Regional cerebral hyperperfusion and nitric oxide pathway dysregulation inFabry disease - Reversal by enzyme replacement therapy

Background-Fabry disease is an X-linked lysosomal deficiency of a-galactosi dase A that results in cellular accumulation of galacto-conjugates such as globotriosylceramide, particularly in blood vessels. It is associated with early-onset stroke and kidney and heart failure. Methods and Results-Using [O-15] H2O and PET, we found increased resting re gional cerebral blood flow in Fabry disease without evidence of occlusive v asculopathy or cerebral hypoperfusion. Because nitric oxide is known to pla y an important role in vascular tone and reactivity, we studied plasma nitr ate, nitrite, and low-molecular-weight S-nitrosothiol levels by chemilumine scence. Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine. Plasma nitrate, nitrite, and low-m olecular-weight S-nitrosothiol were in the normal range; however, enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels. A fter a double-blind, placebo-controlled trial of a-galactosidase A therapy, the resting regional cerebral blood flow in the treated group was signific antly reduced, with a notable decrease of nitrotyrosine staining in dermal blood vessels. Conclusions-These findings suggest a chronic alteration of the nitric oxide pathway in Fabry disease, with critical protein nitration that is reversib le with enzyme replacement therapy.