Vascular complications of Fabry disease: enzyme replacement and other therapies

Abstract

Fabry disease is an X-linked glycosphingolipid storage disorder resulting from deficiency of a-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 endorgan 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. Conclusion: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.

Ocular manifestations of Fabry's disease: data from the Fabry Outcome Survey

“…Hence conjunctival and retinal vessel abnormalities may represent a clinically significant marker of a diffuse microvascular disorder leading to end-organ pathology throughout the body. 27 The data also suggest a positive predictive value in performing regular eye examinations (particularly focusing on vessel tortuosity) in patients with systemic involvement. indicate that cornea verticillata is the most frequently reported eye abnormality in both hemizygotic males and heterozygotic females with Fabry's disease, and, at present, can be considered the most significant ophthalmological marker for the diagnosis of Fabry's disease.…”

Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals

“…80 -82 GL-3 accumulation in the vascular endothelium and other cells leads to hearing loss, myocardial microvascular ischemia, dysrhythmias, hypertrophic cardiomyopathy, valvular insufficiency, gastrointestinal symptoms, hypohidrosis, temperature and exercise intolerance, dysregulation of vascular tone and autonomic functions, obstructive lung disease, progressive renal insufficiency leading to kidney failure, and increases the risk of cerebrovascular accidents and myocardial infarctions. [83][84][85][86][87][88][89][90][91][92][93] Early death in hemizygotes occurs typically in the late fifth to early sixth decade from kidney failure, strokes, and cardiac events. 94 -95 Heterozygous females, previously thought to be asymptomatic "carriers," can have significant symptomatology, generally at a later age than hemizygous men.…”

Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life

“…1 Affected patients have an impaired ability to degrade membrane glycosphingolipids containing a terminal ␣-glycosidic galactose, especially globotriaosylceramide/ceramide trihexoside (GL 3 ), which accumulates in tissues. Storage in the vascular endothelium increases the risk for cerebrovascular accidents (CVA) and myocardial microvascular ischemia [2][3][4] ; in the heart causes dysrhythmias, hypertrophic cardiomyopathy, and valvular insufficiency 5 ; in the kidney leads to progressive renal insufficiency and eventually failure 6 ; in the peripheral nervous system gives rise to gastrointestinal dysmotility, hypohidrosis, temperature intolerance, dysregulation of vascular tone, and characteristic acroparesthesias of the hands and feet. [7][8][9] Obstructive lung disease and impaired exercise tolerance are also seen.…”