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 performed an open-label continuation study 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. Patients who had been initially on placebo experienced the same benefit when treated with enzyme. Additional findings revealed that patients receiving the enzyme had a delayed onset of end-stage renal disease, improvement of their ability to sense cold and warm temperature, and correction of their sweating deficiency. 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. The enzyme has already been approved for these patients in the European Union and seven other countries. We found mutations in subunits of the eucaryotic initiation factor 2B (eIF2B) in patients with a leukodystrophy we first identified and called Childhood Ataxia with CNS Hypomyelination (CACH). We discovered that patients with Cree leukoencephalopathy, a very severe genetic disease of infancy, also have mutations in the eIF2B5 gene. Brains of patients with Cree leukoencephalopathy were found to have the same """"""""foamy"""""""" oligodendrocytes that we previously described as a hallmark of CACH. We also found that patients with another leukodystrophy we previously described and called ovarioleukodystrophy also have mutations in subunits of the protein eIF2B. We developed an electronic technique to measure the velocity of saccadic eye movement in patients with neuronopathic Gaucher disease. We found that all these patients have slow vertical saccades. This abnormality will be used as an important outcome measure to test the efficacy of novel therapies under development in DMNB for the neurologic disease in these patients.
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