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.

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.

Prevalência da doença de fabry em pacientes portadores de doençarenal crônica submetidos à hemodiálise em Natal – RN / Prevalence of fabry disease in patients with chronic kidney disease onhemodialysis in Natal – RN, Brazil

Introdução: A Doença de Fabry é uma doença genética de depósito lisossômico caracterizada pela deficiência da enzima α-galactosidase A (ceramidatrihexosidase). Isso gera acúmulo de globotriaosilceramida (GL-3) no endotélio vascular, podendo ocasionar complicações renais, cardíacas ecerebrovasculares. Diante da terapia de reposição enzimática, torna-se essencial o diagnóstico desta doença, o que pode ser conseguido através de umrastreamento de pacientes em hemodiálise. Objetivos: O presente estudo objetivou determinar a prevalência da doença em pacientes portadores dedoença renal crônica em hemodiálise na cidade de Natal – RN, avaliando as principais co-morbidades associadas. Métodos: Foram selecionadosindivíduos do sexo masculino em hemodiálise, entre 18 e 65 anos, excluindo-se pacientes cuja etiologia da falência renal era: diabetes mellitus, lupuseritematoso sistêmico, nefropatia obstrutiva, pielonefrite crônica e doença renal policística. Uma amostra sanguínea foi coletada para avaliação da atividadeda α-galactosidase A em papel de filtro. Os pacientes com valores inferiores a 2,5μmol/L/h tiveram a atividade enzimática testada em leucócitos eresponderam a um questionário sobre as manifestações clínicas relacionadas. Resultados: Dos 191 pacientes, 16 (8,3%) cursaram com atividadeenzimática em papel de filtro inferior a 2,5μmol/L/h. Apenas um paciente (0,52%) apresentou dosagem da atividade enzimática em leucócitos inferior aovalor da normalidade, sendo compatível com Doença de Fabry. Não foram encontradas as manifestações típicas da doença neste paciente. Conclusão:Observou-se uma prevalência da Doença de Fabry de 0,52% dentre os pacientes estudados nos centros de hemodiálise de Natal – RN no ano de 2006.

Introduction: Fabry Disease is a genetic illness of lisosomic deposition characterized by the deficiency of the enzyme alpha-galactosidase A (ceramidetrihexosidase), generating an accumulation of globotriaosilceramide (GL-3) in the vascular endothelium, capable of leading to renal, cardiac andcerebrovascular complications. Faced with the therapeutic possibility of enzymatic supplementation, the diagnosis of this disease becomes essential, andcan be achieved through the screening of hemodialysis patients. Aims: The present study aimed at determining the prevalence of Fabry Disease in patientswith chronic kidney disease undergoing hemodialysis in the city of Natal, Rio Grande do Norte, Brazil, evaluating the main associated comorbidities.Methods: The sample consisted of male subjects between 18 and 65 years of age, undergoing hemodialysis, excluding patients whose etiology of renalfailure was diabetes mellitus, systemic lupus erythematosus, obstructive nephropathy, chronic pyelonephritis, or polycystic kidney disease. A blood samplewas collected for an evaluation of alpha-galactosidase A activity in filter paper. Patients with values inferior to 2.5 μmol/L/h had their enzymatic activity testedin leukocytes, and a questionnaire about related clinical manifestations was applied. Results: From 191 patients, 16 (8.3%) had an enzymatic activity infilter paper inferior to 2.5 μmol/L/h. Only one patient (0.52%) exhibited a level of enzymatic activity in leukocytes inferior to the normal value, compatible withFabry Disease. The typical manifestations of the disease were not found in this case. Conclusion: A prevalence of Fabry Disease of 0.52% was observedamong patients studied in hemodialysis centers in Natal in 2006.