globotriaosylceramide and Cardiomyopathy--Hypertrophic

Fabry disease (FD) is a rare inherited disorder characterized by a wide range of systemic symptoms; it is particularly associated with cardiovascular and renal problems. Enzyme replacement therapy and pharmacological chaperone migalastat are the only approved and effective treatment strategies for FD patients. It is well documented that alpha-galactosidase A (GLA) enzyme activity deficiency causes globotriaosylceramide (Gb3) accumulation, which plays a crucial role in the etiology of FD. However, the detailed mechanisms remain unclear, and the lack of a reliable and powerful disease model is an obstacle. In this study, we created such a model by using CRISPR/Cas9-mediated editing of GLA gene to knockout its expression in human embryonic stem cells (hESCs). The cardiomyocytes differentiated from these hESCs (GLA-null CMs) were characterized by the accumulation of Gb3 and significant increases of cell surface area, the landmarks of FD-associated cardiomyopathy. Furthermore, we used mass spectrometry to compare the proteomes of GLA-null CMs and parental wild type CMs and found that the Rab GTPases involved in exocytotic vesicle release were significantly downregulated. This caused impairment of autophagic flux and protein turnover, resulting in an increase of reactive oxygen species and apoptosis. To summarize, we established a FD model which can be used as a promising tool to study human hypertrophic cardiomyopathy in a physiologically and pathologically relevant manner and to develop new therapies by targeting Rab GTPases signaling-related exosomal vesicles transportation.

Topics: alpha-Galactosidase; Apoptosis; Autophagy; Cardiomyopathy, Hypertrophic; Cell Line; CRISPR-Cas Systems; Exosomes; Fabry Disease; Gene Knockout Techniques; Human Embryonic Stem Cells; Humans; Models, Biological; Myocytes, Cardiac; Reactive Oxygen Species; Trihexosylceramides

Topics: Algorithms; Arrhythmias, Cardiac; Cardiomyopathy, Hypertrophic; Electrocardiography; Enzyme Therapy; Fabry Disease; Female; Fibrosis; Humans; Hypertrophy, Left Ventricular; Male; Myocardium; Sex Factors; Trihexosylceramides; Vascular Diseases

Fabry disease, an X-linked lysosomal storage disorder due to alpha-galactosidase A deficiency, leads to an accumulation of globotriaosylceramide resulting in a multisystemic disorder. The initial manifestations of the disease are not specific, leading to a delayed diagnosis. We report a patient in whom the diagnosis was obtained by family screening and the confrontation of clinical signs. We also present a 4 year follow-up under enzyme replacement therapy (agalsidase β, 1 mg/kg/14 days).

Topics: alpha-Galactosidase; Biomarkers; Cardiomyopathy, Hypertrophic; Fabry Disease; Follow-Up Studies; Genetic Testing; Humans; Isoenzymes; Male; Medical History Taking; Middle Aged; Mutation; Pedigree; Renal Insufficiency, Chronic; Treatment Outcome; Trihexosylceramides