Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

CONTEXT Fabry disease is a metabolic disorder without a specific treatment, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Most patients experience debilitating neuropathic pain and premature mortality because of renal failure, cardiovascular disease, or cerebrovascular disease. OBJECTIVE To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease. DESIGN AND SETTING Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health. PATIENTS Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay. INTERVENTION A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total). MAIN OUTCOME MEASURE Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory (BPI). RESULTS Mean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46) to 4.3 (0.73) in patients treated with alpha-gal A vs no significant change in the placebo group (P =.02). Pain-related quality of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving alpha-gal A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P =.05). In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving alpha-gal vs a 16.5% increase for placebo (P =.01). Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo (P =.19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min (0.3 mL/s) for placebo (P =.02). In patients treated with alpha-gal A, there was an approximately 50% reduction in plasma glycosphingolipid levels, a significant improvement in cardiac conduction, and a significant increase in body weight. CONCLUSION Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.