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Title: Vascular events in Fabry and Gaucher disease
Author: Thomas, A. S. B.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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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.
Supervisor: Hughes, D. A. ; Gomez, K. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available