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. We found that enzyme replacement therapy significantly improved cerebrovascular function and vascular reactivity. 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 countries that are members of the European Union. We identified two new leukodystrophy syndromes. The first involves a dysmyelinating disorder affecting both central and peripheral myelin. Detailed histology, immunohistochemistry, immunoelectron microscopy and Western blot studies revealed an absence of myelin-associated glycoprotein in the internodal regions although it was present in the Schmidt-Lanterman incisures. This alteration was accompanied by an abnormal aggregation of myelin basic protein in myelin. The findings suggest a disorder of myelin protein trafficking and abnormal localization 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. We performed an extensive study of the neuropathology of Gaucher disease. All brains examined (including the non-neuronopathic, type 1) had a unique pattern of abnormalities, especially in the hippocampus. We found that some patients who also develop parkinsonian symptoms have Lewy bodies in a similar distribution pattern. Immature Lewy bodies were seen infants with neuronopathic Gaucher disease. The areas in the brain that are involved in Gaucher disease also had the highest expression of glucocerebrosidase. Staining for the storage material revealed its presence in the cellular membrane of neurons suggesting that glycolipid accumulation disturbs cellular functions located in those areas. This study deminstrates that: 1. This enzyme deficiency is probably critical to certain types of neurons and therefore the glycolipid metabolic abnormality plays a role in specific neuronal functions. 2. The cellular dysfunction in Gaucher disease has similarities to metabolic disturbances that occur in more common disorders such as dementia with Lewy bodies (also called Parkinson Dementia Complex). Therefore, the study of this disorder may be relevant other dementias with Lewy bodies.
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