Abstract
Fabry disease (FD) is a rare X-linked recessive genetic disorder caused by a deficient activity of the lysosomal enzyme alpha-galactosidase A (GLA) and is characterised by intra-lysosomal accumulation of globotriaosylceramide (Gb3). We performed a meta-analysis of peer-reviewed publications including high-throughput omics technologies including naïve patients and those undergoing enzyme replacement therapy (ERT). This study describes FD on a systems level using a systems biology approach, in which molecular data sourced from multi-omics studies is extracted from the literature and integrated as a whole in order to reveal the biochemical processes and molecular pathways potentially affected by the dysregulation of differentially expressed molecules. In this way new insights are provided that describe the pathophysiology of this rare disease. Using gene ontology and pathway term clustering, FD displays the involvement of major biological processes such as the acute inflammatory response, regulation of wound healing, extracellular matrix (ECM) remodelling, regulation of peptidase activity, and cellular response to reactive oxygen species (ROS). Differential expression of acute-phase response proteins in the groups of naïve (up-regulation of ORM1, ORM2, ITIH4, SERPINA3 and FGA) and ERT (down-regulation of FGA, ORM1 and ORM2) patients could be potential hallmarks for distinction of these two patient groups.
Highlights
Fabry disease (FD) is a rare X-linked recessive genetic disorder caused by a deficient activity of the lysosomal enzyme alpha-galactosidase A (GLA)
FD is associated with vascular injury and a high recurrence rate of thrombotic events, caused by decreased levels of thrombomodulin (TM) and increased levels of plasminogen activator inhibitor (PAI), both playing a role in the regulation of the endothelium and leukocyte interactions [3]
We describe FD at a systems level using a systems biology approach, in which molecular data sourced from multi-omics studies was extracted from the literature and integrated as a whole, in order to reveal the biochemical processes and molecular pathways potentially affected by the dysregulation of differentially expressed molecules and in this way provide new insights that describe the pathophysiology of this rare disease
Summary
Fabry disease (FD) is a rare X-linked recessive genetic disorder caused by a deficient activity of the lysosomal enzyme alpha-galactosidase A (GLA). It is characterised by intra-lysosomal accumulation of globotriaosylceramide (Gb3) and other related glycolipids sub-types (e.g., glycosphingolipids) in many cell types, including blood vessels throughout the body. This buildup initiates a cascade of events, starting with the disruption of basic metabolic processes at the cellular level and progressing to inflammatory events and cell death, thereby affecting the system as a whole with an increase of renal, cardiac, cerebrovascular, and skin complications [1,2]. When racial origins are taken into account, the majority of the patients are Caucasians; it is found in African Americans and in subjects of Asian ancestry [5]
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