Identification of lysosomal and extralysosomal globotriaosylceramide (Gb3) accumulations before the occurrence of typical pathological changes in the endomyocardial biopsies of Fabry disease patients

Abstract

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.

Fabry disease cardiac variant IVS4+919 G>A is associated with multiple cardiac gene variants in patients with severe cardiomyopathy and fatal arrhythmia

“…We wish to respond to the recent Genetics in Medicine article on the endomyocardial biopsies of cardiac variant GLA IVS4+919A Fabry disease patients. 1 In the report, the authors have tried to emphasize the early initiation to prevent irreversible tissue damage in IVS4+919A individuals; however, they also noted the possibility of coincident conditions. The variant GLA IVS4+919A, with an allele frequency of 1/ 800 in Taiwanese males, 2 is occasionally associated with severe cardiomyopathy and cardiac arrhythmia.…”

Response to Juang et al.

“…We appreciate the interesting response by Juang et al 1 to our article. 2 The authors provide a completely different point of view and argue that IVS4+919 G>A is not a diseasecausing variant per se, but just a benign marker for other pathogenic variants that cause hypertrophic cardiomyopathy (HCM). However, to us the mounting weight of evidence points toward a direct involvement of the IVS4+919 G>A variant in the pathogenesis of this form of Fabry disease.…”

“…First, the variant is in the galactosidase A gene and results in the production of a defective enzyme. Second, patients with the IVS4+919 G>A variant have an accumulation of glycosphingolipid substrate (Gb3) in their hearts at both early and late stages, 2 including the three patients reported by Juang et al Third, the association of IVS4+919 G>A variant with the later-onset phenotype of Fabry disease manifested as HCM has been shown in multiple publications, [3][4][5][6][7] and patients carrying the IVS4+919 G>A variant with cardiac symptoms are continuously being identified worldwide. Juang et al argued that the reported three patients only had mild elevation of plasma lysoGb3 (3.35-4.33 ng/mL, N < 0.8) and suggested that Fabry disease might not be the major pathological factor for their cardiomyopathy.…”

“…This argument truly reflects the difficulties in diagnosis due to the nonspecific nature of the inclusion bodies, yet highlights the importance of using Gb3-specific detection methods as we suggested. 2 Most likely, the disagreement whether or not IVS4+919 G>A is a major pathogenic variant stems from the different patient cohorts used in the different studies. For example, screening efforts focused on hypertrophic cardiomyopathy patients found that about 1% of those screened had GLA variants.…”

Does administration of hydroxychloroquine/amiodarone accelerate accumulation of globotriaosylceramide and globotriaosylsphingosine in Fabry mice?

“…The pathological features of biopsied tissues in Fabry patients are characteristic, exhibiting the ultrastructural appearance of lamellar inclusion bodies, zebra bodies, myeloid bodies or concentric electron dense bodies in cells. The existence of such pathological findings had been thought to constitute strong evidence that a patient had Fabry disease [ 1 ], although exceptional cases, in which a significant Gb3 deposits could be observed in cardiac tissue before the formation of inclusion bodies, have been reported, suggesting the cardiomyocytes might be affected early on, before the appearance of typical pathological changes during the disease progression [ 4 ].…”