Epigenetic Mechanisms in Fabry Disease: A Thematic Analysis Linking Differential Methylation Profiles and Genetic...

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-phenotype 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.