Fabry Cardiomyopathy: Current Practice and Future Directions

Abstract

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficient galactosidase A enzyme and subsequent accumulation of glycosphingolipids throughout the body. The result is a multi-system disorder characterized by cutaneous, corneal, cardiac, renal, and neurological manifestations. Increased left ventricular wall thickness represents the predominant cardiac manifestation of FD. As the disease progresses, patients may develop arrhythmias, advanced conduction abnormalities, and heart failure. Cardiac biomarkers, point-of-care dried blood spot testing, and advanced imaging modalities including echocardiography with strain imaging and magnetic resonance imaging (MRI) with T1 mapping now allow us to detect Fabry cardiomyopathy much more effectively than in the past. While enzyme replacement therapy (ERT) has been the mainstay of treatment, several promising therapies are now in development, making early diagnosis of FD even more crucial. Ongoing initiatives involving artificial intelligence (AI)-empowered interpretation of echocardiographic images, point-of-care dried blood spot testing in the echocardiography laboratory, and widespread dissemination of point-of-care ultrasound devices to community practices to promote screening may lead to more timely diagnosis of FD. Fabry disease should no longer be considered a rare, untreatable disease, but one that can be effectively identified and treated at an early stage before the development of irreversible end-organ damage.

Unexplained Left Ventricular Hypertrophy with Symptomatic High-Grade Atrioventricular Block in Elderly Patients: A Case Report

“…To date, the management of FD includes disease-specific therapy, as well as therapies to manage multiorgan diseases. Approved FD-specific treatments include enzyme replacement therapy (ERT) and pharmacological chaperone therapy, while other novel therapeutic approaches, such as substrate reduction therapy, gene therapy, and mRNA-based therapy, are still in development ( Table 3 ) [ 14 , 15 ]. To begin with, ERT is indicated in all symptomatic patients with an established FD diagnosis, which can delay FD advancement and reduce the burden of cardiac events when started at earlier stage [ 5 ].…”

“…Lastly, other novel treatments, including substrate reduction therapy, result in decreased Gb3 synthesis, which directly lower the cellular load. All gene therapy or mRNA-based therapy aims to restore the defective α-Gal A activity [ 15 , 17 ]. These new therapies will expand in the foreseeable future and hold promise for FD patients.…”

Cardiovascular magnetic resonance native T1 mapping in Anderson-Fabry disease: a systematic review and meta-analysis

“…Anderson-Fabry disease (AFD) is a rare multisystem X-linked lysosomal storage disorder caused by α-galactosidase A enzyme deficiency, resulting in progressive intracellular accumulation of glycosphingolipids in endothelial and smooth muscle cells [ 1 , 2 ]. Clinical features of classic AFD phenotype consist in skin disorders, corneal alterations, cerebrovascular complications, kidney failure, and cardiovascular disease, which represents a major cause of morbidity and mortality [ 3 , 4 ]. Long-term cardiac involvement in AFD results in left ventricular (LV) hypertrophy (LVH) and myocardial fibrosis, inducing several complications, mainly arrhythmias, valvular dysfunction, and coronary artery disease [ 5 ].…”

A Journey towards Understanding the Molecular Pathology and Developing Therapies for Lysosomal Storage Disorders

“…LSDs frequently present as multi-system disorders that require the management of symptoms that are present in various organ systems. Yim et al provide an overview and clinical recommendations for the management of cardiomyopathy in Fabry disease (FD), an X-linked LSD [ 3 ]. They stress that FD should be considered as a potential diagnosis in patients that show a thickening of the left ventricular wall that cannot be otherwise explained [ 3 ], since as much as 4 to 12% of such cases may be caused by FD [ 4 , 5 , 6 ].…”

“…Yim et al provide an overview and clinical recommendations for the management of cardiomyopathy in Fabry disease (FD), an X-linked LSD [ 3 ]. They stress that FD should be considered as a potential diagnosis in patients that show a thickening of the left ventricular wall that cannot be otherwise explained [ 3 ], since as much as 4 to 12% of such cases may be caused by FD [ 4 , 5 , 6 ]. As treatment options including ERT, substrate reduction and oral chaperones are available for FD, the early identification of FD in patients is of particular importance.…”