FATTY ACID METABOLISM IN ADRENOLEUKODYSTROPHY

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 is 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.