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Vascular events in Fabry and Gaucher disease

Thomas, ASB; (2014) Vascular events in Fabry and Gaucher disease. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Fabry (FD) and Gaucher (GD) disease are lysosomal storage disorders, caused by single enzyme deficiencies on the glycosphingolipid degradation pathway as a result of genetic mutations in the GLA and GBA genes respectively. These result in a functional enzyme deficiency within the lysosome and accumulation of un-degraded substrate. GD is characterised by a bleeding tendency and bone infarction. Patients with FD suffer from a vasculopathy with strokes, proteinuric renal failure and cardiac conduction defects, but both disorders are highly heterogeneous. Abnormal cytokine profiles and a pro-inflammatory state have been found in both FD and GD, leading to the hypothesis that abnormalities at the blood-endothelial interface affecting coagulation and leucocyte adhesion contribute to the pathology of these disorders. This thesis demonstrates the importance of vascular manifestations in the presentation of both GD and FD with failure to identify the underlying cause of these manifestations resulting in delays between the onset of clinical manifestations and arrival at the correct diagnosis. Abnormalities at the blood-endothelial interface identified in GD include up-regulation of adhesion molecules on lymphocytes that may be of importance in the pathogenesis of bone disease, and increased thrombin generation in an endothelial cell model of GD. In FD, whilst cardiac and renal manifestations occur at earlier onset and with greater severity in men, cerebrovascular disease seems to affect both sexes to a similar degree. Monocytes from females with FD exhibit an age-dependent increase in adhesion mimicking the age-dependent increase in cardiac and renal disease seen in these patients but the mechanisms underlying cerebrovascular disease remain uncertain. Initial investigations of platelet prothrombinase activity suggest this may be enhanced in FD. Further investigation of these abnormalities at the cellular level may shed new insights on, and open up new therapeutic options, for the management of the vascular complications of these disorders.

Type: Thesis (Doctoral)
Title: Vascular events in Fabry and Gaucher disease
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Fabry, Gaucher, Lysosomal, Stroke, Vascular
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/1433363
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