{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:30:29Z","timestamp":1791304229107,"version":"4.3.1"},"reference-count":105,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Anderson\u2013Fabry disease (AFD) is a rare disease with an incidenceof approximately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) is the element characterizing Fabry disease due to a hereditary deficiency \u03b1-galactosidase A (GLA) enzyme. The accumulation of Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition of sphingolipids occurs in the autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system cells, and myocardial cells, resulting in organ failure. This manuscript will review the molecular pathogenetic pathways involved in Anderson\u2013Fabry disease and in its organ damage. Some studies reported that inhibition of mitochondrial function and energy metabolism plays a significant role in AFD cardiomyopathy and in kidney disease of AFD patients. Furthermore, mitochondrial dysfunction has been reported as linked to the dysregulation of the autophagy\u2013lysosomal pathway which inhibits the mechanistic target of rapamycin kinase (mTOR) mediated control of mitochondrial metabolism in AFD cells. Cerebrovascular complications due to AFD are caused by cerebral micro vessel stenosis. These are caused by wall thickening resulting from the intramural accumulation of glycolipids, luminal occlusion or thrombosis. Other pathogenetic mechanisms involved in organ damage linked to Gb3 accumulation are endocytosis and lysosomal degradation of endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via a clathrin-dependent process. This process represents a crucial event in endothelial dysfunction. Several studies have identified the deacylated form of Gb3, globotriaosylsphingosine (Lyso-Gb3), as the main catabolite that increases in plasma and urine in patients with AFD. The mean concentrations of Gb3 in all organs and plasma of Galactosidase A knockout mice were significantly higher than those of wild-type mice. The distributions of Gb3 isoforms vary from organ to organ. Various Gb3 isoforms were observed mainly in the kidneys, and kidney-specific Gb3 isoforms were hydroxylated. Furthermore, the action of Gb3 on the KCa3.1 channel suggests a possible contribution of this interaction to the Fabry disease process, as this channel is expressed in various cells, including endothelial cells, fibroblasts, smooth muscle cells in proliferation, microglia, and lymphocytes. These molecular pathways could be considered a potential therapeutic target to correct the enzyme in addition to the traditional enzyme replacement therapies (ERT) or drug chaperone therapy.<\/jats:p>","DOI":"10.3390\/ijms221810088","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:04:23Z","timestamp":1632211463000},"page":"10088","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Pathogenesis and Molecular Mechanisms of Anderson\u2013Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-7318","authenticated-orcid":false,"given":"Antonino","family":"Tuttolomondo","sequence":"first","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant Excellence and Internal and Specialized Medicine (ProMISE) G. D\u2019Alessandro, University of Palermo (Italy), Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Centro di Riferimento Regionale per la Cura e Diagnosi della Malattia di Anderson\u2013Fabry, 90127 Palermo, Italy"},{"name":"Molecular and Clinical Medicine PhD Programme, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1574-104X","authenticated-orcid":false,"given":"Irene","family":"Simonetta","sequence":"additional","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant Excellence and Internal and Specialized Medicine (ProMISE) G. D\u2019Alessandro, University of Palermo (Italy), Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Centro di Riferimento Regionale per la Cura e Diagnosi della Malattia di Anderson\u2013Fabry, 90127 Palermo, Italy"},{"name":"Molecular and Clinical Medicine PhD Programme, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Riolo","sequence":"additional","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant Excellence and Internal and Specialized Medicine (ProMISE) G. D\u2019Alessandro, University of Palermo (Italy), Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Centro di Riferimento Regionale per la Cura e Diagnosi della Malattia di Anderson\u2013Fabry, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Todaro","sequence":"additional","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant Excellence and Internal and Specialized Medicine (ProMISE) G. D\u2019Alessandro, University of Palermo (Italy), Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Centro di Riferimento Regionale per la Cura e Diagnosi della Malattia di Anderson\u2013Fabry, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Di Chiara","sequence":"additional","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant Excellence and Internal and Specialized Medicine (ProMISE) G. D\u2019Alessandro, University of Palermo (Italy), Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Centro di Riferimento Regionale per la Cura e Diagnosi della Malattia di Anderson\u2013Fabry, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Miceli","sequence":"additional","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant Excellence and Internal and Specialized Medicine (ProMISE) G. D\u2019Alessandro, University of Palermo (Italy), Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Centro di Riferimento Regionale per la Cura e Diagnosi della Malattia di Anderson\u2013Fabry, 90127 Palermo, Italy"},{"name":"Molecular and Clinical Medicine PhD Programme, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pinto","sequence":"additional","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant Excellence and Internal and Specialized Medicine (ProMISE) G. D\u2019Alessandro, University of Palermo (Italy), Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Centro di Riferimento Regionale per la Cura e Diagnosi della Malattia di Anderson\u2013Fabry, 90127 Palermo, Italy"},{"name":"Molecular and Clinical Medicine PhD Programme, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1750-1172-5-30","article-title":"Fabry disease","volume":"5","author":"Germain","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5974","DOI":"10.2174\/13816128113199990352","article-title":"Anderson\u2013Fabry Disease: A Multiorgan Disease","volume":"19","author":"Tuttolomondo","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/BF01986897","article-title":"Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis (Purpura papulosa haemorrhagica Hebrae)","volume":"43","author":"Fabry","year":"1898","journal-title":"Arch. Dermatol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1365-2133.1898.tb16317.x","article-title":"A Case of \u201cAngeio-Keratoma\u201d","volume":"10","author":"Anderson","year":"1898","journal-title":"Br. J. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1097\/00005792-200203000-00003","article-title":"Natural History of Fabry Renal Disease","volume":"81","author":"Branton","year":"2002","journal-title":"Medicine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/modpathol.3800344","article-title":"Chloroquine-induced lipidosis mimicking Fabry disease","volume":"18","author":"Albay","year":"2004","journal-title":"Mod. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/1750-1172-8-116","article-title":"Fibrosis: A key feature of Fabry disease with potential therapeutic implications","volume":"8","author":"Weidemann","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5720","DOI":"10.1093\/hmg\/ddv291","article-title":"Lyso-Gb3 activates Notch1 in human podocytes","volume":"24","author":"Carpio","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Waldek, S., and Feriozzi, S. (2014). Fabry nephropathy: A review\u2014How can we optimize the management of Fabry nephropathy?. BMC Nephrol., 15.","DOI":"10.1186\/1471-2369-15-72"},{"key":"ref_10","first-page":"109","article-title":"Renal ultrastructural findings in Anderson\u2013Fabry disease","volume":"15","author":"Sessa","year":"2002","journal-title":"J. Nephrol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13382","DOI":"10.1021\/acs.analchem.7b03609","article-title":"Separation and Analysis of Lactosylceramide, Galabiosylceramide, and Globotriaosylceramide by LC-MS\/MS in Urine of Fabry Disease Patients","volume":"89","author":"Boutin","year":"2017","journal-title":"Anal. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1016\/j.bbamem.2006.05.027","article-title":"Sphingolipid metabolism diseases","volume":"1758","author":"Kolter","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1073\/pnas.0712309105","article-title":"Elevated globotriaosylsphingosine is a hallmark of Fabry disease","volume":"105","author":"Aerts","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0065-2423(09)49003-6","article-title":"Chapter 3 Biochemical Basis of Fabry Disease with Emphasis on Mitochondrial Function and Protein Trafficking","volume":"49","author":"Das","year":"2009","journal-title":"Adv. Clin. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0960-9822(98)70018-1","article-title":"A novel role for Rab5\u2013GDI in ligand sequestration into clathrin-coated pits","volume":"8","author":"McLauchlan","year":"1998","journal-title":"Curr. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1083\/jcb.201208152","article-title":"Lysosomal storage disorders: The cellular impact of lysosomal dysfunction","volume":"199","author":"Platt","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ceca.2007.12.005","article-title":"Mitochondrial Ca2+ homeostasis in lysosomal storage diseases","volume":"44","author":"Kiselyov","year":"2008","journal-title":"Cell Calcium"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1136\/jmg.38.11.769","article-title":"Anderson\u2013Fabry disease: Clinical manifestations and impact of disease in a cohort of 60 obligate carrier females","volume":"38","author":"MacDermot","year":"2001","journal-title":"J. Med. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1093\/eurjhf\/hfq211","article-title":"Cardiac energy metabolism is disturbed in Fabry disease and improves with enzyme replacement therapy using recombinant human galactosidase A","volume":"13","author":"Machann","year":"2011","journal-title":"Eur. J. Hear. Fail."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.stemcr.2019.07.004","article-title":"A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology","volume":"13","author":"Birket","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Liebau, M.C., Braun, F., H\u00f6pker, K., Weitbrecht, C., Bartels, V., M\u00fcller, R.-U., Brodesser, S., Saleem, M.A., Benzing, T., and Schermer, B. (2013). Dysregulated Autophagy Contributes to Podocyte Damage in Fabry\u2019s Disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063506"},{"key":"ref_22","unstructured":"(2021, March 26). Urine-Derived Cells: A Promising Diagnostic Tool in Fabry Disease Patients. Available online: https:\/\/europepmc.org\/article\/pmc\/pmc6056427."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s00424-013-1407-9","article-title":"The sodium chloride cotransporter SLC12A3: New roles in sodium, potassium, and blood pressure regulation","volume":"466","author":"Moes","year":"2013","journal-title":"Pfl\u00fcg. Arch."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4544","DOI":"10.1096\/fj.201701374R","article-title":"Medullary thick ascending limb impairment in the Gla tm Tg(CAG-A4GALT) Fabry model mice","volume":"32","author":"Maruyama","year":"2018","journal-title":"FASEB J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1093\/hmg\/ddw185","article-title":"Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: Relevance to Parkinson disease","volume":"25","author":"Magalhaes","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1242\/jcs.146365","article-title":"TFEB at a glance","volume":"129","author":"Napolitano","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e98804","DOI":"10.15252\/embj.201798804","article-title":"The complex relationship between TFEB transcription factor phosphorylation and subcellular localization","volume":"37","author":"Puertollano","year":"2018","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.1242\/jcs.051011","article-title":"mTOR signaling at a glance","volume":"122","author":"Laplante","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"473","DOI":"10.4161\/15384101.2014.991572","article-title":"mTOR coordinates protein synthesis, mitochondrial activity and proliferation","volume":"14","author":"Morita","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1056\/NEJM195612132552411","article-title":"Case 42502","volume":"255","author":"Cabot","year":"1956","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/S0025-6196(11)62969-8","article-title":"Genetics of Cerebrovascular Disorders","volume":"80","author":"Meschia","year":"2005","journal-title":"Mayo Clin. Proc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/BF00868342","article-title":"Stroke in Fabry\u2019s disease","volume":"241","author":"Grewal","year":"1993","journal-title":"J. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/ana.410230513","article-title":"Nervous system involvement in Fabry\u2019s disease: Clinicopathological and biochemical correlation","volume":"23","author":"Kaye","year":"1988","journal-title":"Ann. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1136\/jnnp.51.9.1240","article-title":"Magnetic resonance imaging in Fabry\u2019s disease","volume":"51","author":"Menzies","year":"1988","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1159\/000106640","article-title":"The vascular dementia of Fabry\u2019s disease","volume":"8","author":"Mendez","year":"1997","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1136\/jnnp.73.3.340","article-title":"Neurological presentation of Fabry\u2019s disease in a 52 year old man","volume":"73","author":"Mohanraj","year":"2002","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_37","first-page":"S69","article-title":"Anderson\u2013Fabry Disease: A Case Report with MR, CT, and Cerebral Angiography","volume":"10","author":"Moumdjian","year":"1989","journal-title":"Am. J. Neuroradiol."},{"key":"ref_38","first-page":"491","article-title":"The neurological complications of Anderson\u2013Fabry disease (alpha-galactosidase A deficiency)--investigation of symptomatic and presymptomatic patients","volume":"75","author":"Morgan","year":"1990","journal-title":"Q. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ana.410400105","article-title":"Cerebrovascular complications of Fabry\u2019s disease","volume":"40","author":"Mitsias","year":"1996","journal-title":"Ann. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1212\/WNL.50.6.1746","article-title":"Quantitative analysis of cerebral vasculopathy in patients with Fabry disease","volume":"50","author":"Crutchfield","year":"1998","journal-title":"Neurology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/01.nrl.0000187495.16824.a6","article-title":"Magnetic Resonance Image Findings in 5 Young Patients with Fabry Disease","volume":"12","author":"Politei","year":"2006","journal-title":"Neurologist"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1001\/archneur.1963.00460100061007","article-title":"The Neuropathology of Hereditary Dystopic Lipidosis","volume":"9","author":"Rahman","year":"1963","journal-title":"Arch. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1097\/00000478-197906000-00003","article-title":"Fabry\u2019s disease. Primary diagnosis by electron microscopy","volume":"3","author":"Schatzki","year":"1979","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/ana.410310410","article-title":"Fabry disease: Immunocytochemical characterization of neuronal involvement","volume":"31","author":"Schwarting","year":"1992","journal-title":"Ann. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1159\/000488121","article-title":"Fabry Nephropathy: An Evidence-Based Narrative Review","volume":"43","author":"Paniagua","year":"2018","journal-title":"Kidney Blood Press. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1093\/cvr\/cvq333","article-title":"Globotriaosylceramide leads to K(Ca)3.1 channel dysfunction: A new insight into endothelial dysfunction in Fabry disease","volume":"89","author":"Park","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"17938","DOI":"10.1074\/jbc.M109.086553","article-title":"Recycling of the Ca2+-activated K+ Channel, KCa2.3, Is Dependent upon RME-1, Rab35\/EPI64C, and an N-terminal Domain","volume":"285","author":"Gao","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"C1015","DOI":"10.1152\/ajpcell.00120.2010","article-title":"ESCRT-dependent targeting of plasma membrane localized KCa3.1 to the lysosomes","volume":"299","author":"Balut","year":"2010","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1161\/ATVBAHA.113.302200","article-title":"Globotriaosylceramide Induces Lysosomal Degradation of Endothelial K Ca 3.1 in Fabry Disease","volume":"34","author":"Choi","year":"2014","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1161\/01.RES.0000238377.08219.0c","article-title":"Impaired Endothelium-Derived Hyperpolarizing Factor-Mediated Dilations and Increased Blood Pressure in Mice Deficient of the Intermediate-Conductance Ca2+-Activated K+ Channel","volume":"99","author":"Si","year":"2006","journal-title":"Circ. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"20960","DOI":"10.1074\/jbc.M702436200","article-title":"Caveolin-associated Accumulation of Globotriaosylceramide in the Vascular Endothelium of \u03b1-Galactosidase A Null Mice","volume":"282","author":"Shu","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"102633","DOI":"10.1016\/j.ebiom.2020.102633","article-title":"Enhanced thrombospondin-1 causes dysfunction of vascular endothelial cells derived from Fabry disease-induced pluripotent stem cells","volume":"52","author":"Do","year":"2020","journal-title":"EBioMedicine"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3389\/fcvm.2018.00108","article-title":"Serum Biomarkers of Endothelial Dysfunction in Fabry Associated Cardiomyopathy","volume":"5","author":"Loso","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1161\/CIRCULATIONAHA.108.846634","article-title":"Genetic Deficit of SK3 and IK1 Channels Disrupts the Endothelium-Derived Hyperpolarizing Factor Vasodilator Pathway and Causes Hypertension","volume":"119","author":"Kaistha","year":"2009","journal-title":"Circulation"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kim, S.-Y., Park, S., Lee, S.-W., Lee, J.-H., Lee, E., Kim, M., Kim, Y., Kang, J., Chung, C., and Moon, J.-S. (2021). RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death. Cells, 10.","DOI":"10.3390\/cells10020245"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.2215\/CJN.04340510","article-title":"Prognostic Indicators of Renal Disease Progression in Adults with Fabry Disease: Natural History Data from the Fabry Registry","volume":"5","author":"Wanner","year":"2010","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1038\/sj.ki.5001794","article-title":"Predicting initiation and progression of chronic kidney disease: Developing renal risk scores","volume":"70","author":"Taal","year":"2006","journal-title":"Kidney Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/sj.ejhg.5201184","article-title":"Remarkable variability in renal disease in a large Slovenian family with Fabry disease","volume":"12","author":"Verovnik","year":"2004","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"S134","DOI":"10.1097\/01.ASN.0000016684.07368.75","article-title":"Renal Pathology in Fabry Disease","volume":"13","author":"Alroy","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1681\/ASN.2019050497","article-title":"Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss","volume":"31","author":"Najafian","year":"2020","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Fall, B., Scott, C.R., Mauer, M., Shankland, S., Pippin, J., Jefferson, J.A., Wallace, E., Warnock, D., and Najafian, B. (2016). Urinary Podocyte Loss Is Increased in Patients with Fabry Disease and Correlates with Clinical Severity of Fabry Nephropathy. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168346"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1093\/ckj\/sfy053","article-title":"Early decrease in the podocalyxin to synaptopodin ratio in urinary Fabry podocytes","volume":"12","author":"Trimarchi","year":"2019","journal-title":"Clin. Kidney J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"49","DOI":"10.5935\/0101-2800.20160008","article-title":"Podocyturia in Fabry disease","volume":"38","author":"Pereira","year":"2016","journal-title":"Braz. J. Nephrol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1093\/ndt\/gfq306","article-title":"Globotriaosylsphingosine actions on human glomerular podocytes: Implications for Fabry nephropathy","volume":"26","author":"Sanz","year":"2011","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Trimarchi, H., Ortiz, A., and S\u00e1nchez-Ni\u00f1o, M.D. (2020). Lyso-Gb3 Increases \u03b1v\u03b23 Integrin Gene Expression in Cultured Human Podocytes in Fabry Nephropathy. J. Clin. Med., 9.","DOI":"10.3390\/jcm9113659"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"107558","DOI":"10.18632\/oncotarget.22505","article-title":"Genetic variants associated with Fabry disease progression despite enzyme replacement therapy","volume":"8","author":"Scionti","year":"2017","journal-title":"Oncotarget"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1212\/01.WNL.0000166000.24321.4F","article-title":"Effect of genetic modifiers on cerebral lesions in Fabry disease","volume":"64","author":"Altarescu","year":"2005","journal-title":"Neurology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10545-007-0716-6","article-title":"Correlation between interleukin-6 promoter and C-reactive protein (CRP) polymorphisms and CRP levels with the Mainz Severity Score Index for Fabry disease","volume":"31","author":"Altarescu","year":"2008","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_69","first-page":"4980942","article-title":"High Lyso-Gb3 Plasma Levels Associated with Decreased miR-29 and miR-200 Urinary Excretion in Young Non-Albuminuric Male Patient with Classic Fabry Disease","volume":"2019","author":"Jaurretche","year":"2019","journal-title":"Case Rep. Nephrol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"15277","DOI":"10.1038\/s41598-019-51805-6","article-title":"Circulating microRNAs in Fabry Disease","volume":"9","author":"Xiao","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_71","first-page":"1","article-title":"Aberrant DNA methylation of calcitonin receptor in Fabry patients treated with enzyme replacement therapy","volume":"5","author":"Metz","year":"2015","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_72","first-page":"100497","article-title":"Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene","volume":"20","author":"Hossain","year":"2019","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3476","DOI":"10.1021\/ac404000d","article-title":"Multiplex Tandem Mass Spectrometry Analysis of Novel Plasma Lyso-Gb3-Related Analogues in Fabry Disease","volume":"86","author":"Boutin","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.cca.2015.11.018","article-title":"Tandem mass spectrometry multiplex analysis of methylated and non-methylated urinary Gb3 isoforms in Fabry disease patients","volume":"452","author":"Abaoui","year":"2016","journal-title":"Clin. Chim. Acta"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/BF01606034","article-title":"Belohlavek Cardiocyte storage and hypertrophy as a sole manifestation of Fabry\u2019s disease","volume":"417","author":"Elleder","year":"1990","journal-title":"Virchows Arch. A Pathol. Anat. Histopathol."},{"key":"ref_76","unstructured":"(2021, March 31). Hypertrophic Cardiomyopathy: A Paradigm for Myocardial Energy Depletion, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/12711218\/."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ymgme.2004.01.011","article-title":"Fabry disease: Reduced activities of respiratory chain enzymes with decreased levels of energy-rich phosphates in fibroblasts","volume":"82","year":"2004","journal-title":"Mol. Genet. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1136\/hrt.2010.204586","article-title":"The right ventricle in Fabry disease: Natural history and impact of enzyme replacement therapy","volume":"96","author":"Niemann","year":"2010","journal-title":"Heart"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1016\/j.humpath.2015.07.017","article-title":"Increased oxidative stress contributes to cardiomyocyte dysfunction and death in patients with Fabry disease cardiomyopathy","volume":"46","author":"Chimenti","year":"2015","journal-title":"Hum. Pathol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/j.cjca.2015.10.033","article-title":"Evaluation of Proinflammatory Prognostic Biomarkers for Fabry Cardiomyopathy With Enzyme Replacement Therapy","volume":"32","author":"Chen","year":"2016","journal-title":"Can. J. Cardiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.carpath.2009.05.003","article-title":"A detailed pathologic examination of heart tissue from three older patients with Anderson\u2013Fabry disease on enzyme replacement therapy","volume":"19","author":"Sheppard","year":"2010","journal-title":"Cardiovasc. Pathol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"S130","DOI":"10.1097\/01.ASN.0000015236.70757.C4","article-title":"Biochemical and Molecular Genetic Basis of Fabry Disease","volume":"13","author":"Pastores","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1001\/jama.285.21.2743","article-title":"Enzyme Replacement Therapy in Fabry Disease","volume":"285","author":"Schiffmann","year":"2001","journal-title":"JAMA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1136\/hrt.2006.104026","article-title":"Effects of enzyme replacement therapy on the cardiomyopathy of Anderson Fabry disease: A randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa","volume":"94","author":"Hughes","year":"2008","journal-title":"Heart"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/bs.apcsb.2015.10.001","article-title":"Personalized Pharmacoperones for Lysosomal Storage Disorder","volume":"102","author":"Haneef","year":"2016","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1038\/mt.2015.62","article-title":"Pharmacological Chaperone Therapy: Preclinical Development, Clinical Translation, and Prospects for the Treatment of Lysosomal Storage Disorders","volume":"23","author":"Parenti","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_87","first-page":"4179","article-title":"In vitroinhibition and intracellular enhancement of lysosomal \u03b1-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives","volume":"267","author":"Asano","year":"2000","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1056\/NEJMoa1510198","article-title":"Treatment of Fabry\u2019s Disease with the Pharmacologic Chaperone Migalastat","volume":"375","author":"Germain","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_89","unstructured":"(2021, March 31). Oral Pharmacological Chaperone Migalastat Compared with Enzyme Replacement Therapy in Fabry Disease: 18-Month Results from the Randomised Phase III ATTRACT Study, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/27834756\/."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1002\/cpt.1321","article-title":"Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year","volume":"105","author":"Gensler","year":"2019","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.omtm.2020.08.012","article-title":"In Vitro and In Vivo Amenability to Migalastat in Fabry Disease","volume":"19","author":"Lenders","year":"2020","journal-title":"Mol. Ther.-Methods Clin. Dev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrd.2017.214","article-title":"Emptying the stores: Lysosomal diseases and therapeutic strategies","volume":"17","author":"Platt","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1002\/cpt.790","article-title":"Lucerastat, an Iminosugar for Substrate Reduction Therapy: Tolerability, Pharmacodynamics, and Pharmacokinetics in Patients With Fabry Disease on Enzyme Replacement","volume":"103","author":"Oder","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13023-017-0565-9","article-title":"Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: Safety, tolerability, and pharmacokinetics in healthy subjects","volume":"12","author":"Morand","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1172\/JCI73943","article-title":"Autophagy in cardiovascular biology","volume":"125","author":"Lavandero","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3326","DOI":"10.1038\/s41598-018-21602-8","article-title":"Small-Vessel Vasculopathy Due to Aberrant Autophagy in LAMP-2 Deficiency","volume":"8","author":"Nguyen","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_97","unstructured":"(2021, March 28). Autophagy-Lysosome Pathway Associated Neuropathology and axonal Degeneration in the Brains of Alpha-Galactosidase A-Deficient Mice, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/24529306\/."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.bbalip.2013.11.004","article-title":"Gaucher disease and Fabry disease: New markers and insights in pathophysiology for two distinct glycosphingolipidoses","volume":"1841","author":"Ferraz","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1161\/01.ATV.0000209649.60409.38","article-title":"Cardiac and Vascular Hypertrophy in Fabry Disease","volume":"26","author":"Barbey","year":"2006","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.ymgme.2018.10.007","article-title":"Dissociation of globotriaosylceramide and impaired endothelial function in \u03b1-galactosidase-A deficient EA.hy926 cells","volume":"125","author":"Kaissarian","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ymgme.2009.10.004","article-title":"Vasculopathy in patients with Fabry disease: Current controversies and research directions","volume":"99","author":"Rombach","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ymgme.2013.02.003","article-title":"Fabry disease peripheral blood immune cells release inflammatory cytokines: Role of globotriaosylceramide","volume":"109","author":"Mucci","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ymgme.2017.09.004","article-title":"Contribution of inflammatory pathways to Fabry disease pathogenesis","volume":"122","author":"Rozenfeld","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_104","first-page":"1019","article-title":"Stroke and Fabry disease","volume":"259","year":"2011","journal-title":"J. Neurol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1023\/A:1010335505357","article-title":"Inhibition of substrate synthesis as a strategy for glycolipid lysosomal storage disease therapy","volume":"24","author":"Platt","year":"2001","journal-title":"J. Inherit. Metab. Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10088\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:01:43Z","timestamp":1760166103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10088"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,18]]},"references-count":105,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms221810088"],"URL":"https:\/\/doi.org\/10.3390\/ijms221810088","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,18]]}}}