We will investigate the abnormal metabolism of very long chain fatty acids (VLFA) in patients with the inherited disorders, adrenoleukodystrophy (ALD), who are deficient in VLFA oxidation. The long-term goals of this research are to elucidate the primary enzymatic defect in ALD, understand the basis for phenotypic variation and devise an effective therapy. Residual VLFA oxidative activity will be correlated with the clinical phenotype using cultured skin fibroblasts from ALD patients that differ in clinical severity (childhood ALD or adrenomyeloneuropathy). In particular, the effects of competing fatty acids on VLFA oxidative activity will be investigated to determine whether differences in metabolism of shorter-chain fatty acids are responsible for phenotypic variation in ALD.
A specific aim i s to establish whether deficiency of lignoceroyl CoA synthetase is the primary defect in this disease, and methods will be developed to assay this enzyme in cultured skin fibroblasts. With the goal to identify new therapeutic approaches to ALD, we will explore the potential for acetylenic fatty acids to selectively lower saturated VLFA levels in ALD fibroblasts. The effects of acetylenic fatty acids on de nov VLFA synthesis and fatty acids elongation will be studied in intact cells and homogenates. Using a variety of radiochemical and biochemical techniques, the mechanism whereby erucic acid lowers saturated VLFA levels in ALD fibroblasts will be elucidated. A clinical trial will be conducted to determined whether dietary erucic acid supplementation is effective in the therapy of ALD. The clinical response to erucic acid therapy will be monitored with objective neuro-physiological, endocrine and biochemcial tests. These studies will provide fundamental information concerning the etiology and therapy of ALD.
