{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:10:22Z","timestamp":1790698222814,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Fabry disease is a rare X-linked lysosomal storage disorder characterized by progressive glycosphingolipid accumulation and multisystem organ involvement. Globotriaosylsphingosine (Lyso-Gb3) has emerged as a promising biomarker of disease burden; however, its relationship with validated clinical severity scoring systems remains incompletely understood. This study aimed to evaluate the associations between serum Lyso-Gb3 concentrations and the overall scores of three validated clinical severity assessment tools\u2014the Mainz Severity Score Index (MSSI), Disease Severity Scoring System (DS3), and Fabry Stabilization Index (FASTEX)\u2014in patients with Fabry disease. This retrospective observational study included 18 adult patients with genetically and\/or enzymatically confirmed Fabry disease who were regularly followed at a tertiary referral center. Baseline and 12-month serum Lyso-Gb3 concentrations, MSSI scores, DS3 scores, and FASTEX values were evaluated. Correlations between Lyso-Gb3 concentrations and disease severity scores were assessed using Spearman correlation analysis. Exploratory sex-stratified analyses and univariable linear regression analyses were additionally performed to examine associations with disease severity; these analyses were considered hypothesis-generating because of the limited sample size. Median baseline Lyso-Gb3 concentration was 6.77 ng\/mL (IQR: 3.94\u201350.10), median baseline MSSI score was 27.0 (IQR: 16.3\u201334.3), and median baseline DS3 score was 19.0 (IQR: 15.3\u201322.0). Significant reductions were observed in Lyso-Gb3 concentrations, MSSI scores, and DS3 scores after 12 months of follow-up (all p &lt; 0.001). Baseline Lyso-Gb3 concentrations demonstrated strong positive correlations with baseline MSSI (\u03c1 = 0.845, p &lt; 0.001) and baseline DS3 scores (\u03c1 = 0.854, p &lt; 0.001), while no significant correlation was observed with FASTEX scores (\u03c1 = \u22120.117, p = 0.644). Similar significant correlations were identified between 12-month Lyso-Gb3 concentrations and corresponding MSSI (\u03c1 = 0.812, p &lt; 0.001) and DS3 scores (\u03c1 = 0.697, p = 0.001). In sex-stratified analyses, significant correlations between Lyso-Gb3 and disease severity scores were observed predominantly among male patients. In exploratory univariable linear regression analyses, baseline Lyso-Gb3 concentrations were strongly associated with baseline MSSI (R2 = 0.758) and DS3 scores (R2 = 0.579); however, these estimates should be interpreted cautiously because of the small sample size. Serum Lyso-Gb3 concentrations were strongly associated with MSSI and DS3 scores in this small retrospective cohort, whereas no statistically significant association was observed with FASTEX. The observed associations, particularly those derived from sex-stratified and regression analyses, should be considered exploratory and hypothesis-generating because of the limited sample size. Larger prospective multicenter studies are required to confirm the magnitude, independence, and clinical applicability of these relationships.<\/jats:p>","DOI":"10.3390\/ijms27146526","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:01:28Z","timestamp":1784768488000},"page":"6526","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bridging Biochemical and Clinical Disease Burden in Fabry Disease: A Comparative Analysis of Lyso-Gb3, MSSI, DS3, and FASTEX"],"prefix":"10.3390","volume":"27","author":[{"given":"Sadettin","family":"Ozturk","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Gaziantep City Hospital, Gaziantep 27100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8719-6701","authenticated-orcid":false,"given":"Elif Melis Balo\u011flu","family":"Akyol","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Gaziantep City Hospital, Gaziantep 27100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13023-016-0441-z","article-title":"Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant","volume":"11","author":"Lenders","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Desnick, R.J. (2025). Fabry disease: \u03b1-galactosidase A deficiency. Rosenberg\u2019s Molecular and Genetic Basis of Neurological and Psychiatric Disease, Elsavier.","DOI":"10.1016\/B978-0-443-19041-4.00079-0"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Li, P., Xi, Y., Zhang, Y., Samad, A., Lan, W., Wu, Y., Zhao, J., Chen, G., Wu, C., and Xiong, Q. (2024). GLA Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease. Cells, 13.","DOI":"10.3390\/cells13050437"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Modrego, A., Amaranto, M., Godino, A., Mendoza, R., Barra, J.L., and Corchero, J.L. (2021). Human \u03b1-Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126518"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Giacalone, I., Ruzzi, L., Anania, M., Cuonzo, M., Marsana, E.M., Mastrippolito, S., Francofonte, D., Bucco, S., D\u2019Errico, A., and Longo, M.O. (2025). The Identification of a Novel Pathogenic Variant of the GLA Gene Associated with a Classic Phenotype of Anderson\u2013Fabry Disease: A Clinical and Molecular Study. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26020470"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Faro, D.C., Di Pino, F.L., and Monte, I.P. (2024). Inflammation, Oxidative Stress, and Endothelial Dysfunction in the Pathogenesis of Vascular Damage: Unraveling Novel Cardiovascular Risk Factors in Fabry Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158273"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kurdi, H., Lavalle, L., Moon, J.C.C., and Hughes, D. (2024). Inflammation in Fabry disease: Stages, molecular pathways, and therapeutic implications. Front. Cardiovasc. Med., 11.","DOI":"10.3389\/fcvm.2024.1420067"},{"key":"ref_8","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_9","doi-asserted-by":"crossref","unstructured":"Tuttolomondo, A., Simonetta, I., Daidone, M., Mogavero, A., Ortello, A., and Pinto, A. (2019). Metabolic and Vascular Effect of the Mediterranean Diet. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194716"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.amjms.2020.07.011","article-title":"When and How to Diagnose Fabry Disease in Clinical Pratice","volume":"360","author":"Michaud","year":"2020","journal-title":"Am. J. Med. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.12669\/pjms.38.8.7063","article-title":"Fabry disease: Definition, Incidence, Clinical presentations and Treatment\u2014Focus on cardiac involvement","volume":"38","author":"Saeed","year":"2022","journal-title":"Pak. J. Med. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/cge.12613","article-title":"X-chromosome inactivation in female patients with Fabry disease","volume":"89","author":"Echevarria","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Izhar, R., Borriello, M., La Russa, A., Di Paola, R., De, A., Capasso, G., Ingrosso, D., Perna, A., and Simeoni, M. (2023). Fabry Disease in Women: Genetic Basis, Available Biomarkers, and Clinical Manifestations. Genes, 15.","DOI":"10.3390\/genes15010037"},{"key":"ref_14","first-page":"618","article-title":"Role of Circulating X-Chromosome Inactivation and Xist as Biomarkers in Female Carriers of Fabry Disease","volume":"4","author":"Rossi","year":"2024","journal-title":"Int. J. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.ymgme.2018.02.014","article-title":"Fabry disease revisited: Management and treatment recommendations for adult patients","volume":"123","author":"Ortiz","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1159\/000448968","article-title":"Long Term Treatment with Enzyme Replacement Therapy in Patients with Fabry Disease","volume":"134","author":"Oder","year":"2016","journal-title":"Nephron"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chen, C.-Y., Li, C.-T., Lin, C.-J., Shih, H.-M., Liu, S.-J., Sun, F.-J., and Wu, C.-J. (2025). Long-Term Enzyme Replacement Therapy and Renal Outcomes in Fabry Disease: A Systematic Review and Meta-Analysis. Biomedicines, 13.","DOI":"10.37766\/inplasy2025.10.0029"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/j.1399-0004.2004.00219.x","article-title":"The Mainz Severity Score Index: A new instrument for quantifying the Anderson\u2013Fabry disease phenotype, and the response of patients to enzyme replacement therapy","volume":"65","author":"Whybra","year":"2004","journal-title":"Clin. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1080\/08035320600618825","article-title":"The Mainz Severity Score Index (MSSI): Development and validation of a system for scoring the signs and symptoms of Fabry disease","volume":"95","author":"Beck","year":"2007","journal-title":"Acta Paediatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1111\/j.1399-0004.2008.01012.x","article-title":"Enzyme replacement therapy with agalsidase alfa in a cohort of Italian patients with Anderson\u2013Fabry disease: Testing the effects with the Mainz Severity Score Index","volume":"74","author":"Parini","year":"2008","journal-title":"Clin. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.ymgme.2009.10.178","article-title":"A validated disease severity scoring system for Fabry disease","volume":"99","author":"Giannini","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Weedon-Fekj\u00e6r, M.S., Pihlstr\u00f8m, H.K., Weedon-Fekj\u00e6r, H., Berentsen, B., Hatlebakk, J.G., Bjerkely, B., Solberg, O.K., Heimdal, K.R., \u00d8rstavik, K., and Jenssen, T.G. (2025). Gastrointestinal symptoms in adults with Fabry disease and their associations with physical and mental health. BMC Gastroenterol., 25.","DOI":"10.1186\/s12876-025-04439-0"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1093\/ckj\/sfw082","article-title":"FAbry STabilization indEX (FASTEX): An innovative tool for the assessment of clinical stabilization in Fabry disease","volume":"9","author":"Mignani","year":"2016","journal-title":"Clin. Kidney J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ymgme.2019.12.010","article-title":"FAbry STabilization indEX (FASTEX): Clinical evaluation of disease progression in Fabry patients","volume":"129","author":"Lenders","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1093\/ckj\/sfy108","article-title":"New insights from the application of the FAbry STabilization indEX in a large population of Fabry cases","volume":"12","author":"Mignani","year":"2019","journal-title":"Clin. Kidney J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1093\/ckj\/sfy126","article-title":"Will the FAbry STabilization indEX make its way to everyday clinical practice?","volume":"12","author":"Cairns","year":"2019","journal-title":"Clin. Kidney J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ymgme.2016.10.006","article-title":"Plasma LysoGb3: A useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes","volume":"120","author":"Nowak","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Magnusen, A.F., and Pandey, M.K. (2024). Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212252"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Biddeci, G., Spinelli, G., Colomba, P., Duro, G., Giacalone, I., and Di Blasi, F. (2025). Fabry Disease Beyond Storage: The Role of Inflammation in Disease Progression. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157054"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Simonetta, I., Baglio, I., and Tuttolomondo, A. (2026). Molecular, Metabolic and Inflammatory Patterns Involved in Pathogenesis of Anderson-Fabry Disease. Cells, 15.","DOI":"10.3390\/cells15050443"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"119824","DOI":"10.1016\/j.cca.2024.119824","article-title":"LysoGb3 quantification facilitates phenotypic categorization of Fabry disease patients: Insights gained by a novel MS\/MS method","volume":"561","author":"Kuchar","year":"2024","journal-title":"Clin. Chim. Acta"},{"key":"ref_32","first-page":"3733","article-title":"Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease","volume":"15","author":"Ouyang","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"440","DOI":"10.2174\/1570159X20666220601124117","article-title":"Fabry Disease: Current and Novel Therapeutic Strategies. A Narrative Review","volume":"21","author":"Palaiodimou","year":"2023","journal-title":"Curr. Neuropharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1136\/jmedgenet-2020-107338","article-title":"Lyso-Gb3 associates with adverse long-term outcome in patients with Fabry disease","volume":"59","author":"Nowak","year":"2022","journal-title":"J. Med. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1093\/hmg\/ddad073","article-title":"Elucidating the toxic effect and disease mechanisms associated with Lyso-Gb3 in Fabry disease","volume":"32","author":"Nikolaenko","year":"2023","journal-title":"Hum. Mol. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1136\/jmedgenet-2020-107162","article-title":"Globotriaosylsphingosine (lyso-Gb3) and analogues in plasma and urine of patients with Fabry disease and correlations with long-term treatment and genotypes in a nationwide female Danish cohort","volume":"58","author":"Effraimidis","year":"2021","journal-title":"J. Med. Genet."},{"key":"ref_37","first-page":"e61380","article-title":"Potential Usefulness of Lifetime Globotriaosylsphingosine Exposure at Diagnosis and Baseline Modified Disease Severity Score in Early-Diagnosed Patients with Fabry Disease","volume":"16","author":"Hotta","year":"2024","journal-title":"Cureus"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.bbadis.2010.05.003","article-title":"Plasma globotriaosylsphingosine: Diagnostic value and relation to clinical manifestations of Fabry disease","volume":"1802","author":"Rombach","year":"2010","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_39","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_40","first-page":"70","article-title":"Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy","volume":"1812","author":"Rombach","year":"2011","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.ymgme.2017.05.001","article-title":"Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease","volume":"121","author":"Arends","year":"2017","journal-title":"Mol. Genet. Metab."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6526\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:19:50Z","timestamp":1784866790000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6526"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":41,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146526"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146526","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]}}}