FATTY ACID METABOLISM IN ADRENOLEUKODYSTROPHY

Fundamental knowledge concerning the metabolism and function of very long
chain fatty acids (VLFA) in man is lacking. Current interest in VLFA
metabolism has been heightened by the demonstration that patients with the
X-linked inherited disease adrenoleukodystrophy (ALD) accumulate VLFA in
various tissues, including cultured fibroblasts. Long-term objectives of
the proposed research are to establish the biochemical basis for VLFA
accumulation in ALD, determine whether genetic heterogeneity is responsible
for phenotypic variability in affected individuals, and uncover the
pathogenetic mechanisms resulting in organ dysfunction. Accordingly, we
will investigate the rate and control of VLFA synthesis and turnover in
normal and ALD fibroblasts using radio-chemical techniques. These methods
will be used to clarify the mechanism whereby VLFA accumulation in ALD
fibroblasts is decreased by incubation in the presence of oleic acid. The
relative contribution of peroxisomal and mitochondrial pathways to total
VLFA oxidation will be determined in cultured fibroblasts, adrenocortical
cells, hepatocytes, and glioma cells. Individual VLFA Beta-oxidation
enzymatic activities will be characterized in rat liver, and these assays
will be applied to normal and ALD fibroblasts in an attempt to identify the
putative enzymatic defect in ALD. Genetic complementation studies with
fibroblasts will be used to investigate possible genetic heterogeneity in
ALD, and the ALD gene will be further mapped on the X-chromosome by
chromosome-mediated gene transfer techniques. The pathophysiologic basis
for adrenal insufficiency in ALD will be investigated in a model system
employing adrenocortical cells cultured in the presence of VLFA. These
studies will provide fundamental information about normal VLFA metabolism
and the deranged VLFA metabolism in ALD.