{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:19:08Z","timestamp":1788135548827,"version":"build-2803163510"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":75,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000691","name":"Academy of Medical Sciences","doi-asserted-by":"publisher","award":["DTTFR11\\100075"],"award-info":[{"award-number":["DTTFR11\\100075"]}],"id":[{"id":"10.13039\/501100000691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000860","name":"European Society of Cardiology","doi-asserted-by":"crossref","award":["European Society of Cardiology"],"award-info":[{"award-number":["European Society of Cardiology"]}],"id":[{"id":"10.13039\/501100000860","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003973","name":"Israel Academy of Sciences and Humanities","doi-asserted-by":"crossref","award":["Israel Academy of Sciences and Humanities"],"award-info":[{"award-number":["Israel Academy of Sciences and Humanities"]}],"id":[{"id":"10.13039\/501100003973","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Fabry disease (FD) is a rare lysosomal storage disorder with cardiac involvement. The efficacy of cardiac assessments in predicting disease progression is uncertain and few long-term studies have evaluated a clinically comprehensive approach in tracking cardiac outcomes. We developed a multi-modal framework integrating sex, genetics, clinical assessments, electrocardiography (ECG), imaging, and biomarkers to characterize the progression of cardiac involvement in FD and assess the predictive value of each modality for adverse cardiovascular outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our cohort encompassed 525 \u201cvisit years\u201d across 98 participants (60 females; 60 with classic mutations; mean age at presentation: 42.5\u2009\u00b1\u200917). We defined four cardiac phenotypic clusters (CPC): abnormal ECG, elevated cardiac biomarkers, left ventricular hypertrophy (LVH) (by echocardiography or cardiac magnetic resonance [CMR]), and late gadolinium enhancement (LGE) (by CMR). The primary outcome was a composite of cardiac hospitalization, device implantation, or cardiovascular\/cerebrovascular death. A CPC progression map was plotted, outlining the course of events in FD cardiomyopathy, where changes in ECG and the occurrence of hypertrophy precede increase in cardiac biomarkers and the formation of LGE. Mutation type (classic vs. late-onset) and sex (female vs. male) showed a significant link with a composite outcome of cardiac-related hospitalizations, device implantations (defibrillator\/pacemaker), and cardiovascular or cerebrovascular mortality [Hazard ratio, HR (95% confidence interval, CI, p-value): 12.8 (3.5,46.7),\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0001 and 0.09 (0.03,0.33),\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0002, respectively]. The presence of LGE CPC was associated with an increased likelihood of encountering the composite outcome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We propose a readily-applied \u201c4 domain CPC\u201d model, that can be routinely used in clinical practice, as a prospective \u201cguide-map\u201d for FD cardiomyopathy progression. Its utility is demonstrated in showing the expected role of sex, mutation and CMR findings in the cardiac trajectory of FD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04401-7","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T13:13:15Z","timestamp":1781701995000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multimodal phenotypic clustering predicts cardiac outcomes in Fabry disease"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1162-2991","authenticated-orcid":false,"given":"Elad","family":"Shemesh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Feigin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong Yew","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"Rusk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Gopalan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Deegan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"issue":"4","key":"4401_CR1","doi-asserted-by":"publisher","first-page":"338","DOI":"10.7326\/0003-4819-138-4-200302180-00014","volume":"138","author":"RJ Desnick","year":"2003","unstructured":"Desnick RJ, Brady R, Barranger J, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138(4):338\u201346. https:\/\/doi.org\/10.7326\/0003-4819-138-4-200302180-00014.","journal-title":"Ann Intern Med"},{"issue":"6","key":"4401_CR2","doi-asserted-by":"publisher","first-page":"425","DOI":"10.7326\/0003-4819-146-6-200703200-00007","volume":"146","author":"JTR Clarke","year":"2007","unstructured":"Clarke JTR. Narrative review: Fabry disease. Ann Intern Med. 2007;146(6):425\u201333.","journal-title":"Ann Intern Med"},{"issue":"1","key":"4401_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/jmedgenet-2013-101857","volume":"51","author":"L van der Tol","year":"2014","unstructured":"van der Tol L, Smid BE, Poorthuis BJHM, et al. A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. J Med Genet. 2014;51(1):1\u20139. https:\/\/doi.org\/10.1136\/jmedgenet-2013-101857.","journal-title":"J Med Genet"},{"issue":"9813","key":"4401_CR4","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/S0140-6736(11)61266-X","volume":"379","author":"TP Mechtler","year":"2012","unstructured":"Mechtler TP, Stary S, Metz TF, et al. Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria. Lancet. 2012;379(9813):335\u201341. https:\/\/doi.org\/10.1016\/S0140-6736(11)61266-X.","journal-title":"Lancet"},{"key":"4401_CR5","doi-asserted-by":"publisher","unstructured":"Reisin R, Perrin A, Garc\u00eda-Pav\u00eda P. Time delays in the diagnosis and treatment of Fabry disease. 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J Inherit Metab Dis. 2001;24(Suppl 2):75\u201383. https:\/\/doi.org\/10.1023\/a:1012428009627. discussion 65.","journal-title":"J Inherit Metab Dis"},{"issue":"7","key":"4401_CR8","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1016\/j.jacc.2020.12.024","volume":"77","author":"M Pieroni","year":"2021","unstructured":"Pieroni M, Moon JC, Arbustini E, et al. Cardiac involvement in fabry disease: JACC review topic of the week. J Am Coll Cardiol. 2021;77(7):922\u201336. https:\/\/doi.org\/10.1016\/j.jacc.2020.12.024.","journal-title":"J Am Coll Cardiol"},{"key":"4401_CR9","doi-asserted-by":"publisher","first-page":"35","DOI":"10.2147\/TACG.S146022","volume":"12","author":"JP Oliveira","year":"2019","unstructured":"Oliveira JP, Ferreira S. Multiple phenotypic domains of Fabry disease and their relevance for establishing genotype- phenotype correlations. 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Eur Heart J Cardiovasc Imaging. 2018;19(12):1313\u201322. https:\/\/doi.org\/10.1093\/ehjci\/jey132.","journal-title":"Eur Heart J Cardiovasc Imaging"},{"issue":"8","key":"4401_CR12","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1136\/jmedgenet-2019-106467","volume":"57","author":"DP Germain","year":"2020","unstructured":"Germain DP, Oliveira JP, Bichet DG, et al. Use of a rare disease registry for establishing phenotypic classification of previously unassigned GLA variants: a consensus classification system by a multispecialty Fabry disease genotype-phenotype workgroup. J Med Genet. 2020;57(8):542\u201351. https:\/\/doi.org\/10.1136\/jmedgenet-2019-106467.","journal-title":"J Med Genet"},{"issue":"1","key":"4401_CR13","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13023-022-02599-w","volume":"18","author":"R S\u00e1nchez","year":"2023","unstructured":"S\u00e1nchez R, Ripoll-Vera T, L\u00f3pez-Mendoza M, et al. 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As patients did not undergo any study procedures and as only aggregate data is reported, it was adjudicated that individual informed consent was not required. Human Ethics and Consent to Participate declarations: not applicable.","order":1,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"None.","order":2,"name":"Ethics","label":"Disclosure","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors declare that they have no competing interests.","order":3,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"308"}}