doi: 10.1161/hc3801.096352
(Circulation. 2001;104:1506.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Regional Cerebral Hyperperfusion and Nitric Oxide Pathway Dysregulation in Fabry Disease
Reversal by Enzyme Replacement Therapy
From the Developmental and Metabolic Neurology Branch (D.F.M., G.A., C.K., R.F., R.O.B., R.S.), National Institute of Neurological Disorders and Stroke, the PET Department (P.H.), Clinical Center, and the Critical Care Medicine Department (M.T.G., M.P.-F.), Clinical Center, National Institutes of Health, Bethesda, Md; the Department of Neurology (L.T.C.S.), University of Vermont, Burlington; and the Department of Pathology and Laboratory Medicine (K.S.), School of Medicine, University of North Carolina at Chapel Hill.
Correspondence to Raphael Schiffmann, MD, National Institutes of Health, Bldg 10, Room 3D03, 9000 Rockville Pike, Bethesda, MD 20892-1260. E-mail RS4e{at}nih.gov
Background— Fabry disease is an X-linked lysosomal deficiency of 
-galactosidase 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 [15O] H2O and PET, we found increased resting regional cerebral blood flow in Fabry disease without evidence of occlusive vasculopathy or cerebral hypoperfusion. Because nitric oxide is known to play an important role in vascular tone and reactivity, we studied plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol levels by chemiluminescence. Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine. Plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol were in the normal range; however, enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels. After a double-blind, placebo-controlled trial of -galactosidase A therapy, the resting regional cerebral blood flow in the treated group was significantly 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 reversible with enzyme replacement therapy.
Key Words: cerebrovascular disorders • nitric oxide • tomography • regional blood flow • cerebrovascular circulation
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