Eficácia e segurança da alfa-agalsidase e a beta-agalsidase para intervenção na doença de Fabry: revisão rápida / Effectiveness and safety of agalsidase alfa and agalsidase beta for intervention in fabry disease: rapid review

Tecnologia: Alfa-agalsidase e/ou beta-agalsidase, comparada aos cuidados paliativos e ao tratamento sintomático associado aos órgãos alvos da doença de Fabry. Indicação: Manejo e intervenção aos desfechos clínicos em pacientes com a doença de Fabry. Pergunta: A intervenção por alfa-agalsidase e/ou beta-agalsidase é mais eficaz e segura que o manejo para o tratamento de sintomas ou paliativo aos desfechos clínicos esperados para a doença de Fabry? Métodos: Estudo de revisão sistemática rápida. A base consultada foi a Medline/Pubmed por meio de estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews version 2). Resultados: Foram selecionadas 3 revisões sistemáticas, que atendiam aos critérios de inclusão. Conclusão: A intervenção com alfa-agalsidase e/ou beta-agalsidase promove redução para acúmulo de globotriaosilceramida; no entanto a redução é dependente do período de intervenção e concentração do fármaco, assim como o tecido avaliado e o tempo de sinais clínicos da doença. Há evidências de melhora na função renal, dor, desconfortos gastrointestinais e qualidade de vida. É importante considerar a heterogeneidade para as diferentes características dos grupos afetados, como idade, sexo e estágio da doença. No entanto, a compreensão consistente da relação tratamento e os desfechos são afetados pela baixa frequência de pessoas atingidas, e isso diminui o poder para inferências entre os diferentes estudos, reportando para as limitações da geração de protocolos de intervenção mais robustos e assertivos. Portanto, há necessidade de se seguir com novas avaliações, sobretudo para os estudos clínicos aleatorizados

Technology: Alphagalsity and/or beta-agalsidase compared to palliative care and symptomatic treatment associated with target organs in Fabry disease. Indication: Management and intervention to clinical outcomes in patients with Fabry disease. Question: Is alfagalsidase and/or beta-agalsidase intervention more effective and safer than management to treat symptoms or palliate expected clinical outcomes for Fabry disease? Methods: Rapid systematic review. Medline/Pubmed was consulted using predefined search strategies. The methodological quality of systematic reviews was assessed using the AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews version 2) tool. Results: Three systematic reviews were selected that met the inclusion criteria. Conclusion: Intervention with alfagalsidase and/or beta-agalsidase promotes a reduction in the accumulation of globotriaosylceramide; however, the reduction is dependent on the period of intervention and concentration of the drug, as well as the evaluated tissue and the time of clinical signs of the disease. There is evidence for improvements in kidney function, pain, gastrointestinal discomfort and quality of life. It is important to consider heterogeneity for different characteristics of affected groups, such as age, sex and disease stage; however, the consistent understanding of the relationship between treatment and outcomes is affected by the low frequency of people affected, and this reduces the power for inferences between different studies, referring to the limitations of generating more robust and assertive intervention protocols. There is therefore a need to continue with new assessments, especially for randomized clinical studies

Reporte de caso: enfermedad de Fabry en un adulto con enfermedad renal crónica y síntomas sistémicos característicos / A case report: Fabry disease in an adult with chronic kidney disease and characteristic systemic symptoms / Relato de um caso: doença de Fabry em um adulto com doença renal crônica e sintomas sistémicos característicos

Se presenta el caso de un paciente de sexo masculino, de 62 años, con antecedentes familiares de cardiopatía y enfermedad renal, y antecedentes personales de enfermedad renal crónica severa, por la que recibió trasplante renal. Es enviado a consulta cardiológica por dolores torácicos atípicos y episodios de hipotensión sintomática, se constata en el ecocardiograma: hipertrofia ventricular izquierda concéntrica y deformación miocárdica longitudinal del ventrículo izquierdo patológica. La resonancia magnética cardíaca encuentra un patrón de realce tardío sugestivo de enfermedad de Fabry, diagnóstico que se confirma con dosificación enzimática y estudio genético. Recibe tratamiento específico con una buena respuesta inicial. Esta es una enfermedad sistémica metabólica congénita en la que el diagnóstico y el tratamiento específico se realiza en la edad adulta.

It is presented a 62-year-old male patient with a family history of heart and kidney disease, and a personal history of chronic kidney disease, for which he received a kidney transplant. He was sent to the cardiology department due to atypical chest pain and episodes of symptomatic hypotension. The echocardiogram revealed: concentric left ventricular hypertrophy and pathological longitudinal myocardial deformation of the left ventricle. Cardiac magnetic resonance finds a pattern of late enhancement suggestive of Fabry disease, a diagnosis that is confirmed with enzyme dosage and genetic study. He receives specific treatment with a good initial response. This is a congenital metabolic systemic disease in which the diagnosis and specific treatment is carried out in adulthood.

Se apresenta o caso de um paciente do sexo masculino, 62 anos, com histórico familiar de cardiopatia e doença renal e histórico pessoal de doença renal crônica grave, para o qual recebeu transplante de rim. Foi encaminhado ao serviço de cardiologia por dor torácica atípica e episódios de hipotensão sintomática. O ecocardiograma revelou: hipertrofia ventricular esquerda concêntrica e deformação miocárdica longitudinal patológica do ventrículo esquerdo. A ressonância magnética cardíaca encontra um padrão de realce tardio sugestivo de doença de Fabry, diagnóstico confirmado com dosagem enzimática e estudo genético. Recebe tratamento específico com boa resposta inicial. Tratase de uma doença sistêmica metabólica congênita em que o diagnóstico e o tratamento específico são realizados na idade adulta.

Enfermedad de Fabry: revisión para el cardiólogo clínico / Fabry disease: review for the clinical cardiologist / Doença de Fabry: revisão para o cardiologista clínico

La enfermedad de Fabry es una afección genética producida por un déficit total o parcial de la enzima alfagalactosidasa A implicada en el catabolismo de glicoesfingolípidos. Dicha alteración genera el depósito lisosomal del residuo globotriasilceramida (Gb-3) a nivel multitisular, a predominio de los sistemas renal, cardíaco, nervioso y cutáneo. Debido a su baja prevalencia y su variada presentación clínica representa un verdadero reto diagnóstico. La combinación de antecedentes familiares de cardiopatía y afección renal, diferentes grados de hipertrofia del ventrículo izquierdo, sumado a afecciones cutáneas, neurológicas y enfermedad renal progresiva, deben hacer plantear la posibilidad de una enfermedad de Fabry. El cardiólogo que estudia un paciente con hipertrofia ventricular es quien debe sospecharla, y debe hacer un diagnóstico diferencial con miocardiopatías hipertróficas, cardiopatía hipertensiva u otras miocardiopatías por depósitos. Los aportes diagnósticos de la resonancia magnética cardíaca han sido de suma importancia en los últimos años. Los estudios enzimáticos y genéticos, antes de muy difícil adquisición en nuestro medio, son factibles en la actualidad. Un diagnóstico temprano es clave para iniciar el tratamiento enzimático sustitutivo, evitar un daño más extenso e irreversible, e identificar los familiares afectados en fases iniciales.

Fabry disease is a genetic condition caused by a total or partial deficiency of the enzyme alphagalactosidase A involved in the catabolism of glycosphingolipids. This alteration generates the lysosomal deposit of the globotriasylceramide residue (Gb-3) at the multi-tissue level, predominantly in the kidneys, heart, nervous system and skin. Due to its low prevalence and its varied clinical presentation, it represents a true diagnostic challenge. The combination of family history of heart disease and kidney disease, different degrees of hypertrophy of the left ventricle, added to skin and neurological conditions and progressive kidney disease, should raise the possibility of Fabry disease. The cardiologist who studies a patient with ventricular hypertrophy is the one who should suspect it and make a differential diagnosis of hypertrophic cardiomyopathies, hypertensive heart disease or other cardiomyopathies due to deposits. Diagnostic complementation with a cardiac resonance study has been extremely important in recent years. Enzymatic and genetic studies, previously very difficult to acquire in our environment, are currently feasible. An early diagnosis is key to starting enzyme replacement therapy, avoiding more extensive and irreversible damage, and allowing affected family members to be identified in the early stages.

A doença de Fabry é uma condição genética causada por uma deficiência total ou parcial da enzima alfagalactosidase A envolvida no catabolismo de glicoesfingolipídeos. Essa alteração gera o depósito lisossomal do resíduo globotriasilceramida (Gb-3) em nível multitecidual, predominantemente nos rins, coração, sistema nervoso e pele. Devido à sua baixa prevalência e à sua apresentação clínica variada, representa um verdadeiro desafio diagnóstico. A combinação de história familiar de cardiopatia e doença renal, diferentes graus de hipertrofia do ventrículo esquerdo, somada a condições dermatológicas e neurológicas e doença renal progressiva, deve levantar a possibilidade de doença de Fabry. O cardiologista que estuda um paciente com hipertrofia ventricular é quem deve suspeitar e fazer um diagnóstico diferencial de cardiomiopatias hipertróficas, cardiopatias hipertensivas ou outras cardiomiopatias por depósitos. A complementação diagnóstica com estudo de ressonância cardíaca tem sido de extrema importância nos últimos anos. Estudos enzimáticos e genéticos, anteriormente muito difíceis de adquirir em nosso meio, são atualmente viáveis. O diagnóstico precoce é fundamental para iniciar a terapia de reposição enzimática, para evitar danos mais extensos e irreversíveis, e permite que os familiares afetados sejam identificados nos estágios iniciais.

Recommendations for the diagnosis and management of Fabry disease in pediatric patients: a document from the Rare Diseases Committee of the Brazilian Society of Nephrology (Comdora-SBN) / Recomendações para o diagnóstico e manejo de pacientes pediátricos com doença de Fabry: documento do comitê de doenças raras da Sociedade Brasileira de Nefrologia (Comdora-SBN)

Fabry disease (FD) is a genetic disease, with X-chromosome linked inheritance, due to variants in the GLA gene that encodes the α-galactosidase A (α-GAL) enzyme. The purpose of the present study was to create a consensus aiming to standardize the recommendations regarding the renal involvement of FD with guidelines on the diagnosis, screening, and treatment of pediatric patients. This consensus is an initiative of the Rare Diseases Committee (Comdora) of the Brazilian Society of Nephrology (SBN). Randomized controlled clinical studies and studies with real-life data added to the authors' experience were considered for this review. The result of this consensus was to help manage patient and physician expectations regarding treatment outcomes. Thus, this consensus document recommends the investigation of the pediatric family members of an index case, as well as cases with suggestive clinical signs. From the diagnosis, assess all possible FD impairments and grade through scales. From an extensive review of the literature including pediatric protocols and particularly evaluating pediatric cases from general studies, it can be concluded that the benefits of early treatment are great, especially in terms of neuropathic pain and renal impairment parameters and outweigh the possible adverse effects that were mainly manifested by infusion reactions.

A doença de Fabry (DF) é uma doença genética, com herança ligada ao cromossomo X, devido a variantes no gene GLA que codifica a enzima α-galactosidase A (α-GAL). O propósito do presente estudo foi criar um consenso objetivando padronizar as recomendações em relação ao acometimento renal da DF com orientações sobre o diagnóstico, rastreamento, e tratamento de pacientes pediátricos. Esse consenso é uma iniciativa do Comitê de Doenças Raras (Comdora) da Sociedade Brasileira de Nefrologia (SBN). Foram considerados para esta revisão estudos clínicos controlados randomizados e estudos com dados de vida real somados à experiência dos autores. O resultado desse consenso foi auxiliar no gerenciamento das expectativas de pacientes e médicos quanto aos resultados do tratamento. Assim, este documento de consenso recomenda a investigação dos familiares pediátricos de um caso índice, assim como de casos com clínica sugestiva. A partir do diagnóstico, avaliar todos os possíveis acometimentos da DF e graduar através de escalas. A partir de uma revisão extensa da literatura incluindo protocolos pediátricos e avaliando particularmente os casos pediátricos de estudos gerais, pode-se concluir que os benefícios do tratamento precoce são grandes, principalmente quanto aos parâmetros de dor neuropática e do acometimento renal, e suplantam os possíveis adversos que foram sobretudo manifestados por reações infusionais.

Caracterización neurofisiológica de la función de fibra pequeña en mujeres heterocigotas con enfermedad de Fabry / Neurophysiologic characterization of small fiber function in heterozigous women with Fabry disease

RESUMEN INTRODUCCIÓN: La enfermedad de Fabry (EF) es una enfermedad genética, causada por el déficit de la enzima alfa galactosidasa A (α-Gal A), lo que provoca la acumulación de glicoesfingolípidos en los tejidos. Sus manifestaciones clínicas son variables. Estudios en mujeres heterocigotas reportan la existencia de dolor neuropático como manifestación de neuropatía de fibra pequeña. OBJETIVO: Determinar la presencia de neuropatía de fibra pequeña en mujeres heterocigotas para la EF, mediante la prueba cuantitativa sensorial. MATERIALES Y MÉTODOS: Se evaluaron 33 mujeres heterocigotas para EF y 33 mujeres sanas, con características demográficas similares. A todas se les aplicó la prueba cuantitativa sensorial (Quantitative Sensory Testing por medio de la detección de umbrales de frío (Colà Detection Threshold), calor (Warm Detection Threshold), dolor inducido por calor (Heat-pain Detection Thresholds) y vibración (Vibratory Detection Threshold) en los miembros superior e inferior, utilizando un sistema asistido por computador versión IV (CASE IV, WR Medical Electronics Co., Stillwater, MN). Adicionalmente, al grupo de mujeres heterocigotas para EF, se le evaluó la percepción subjetiva de dolor neuropàtico mediante el cuestionario de síntomas sensitivos neuropáticos positivos (Positive Neuropathic Sensory Symptom). Los resultados de la prueba cuantitativa sensorial se compararon entre los grupos. También se estableció la correlación entre la prueba cuantitativa sensorial y los resultados del cuestionario de síntomas sensitivos neuropáticos positivos. RESULTADOS: Se encontró una diferencia estadísticamente significativa en las pruebas de vibración (p = 0,008), calor (p = 0,017) y dolor inducido por calor (p = 0,04) en el miembro inferior en las mujeres heterocigotas para EF, comparado con el grupo control. Se encontró una correlación inversa estadísticamente significativa entre la intensidad del dolor quemante y el dolor inducido por calor en el miembro inferior (p = 0,018, r = -0,48) y entre la intensidad del dolor al ser rozado o tocado y el dolor inducido por calor en el miembro inferior (p = 0,006, r = -0,49). CONCLUSIÓN: En las mujeres heterocigotas para EF, las pruebas objetivas para establecer la presencia de neuropatía de fibra pequeña son anormales en miembros inferiores y se correlacionan con los síntomas sensitivos.

SUMMARY INTRODUCTION: Fabry disease is a genetic condition caused by alpha-galactosidase A deficiency triggering glycosphingolipid accumulation in tissues. Clinical manifestations are variable. Studies in heterozigous females report the existence of neuropathic pain as manifestation of small fiber neuropathy. OBJECTIVE: To determine presence of small fiber neuropathy in heterozigous females with Fabry disease through Quantitative Sensory Testing (QST). MATERIALS AND METHODS: 33 heterozigous females with fabry disease and 33 healthy females with similar demographic characteristics were evaluated. QST was performed to every female evaluating Cold detection Threshold (CDT), Warm Detection Threshold (WDT), Heat-pain Detection Threshold (HPDT) and Vibratory Detection Threshold (VDT) in upper and lower limbs through Computer Assisted Sensory Examination software (CASE IV, WR Medical Electronics Co., Stillwater, MN). Subjective perception of neuropathic pain was measured through Positive Neuropathic Sensory Symptom questionnaire (P-NSS) in heterozigous females with Fabry disease. QST results were compared between groups. Correlations between QST and P-NSS were established. RESULTS: Statistically significant differences were observed in VDT (p= 0,008), WDT (p= 0,017) and HPDT (p= 0,04) in lower limbs of heterozigous females with Fabry disease compared with control group. Negative correlation was found among burning pain intensity and HPDT at lower limbs (p= 0,018, r= -0,48) and among pain intensity to light touch and HPDT in lower limbs (p= 0,006, r=-0,49). CONCLUSIONS: Objective tests to establish presence of small fiber neuropathy in heterozigous females with Fabry disease are abnormal at lower limbs and correlate with sensory symptoms.

Major cardiovascular adverse events in Fabry disease patients receiving agalsidase alfa / Eventos cardiovasculares mayores en pacientes con enfermedad de Fabry tratados con agalsidasa alfa

Abstract Cardiovascular mortality (CVM) has become the major contributor to overall Fabry disease (FD) mortality in the enzyme replacement therapy (ERT) era. Our objectives were to describe causes and potential predictors of mortality in FD adult patients in Argentina, and to assess risk of major adverse cardio vascular events (MACE) in the ERT era. We retrospectively studied 93 consecutive patients treated with alpha-galactosidase A (median follow up: 9.5 years from start of ERT). Mean age at ERT starting was 35±16.3 years. Prevalence of cardiomyopathy and renal disease reached 47% and 41%, respectively. Eleven subjects (11.8%, 95%CI: 5-18%) died during follow up (1.24/100 patient-years). Mean overall survival was 71 years (95%CI: 66-75 years). Seven cases were considered as CVM; main causes were sudden death and stroke. Risk of MACE was 14% (95%CI: 6.9-21.1%; 1.47 events/100 patient-years from start of ERT). All but 2 subjects had at least one comorbid cardiovascular risk factor; however, 86% of patients remained free of MACE during follow-up. CVM remained low and our study was underpowered for detection of predictors of mortality, but it is worth noting that age at diagnosis and ERT starting, left ventricular mass index and renal disease trended to correlate with CVM. Prevalence of hypertension, diabetes and dyslipidemia were lower in FD patients when compared to population level data. As in the Argentinean general population, CVM was the leading cause of mortality among this cohort of consecutive FD patients treated with agalsidase alfa.

Resumen La mortalidad cardiovascular (MCV) se ha convertido en el principal contribuyente a la mortalidad general por enfermedad de Fabry (EF) en la era de la terapia de reemplazo enzimático (TRE). Nuestros objetivos fueron describir las causas y posibles predictores de mortalidad en pacientes adultos con EF en la Argentina, y evaluar el riesgo de eventos cardiovasculares mayores (MACE) en la actual era de TRE. Se estudiaron 93 pacientes consecutivos tratados con agalsidasa-alfa por una mediana de 9.5 años tras iniciar TRE. La edad al inicio de TRE fue 35 ± 16.3 años. La prevalencia de cardiomiopatía y enfermedad renal alcanzó 47% y 41%, respectivamente. Once sujetos (11.8%; IC95%: 5-18%) murieron durante el seguimiento (1.24/100 pacientes/año). La supervivencia global fue 71 años (IC95%: 66-75 años). Siete casos fueron considerados como MCV; las principales causas fueron muerte súbita e ictus. El riesgo de MACE fue 14% (IC95%: 6.9-21.1%; 1.47 eventos/100 pacientes/año desde la ERT). Todos menos 2 sujetos tenían al menos un factor de riesgo cardiovascular, pero el 86% permaneció libre de MACE. Los eventos de MCV fueron escasos. El estudio tuvo reducido poder estadístico para detectar predictores de mortalidad, pero la edad al diagnóstico y al iniciar la TRE, índice de masa ventricular izquierda y enfermedad renal tendieron a correlacionarse con MCV. La prevalencia de hipertensión, diabetes y dislipidemia fue menor en comparación con la población general. Como ocurre con la población general en Argentina, los eventos cardiovasculares fueron la principal causa de muerte en esta cohorte de pacientes consecutivos con EF tratados con agalsidasa-alfa.

Cardiólogo encuentra un caso de enfermedad de Fabry / Cardiologist finds a case with Fabry disease

Resumen En este reporte se llama la atención de los colegas ante la posibilidad de encontrar un caso de enfermedad de Fabry entre múltiples pacientes que consultan. Se exponen las condiciones clínicas de estos pacientes que los hacen únicos, a causa de una enfermedad huérfana. Es posible que muchas de estas condiciones clínicas hayan pasado inadvertidas y al no tenerlas presentes no se tenga un grado de sospecha que lleve al diagnóstico.

Abstract In this report is call the attention of our colleagues the possibility of finding a case of Fabry's disease within the multitude of patients in our practice. It is expose the clinical conditions of these patients which make them unique, due to a disease denominated as orphan. It is possible that many of these clinical conditions have gone unnoticed and by not having them present prevent/impide us from having a high degree of suspicion which would lead to a diagnosis.

Screening of family members of chronic kidney disease patients with Fabry disease mutations: a very important and underrated task / Triagem de familiares de pacientes com doença renal crônica com mutação na doença de Fabry: uma tarefa muito importante e subestimada

ABSTRACT Introduction: Fabry disease is a chronic, progressive, and multi-system hereditary condition, related to an Xq22 mutation in X chromosome, which results in deficiency of alpha-galactosidase enzyme, hence reduced capacity of globotriaosylceramide degradation. Objectives: to evaluate the prevalence of Fabry disease (FD) mutations, as well as its signs and symptoms, among relatives of chronic kidney disease (CKD) patients diagnosed with FD during a previously conducted study, named "Clinical and epidemiological analysis of Fabry disease in dialysis centers in Brazil". Methods: a cross-sectional study was carried out, and data was collected by interviewing the relatives of patients enrolled in the Brazil Fabry Kidney Project and blood tests for both Gb3 dosage and genetic testing. Results: Among 1214 interviewed relatives, 115 (9.47%) were diagnosed with FD, with a predominance of women (66.10%). The most prevalent comorbidities were rheumatologic conditions and systemic hypertension (1.7% each), followed by heart, neurological, cerebrovascular diseases, and depression in 0.9% of individuals. Intolerance to physical exercise and tiredness were the most observed symptoms (1.7%), followed by periodic fever, intolerance to heat or cold, diffuse pain, burn sensation or numbness in hands and feet, reduced or absent sweating, as well as abdominal pain after meals in 0.9%. Conclusion: We found a prevalence of Fabry disease in 9.47% of relatives of CKD patients with this condition, remarkably with a 66.1% predominance of women, which contrasts with previous reports. The screening of family members of FD patients is important, since it can lead to early diagnosis and treatment, thus allowing better quality of life and improved clinical outcomes for these individuals.

RESUMO Introdução: A doença de Fabry é uma condição hereditária crônica, progressiva e multissistêmica, relacionada a uma mutação Xq22 no cromossomo X, que resulta em deficiência da enzima alfa-galactosidase, diminuindo a capacidade de degradação da globotriaosilceramida. Objetivos: avaliar a prevalência de mutações na doença de Fabry, bem como seus sinais e sintomas, em familiares de pacientes com doença renal crônica (DRC) diagnosticados com DF durante um estudo realizado anteriormente, denominado "Análise clínica e epidemiológica da doença de Fabry em centros de diálise no Brasil". Métodos: foi realizado um estudo transversal e os dados foram coletados através da entrevista com familiares de pacientes inscritos no Projeto Rim Fabry Brasil e exames de sangue para dosagem de Gb3 e testes genéticos. Resultados: Dos 1,214 familiares entrevistados, 115 (9,47%) foram diagnosticados com DF, com predomínio de mulheres (66,10%). As comorbidades mais prevalentes foram condições reumatológicas e hipertensão arterial sistêmica (1,7% cada), seguidas por doenças cardíacas, neurológicas, cerebrovasculares e depressão em 0,9% dos indivíduos. Intolerância ao exercício físico e cansaço foram os sintomas mais observados (1,7%), seguidos de febre periódica, intolerância ao calor ou ao frio, dor difusa, sensação de queimação ou dormência nas mãos e nos pés, sudorese reduzida ou ausente, além de dor abdominal após refeições em 0,9%. Conclusão: Encontramos uma prevalência da doença de Fabry em 9,47% dos familiares de pacientes com DRC com essa condição, notadamente com uma predominância de 66,1% de mulheres, o que contrasta com relatos anteriores. A triagem de familiares de pacientes com DF é importante, pois pode levar ao diagnóstico e tratamento precoces, permitindo melhor qualidade de vida e melhores resultados clínicos para esses indivíduos.

Increased serum interleukin-6 and tumor necrosis factor alpha levels in fabry disease: correlation with disease burden

OBJECTIVES: Fabry disease (FD) is an X-linked lysosomal disease caused by variants of the GLA gene; the formation of defective alpha-galactosidase A contributes to the accumulation of substrates in several organs. Chronic inflammation is thought to contribute to organ damage in FD patients. METHODS: In total, 36 classic FD patients (15 men/21 women) and 25 healthy controls (20 men/8 women) were assessed. The Mainz Severity Score Index (MSSI) was established after conducting interviews with the patients and chart review. Serum IL-6, IL-1β, and TNF-α levels were evaluated in both groups. RESULTS: The mean age (years) for FD patients was 43.1±15.4 and that for the controls was 47.4±12.2 (p>0.05). Twenty-two patients (59.5%) were treated with enzyme replacement therapy (ERT). Serum IL-6 and TNF-α levels were significantly higher in FD patients than in the controls. Patients treated with ERT had higher serum IL-6 and TNF-α levels than those not treated with ERT. There was no difference in the serum IL-1β levels between patients treated with ERT and those who were not. The MSSI scores in the patients were correlated with serum levels of IL-6 (r=0.60, p<0.001) and TNF-α (r=0.45, p<0.001). CONCLUSION: FD was associated with elevated serum levels of IL-6 and TNF-α in this cohort. The FD patients treated with ERT, particularly, women, exhibited higher levels of serum IL-6 and TNF-α than those not treated with ERT; the serum IL-6 and TNF-α levels were correlated with the MSSI scores reflecting greater disease burden.

Enfermedad de Fabry clásica en pacientes pediátricos asintomáticos: aspectos bioéticos de la terapia enzimática / Classic Fabry disease in asymptomatic pediatric patients: Bioethical aspects of enzyme therapy / Doença de Fabry clássica em pacientes pediátricos assintomáticos: aspectos bioéticos da terapia enzimática

Resumen: El propósito de este artículo es proponer un marco bioético para la administración de la terapia enzimática en niños con enfermedad de Fabry asintomáticos. Se realizó un estudio de campo transversal, observacional, descriptivo, con análisis cuantitativo y cualitativo, a la luz de la bioética en médicos que han diagnosticado y tratado pacientes con la enfermedad a nivel nacional e internacional, mediante una encuesta con preguntas cerradas validada por juicio de expertos, se evaluó la aplicación de los principios de no maleficencia, justicia y sacralidad de la vida en la administración del tratamiento enzimático para estos pacientes. La información se agrupó y procesó con estadística descriptiva. El 83,33 % de los encuestados consideró que un niño con enfermedad de Fabry asintomático debe recibir tratamiento enzimático específico, independientemente de su costo (justicia), además, que el tratamiento debe ser financiado por el Estado a fin de prevenir las complicaciones de la enfermedad; esto fue reconocido por el 75 % de los médicos encuestados (no maleficencia). El 66,66 % consideró que la sacralidad de la vida está en función de prevenir las complicaciones que condicionan la muerte. Así, con base en la bioética principialista se justifica iniciar la terapia enzimática específica para el tratamiento de niños con enfermedad de Fabry asintomáticos.

Abstract: This paper aims to propose a bioethical framework for the administration of enzyme therapy in children with asymptomatic Fabry disease. A cross-sectional, observational, descriptive field study was conducted with quantitative and qualitative analysis, in the light of bioethics with physicians who have diagnosed and treated patients with classic Fabry disease at the local and international level, using a survey with closed questions validated by expert judgment. The application of the principles of non-maleficence, justice, and sacredness of life in the administration of enzymatic treatment for these patients was evaluated. The information was grouped and processed with descriptive statistics. 83,33 % of respondents considered that a child with asymptomatic Fabry disease should receive specific enzymatic treatment, regardless of its cost (justice), and that treatment should be funded by the State in order to prevent complications of the disease. This was recognized by 75% of the physicians surveyed (not maleficence). 66,66 % considered that the sacredness of life must prevent the complications that condition death. Thus, based on the principles of bioethics, initiating specific enzymatic therapy for the treatment of children with asymptomatic Fabry disease is sustained.

Resumo: o propósito deste artigo é propor um referencial bioético para administrar a terapia enzimática em crianças com doença de Fabry assintomáticos. Foi realizado um estudo de campo transversal, observacional, descritivo, com análise quantitativa e qualitativa, à luz da bioética em médicos que diagnosticaram e trataram pacientes com a doença no contexto nacional e internacional, mediante questionário com perguntas fechadas validada porjulga- mento de especialistas; foi avaliada a aplicação dos princípios de não maleficência, justiça e sacralidade da vida na administração do tratamento enzimático para esses pacientes. A informação foi agrupada e processada com estatística descritiva. 83,33 % dos pesquisados consideraram que uma criança com doença de Fabry assintomática deve receber tratamento enzimático específico, independentemente de seu custo (justiça), além disso que o tratamento deve ser financiado pelo Estado para prevenir as complicações da doença. Isso foi reconhecido por 75 % dos médicos investigados (não maleficência). 66,66 % consideraram que a sacralidade da vida está em função de prevenir as complicações que condicionam a morte. Assim, com base na bioética principialista, justifica-se iniciar a terapia enzimática específica para tratar crianças com doença de Fabry assintomáticas.

Trasplante renal en la enfermedad de Fabry: una historia de idas y vueltas / Kidney transplant in Fabry disease: a round-trip story

La enfermedad de Fabry es una patología por depósito lisosomal causada por mutaciones en el gen GLA que resulta en la deficiencia de alfa galactosidasa A. Dentro de las complicaciones tardías más comunes se encuentra la insuficiencia renal terminal. Por medio de una revisión bibliográfica en la base PUBMed se busca evidenciar si el trasplante renal representa una opción terapéutica indiscutible para el tratamiento de la nefropatía de Fabry. Hallazgos demuestran la posibilidad de la terapia de reemplazo enzimático que permite proteger al sistema cardiovascular y nervioso del daño progresivo por acumulo lisosomal.

Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene that results in alpha galactosidase A deficiency. One of the most common late complications is end stage renal disease. Through a bibliographic review in the PUBMed database, we seek to demonstrate whether kidney transplantation represents an indisputable therapeutic option for the treatment of Fabry nephropathy. Findings demonstratethepossibility of enzymereplacementtherapythatprotects the cardiovascular and nervoussystemfromprogressivedamagebylysosomalaccumulation.

Rare inherited kidney diseases: an evolving field in Nephrology / Doenças renais hereditárias raras: um campo em evolução na Nefrologia

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.

Fabry disease: genetics, pathology, and treatment

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.

Trombose arterial recorrente em paciente com doença de Fabry: relato de caso / Recurrent arterial thrombosis in a patient with Fabry disease: case report

Resumo A doença de Fabry é definida como uma doença rara de depósito lisossomal ligada ao cromossomo X que apresenta sintomas multissistêmicos, incluindo comprometimento vascular com eventos trombóticos. Paciente do sexo feminino, 57 anos, com diagnóstico de doença de Fabry há 11 anos, apresentava hiperidrose, hipoacusia e angioqueratoma nas mãos. Na história patológica pregressa, relatou episódio de acidente vascular encefálico isquêmico prévio aos 40 anos de idade e trombose arterial crônica agudizada em membro inferior direito há 1 ano, a qual foi tratada por meio de angioplastia com uso de stent, apresentando melhora temporária e recente recidiva do quadro. Os eventos trombóticos se enquadram nos sintomas típicos da doença de Fabry, e são resultantes do depósito de globotriaosilceramida no endotélio vascular, implicando em um estado pró-trombótico, justificando a reincidência dos sintomas e da trombose arterial em membro inferior.

Abstract Fabry disease is a rare disease, defined as an X-linked lysosomal deposition disease that presents with multisystemic symptoms, including vascular impairment with thrombotic events. A 57-year-old female patient diagnosed with Fabry disease 11 years previously, presented with hyperhidrosis, hypoacusis, and angiokeratoma on the hands. Her previous pathological history included an episode of ischemic stroke before the age of 40 years and chronic acute thrombosis in the right lower limb, 1 year previously, which had been treated with stent angioplasty, with temporary improvement followed by recent relapse of the condition. Thrombotic events fit the typical symptoms of Fabry disease and are caused by deposition of globotriaosylceramide in the vascular endothelium, constituting a prothrombotic state and explaining the recurrence of symptoms and arterial thrombosis in the lower limb.

Higher rate of rheumatic manifestations and delay in diagnosis in Brazilian Fabry disease patients

Abstract Background: Fabry disease (FD) is an X-linked lysosomal disorder due to mutations in the GLA gene resulting in defective enzyme alpha-galactosidase A. FD patients are frequently misdiagnosed, commonly for rheumatic diseases. Determining pathogenicity of a mutation depends of in silico predictions but mostly on available clinical information and interpretation may change in light of evolving knowledge. Similar signs and symptoms in carriers of GLA gene genetic variants of unknown significance or of benign variants may hamper diagnosis. This study reviews rheumatic and immune-mediated manifestations in a cohort of Brazilian FD patients with classic mutations and also in subjects with GLA gene A143T and R118C mutations. Misdiagnoses, time to correct diagnosis or determination of GLA gene status, time to treatment initiation and reasons for treatment prescription in A143T and R118C subjects are reviewed. Methods: Genotype confirmed classic FD patients (n = 37) and subjects with GLA gene mutations A143T and R118C (n = 19) were referred for assessment. Subjects with R118C and A143T mutations had been previously identified during screening procedures at hemodialysis units. All patients were interviewed and examined by a rheumatologist with previous knowledge of disease and/or mutation status. A structured tool developed by the authors was used to cover all aspects of FD and of common rheumatic conditions. All available laboratory and imaging data were reviewed. Results: Thirty-seven consecutive FD patients were interviewed - 16 male / 21 female (mean age: 43.1 years) and 19 consecutive subjects with GLA gene mutations R118C and A143T were evaluated - 8 male / 11 female (mean age: 39.6 years); 15 [R118C] / 4 [A143T]. Misdiagnosis in FD patients occurred in 11 males (68.8%) and 13 females (61.9%) of which 10 males and 9 females were previously diagnosed with one or more rheumatic conditions, most frequently rheumatic fever or "rheumatism" (unspecified rheumatic disorder). Median time for diagnosis after symptom onset was 16 years (range, 0-52 years). Twenty-two patients were treated with enzyme replacement therapy (ERT) - 13 male and 9 female. Median time to ERT initiation after FD diagnosis was 0.5 years (range, 0-15 years). Rheumatic manifestations occurred in 68.4% of R118C and A143T subjects. Two subjects had been prescribed ERT because of renal disease [R118C] and neuropsychiatric symptoms [A143T]. Conclusion: Misdiagnoses occurred in 64.8% of FD patients, most frequently for rheumatic conditions. Median time for correct diagnosis was 16 years. Rheumatic manifestations are also frequent in subjects with GLA gene R118C and A143T mutations. These results reinforce the need to raise awareness and increase knowledge about Fabry disease among physicians, notably rheumatologists, who definitely have a role in identifying patients and determining disease burden. Decision to start treatment should consider expert opinion and follow local guidelines.(AU)

Ocular findings in Fabry disease in Colombian patients / Manifestaciones oculares de la enfermedad de Fabry en pacientes colombianos

ABSTRACT Fabry disease is a rare X-linked disorder caused by an alpha-galactosidase enzyme deficiency, which leads to a progressive lysosomal glycosphingolipids accumulation, mainly globotriaosylceramide, in multiple organism tissues including the eye. This case series describes the first ophthalmological Colombian report of Fabry disease highlighting the importance of ocular signs as markers of the disease, useful in diagnosis and treatment to avoid long-term complications that lead to a morbi-mortality increment. We describe five cases of Fabry disease from Bogotá, Colombia, including a complete clinical history, ophthalmologic, optometric examination, and photographs. We found that all patients had refractive defects and that in all cases corneal verticillata pattern was found. Four patients presented with posterior capsule lens brown-beige deposits and four patients had conjunctival and retinal tortuous vessels. A complete ophthalmologic examination is important for prompt diagnosis, which is key to starting a multidisciplinary treatment and reducing morbi-mortality.

RESUMEN La enfermedad de Fabry es un raro trastorno ligado al cromosoma X causado por deficiencia de la enzima alfa-galactosidasa y la consiguiente y progresiva acumulación lisosómica de glucoesfingolípidos, especialmente la globotriaosilceramida, en múltiples tejidos del organismo, incluido el ojo. En este reporte se presenta la primera serie de casos de manifestaciones oculares de la enfermedad de Fabry en Colombia, resaltando la importancia de los signos oculares como ayuda para el diagnóstico temprano. Se presentan cinco casos de la enfermedad en Bogotá y se da cuenta de las historias clínicas y los exámenes oftalmológicos y de optometría, y se incluyen fotografías. En todos los pacientes se hallaron errores de refracción y se evidenció el patrón de córnea verticillata. Cuatro pacientes presentaban depósitos de color café y castaño claro en la cápsula posterior del cristalino, y cuatro tenían tortuosidad vascular conjuntival y retiniana. El examen oftalmológico completo es importante para hacer un diagnóstico oportuno con el fin de iniciar el tratamiento multidisciplinario y reducir la morbimortalidad.