Fabry Disease

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Case Report

Hypertrophic Phenotype in an Adolescent from the Amazon Region Associated with Combined Variants in the GLA, TTR, and PRKAG2 genes

Matheus Martins Monteiro et al. Kemelly Ferreira da Silva Jessica Vanina Ortiz Marcos Leite Barbosa Ferreira … Kátia do Nascimento Couceiro Rodrigo Fernandes de Castro Fábio Fernandes João Marcos Bemfica Barbosa Ferreira Investigadores do Mapa Genoma Brasil Investigadores do Mapa Genoma Brasil Bianca Domit Wener Linnenkamp Emanuelle Leonilia Marques José Eduardo Krieger

Introduction

Hypertrophic cardiomyopathy (HCM) phenotype is defined as increased wall thickness of the left and/or right ventricle without loading conditions that explain this. Its diagnosis is confirmed by imaging tests such as echocardiogram and cardiac magnetic resonance (CMR) with the presence of wall thickness ≥ 15 mm in any myocardial segment or 13 mm in first-grade relatives of patients with a confirmed diagnosis. The most common cause of this phenotype is genetic HCM caused by mutations in genes encoding sarcomeric proteins. Most patients with HCM are asymptomatic, but some patients may present significant symptoms, and this is an important cause of sudden death in young people. However, it is important to consider other conditions known as phenocopies because they may have similar characteristics in imaging tests, but with specific etiologies that have different pathophysiological mechanisms. Among these phenocopies, we highlight mitochondrial diseases, RASopathies, muscular dystrophies, PRKAG2 syndrome, Fabry disease, and cardiac amyloidosis. Their differential diagnosis is essential because these phenocopies present specific diagnostic and therapeutic strategies that can impact the natural evolution of disease. The present report reveals the case of a young patient in which this differential diagnosis was challenging, both due to difficulties in accessing specific exams and the overlapping of diseases that made his diagnosis hard, and describes the disease distribution in his family. This patient is part of a broader research project approved by the Research Ethics Committee of the Universidade do Estado do Amazonas under approval number 7.108.530 and CAAE 55200322.5.3009.516.

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ABC

Research Letter

Late-Onset Fabry Disease: Diagnostic Challenges and Clinical Evolution

Hernán Patricio García Mejía et al. Heleuterio da Conceição Nicolau Madogolele Manuela Cristina Ribeiro Dias Barroso Matheus Carvalho Alves Nogueira … Kevin Rafael de Paula Morales Cristhian Espinoza Romero Luciano Nastari Fábio Fernandes

Introduction

Simultaneous cardiac and renal involvement can result from various systemic conditions, such as hypertension, autoimmune diseases, infiltrative diseases, and hereditary syndromes. Fabry disease (FD) is an X-linked genetic disorder caused by a deficiency or absence of the enzyme α-galactosidase A, leading to the progressive accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3), in various tissues. This accumulation of Gb3 promotes multisystemic dysfunctions, with heterogeneous clinical manifestations that vary according to sex, the degree of residual enzymatic activity, and the form of presentation, classic or non-classic.^,

The estimated incidence of FD ranges from 1 in 40,000 to 1 in 117,000 individuals worldwide. In Brazil, the epidemiology of FD remains poorly defined due to the rarity of the condition and underreporting of cases, which reinforces the value of clinical reports such as this one.

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Review Article

My Approach to Diagnose Fabry Disease

Sandra Marques e Silva

Abstract

Fabry disease (FD) is an inherited lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A (α-Gal A). This enzymatic defect leads to the cytoplasmic lysosomal accumulation of globotriaosylceramides (GB3 and LysoGB3), resulting in multisystemic clinical manifestations. Cardiovascular involvement, often mimicking hypertrophic cardiomyopathy, is the main determinant of morbidity and mortality, due to the development of arrhythmia, myocardial ischemia, and heart failure. Although FD is a rare condition in the general population, the availability of specific enzyme replacement therapy, which can alter the natural course of the disease, underscores the importance of including FD as a key differential diagnosis among storage cardiomyopathies. Diagnostic evaluation should encompass a thorough clinical assessment, with particular attention to patient history and physical examination, complemented by laboratory testing and imaging studies, such as electrocardiography and echocardiography. Cardiac magnetic resonance imaging, including late gadolinium enhancement and T1 and T2 parametric mapping, provides additional diagnostic and prognostic information and should ideally be performed at the time of initial diagnosis. Definitive diagnosis is established by genetic sequencing of the GLA gene, located on the long arm of the X chromosome, enabling the selection of the most appropriate therapeutic strategy for each patient.

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Research Letter

Fabry Disease and Its Different Phenotypes

Murillo Oliveira Antunes et al. Rafael Ruas Nastari Edmundo Arteaga-Fernandez Marcelle G. Henriques Lizandro … William Batah El-Feghaly Guilherme José dos Santos Ferreira Alan Silva Martins Juliana Alzira Gonzales Oliveira Leguizamon Vinicius Machado Correia Vagner Madrini Junior Fábio Fernandes

Abstract

Fabry disease (FD) is an X-linked genetic condition caused by variants in the GLA gene causing enzyme α-galactosidase A deficiency and accumulation of globotriaosylceramide (Gb3) in tissues such as the heart, kidneys, and the nervous system. This study reports a case series of patients with FD, highlighting the phenotypic diversity of the disease, which can be confused with other cardiological conditions. When properly indicated, genetic evaluation, combined with biomarker dosage and α-galactosidase enzymatic activity, is key for an accurate diagnosis. Early diagnosis of FD is fundamental for initiating treatments that can slow disease progression and prevent serious complications, reinforcing the need for greater awareness about this condition among cardiologists.

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Original Article

Differences Between Two Distinct Hypertrophic Cardiac Conditions: Fabry Disease versus Hypertrophic Cardiomyopathy

Onur Akhan et al. Mehmet Kış Tuncay Güzel Mehdi Zoghi

Abstract

Background

Hypertrophic cardiomyopathy (HCM) and Fabry disease (FD) are genetically inherited diseases with left ventricular hypertrophy (LVH) phenotype characteristics that cause adverse cardiac outcomes.

Objectives

To investigate the demographic, clinical, biochemical, electrocardiographic (ECG), and echocardiographic (ECHO) differences between HCM and FD.

Methods

60 HCM and 40 FD patients were analyzed retrospectively as a subanalysis of the ‘LVH-TR study’ after excluding patients with atrial fibrillation, pace rhythm, bundle branch blocks, and second and third-degree atrioventricular (AV) blocks. The significance level was accepted as <0.05.

Results

Male gender (p=0.048) and creatinine (p=0.010) are significantly higher in favor of FD; however, ST depression (p=0.028), QT duration (p=0.041), interventricular septum thickness (IVSd) (p=0.003), posterior wall thickness (PWd) (p=0.009), moderate-severe mitral regurgitation (MR) (p=0.013), and LV mass index (LVMI) (p=0.041) are significantly higher in favor of HCM in the univariate analyses. In multivariate analysis, statistical significance only continues in creatinine (p=0.018) and QT duration (0.045). FD was positively correlated with creatinine (rho=0.287, p=0.004) and HCM was positively correlated with PWd (rho=0.306, p=0.002), IVSd (rho=0.395, p<0.001), moderate-severe MR (rho=0.276, p<0.005), LVMI (rho=0.300, p=0.002), relative wall thickness (RWT) (rho=0.271, p=0.006), QT duration (rho=0.213, p=0.034) and ST depression (rho=0.222, p=0.026).

Conclusion

Specific biochemical, ECG, and ECHO characteristics can aid in the differentiation and early diagnosis of HCM and FD.

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My Approach To

My Approach to the Echocardiographic Assessment of Anderson-Fabry Disease

Sandra Marques e Silva

Echocardiographic assessment of anderson-fabry disease

Anderson-Fabry disease (AFD) is a rare lysosomal inborn metabolism error due to changes to the long arm of the X chromosome that result in deficiencies of the alpha-galactosidase enzyme, which is responsible for metabolizing glycosphingolipids. Systemic presentations result from the accumulation of these substances in the cells of organs such as the heart, central and peripheral nervous system, kidneys, eyes, skin, and others. This heart disease, which resembles a sarcomeric hypertrophic cardiomyopathy phenocopy, is a main cause of mortality due to heart failure, arrhythmia, and/or myocardial ischemia in this population in Brazil. The natural disease progression can be changed by an accurate and early diagnosis and the availability of specific intravenous enzyme replacement or oral chaperone therapy, thereby increasing quality of life and life expectancy. Thus, echocardiography plays an essential role as a diagnostic and risk stratification tool in the assessment of therapeutic efficacy and the investigation of cardiac complications.

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Review Article

Deposit Diseases as Differential Diagnosis of Left Ventricular Hypertrophy in Patients with Heart Failure and Preserved Systolic Function

Fábio Fernandes et al. Murillo Oliveira Antunes Viviane Tiemi Hotta Carlos Eduardo Rochitte Charles Mady

Fabry’s disease FD is a genetic, lysosomal storage disorder caused by total or partial alpha-galactosidase (α-Gal A) deficiency of the enzyme that degrades glycolipid globotriaosylceramide (Gb3) in lysosomes. Therefore Gb3 deposits accumulate in the endothelial cells and heart, resulting in organic dysfunction. The gene that causes FD is located in the long arm of the X chromosome (locus Xq22) and currently hundreds of pathogenic mutations have been described. Thus, male homozygous patients develop the classic disease, while female heterozygous patients present variable clinical manifestations from conditions without apparent clinical disease to the complete expression of the disease.^–

In clinical practice, early diagnosis is important because actually there are specific treatment with enzyme replacement therapy (ERT) that may change the natural history, reducing and/or stabilizing the progression of the disease.^,

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