Evaluation standards and treatment initiation timing have been debated for a long time, particularly for late-onset Fabry disease (FD), because of its slow progression. However, early initiation of enzyme replacement therapy (ERT) for FD could be effective in stabilizing the disease progression and potentially preventing irreversible organ damage. We aimed to examine globotriaosylceramide (Gb3) deposits in patients’ endomyocardial biopsies to understand the early pathogenesis of FD cardiomyopathy.
Immunofluorescent (IF) staining of Gb3 and lysosomal-associated membrane protein 1 (LAMP-1) was performed on endomyocardial biopsies of patients suspected of Fabry cardiomyopathy who had negative or only slight Gb3 accumulation determined by toluidine blue staining and electron microscopic examination.
The IF staining results revealed that all patients examined had abundant Gb3 accumulation in their cardiomyocytes, including the ones who are negative for inclusion bodies. Furthermore, we found that early Gb3 deposits were mostly confined within lysosomes, while they appeared extralysosomally at a later stage.
A significant amount of lysosomal Gb3 deposits could be detected by IF staining in cardiac tissue before the formation of inclusion bodies, suggesting the cardiomyocytes might have been experiencing cellular stress and damage early on, before the appearance of typical pathological changes of FD during the disease progression.
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We would like to thank Dr. Sakuraba for his generosity in sharing the anti-Gb3 monoclonal antibody with us, and Dr. Nien-Jung Chen and Dr. Cheun-Minn Liu for insightful discussions.
This work was supported in part by the Taipei Veterans General Hospital and University System of Taiwan Joint Research Program (VGHUST105-G7-6-1, VGHUST106-G7-3-1 to C.-L. Hsu and D.-M. Niu) and the Ministry of Science and Technology (MOST), Taiwan (MOST-104-2323-B-010-024 to C.-L. Hsu).
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Fabry disease cardiac variant IVS4+919 G>A is associated with multiple cardiac gene variants in patients with severe cardiomyopathy and fatal arrhythmia
Genetics in Medicine (2019)
Genetics in Medicine (2019)