{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:05:07Z","timestamp":1791993907654,"version":"4.4.0"},"reference-count":103,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Background\/Objectives: Fabry disease is an X-linked lysosomal storage disorder. It is characterised by impaired metabolism of glycosphingolipids whose accumulation causes irreversible organ damage and life-threatening complications. Genotype\u2013phenotype correlations have a limited scope in Fabry disease as the disorder presents with wide-ranging clinical variability. In other X-linked disorders, epigenetic profiling has identified methylation patterns and disease modifiers that may explain clinical heterogeneity. In this narrative review and thematic analysis, the role of DNA methylation and epigenetics on the clinical phenotype in Fabry disease was investigated. Methods: Embase, PubMed, and PsycINFO were searched to identify literature on DNA methylation and epigenetics in Fabry disease. Based on the eligibility criteria, 20 articles were identified, and a thematic analysis was performed on the extracted data to identify themes. Results: Three themes emerged: (I) genetic modifiers, (II) methylation profiling, and (III) insights into X chromosome inactivation (XCI). The evidence synthesis revealed that telomere length, especially in early disease stages, bidirectional promoter (BDP) methylation by sphingolipids, epigenetic reader proteins, mitochondrial DNA haplogroups, and DNA methylation of the promoter region of the calcitonin receptor gene are potential genetic modifiers in Fabry disease. Methylation patterns also reveal episignatures in Fabry disease evolution and genes implicated in the maintenance of basement membranes. Studies on XCI further emphasise disease heterogeneity and draw attention to methodological issues in the assessment of XCI. Conclusions: This thematic review shows that DNA methylation and genetic modifiers are key factors modifying clinical variability in Fabry disease. More broadly, it underscores a crucial role for epigenetic processes in driving disease onset, progression, and severity in X-linked disorders.<\/jats:p>","DOI":"10.3390\/cimb47100855","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T11:39:34Z","timestamp":1760701174000},"page":"855","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Epigenetic Mechanisms in Fabry Disease: A Thematic Analysis Linking Differential Methylation Profiles and Genetic Modifiers to Disease Phenotype"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0205-856X","authenticated-orcid":false,"given":"Jatinder","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4830-5893","authenticated-orcid":false,"given":"Paramala","family":"Santosh","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4703-7447","authenticated-orcid":false,"given":"Uma","family":"Ramaswami","sequence":"additional","affiliation":[{"name":"Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"},{"name":"Genetics and Genomic Medicine, University College London, London WC1N 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S1550-8579(07)80024-6","article-title":"Why females are mosaics, X-chromosome inactivation, and sex differences in disease","volume":"4","author":"Migeon","year":"2007","journal-title":"Gend. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102096","DOI":"10.1016\/j.gde.2023.102096","article-title":"Modeling X-chromosome inactivation and reactivation during human development","volume":"82","author":"Khan","year":"2023","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/190372a0","article-title":"Gene action in the X-chromosome of the mouse (Mus musculus L.)","volume":"190","author":"Lyon","year":"1961","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.neuron.2013.10.051","article-title":"Cellular resolution maps of X chromosome inactivation: Implications for neural development, function, and disease","volume":"81","author":"Wu","year":"2014","journal-title":"Neuron"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ceb.2017.01.007","article-title":"X chromosome inactivation: Silencing, topology and reactivation","volume":"46","author":"Gribnau","year":"2017","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/ajmg.a.30123","article-title":"Inheritance of most X-linked traits is not dominant or recessive, just X-linked","volume":"129","author":"Dobyns","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1172\/JCI112967","article-title":"Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation","volume":"79","author":"Puck","year":"1987","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1172\/JCI33166","article-title":"No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans","volume":"118","author":"Bolduc","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1086\/507565","article-title":"X chromosome-inactivation patterns of 1005 phenotypically unaffected females","volume":"79","author":"Cottle","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Posynick, B.J., and Brown, C.J. (2019). Escape From X-Chromosome Inactivation: An Evolutionary Perspective. Front. Cell Dev. Biol., 7.","DOI":"10.3389\/fcell.2019.00241"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/cns3.20086","article-title":"Rett syndrome: The natural history study journey","volume":"2","author":"Percy","year":"2024","journal-title":"Ann. Child Neurol. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e1917","DOI":"10.1002\/mgg3.1917","article-title":"Analysis of X-inactivation status in a Rett syndrome natural history study cohort","volume":"10","author":"Fang","year":"2022","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_13","unstructured":"Xiol, C., Vidal, S., Pascual-Alonso, A., Blasco, L., Brandi, N., Pacheco, P., Gerotina, E., O\u2019callaghan, M., Pineda, M., and Armstrong, J. (2019). Rett Working Group. X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients. Sci. Rep., 9."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1136\/jmg.2006.045260","article-title":"Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation","volume":"44","author":"Archer","year":"2007","journal-title":"J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Merritt, J.K., Fang, X., Caylor, R.C., Skinner, S.A., Friez, M.J., Percy, A.K., and Neul, J.L. (2024). Normalized Clinical Severity Scores Reveal a Correlation between X Chromosome Inactivation and Disease Severity in Rett Syndrome. Genes, 15.","DOI":"10.20944\/preprints202403.1844.v1"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13148-021-01019-3","article-title":"DNA methylation impact on Fabry disease","volume":"13","author":"Vinciguerra","year":"2021","journal-title":"Clin. Epigenet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/cge.14102","article-title":"Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease","volume":"101","author":"Germain","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1007\/s40620-024-01934-7","article-title":"Oxidative stress and its role in Fabry disease","volume":"37","author":"Cacciapuoti","year":"2024","journal-title":"J. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3741","DOI":"10.1007\/s00415-020-10044-w","article-title":"Oxidative stress biomarkers in Fabry disease: Is there a room for them?","volume":"267","author":"Simoncini","year":"2020","journal-title":"J. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"480980","DOI":"10.1155\/2014\/480980","article-title":"Subclinical inflammatory status in Rett syndrome","volume":"2014","author":"Cortelazzo","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41572-024-00568-0","article-title":"Rett syndrome","volume":"10","author":"Gold","year":"2024","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/ncpneuro0407","article-title":"Neurological manifestations in Fabry\u2019s disease","volume":"3","author":"Jensen","year":"2007","journal-title":"Nat. Clin. Pract. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"RettSearch Consortium. Rett syndrome: Revised diagnostic criteria and nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Singh, J., Wilkins, G., Goodman-Vincent, E., Chishti, S., Bonilla Guerrero, R., McFadden, L., Zahavi, Z., and Santosh, P. (2024). Co-Occurring Methylenetetrahydrofolate Reductase (MTHFR) rs1801133 and rs1801131 Genotypes as Associative Genetic Modifiers of Clinical Severity in Rett Syndrome. Brain Sci., 14.","DOI":"10.3390\/brainsci14070624"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/jhg.2011.50","article-title":"Investigation of modifier genes within copy number variations in Rett syndrome","volume":"56","author":"Artuso","year":"2011","journal-title":"J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41583-025-00926-1","article-title":"Exploring the complexity of MECP2 function in Rett syndrome","volume":"26","author":"Liu","year":"2025","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, L., Chen, R., Zhang, H., Li, J., Huang, H., Weng, J., Tan, H., Guo, T., Wang, M., and Xie, J. (2024). The epigenetic modification of DNA methylation in neurological diseases. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1401962"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Vuu, Y.M., Roberts, C.T., and Rastegar, M. (2023). MeCP2 Is an Epigenetic Factor That Links DNA Methylation with Brain Metabolism. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24044218"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1034\/j.1399-0004.2000.580504.x","article-title":"The causes and consequences of random and non-random X chromosome inactivation in humans","volume":"58","author":"Brown","year":"2000","journal-title":"Clin. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1101\/gr.112680.110","article-title":"DNA methylation profiles of human active and inactive X chromosomes","volume":"21","author":"Sharp","year":"2011","journal-title":"Genome Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rodrigues, B., Gon\u00e7alves, A., Sousa, V., Maia, N., Marques, I., Vale-Fernandes, E., Santos, R., Nogueira, A.J.A., and Jorge, P. (2022). Use of the FMR1 Gene Methylation Status to Assess the X-Chromosome Inactivation Pattern: A Stepwise Analysis. Genes, 13.","DOI":"10.3390\/genes13030419"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"De Riso, G., Cuomo, M., Di Risi, T., Della Monica, R., Buonaiuto, M., Costabile, D., Pisani, A., Cocozza, S., and Chiariotti, L. (2020). Ultra-Deep DNA Methylation Analysis of X-Linked Genes: GLA and AR as Model Genes. Genes, 11.","DOI":"10.3390\/genes11060620"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1186\/s13023-022-02392-9","article-title":"Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry","volume":"17","author":"Beck","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s13023-016-0473-4","article-title":"Multicenter Female Fabry Study (MFFS)\u2014Clinical survey on current treatment of females with Fabry disease","volume":"11","author":"Lenders","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"99","DOI":"10.4331\/wjbc.v11.i3.99","article-title":"Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy","volume":"11","author":"Palakuzhiyil","year":"2020","journal-title":"World J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"R285","DOI":"10.1093\/hmg\/ddab221","article-title":"X-factors in human disease: Impact of gene content and dosage regulation","volume":"30","author":"Fang","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.nedt.2012.02.022","article-title":"A structured approach to documenting a search strategy for publication: A 12 step guideline for authors","volume":"32","author":"Kable","year":"2012","journal-title":"Nurse Educ. Today"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Voniati, L., Papadopoulos, A., Ziavra, N., and Tafiadis, D. (2025). Communication Abilities, Assessment Procedures, and Intervention Approaches in Rett Syndrome: A Narrative Review. Brain Sci., 15.","DOI":"10.3390\/brainsci15070753"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s41073-019-0064-8","article-title":"SANRA-a scale for the quality assessment of narrative review articles","volume":"4","author":"Baethge","year":"2019","journal-title":"Res. Integr. Peer Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Singh, J., and Santosh, P. (2025). Molecular Insights into Neurological Regression with a Focus on Rett Syndrome-A Narrative Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115361"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16094069231205789","DOI":"10.1177\/16094069231205789","article-title":"A Step-by-Step Process of Thematic Analysis to Develop a Conceptual Model in Qualitative Research","volume":"22","author":"Naeem","year":"2023","journal-title":"Int. J. Qual. Methods"},{"key":"ref_44","unstructured":"O\u2019Leary, Z. (2004). The Essential Guide to Doing Your Research Project, Sage. [2nd ed.]."},{"key":"ref_45","first-page":"80","article-title":"Demonstrating rigor using thematic analysis: A hybrid approach of inductive and deductive coding and theme development","volume":"5","author":"Fereday","year":"2006","journal-title":"Int. J. Qual. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ymgme.2017.01.002","article-title":"The severe clinical phenotype for a heterozygous Fabry female patient correlates to the methylation of non-mutated allele associated with chromosome 10q26 deletion syndrome","volume":"120","author":"Hossain","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4926","DOI":"10.21037\/apm-19-635","article-title":"A late-onset male Fabry disease patient with somatic mosaicism of a classical GLA mutation: A case report","volume":"10","author":"Bae","year":"2021","journal-title":"Ann. Palliat. Med."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"\u010cerkauskait\u0117, A., \u010cerkauskien\u0117, R., Miglinas, M., Laurinavi\u010dius, A., Ding, C., Rolfs, A., Vencevi\u010dien\u0117, L., Barysien\u0117, J., Kaz\u0117nait\u0117, E., and Sadauskien\u0117, E. (2019). Genotype-Phenotype Correlation in a New Fabry-Disease-Causing Mutation. Medicina, 55.","DOI":"10.3390\/medicina55050122"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Al-Obaide, M.A., Al-Obaidi, I.I., and Vasylyeva, T.L. (2022). The potential consequences of bidirectional promoter methylation on GLA and HNRNPH2 expression in Fabry disease phenotypes in a family of patients carrying a GLA deletion variant. Biomed. Rep., 17.","DOI":"10.3892\/br.2022.1554"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"324","DOI":"10.2174\/1871530320666200708135826","article-title":"Genetic Management Algorithm in High-Risk Fabry Disease Cases; Especially in Female Indexes with Mutations","volume":"21","author":"Sezer","year":"2021","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.ymgme.2019.03.003","article-title":"Dysregulated DNA methylation of GLA gene was associated with dysfunction of autophagy","volume":"126","author":"Yanagisawa","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_52","first-page":"100919","article-title":"Dysregulated DNA methylation in the pathogenesis of Fabry disease","volume":"33","author":"Shen","year":"2022","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e20230007","DOI":"10.1590\/2326-4594-jiems-2024-0007","article-title":"DNA Methylation Analysis and Phenotype Severity in Fabry Disease","volume":"13","author":"Iza","year":"2025","journal-title":"J. Inborn Errors Metab. Screen."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1007\/s10157-021-02099-4","article-title":"X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay","volume":"25","author":"Rossanti","year":"2021","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.gene.2017.10.064","article-title":"Female Fabry disease patients and X-chromosome inactivation","volume":"641","author":"Juchniewicz","year":"2018","journal-title":"Gene"},{"key":"ref_56","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_57","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_58","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_59","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":"2016","journal-title":"Clin. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.neulet.2016.06.051","article-title":"Mitochondrial DNA haplogroups may influence Fabry disease phenotype","volume":"629","author":"Simoncini","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Pan, X., Ouyang, Y., Wang, Z., Ren, H., Shen, P., Wang, W., Xu, Y., Ni, L., Yu, X., and Chen, X. (2016). Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161330"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Di Risi, T., Cuomo, M., Vinciguerra, R., Ferraro, S., Della Monica, R., Costabile, D., Buonaiuto, M., Trio, F., Capoluongo, E., and Visconti, R. (2022). Methylome Profiling in Fabry Disease in Clinical Practice: A Proof of Concept. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012110"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Levstek, T., Breznik, N., Vujkovac, B., Nowak, A., and Trebu\u0161ak Podkraj\u0161ek, K. (2024). Dynamics of Leukocyte Telomere Length in Patients with Fabry Disease. Biomedicines, 12.","DOI":"10.3390\/biomedicines12081724"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e00949","DOI":"10.1002\/prp2.949","article-title":"Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy","volume":"10","author":"Fu","year":"2022","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e2029","DOI":"10.1002\/mgg3.2029","article-title":"X-chromosomal inactivation patterns in women with Fabry disease","volume":"10","author":"Rickert","year":"2022","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1002\/ajmg.a.62728","article-title":"Pitfalls of X-chromosome inactivation testing in females with Fabry disease","volume":"188","author":"Sikora","year":"2022","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1159\/000502909","article-title":"Aging in Fabry Disease: Role of Telomere Length, Telomerase Activity, and Kidney Disease","volume":"144","author":"Vujkovac","year":"2020","journal-title":"Nephron"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Mignani, R., Berti, G.M., Vischini, G., Di Costanzo, R., Ciurli, F., Fabbrizio, B., Pasquinelli, G., La Manna, G., and Capelli, I. (2025). The Fabry Nephropathy in Patients with N215S Variant. Nephron, 1\u20135.","DOI":"10.1159\/000545611"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/cardiogenetics11010001","article-title":"Mosaic Fabry Disease in a Male Presenting as Hypertrophic Cardiomyopathy","volume":"11","author":"Xu","year":"2021","journal-title":"Cardiogenetics"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1124\/jpet.122.001250","article-title":"Mitochondrial microRNAs Are Dysregulated in Patients with Fabry Disease","volume":"384","author":"Gambardella","year":"2023","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Esposito, R., Santoro, C., Mandoli, G.E., Cuomo, V., Sorrentino, R., La Mura, L., Pastore, M.C., Bandera, F., D\u2019ascenzi, F., and Malagoli, A. (2021). Cardiac Imaging in Anderson-Fabry Disease: Past, Present and Future. J. Clin. Med., 10.","DOI":"10.3390\/jcm10091994"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"537","DOI":"10.2217\/epi-2021-0521","article-title":"Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders","volume":"14","author":"Lee","year":"2022","journal-title":"Epigenomics"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s41431-023-01474-x","article-title":"Episignatures in practice: Independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders","volume":"32","author":"Husson","year":"2024","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13023-024-03500-7","article-title":"Clinical management of female patients with Fabry disease based on expert consensus","volume":"20","author":"Brand","year":"2025","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/jimd.12373","article-title":"Defective lysosomal storage in Fabry disease modifies mitochondrial structure, metabolism and turnover in renal epithelial cells","volume":"44","author":"Schumann","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ymgme.2017.07.012","article-title":"The role of epigenetics in lysosomal storage disorders: Uncharted territory","volume":"122","author":"Hassan","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Fadra, N., Schultz-Rogers, L.E., Chanana, P., Cousin, M.A., Macke, E.L., Ferrer, A., Pinto E Vairo, F., Olson, R.J., Oliver, G.R., and Mulvihill, L.A. (2024). Identification of skewed X chromosome inactivation using exome and transcriptome sequencing in patients with suspected rare genetic disease. BMC Genom., 25.","DOI":"10.1186\/s12864-024-10240-2"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"107603","DOI":"10.1016\/j.ymgme.2023.107603","article-title":"Global reach of over 20 years of experience in the patient-centered Fabry Registry: Advancement of Fabry disease expertise and dissemination of real-world evidence to the Fabry community","volume":"139","author":"Wanner","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Tebani, A., Mauhin, W., Abily-Donval, L., Lesueur, C., Berger, M.G., Nadjar, Y., Berger, J., Benveniste, O., Lamari, F., and Lafor\u00eat, P. (2020). A Proteomics-Based Analysis Reveals Predictive Biological Patterns in Fabry Disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9051325"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.trsl.2023.02.006","article-title":"Deep next-generation proteomics and network analysis reveal systemic and tissue-specific patterns in Fabry disease","volume":"258","author":"Tebani","year":"2023","journal-title":"Transl. Res."},{"key":"ref_82","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_83","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_84","doi-asserted-by":"crossref","unstructured":"Gragnaniello, V., Burlina, A.P., Commone, A., Gueraldi, D., and Puma, A. (2023). Newborn Screening for Fabry Disease: Current Status of Knowledge. Int. J. Neonatal Screen., 9.","DOI":"10.3390\/ijns9020031"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"109110","DOI":"10.1016\/j.ymgme.2025.109110","article-title":"The use and performance of lyso-Gb3 for the diagnosis and monitoring of Fabry disease: A systematic literature review","volume":"145","author":"Ramaswami","year":"2025","journal-title":"Mol. Genet. Metab."},{"key":"ref_86","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_87","doi-asserted-by":"crossref","first-page":"107585","DOI":"10.1016\/j.ymgme.2023.107585","article-title":"An expert consensus on the recommendations for the use of biomarkers in Fabry disease","volume":"139","author":"Burlina","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1186\/s13023-025-03922-x","article-title":"Fabry disease in females: Organ involvement and clinical outcomes compared with the general population","volume":"20","author":"Hopkin","year":"2025","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Stepien, K.M., Roncaroli, F., Turton, N., Hendriksz, C.J., Roberts, M., Heaton, R.A., and Hargreaves, I. (2020). Mechanisms of Mitochondrial Dysfunction in Lysosomal Storage Disorders: A Review. J. Clin. Med., 9.","DOI":"10.3390\/jcm9082596"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.1651-2227.2005.tb02106.x","article-title":"Natural history of the cerebrovascular complications of Fabry disease","volume":"94","author":"Mehta","year":"2005","journal-title":"Acta Paediatr. Suppl."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1136\/jmg.2008.065904","article-title":"Natural course of Fabry disease: Changing pattern of causes of death in FOS\u2014Fabry Outcome Survey","volume":"46","author":"Mehta","year":"2009","journal-title":"J. Med. Genet."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Moreno-Mart\u00ednez, D., Le\u00f3n-Cejas, L., and Reisin, R. (2024). Cerebrovascular disorders and Fabry disease. Rare Dis. Orphan Drugs J., 3.","DOI":"10.20517\/rdodj.2023.51"},{"key":"ref_93","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_94","doi-asserted-by":"crossref","unstructured":"Faro, D.C., Di Salvo, S., Rodolico, M.S., Losi, V., Capodanno, D., and Monte, I.P. (2025). Cardiac Phenotypes in Fabry Disease: Genetic Variability and Clinical Severity Staging Correlation in a Reference Center Cohort. Genes, 16.","DOI":"10.3390\/genes16091086"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"R97","DOI":"10.1093\/hmg\/dds346","article-title":"COL4A1 and COL4A2 mutations and disease: Insights into pathogenic mechanisms and potential therapeutic targets","volume":"21","author":"Kuo","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_96","first-page":"100140","article-title":"Main features of COL4A1-COL4A2 related cerebral microangiopathies","volume":"3","year":"2022","journal-title":"Cereb. Circ. Cogn. Behav."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1212\/01.wnl.0000196491.42058.6f","article-title":"Methionine metabolism and phenotypic variability in X-linked adrenoleukodystrophy","volume":"66","author":"Linnebank","year":"2006","journal-title":"Neurology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3561","DOI":"10.2147\/DDDT.S313789","article-title":"Prompt Agalsidase Alfa Therapy Initiation is Associated with Improved Renal and Cardiovascular Outcomes in a Fabry Outcome Survey Analysis","volume":"15","author":"Hughes","year":"2021","journal-title":"Drug Des. Devel Ther."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Weidemann, F., Jovanovic, A., Herrmann, K., and Vardarli, I. (2022). Chaperone Therapy in Fabry Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031887"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1503\/jpn.190033","article-title":"Autonomic dysfunction and sudden death in patients with Rett syndrome: A systematic review","volume":"45","author":"Singh","year":"2020","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Singh, J., Manginas, A., Wilkins, G., and Santosh, P. (2025). A Comprehensive Analysis Examining the Role of Genetic Influences on Psychotropic Medication Response in Children. Genes, 16.","DOI":"10.3390\/genes16091055"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s13023-025-03655-x","article-title":"Applying artificial intelligence to rare diseases: A literature review highlighting lessons from Fabry disease","volume":"20","author":"Germain","year":"2025","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_103","first-page":"101152","article-title":"Using artificial intelligence and promoter-level transcriptome analysis to identify a biomarker as a possible prognostic predictor of cardiac complications in male patients with Fabry disease","volume":"41","author":"Kobayashi","year":"2024","journal-title":"Mol. Genet. Metab. Rep."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/10\/855\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T12:42:20Z","timestamp":1760704940000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/10\/855"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":103,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["cimb47100855"],"URL":"https:\/\/doi.org\/10.3390\/cimb47100855","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,16]]}}}