{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T02:51:15Z","timestamp":1786935075909,"version":"build-2736575974"},"reference-count":89,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T00:00:00Z","timestamp":1703030400000},"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>Fabry disease (FD) is a recessive monogenic disease linked to chromosome X due to more than two hundred mutations in the alfa-galactosidase A (GLA) gene. Modifications of the GLA gene may cause the progressive accumulation of globotriaosylceramide (Gb3) and its deacylated form, globotriasylsphingosine (lyso-Gb3), in lysosomes of several types of cells of the heart, kidneys, skin, eyes, peripheral and central nervous system (not clearly and fully demonstrated), and gut with different and pleiotropic clinical symptoms. Among the main symptoms are acroparesthesias and pain crisis (involving the peripheral nervous system), hypohidrosis, abdominal pain, gut motility abnormalities (involving the autonomic system), and finally, cerebrovascular ischemic events due to macrovascular involvement (TIA and stroke) and lacunar strokes and white matter abnormalities due to a small vessel disease (SVS). Gb3 lysosomal accumulation causes cytoplasmatic disruption and subsequent cell death. Additional consequences of Gb3 deposits are inflammatory processes, abnormalities of leukocyte function, and impaired trafficking of some types of immune cells, including lymphocytes, monocytes, CD8+ cells, B cells, and dendritic cells. The involvement of inflammation in AFD pathogenesis conflicts with the reported poor correlation between CRP levels as an inflammation marker and clinical scores such as the Mainz Severity Score Index (MSSI). Also, some authors have suggested an autoimmune reaction is involved in the disease\u2019s pathogenetic mechanism after the \u03b1-galactosidase A deficiency. Some studies have reported a high degree of neuronal apoptosis inhibiting protein as a critical anti-apoptotic mediator in children with Fabry disease compared to healthy controls. Notably, this apoptotic upregulation did not change after treatment with enzymatic replacement therapy (ERT), with a further upregulation of the apoptosis-inducing factor after ERT started. Gb3-accumulation has been reported to increase the degree of oxidative stress indexes and the production of reactive oxygen species (ROS). Lipids and proteins have been reported as oxidized and not functioning. Thus, neurological complications are linked to different pathogenetic molecular mechanisms. Progressive accumulation of Gb3 represents a possible pathogenetic event of peripheral nerve involvement. In contrast, central nervous system participation in the clinical setting of cerebrovascular ischemic events seems to be due to the epitheliopathy of Anderson\u2013Fabry disease with lacunar lesions and white matter hyperintensities (WMHs). In this review manuscript, we revised molecular mechanisms of peripheral and central neurological complications of Anderson\u2013Fabry Disease. The management of Fabry disease may be improved by the identification of biomarkers that reflect the clinical course, severity, and progression of the disease. Intensive research on biomarkers has been conducted over the years to detect novel markers that may potentially be used in clinical practice as a screening tool, in the context of the diagnostic process and as an indicator of response to treatment. Recent proteomic or metabolomic studies are in progress, investigating plasma proteome profiles in Fabry patients: these assessments may be useful to characterize the molecular pathology of the disease, improve the diagnostic process, and monitor the response to treatment.<\/jats:p>","DOI":"10.3390\/ijms25010061","type":"journal-article","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T03:51:45Z","timestamp":1703044305000},"page":"61","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Molecular Pathogenesis of Central and Peripheral Nervous System Complications in Anderson\u2013Fabry Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-7318","authenticated-orcid":false,"given":"Antonino","family":"Tuttolomondo","sequence":"first","affiliation":[{"name":"Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, \u201cG. D\u2019Alessandro\u201d, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Fabry Disease Regional Reference Centre, Internal Medicine and Stroke Care Ward, University Hospital Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Baglio","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, \u201cG. D\u2019Alessandro\u201d, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Fabry Disease Regional Reference Centre, Internal Medicine and Stroke Care Ward, University Hospital Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4162-3517","authenticated-orcid":false,"given":"Renata","family":"Riolo","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, \u201cG. D\u2019Alessandro\u201d, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Fabry Disease Regional Reference Centre, Internal Medicine and Stroke Care Ward, University Hospital Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Todaro","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, \u201cG. D\u2019Alessandro\u201d, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Fabry Disease Regional Reference Centre, Internal Medicine and Stroke Care Ward, University Hospital Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaspare","family":"Parrinello","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, \u201cG. D\u2019Alessandro\u201d, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Miceli","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, \u201cG. D\u2019Alessandro\u201d, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Fabry Disease Regional Reference Centre, Internal Medicine and Stroke Care Ward, University Hospital Policlinico \u201cP. Giaccone\u201d, 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":"Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, \u201cG. D\u2019Alessandro\u201d, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy"},{"name":"Fabry Disease Regional Reference Centre, Internal Medicine and Stroke Care Ward, University Hospital Policlinico \u201cP. 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