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


METHODS
Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health.


METHODS
Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay.


METHODS
A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total).


METHODS
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.


CONCLUSIONS
Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.
Schiffmann
R
R
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, Bldg 10, Room 3D03, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1260, USA. rs4e@nih.gov
Kopp
J B
JB
Austin
H A
HA
Sabnis
S
S
Moore
D F
DF
Weibel
T
T
Balow
J E
JE
Brady
R O
RO
D000328:Adult; D000704:Analysis of Variance; D001145:Arrhythmias, Cardiac; D001835:Body Weight; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D000795:Fabry Disease / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D007262:Infusions, Intravenous; D007677:Kidney Function Tests; D008297:Male; D010147:Pain Measurement; D014281:Trihexosylceramides / Q000378:metabolism; D000519:alpha-Galactosidase / Q000008:administration & dosage / Q000627:therapeutic use*
D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase