Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme ␣-galactosidase A (␣-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb 3; also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified ␣-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered ␣-gal A, (ii) to assess the pharmacokinetics of i.v.-administered ␣-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb3. ␣-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified ␣-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of ␣-gal A, nine of the 10 patients had significantly reduced Gb3 levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of ␣-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb 3 burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.

These findings provide a predictable outcome measure to assess the effect of molecular interventions on the cerebrovascular circulation in Fabry disease.

Our study provides normal, reference TCD values for a large cohort of healthy subjects across a wide range of age, sex, and race groups. We observed decreased MBFV and increased PI with aging, and higher MBFV in women. There were few differences in MBFV related to side or ethnicity, but the MFBV and PI changes with age were specific to Caucasians. We provide means and standard deviations of MBFVs across various demographic groups in key intracranial arteries. Such normal TCD values across age, gender, and ethnic groups in healthy subjects represent a useful reference tool for detecting individuals with TCD values outside normal limits and at increased vascular risk. TCD studies in large multiethnic populations are still required to determine differences in brain hemodynamics across various ethnic groups.