ABSTRACT
Abstract There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.
Resumo As doenças renais genéticas raras compreendem mais de 150 desordens. Elas podem ser classificadas segundo achados diagnósticos como (i) distúrbios do crescimento e estrutura, (ii) doenças glomerulares, (iii) tubulares e (iv) metabólicas. Nos últimos anos, houve uma mudança de paradigma nesse campo. Os testes moleculares tornaram-se mais acessíveis, nossa compreensão sobre os mecanismos fisiopatológicos subjacentes a essas doenças evoluiu e novas estratégias terapêuticas foram propostas. Portanto, o papel do nefrologista mudou progressivamente de mero espectador a participante ativo, parte de uma equipe multidisciplinar, no diagnóstico e tratamento desses distúrbios. O presente artigo oferece um panorama geral dos recentes avanços a respeito dos distúrbios renais hereditários raros, discutindo aspectos genéticos, manifestações clínicas e abordagens diagnósticas e terapêuticas de alguns desses distúrbios, mais especificamente a glomeruloesclerose segmentar e focal familiar, complexo da esclerose tuberosa, nefropatia de Fabry e doença relacionada ao MYH9.
Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Adult , Genetic Diseases, Inborn/genetics , Kidney/physiopathology , Kidney Diseases/congenital , Kidney Diseases/diagnosis , Thrombocytopenia/congenital , Thrombocytopenia/diagnosis , Thrombocytopenia/therapy , Tuberous Sclerosis/therapy , Genetic Testing/methods , Fabry Disease/diagnosis , Fabry Disease/genetics , Fabry Disease/therapy , Interdisciplinary Communication , Glomerular Filtration Rate/physiology , Hearing Loss, Sensorineural/diagnosis , Genetic Diseases, Inborn/diagnosis , Kidney Tubules/pathology , Metabolic Diseases/pathology , Nephrology/standardsABSTRACT
SUMMARY Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene. Its prevalence is estimated between 1:8,454 and 1:117,000 among males and is probably underdiagnosed. Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system, and may lead to different clinical scenarios. The onset of symptoms occurs during childhood, with acroparesthesia, heat intolerance, and gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and neuropathic pain. Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency. The latter being the main cause of death in FD. The gold standard for diagnosis is the genetic analysis in search of mutation, in addition to family history. In homozygous patients, the enzyme activity can also be used. Once the diagnosis is confirmed, the patient and their family should receive genetic counseling. The treatment, in turn, currently focuses mainly on replacing the enzyme that is absent or deficient by means of enzyme replacement therapy, with the purpose of avoiding or removing deposits of Gb3. Chaperones can also be used for the treatment of some cases. It is considered that the specific treatment should be initiated as soon as a diagnosis is obtained, which can change the prognosis of the disease.
Subject(s)
Humans , Male , Female , Fabry Disease/pathology , Renal Insufficiency, Chronic/pathology , Enzyme Replacement Therapy , Kidney/pathology , Trihexosylceramides , Fabry Disease/complications , Fabry Disease/genetics , Fabry Disease/therapy , Renal Insufficiency, Chronic/etiologyABSTRACT
INTRODUCTION: Fabry disease (FD) also known as Anderson Fabry disease is a rare disorder linked to the X chromosome, which produces mutations in the coding of the GLA gene involved in the production of the enzyme ï¡-galactosidase A, whose complete or partial deficiency leads to the intracellular accumulation of globotriaosylceramide and glycosphingolipids. CLINICAL CASE: We present the case of a 39 year old female patient admitted to hospital with a diagnosis of terminal chronic kidney disease of 8 years of evolution as a possible cause of nephropathy, Fabry disease diagnosed in a patient, after detailed studies, kidney transplantation is considered for improvement of your lifestyle. DISCUSSION: Patients with Fabry disease should be considered as high risk surgical and anesthetic should have a strict assessment and evaluation of cardiovascular and respiratory function, to anticipate the complications associated with reperfusion of the transplanted organ. CONCLUSION: The use of balanced or intravenous modality has been described among the anesthetic possibilities without reaching a consensus so far, however the two modalities can be used and their analgesic management can be performed with plexus blocks or regional anesthesia.
INTRODUCCIÓN: La enfermedad de Fabry (FD) también conocida como enfermedad de Anderson Fabry es un trastorno raro ligado al cromosoma X, que produce mutaciones en la codificación del gen GLA partícipe en la producción de la enzima α-galactosidasa A, cuya deficiencia completa o parcial conduce a la acumulación intracelular de globotriaosilceramida y glicosfingolípidos. CASO CLÍNICO: Se presenta el caso de una paciente femenina de 39 años de edad ingresada a hospitalización con diagnóstico de enfermedad renal crónica terminal de 8 años de evolución como posible causa de nefropatía, enfermedad de Fabry diagnosticada en paciente, tras estudios detallado se considera trasplante renal para mejora de su estilo de vida. DISCUSIÓN: Los pacientes con enfermedad de Fabry deben ser considerados como de alto riesgo quirúrgico y anestésico, deben contar con una estricta valoración y evaluación sobre la función cardiovascular y respiratoria, para así preveer las complicaciones asociadas a la reperfusión del órgano trasplantado. CONCLUSIÓN: Se han descrito entre las posibilidades anestésicas el uso de modalidad balanceada o intravenosa sin llegar aún a un consenso hasta el momento, sin embargo, las dos modalidades pueden ser utilizadas y su manejo analgésico se puede realizar con bloqueos del plexo o anestesia regional.
Subject(s)
Humans , Female , Adult , Kidney Transplantation/methods , Fabry Disease/complications , Renal Insufficiency, Chronic/therapy , Anesthesia/methods , Fabry Disease/therapy , Anesthetics/administration & dosageABSTRACT
Resumo Todas as células do corpo humano apresentam acúmulo de globotriaosilceramida (Gb3) na doença de Fabry devido à mutação que ocorre no gene da enzima α-galactosidase A. Trata-se de uma doença ligada ao sexo. Os achados clínicos são: angioqueratomas cutâneos; acroparestesias e acidentes vasculares encefálicos precoces; sudorese diminuída e intolerância ao calor; alterações oculares; hipertrofia miocárdica, arritmias; alterações gastrointestinais e renais. O envolvimento renal ocorre devido ao acúmulo do Gb3 em todos os tipos de células renais. Portanto, os pacientes podem apresentar distúrbios das funções glomerulares e tubulares. Os podócitos são particularmente acometidos, com apagamento dos pedicélios e desenvolvimento de proteinúria. O diagnóstico é feito por meio da detecção de reduzida atividade plasmática ou leucocitária da α-galactosidase e pela detecção da mutação do gene da α-galactosidase. O tratamento com reposição enzimática contribui para o retardo da progressão da doença renal, principalmente se instituído precocemente.
Abstract Every cell in the human body has globotriaosylceramide accumulation (Gb3) in Fabry disease due to the mutation in gene of the enzyme α-galactosidase A. It is a disease linked to sex. The main clinical features are: cutaneous angiokeratomas; acroparestesias and early strokes; decreased sweating and heat intolerance; ocular changes; myocardial hypertrophy, arrhythmias; gastrointestinal disorders and renal involvement. Renal involvement occurs due to Gb3 accumulation in all types of renal cells. Therefore, patients may present glomerular and tubular function disorders. Podocytes are particularly affected, with pedicels effacement and development of proteinuria. The diagnosis is made by detection of reduced plasma or leukocyte α-galactosidase activity and genetic study for detecting the α-galactosidase gene mutation. Treatment with enzyme replacement contributes to delay the progression of kidney disease, especially if initiated early.
Subject(s)
Humans , Fabry Disease/complications , Kidney Diseases/etiology , Biopsy , Fabry Disease/diagnosis , Fabry Disease/therapy , Kidney Diseases/pathologyABSTRACT
La enfermedad de Fabry es una enfermedad rara ligada al X consecuencia de la deficiencia de α-galactosidasa A lisosomal, lo que genera un depósito excesivo de glicoesfingolípidos, predominantemente globotriaosilceramida (Gl3) y mortalidad de causa renal cardíaca y neurológica. El tratamiento actual consiste en la terapia de reemplazo enzimático, lo que intenta reemplazar por vía intravenosa la enzima deficiente. Existen en el mercado europeo y latinoamericano dos formulaciones de agalsidasa: agalsidasa alfa y agalsidasa beta, lo que permite al médico elegir el tratamiento. Sin embargo, la Food and Drug Administration en Estados Unidos rechazó aprobar la agalsidasa alfa. La diferencia fundamental entre agalsidasa alfa y agalsidasa beta es la dosis autorizada: 0,2 mg/kg y 1 mg/kg cada dos semanas respectivamente. Durante años esta diferencia tan grande de dosis sorprendió a los clínicos. Sin embargo varios estudios recientes sugieren que hay un efecto dosis-respuesta y que para algunos pacientes la dosis de 0,2 mg/kg cada dos semanas puede ser insuficiente. Sin embargo, no existen herramientas que permitan predecir que pacientes van a necesitar una dosis más alta para detener o enlentecer la progresión de la enfermedad. En esta revisión resumimos el estado actual del conocimiento sobre el impacto Tratamiento en la enfermedad de Fabry de las diferentes dosis y su eficacia en tratamiento de la enfermedad de Fabry.
Fabry disease is a rare X-linked inherited disorder due to deficient or absent lysosomal α-galactosidase A activity, resulting in an excessive glycosphingolipid deposit, mainly globotriaosylceramide (gl3) and mortality due renal, cardiac and neurological cause. Current treatment available is enzyme replacement therapy, where the deficient enzyme is substituted. In Latinamerica and Europe two different formulations of agalsidase (alfa and beta) are available. Food and Drug Administration in United States did not approve agalsidasa Alfa. The main difference among these formulations is the licensed dose: 0.2 mg/kg every other week for Alfa and 1 mg/kg every other week for Beta. Recent studies suggest a dose-dependent response, making 0.2 mg/kg every other week not sufficient in some patients. However there are no tools to predict which patients need a higher dose for preventing or decreasing the disease progression. This review, summarize the current knowledge about the impact of different dose and its efficacy in Fabry disease.
Subject(s)
Male , Female , Humans , Dosage , Enzyme Activation , Fabry Disease , Fabry Disease/therapyABSTRACT
La enfermedad de Fabry en un trastorno lisosomal por ausencia o deficiencia de la enzima Alfa galactosidasa A que genera un acúmulo patológico de glicoesfingolípidos principalmente en células endoteliales, musculares lisas de vasos sanguíneos y podocitos entre otras. La terapia de reemplazo enzimático es la única chance de tratamiento específico a la fecha. El creciente conocimiento de los mecanismos fisiopatológicos ha llevado a cambiar el manejo de la enfermedad y por sobretodo el momento de inicio del tratamiento. Actualmente el inicio en edades más tempranas parece ser una forma de evitar y en algunos casos revertir algunos de los signos y síntomas de la enfermedad de Fabry.
Fabry Disease is a lysosomal disorder due to the absence or deficiency of the Alpha galactosidase A enzyme that causes a pathological ac cumulation of glycosphingolipids mainly in the REVISIÓN endothelial cells, vascular smooth muscle cells and podocytes among others. Enzyme replacement therapy is the only option for a specific treatment at present. Increasing knowledge of the physiopathological mechanisms has changed the management of the disease and above all, when treatment should begin. At present, beginning treatment at an early age seems to be a way of preventing and in some cases reverting some of the signs and symptoms of Fabry disease.
Subject(s)
Fabry Disease/therapyABSTRACT
La enfermedad de Fabry es un trastorno de almacenamiento lisosomal hereditario ligado al cromosoma X, ocasionado por el déficit de la enzima alfa galactosidasa A. El conocimiento sobre esta patología, y en particular su manejo médico, ha progresado notablemente en la última década, incluyendo el desarrollo de su tratamiento específico. La presente guía fue desarrollada por profesionales médicos de diversas especialidades involucrados en la atención de pacientes con enfermedad de Fabry. La discusión y análisis de las evidencias científicas disponibles, sumado a la experiencia de cada uno de los participantes, ha permitido desarrollar los conceptos vertidos en esta guía con el objetivo de brindar una herramienta útil para todos los profesionales que asisten a pacientes con enfermedad de Fabry.
Fabry disease is an X-linked hereditary lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. Knowledge about this disease, and its medical management, has made remarkable progress in the last decade, including the development of its specific treatment. This guide was developed by medical professionals from various specialties involved in the care of patients with Fabry disease. The discussion and analysis of the available scientific evidence, coupled with the experience of each of the participants, has allowed us to develop the concepts included in this guide in order to provide a useful tool for all professionals who care for patients with Fabry disease.
Subject(s)
Female , Humans , Male , Fabry Disease/diagnosis , Fabry Disease/therapy , Age Factors , Enzyme Replacement Therapy , Fabry Disease/physiopathology , Time FactorsABSTRACT
Fabry's disease is an X-linked recessive inborn error of metabolism of glycosphingolipids, caused by the deficiency of the lisosomal enzyme alpha-galactosidase. It is a rare disease with an estimated incidence rate of approximately 1:80.000 to 1:117,000 births in the general population. Recently, the growing knowledge about this disease has permitted the development of enzyme replacement therapy, which has modified the prognosis and quality of life of these patients. In Chile, the real incidence is unknown, but the increase in the number of patients diagnosed during the last five years, mainly in the north of the country. This guide was prepared with the intention of establishing a consensus for the diagnosis, treatment and monitoring of the patients with Fabry disease based on the present available scientific evidence.
La enfermedad de Fabry es un error innato del catabolismo de los glucoesfingolipidos, de herencia recesiva ligada al cromosoma X, causado por la deficiencia de la enzima lisosomal alfa-galactosidasa A (alfa-gal A). Es un defecto poco frecuente, con una incidencia estimada de 1:80.000 a 1:117.000, entre la población general. Recientemente, el creciente conocimiento acerca de esta enfermedad, ha permitido el desarrollo de la terapia de reemplazo enzimático, la cual ha modificado el pronóstico y calidad de vida de los pacientes. En Chile, se desconoce la incidencia real, pero el aumento del número de pacientes diagnosticados durante los últimos cinco años, principalmente en la zona norte del país, ha generado un mayor interés por esta enfermedad. Esta guía fue elaborada con la intención de establecer un consenso para el diagnóstico, tratamiento y seguimiento de los pacientes con enfermedad de Fabry, basado en la evidencia científica, actualmente disponible.
Subject(s)
Humans , Fabry Disease/diagnosis , Fabry Disease/therapy , Chile , Consensus , Diagnosis, Differential , Enzyme Replacement Therapy , Fabry Disease/complications , Genetic Counseling , Isoenzymes/administration & dosage , alpha-Galactosidase/administration & dosageABSTRACT
Objetivo: Apresentar os dois primeiros casos da Doença de Fabry do Rio de Janeiro, tratados com a Agalsidase Beta (Alfa Gal Humana Recombinante-Fabrazime). Local: Clínica Santa Helena (Hospital Auxiliar de Ensino da Faculdade de Medicina de Campos). Resultados: Pacientes com Doença de Fabry iniciaram tratamento com a enzima recombinanate (Agalsidase Beta), e apresentaram reversão de alguns sintomas após seis meses. Conclusão: O uso da Agalsidase Beta parece promissor na reversão de alguns sintomas (dor e parestesia dos membros inferiores) da doença de Fabry.