (11%, 26/234). Common symptoms included low energy/fatigue (72%, 201/280), tingling (62%, 174/280) or pain in the hands/feet (60%, 168/280), ringing in ears/hearing loss (54%, 151/280), general body pains/pain crises (51%, 143/280), and abdominal/stomach pain (50%, 140/280). More than half (51%, 144/280) of respondents reported their symptoms as bothersome (38%, 106/280) or difficult to control (14%, 38/280). Temporary symptom worsening between infusions was reported by about half of respondents: 51% (108/211) currently receiving ERT and 48% (14/29) previously receiving ERT. Only 48% (59/122) of respondents reported their symptom worsening to their physician. Of those who reported it, 41% (24/59) said that their physician prescribed medication to manage their symptoms or changed their treatment regimen. CONCLUSIONS: Our analysis highlights the gap between current standard-of-care in disease monitoring and patient perception of disease progression among patients with FD. This information may be helpful for healthcare providers and drug developers seeking to improve the care of patients with FD by addressing unmet needs of high relevance.
Asunto(s)
Enfermedad de Fabry , Femenino , Humanos , Masculino , Persona de Mediana Edad , alfa-Galactosidasa/uso terapéutico , Estudios Transversales , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/diagnóstico , Dolor , Medición de Resultados Informados por el Paciente , Encuestas y Cuestionarios , Brote de los Síntomas , Pueblos de América del Norte , Canadá , Estados UnidosRESUMEN
BACKGROUND: The limited ability of enzyme replacement therapy (ERT) in removing globotriaosylceramide from cardiomyocytes is recognized for advanced Fabry disease cardiomyopathy (FDCM). Prehypertrophic FDCM is believed to be cured or stabilized by ERT. However, no pathologic confirmation is available. We report here on the long-term clinical-pathologic impact of ERT on prehypertrophic FDCM. METHODS AND RESULTS: Fifteen patients with Fabry disease with left ventricular maximal wall thickness ≤10.5 mm at cardiac magnetic resonance required endomyocardial biopsy because of angina and ventricular arrhythmias. Endomyocardial biopsy showed coronary small-vessel disease in the angina cohort, and vacuoles in smooth muscle cells and cardiomyocytes ≈20% of the cell surface containing myelin bodies at electron microscopy. Patients received α-agalsidase in 8 cases, and ß-agalsidase in 7 cases. Both groups experienced symptom improvement except 1 patients treated with α-agalsidase and 1 treated with ß-agalsidase. After ERT administration ranging from 4 to 20 years, all patients had control cardiac magnetic resonance and left ventricular endomyocardial biopsy because of persistence of symptoms or patient inquiry on disease resolution. In 13 asymptomatic patients with FDCM, left ventricular maximal wall thickness and left ventricular mass, cardiomyocyte diameter, vacuole surface/cell surface ratio, and vessels remained unchanged or minimally increased (left ventricular mass increased by <2%) even after 20 years of observation, and storage material was still present at electron microscopy. In 2 symptomatic patients, FDCM progressed, with larger and more engulfed by globotriaosylceramide myocytes being associated with myocardial virus-negative lymphocytic inflammation. CONCLUSIONS: ERT stabilizes storage deposits and myocyte dimensions in 87% of patients with prehypertrophic FDCM. Globotriaosylceramide is never completely removed even after long-term treatment. Immune-mediated myocardial inflammation can overlap, limiting ERT activity.
Asunto(s)
Cardiomiopatías , Enfermedad de Fabry , Cardiopatías , Miocarditis , Trihexosilceramidas , Humanos , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/patología , alfa-Galactosidasa/uso terapéutico , alfa-Galactosidasa/metabolismo , Terapia de Reemplazo Enzimático/métodos , Cardiomiopatías/etiología , Cardiomiopatías/complicaciones , Miocitos Cardíacos/metabolismo , Miocarditis/inducido químicamente , Angina de Pecho/complicaciones , Cardiopatías/complicaciones , Inflamación/metabolismoAsunto(s)
Enfermedad de Fabry , Isoenzimas , alfa-Galactosidasa , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/genética , Enfermedad de Fabry/inmunología , Humanos , alfa-Galactosidasa/uso terapéutico , alfa-Galactosidasa/inmunología , alfa-Galactosidasa/genética , Isoenzimas/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Terapia de Reemplazo Enzimático , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
Fabry disease (FD) is an uncommon, X-linked, lysosomal storage disease that causes defects in the glycosphingolipid metabolic pathway due to deficient or absent lysosomal α-galactosidase (α-Gal A) activity. This leads to the accumulation of globotriaosylceramide (GL-3) within lysosomes in a wide range of cells, including endothelial, cardiac, renal, and corneal cells, and consequently, the progressive appearance of clinical symptoms in target organs. Enzyme replacement therapy (ERT), which involves the exogenous supplementation of α-Gal A enzyme and has been successfully administered for treating FD.Here, we report a case of a 37-year-old male with complaints of recurrent proteinuria and ventricular septal thickening. A renal biopsy revealed vacuolization and foamy changes in podocytes, and the presence of myelin-like bodies and zebra bodies. The white blood cell α-Gal A activity was very low, while the Lyso-GL-3 level was high. Additionally, genetic analysis revealed a gene variant c.902G > A p. Arg301Gln. The patient was diagnosed with FD, and subsequently received intravenous ERT with a dose of Agalsidase α (0.2 mg/kg, 17.5 mg every 2 weeks). Currently, the values of proteinuria and ventricular septum thickness remain stable during the 6-month follow-up. Initiating ERT at an early age can effectively decrease the deposition of GL-3, attenuate the progressive clinical manifestations of FD, and provide greater long-term benefits.
Asunto(s)
Enfermedad de Fabry , Masculino , Humanos , Adulto , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/genética , Terapia de Reemplazo Enzimático , alfa-Galactosidasa/genética , alfa-Galactosidasa/uso terapéutico , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Riñón/patología , Ventrículos Cardíacos/patologíaRESUMEN
Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A), an enzyme that hydrolyzes glycosphingolipids in lysosome. Accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in tissues, induces cellular dysfunction leading to multi-organ disorder. Gene therapy is a promising strategy that can overcome these problems, and virus vectors such as adeno-associated virus (AAV) have been used for study on gene therapy. We used human Gb3 synthetase-transgenic (TgG3S)/α-Gal A knockout (GLAko) mice. TgG3S/GLAko mice have elevated Gb3 accumulation in the major organs compared with GLAko mice, which have been widely used as a model for FD. At the age of 6 weeks, male TgG3S/GLAko were injected with 2 × 1012 vector genome AAV9 vectors containing human α-Gal A cDNA. Eight weeks after intravenous injection of AAV, α-Gal A enzymatic activity was elevated in the plasma, heart, and liver of TgG3S/GLAko mice to levels corresponding to 224%, 293%, and 105% of wild-type, respectively. Gb3 amount 8 weeks after AAV injection in the heart and liver of this group was successfully reduced to levels corresponding to 16% and 3% of untreated TgG3S/GLAko mice. Although the brain and kidney of AAV9-treated TgG3S/GLAko mice showed no significant increases in α-Gal A activity, Gb3 amount was smaller than untreated littermates (48% and 44%, respectively). In this study, systemic AAV administration did not show significant extension of the lifespan of TgG3S/GLAko mice compared with the untreated littermates. The timing of AAV injection, capsid choice, administration route, and injection volume may be important to achieve sufficient expression of α-Gal A in the whole body for the amelioration of lifespan.
Asunto(s)
Enfermedad de Fabry , Ratones , Animales , Masculino , Humanos , Lactante , Enfermedad de Fabry/genética , Enfermedad de Fabry/terapia , Dependovirus/genética , Dependovirus/metabolismo , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo , alfa-Galactosidasa/uso terapéutico , Ratones Noqueados , Glicoesfingolípidos/metabolismo , Glicoesfingolípidos/uso terapéutico , Administración Intravenosa , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Fabry disease is a rare progressive X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A. Agalsidase beta is a recombinant enzyme replacement therapy authorized in Europe at a standard dose of 1.0 mg/kg intravenously every other week at an initial infusion rate of ≤ 0.25 mg/min until patient tolerance is established, after which the infusion rate may be increased gradually. However, specific practical guidance regarding the progressive reduction in infusion time is lacking. This study investigated a new and specific protocol for reducing agalsidase beta infusion time in which a stable dosage of 15 mg/h is infused for the first four months, and the infusion rate is increased progressively from 15 to 35 mg/h for the subsequent four infusions. The shortest infusion time is reached after six months and maintained thereafter. The incidence of infusion-associated reactions (IARs) and the development of anti-drug antibodies were analyzed, and the disease burden and the clinical evolution of the disease at 12 months were evaluated. RESULTS: Twenty-five of the 31 patients were naïve to enzyme or chaperone treatment at baseline and six patients had been switched from agalsidase alfa. The reduced infusion time protocol was well tolerated. Only one patient exhibited an IAR, with mild symptoms that resolved with low-dose steroids. Six patients globally seroconverted during treatment (4 with a classic phenotype and 2 with late-onset disease). All but three patients were seronegative at month 12. All patients were stable at the study's end (FAbry STabilization indEX value < 20%); reducing infusion time did not negatively impact clinical outcomes in any patient. The perceived medical assessment showed that the quality of life of all patients improved. CONCLUSIONS: The study demonstrates that reducing agalsidase beta infusion time is possible and safe from both an immunogenic and clinical point of view. The use of a low infusion rate in the first months when the probability of onset of the development of antibodies is higher contributed to very limited seroconversion to antibody-positive status.
Asunto(s)
Enfermedad de Fabry , Isoenzimas , alfa-Galactosidasa , Humanos , alfa-Galactosidasa/uso terapéutico , Calidad de Vida , Formación de Anticuerpos , Incidencia , Resultado del Tratamiento , Anticuerpos/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Terapia de Reemplazo Enzimático/métodos , ItaliaRESUMEN
Fabry disease (FD) is a multisystem lysosomal storage disorder induced by genetic variants in the alpha-galactosidase A (αGalA) gene. Some FD patients have GLA variants with a reduction in overall αGalA enzymatic activity due to mutated proteins with reduced stability, caused by protein misfolding and premature degradation, but the αGalA catalytic activity remains conserved ("amenable" genetic variants). To correct this misfolding and to prevent premature degradation, migalastat, a small iminosugar molecule was developed. We report the clinical characteristics of FD "amenable" cohort patients from Argentina, prior to starting treatment with migalastat. Seventeen Fabry adult patients were recruited from 13 Argentinian Centers; 8 males (47.1%) and 9 females (52.9%) were included. All genotypes included were missense-type "amenables" mutations. Some classic FD typical early manifestations were more frequent in patients with "classic" versus "late-onset" FD phenotype (pain, p=0.002; cornea verticillata, p=0.019). There was a statistically significant difference in estimated glomerular filtration rate in the "classic" versus "late-onset" phenotype (p=0.026) but no difference between genders (p=0.695). Left ventricular mass was similar between genders (p=0.145) and phenotypes (p=0.303). Cardiovascular risk factors were present among "late-onset" females (obesity 50% and smoke 25%). In patients who started "de novo" migalastat, the main indications were (i) heart disease, (ii) kidney damage, and (iii) pain, while in "switched from prior enzyme replacement therapy" patients, the most frequent indication was "patient decision;" this coincides with publications by other authors.
Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Enfermedad de Fabry , Adulto , Humanos , Masculino , Femenino , Enfermedad de Fabry/epidemiología , Enfermedad de Fabry/genética , Enfermedad de Fabry/tratamiento farmacológico , 1-Desoxinojirimicina/uso terapéutico , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo , alfa-Galactosidasa/uso terapéutico , Dolor/inducido químicamente , Dolor/tratamiento farmacológicoRESUMEN
Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting both males and females caused by genetic abnormalities in the gene encoding the enzyme α-galactosidase A. FD-affected patients represent a highly variable clinical course with first symptoms already appearing in young age. The disease causes a progressive multiple organ dysfunction affecting mostly the heart, kidneys and nervous system, eventually leading to premature death. Disease-specific management of FD includes enzyme replacement therapy with agalsidase α and ß or pharmacological oral chaperone migalastat. Migalastat is a low-molecular-mass iminosugar, that reversibly binds to active site of amenable enzyme variants, stabilizing their molecular structure and improving trafficking to the lysosome. Migalastat was approved in the EU in 2016 and is an effective therapy in the estimated 35-50% of all patients with FD with amenable GLA gene variants. This position statement is the first comprehensive review in Central and Eastern Europe of the current role of migalastat in the treatment of FD. The statement provides an overview of the pharmacology of migalastat and summarizes the current evidence from the clinical trial program regarding the safety and efficacy of the drug and its effects on organs typically involved in FD. The position paper also includes a practical guide for clinicians on the optimal selection of patients with FD who will benefit from migalastat treatment, recommendations on the optimal selection of diagnostic tests and the use of tools to identify patients with amenable GLA mutations. Areas for future migalastat clinical research have also been identified.
Asunto(s)
Enfermedad de Fabry , Adulto , Masculino , Femenino , Humanos , Enfermedad de Fabry/genética , alfa-Galactosidasa/genética , alfa-Galactosidasa/uso terapéutico , alfa-Galactosidasa/metabolismo , 1-Desoxinojirimicina/uso terapéutico , Mutación , Riñón/metabolismoRESUMEN
BACKGROUND: Fabry disease is a rare inherited disorder resulting from deficient α-galactosidase A enzyme activity. Common disease manifestations are sweating abnormalities, neuropathic pain, gastrointestinal symptoms and fatigue. Challenges are faced by health care professionals in evaluating symptom burden in the current clinical setting, and the demand for alternative methods for monitoring disease-specific symptoms has seen an acceleration in recent years. Smartphone technologies offer the potential for continuity of care and surveillance. As a part of a quality improvement project, a disease specific app was developed in collaboration with a software company (Health Touch Ltd) and made available for patient use in May 2018. The Fabry mobile app records five categories: pain, gastrointestinal symptoms, sweating, activity levels, medications. Fabry disease patients with gastrointestinal and pain symptoms attending the Lysosomal Storage Disorders Unit of the Royal Free London NHS Foundation Trust were reviewed to assess eligibility and invited to download the app for recording their symptoms (activity, sweating, pain and gastrointestinal) and medications. Patient-generated data were transmitted to a secure website for clinicians to review. RESULTS: One-hundred and thirty-nine symptomatic Fabry disease patients who had a smartphone (iPhone or android) were invited to download the app. Sixty-seven patients (26 males and 41 females; median age, 49 years [range, 20-81]) downloaded and tracked the Fabry App at least once. The median frequency of use per patient was 6 (range, 1-629). Pain in the hands and abdominal pain were significantly higher (p = 0.009 and p = 0.007, respectively) in patients with classic phenotype compared with patients with non-classic phenotypes. CONCLUSIONS: We demonstrated the feasibility and acceptability of a smartphone app to facilitate the remote assessment and monitoring of Fabry disease symptom burden on a daily/weekly basis, as an alternative to the current standard of care that requires patients to recall their symptoms during 6 to 12 monthly annual clinic visits. Patients who were more likely to use the app had greater disease burden. This innovation has the potential to assess disease progression, early therapeutic intervention, thereby decreasing the burden of morbidity and mortality among Fabry patients, and to record long-term effects of Fabry-specific therapies.
Asunto(s)
Enfermedad de Fabry , Enfermedades Gastrointestinales , Aplicaciones Móviles , Neuralgia , Masculino , Femenino , Humanos , Persona de Mediana Edad , Enfermedad de Fabry/tratamiento farmacológico , alfa-Galactosidasa/uso terapéuticoRESUMEN
Fabry disease is an X-linked inheritable lysosomal storage disease caused by various mutations of the galactosidase α gene resulting in α-galactosidase deficiency. Chronic kidney disease (CKD) is one of the most significant consequences of Fabry disease, with risk of end-stage kidney disease (ESKD) in this population. Like for other patients with ESKD, kidney transplant is the optimal treatment for Fabry disease patients with ESKD. However, enzyme replacement therapy and newer Fabry disease treatments remain important to mitigate other end organ damage such as cardiomyopathy post transplantation. This review is a primer on Fabry disease, which examines the outcomes of disease in the context of kidney transplant prior to, and during, the enzyme replacement treatment era, medical treatment of kidney transplant recipients with Fabry disease, and progress in screening studies.