[Pathophysiological aspects of brain structural disturbances in patients with Fabry disease: literature review]

Fabry Disease (FD) is a rare X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A (alpha-GAL) enzyme activity. Neutral glycosphingolipides (esp. Gb3) accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. Cerebral manifestations that might be mainly due to progressive cerebrovascular dysfunction, are one major and often life-threatening burden of the disease. We reviewed the present literature concerning brain structural alterations in FD and discuss the possibly relevant underlying pathophysiological aspects of these disturbances. Cerebrovascular events (TIA, stroke) occur in FD at a rather early age. In female FD patients who were considered to be less affected "carriers" for a long time, the prevalence of cerebrovascular events seems to be at last as high as in male patients. In structural imaging white matter lesions (WML) can be found frequently even in young FD patients. In a recent study clinically equally affected men and women with FD showed a comparable severity of WML load. Different pathophysiological aspects of cerebral angiopathy and WML development are discussed against the background of current concepts (e. g. accumulation of Gb3 in vascular endothelium with consecutive cell proliferation and luminal stenosis, acceleration of focal intravasal pressure and disturbances of vascular auto-regulation). Pathological increase of pulvinar signal in T1-weighted MRI has also been described in FD. This finding was assumed to be caused by calcification as a consequence of disturbed local circulation. To enhance our knowledge about the relevant neurobiological processes the authors propose a more sensitive and early detection of brain structural changes in FD. New brain structural MRI methods such as diffusion-tensor imaging could provide a pattern of ultrastructural changes even in young patients without visible WML. This strategy could be as well useful for quantification of possible effects of the enzyme replacement therapy on brain structural alterations in FD. Based on recent data a systematic FD-screening by measuring Gb3 in urine of young patients with cryptogenic stroke should be discussed. Basically in such cases FD should be clinically considered.