Terapia de reposição enzimática para doença de Anderson-Fabry: revisão sistemática de ensaios clínicos randomizados / Enzyme synthesis therapy for Anderson-Fabry disease: systematic reviewof randomized clinical trials

A doença de Anderson-Fabry, uma doença rara, é causada por uma deficiência da enzima alfa-galactosidase A. Isso leva ao acúmulo de um material gorduroso denominado globotriaosilceramida em várias células do corpo. Globotriaosilceramida é uma substância gordurosa, formada por três açúcares, comumente denominada ceramida e é encontrada na maioria das células do corpo. Indivíduos não tratados podem apresentar dor, complicações na pele, olhos, e problemas gastrointestinais. A doença de Fabry pode causar complicações potencialmente fatais, como danos aos rins, ataque cardíaco e acidente vascular cerebral. Um dos tipos disponíveis de tratamento é a terapia de reposição enzimática com agalsidase alfa ou beta, que substitui a deficiência enzimática. Avaliamos a eficácia e segurança da terapia de reposição enzimática com agalsidase alfa ou beta para doença de Anderson-Fabry. Para realizar essa revisão analisamos revisões sistemática de ensaios clínicos randomizados (ECRs). Não houve restrições de idiomas. Pesquisamos o registro de ensaios clínicos de erros inatos do metabolismo do grupo Cochrane de fibrose cística e desordens genéticas, e as seguintes bases de dados: MEDLINE, EMBASE, LILACS, e clinicaltrials.gov. Os revisores examinaram de forma independente os artigos elegíveis, extraíram dados e avaliaram o risco de viés. Essa revisão está registrada na Cochrane e foi realizada juntamente com o grupo de Fibrose Cística e Doenças Genéticas. Foram selecionados onze estudos randomizados controlados, os resultados apontam para uma diminuição nos depósitos de Gb3 plasmático para os pacientes que receberam agalsidase beta, nos domínios do rim (MD -1,70 (95% CI -2,09 a -1,31) e coração (MD -0,90 95% CI (-1,18 a -0,62) e uma influência positiva na qualidade de vida relacionada à dor, porém, os estudos apresentam baixa qualidade metodológica e não fornecem evidências robustas que indiquem se a TRE é mais efetiva e segura quando comparada a outras terapias ativas, placebo, ou nenhuma intervenção (AU)

Anderson-Fabry disease, a rare disease, is caused by a deficiency of the enzyme alpha-galactosidase A. This leads to the accumulation of a fatty material called globotriaosylceramide in various cells of the body. Globotriaosylceramide is a fatty substance, made up of three sugars, commonly called ceramide and is found in most cells in the body. Untreated individuals may experience pain, skin, eye, and gastrointestinal problems. Fabry disease can cause life-threatening complications, such as kidney damage, heart attack, and stroke. One of the available types of treatment is enzyme replacement therapy with agalsidase alpha or beta, which replaces the enzyme deficiency. We evaluated the efficacy and safety of enzyme replacement therapy with agalsidase alfa or beta for Anderson-Fabry disease. To perform this review, we analyzed systematic reviews of randomized controlled trials (RCTs). There were no language restrictions. We searched the clinical trial registry ofinborn errors of metabolism from the Cochrane group of cystic fibrosis and genetic disorders, and the following databases: MEDLINE, EMBASE, LILACS, and clinicaltrials.gov. Reviewers independently screened eligible articles, extracted data, and assessed risk of bias. This review is registered in Cochrane and was carried out jointly with the Cystic Fibrosis and Genetic Diseases group. Eleven randomized controlled trials were selected, the results point to a decrease in plasma Gb3 deposits for patients receiving agalsidase beta, in the kidney domains (MD -1.70 (95% CI -2.09to -1.31) and heart (MD -0.90 95% CI (-1.18 to -0.62) and a positive influence on pain-related quality of life, however, studies have low methodological quality and do not provide robust evidence to indicate whether ERT is more effective and safer when compared to other active therapies, placebo, or no intervention (AU)

Cardiac Anderson-Fabry disease: lessons from a 25-year-follow up.

Sarcomeric hypertrophic cardiomyopathy (HCM) is the most common genetic cause of unexplained left ventricular hypertrophy and has no specific treatment. Anderson-Fabry disease (AFD) is rare and usually multisystemic, but occasionally expresses clinically as a predominantly cardiac phenotype mimicking HCM. We describe an illustrative case of a patient followed regularly for 25 years with a diagnosis of familial HCM and no identified sarcomeric mutations. Next-generation sequencing analysis identified a novel pathogenic mutation in the GLA gene, leading to a diagnosis of previously unknown multisystemic AFD, with consequent implications for the patient's treatment and prognosis and familial screening.

Fabry disease presenting as apical left ventricular hypertrophy in a patient carrying the missense mutation R118C.

Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by abnormalities of the GLA gene, which encodes the enzyme α-galactosidase A. A deficiency of this enzyme leads to the lysosomal accumulation of glycosphingolipids, which may cause left ventricular hypertrophy that is typically concentric and symmetric. We present the case of a 60-year-old woman with symptoms of dyspnea, atypical chest pain and palpitations, in whom a transthoracic echocardiogram revealed an apical variant of hypertrophic cardiomyopathy. Analysis of specific sarcomeric genetic mutations was negative. The patient underwent a screening protocol for Anderson-Fabry disease, using a dried blood spot test, which was standard at our institution for patients with left ventricular hypertrophy. The enzymatic activity assay revealed reduced α-galactosidase A enzymatic activity. Molecular analysis identified a missense point mutation in the GLA gene (p.R118C). This case report shows that Anderson-Fabry disease may cause an apical form of left ventricular hypertrophy. The diagnosis was only achieved because of systematic screening, which highlights the importance of screening for Anderson-Fabry disease in patients with unexplained left ventricular hypertrophy, including those presenting with more unusual patterns, such as apical variants of left ventricular hypertrophy. This case also supports the idea that the missense mutation R118C is indeed a true pathogenic mutation of Anderson-Fabry disease.