globotriaosylceramide and Vascular-Diseases

Fabry disease is an X-linked glycosphingolipid storage disorder resulting from deficiency of alpha-galactosidase A. Storage of globotriaosylceramide ultimately results in multiorgan pathology, including cerebrovascular, cardiovascular and renal disease. Vascular involvement is evident throughout the body but the mechanisms by which storage on a cellular level leads to end-organ pathology are unknown. Here the evidence for abnormal blood flow, vessel architecture and endothelial function will be reviewed and possible models of vascular pathology discussed. The effects of reversal of storage within vessels by enzyme replacement therapy (ERT) and the possibilities for intervention with additional agents will be considered.. The pathology of Fabry disease has an important vascular component, although the underlying pathophysiology is unclear. Preliminary evidence suggests that ERT may have beneficial effects on the vascular component of this multisystem disease.

Topics: alpha-Galactosidase; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Aspirin; Blood Coagulation Disorders; Blood Flow Velocity; Dipyridamole; Endothelium, Vascular; Fabry Disease; Humans; Metabolic Clearance Rate; Platelet Aggregation Inhibitors; Trihexosylceramides; Vascular Diseases; Vasodilator Agents

Shiga toxins (Stx) are virulence factors produced by selected bacteria pathogenic for humans. These multicomponent protein complexes are among the more potent toxins known. As inhibitors of eukaryotic protein synthesis, these toxins selectively inactivate ribosomes in an enzymatic manner. Specificity of cell targeting is determined by the high-affinity binding of Stx to its receptor, a glycosphingolipid (Gb3) located in the plasma membrane or some eukaryotic cells. Elaborated by food-borne E. coli O157:H7 bacteria, isotypes of Stx (Stx1 & Stx2) are required for the ensuing vascular changes in humans, including hemorrhagic colitis and renal hemolytic uremic syndrome. Experimental therapeutic intervention of Stx-associated disease includes the Stx receptor immobilized on biologically inert particles designed for oral presentation.

Topics: Animals; Endocytosis; Escherichia coli Infections; Escherichia coli O157; Humans; Receptors, Cell Surface; Shiga Toxins; Trihexosylceramides; Vascular Diseases

Topics: Algorithms; Arrhythmias, Cardiac; Cardiomyopathy, Hypertrophic; Electrocardiography; Enzyme Therapy; Fabry Disease; Female; Fibrosis; Humans; Hypertrophy, Left Ventricular; Male; Myocardium; Sex Factors; Trihexosylceramides; Vascular Diseases

Fabry disease is a complex, multisystemic and clinically heterogeneous disease with prominent urinary excretion of globotriaosylceramide (Gb(3)), the principal substrate of the deficient enzyme, alpha-galactosidase A. Some measure of specific treatment is possible with enzyme replacement therapy, which can be applied safely and effectively to Fabry patients. Incidence estimations of Fabry disease vary widely from 1:55 000 to 1:3000 male births. The true incidence is likely to be higher than originally thought, owing to the existence of milder variants of the disease. The main complications of Fabry disease are a 100-fold increased risk of ischaemic stroke, cardiac disease, a wide variety of arrhythmias, valvular dysfunction and cardiac vascular disease, as well as progressive renal failure usually associated with significant proteinuria. These clinical manifestations are non-specific and are often mistaken for symptoms of other disorders, thus complicating the confirmation of diagnosis. Other clinical features of the disease are often absent (angiokeratoma), subtle (corneal opacities and hypohidrosis), or unaccompanied by specific physical findings (acroparaesthesias) indicating the true nature of the underlying disease. We propose the hypothesis that alpha-galactosidase A deficiency is a modifiable cardiovascular risk factor in the general population. This hypothesis may be tested by a non-invasive high-risk screening protocol for Fabry patients with ischaemic strokes and a variety of cardiac, and renal complications. These patients would benefit from diagnosis, appropriate treatment, follow-up and surveillance. Early detection of Fabry patients would also benefit affected relatives, many of whom do not have a clear diagnosis of their clinical condition.

Topics: Algorithms; alpha-Galactosidase; Brain Ischemia; Chromatography, High Pressure Liquid; Fabry Disease; Humans; Kidney Diseases; Mass Spectrometry; Risk Factors; Specimen Handling; Stroke; Trihexosylceramides; Vascular Diseases