The Central Nervous System Involvement in Fabry Disease: A Review

Abstract Fabry disease (FD) is an X-linked, lysosomal storage disorder caused by a mutation in the alpha galactosidase (GLA) gene leading to a deficiency in α-galactosidase A enzyme (α-Gal A) activity, which in turn results in accumulation of glycosphingolipids in different cells. The 2 major clinical phenotypes are the classic severe phenotype and the milder, later onset phenotype. In severe affected males with little or no α-Gal A activity, the onset of acroparesthesias, hypohidrosis, angiokeratomas, and corneal dystrophy is typically observed in childhood or adolescence. With advancing age, progressive multisystem microvasculopathic disease culminates in renal failure, cardiomyopathy, and/or cerebrovascular disease. Patients with later onset have residual enzyme activity and lack of vascular endothelial glycolipid accumulations; thus, they do not present with the early manifestations of the classic phenotype and typically present cardiac or renal disease in the fourth to seventh decade. Although the pathogenesis of cerebral vasculopathy in FD is poorly understood, it can be hypothesized that white matter changes may reflect the pathophysiology of the disease.

Vertebrobasilar Dolichoectasia in Fabry Disease: The Earliest Marker of Neurovascular Involvement?

Abstract Introduction: Fabry disease (FD) is a lysosomal storage disorder associated with marked cerebrovascular involvement. Conventional magnetic resonance imaging (MRI) shows different abnormalities, like white matter lesions that may already be present at an early stage in the disease. Aim: To present observations from a series of brain MRIs performed among a cohort of patients with FD and the relationship of imaging abnormalities with the presence of cardiovascular risk factors (CVRFs). Methods: A total of 70 patients with FD (43 women) were enrolled. The cardiac, renal, ophthalmic, and peripheral nerve functioning was assessed. The MRI evaluation included assessment for evidence of ischemia, microbleeds, pulvinar sign, Arnold-Chiari type 1 malformation, and vertebrobasilar dolichoectasia (VBD). The presence or absence of CVRFs was examined for all patients. Results: Renal involvement was found in 60%, cardiac compromise in 30%, cornea verticillata in 91.4%, and acroparesthesias in 87.1% of patients. Brain MRI analysis found evidence of cerebral ischemic injury in 25.9% of men and 30.2% of women. Vertebrobasilar dolichoectasia was observed in imaging from 55.5% of men and 34.8% of women. The logistic regression analysis adjusted for cardiovascular risks factors, using ischemia or VBD as a dependent variable, showed no statistically significant results. Discussion: Our results have demonstrated cerebrovascular involvement before the third decade in many patients with FD. This study is further evidence confirming that women are not just carriers of FD and should be followed clinically and evaluated comprehensively to monitor for disease burden and progression. Although silent brain ischemias in MRI should be included as a key feature for the diagnoses of FD, VBD is an earlier and frequent sign.