The objective of the proposed research is to study the biochemical parameters of the genetic neurological disorder metachromatic leukodystrophy (MLD). MLD is a manifestation of a dysfunction in the catabolism of cerebroside sulfate (sulfatide) which results in demyelination and neuropathy. We now know that MLD is not a one gene-one enzyme one mutation-one disease entity. A variety of mutations - some allelic, some nonallelic, and others as yet uncharacterized - can cause dysfunctions of sulfatide catabolism and give rise to genocopies of MLD. Moreover, the recent discovery that deficiency of cerebroside sulfatase activator can cause MLD has indicated that activator is a physiologically essential constituent of the sulfatide catabolism process and that the latter must be viewed and studied as a three component system, enzyme: substrate:activator. Accordingly, the parameters to be examined to understand the biochemistry of MLD have expanded extensively. The present research will consist of three phases. The first phase, Normal Catabolism of Cerebroside Sulfate, will be concerned with modifications of the intact fibroblast sulfatide loading test to characterize the intracellular sulfatidase reaction. A base to identify mutants with anomalies in the reaction will be provided. The second phase, Specific Dysfunctions of Cerebroside Sulfate Catabolism, will focus on variant forms of MLD including cerebroside sulfatase activator deficiency, pseudo arylsulfatase A deficiency, partial cerebroside sulfatase defect, multiple sulfatase deficiency disorder, and classical MLD. Detailed studies will be pursued in an attempt to define the nature of specific lesions at the molecular level. The third phase, Uncharacterized Variants of MLD, will be directed toward identifying new variants of MLD.
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