One of the major goals of the Branch is to develop effective treatment for patients with hereditary neurometabolic disorders. Second to Gaucher disease, the most prevalent condition in this category is Fabry disease. Patients with this disorder have a severely painful peripheral neuropathy, premature strokes and myocardial infarctions, and ultimately, complete renal failure. During the reporting year, we completed a highly successful double-blind placebo-controlled trial of enzyme replacement therapy for Fabry disease. The missing enzyme, alpha-galactosidase A, was prepared in a Good Manufacturing Practices Facility using a continuous human cell line as source of the enzyme. Patients receiving the study drug had significant reduction of the painful acroparesthesias associated with this disorder. Those in the placebo arm had no change in this parameter. Additional findings revealed that patients receiving the enzyme had improvement in renal pathology and abnormal kidney function that are also hallmarks of Fabry disease. Patients in the placebo arm experienced worsening of kidney function and attendant pathology over the period of the trial. These findings have been submitted to the US Food and Drug Administration for a Biological License Application to permit prescribing and distribution of this therapeutic enzyme to patients with Fabry disease. We identified two new leukodystrophy syndromes. The first involves a dysmyelinating disorder affecting both central andperipheral myelin. Detailed histology, immunohistochemistry,immunoelectron microscopy and Western blot studies revealed an absence of myelin-associated glycoprotein in the internodalregions although it was present in the Schmidt-Lantermanincisures. This alteration was accompanied by an abnormal aggregation of myelin basic protein in myelin. The findings suggest a disorder of myelin protein trafficking and abnormallocalization of myelin components. The other previously uncharacterized leukodystrophy is a diffuse dysmyelinating disorder associated with severe global dystonia with selective and progressive atrophy of the putamen and caudate nuclei. All of the patients encountered to date have been sporadic in occurrence. This pattern of inheritance is suggestive of novel dominant mutations in a gene that is critical for the development and maintenance of myelin and a specific population of neurons.
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