Very long chain
fatty acids, which accumulate in plasma and tissues in
X-linked adrenoleukodystrophy (ALD), neonatal ALD, and the Zellweger
cerebrohepatorenal syndrome, are degraded by the peroxisomal beta-oxidation pathway, consisting of
acyl-CoA oxidase, the bifunctional
enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, and
beta-ketothiolase. A marked deficiency of all three
enzyme proteins was reported in livers from patients with the
Zellweger syndrome, a disorder in which peroxisomes are decreased or absent. Peroxisomes are not as markedly decreased in neonatal ALD and appear normal in X-linked ALD. Immunoblot analysis of the peroxisomal beta-oxidation
enzymes revealed an almost complete lack of the bifunctional
enzyme in neonatal ALD liver, similar to the finding in Zellweger tissue. In contrast,
acyl-CoA oxidase and
beta-ketothiolase were present in neonatal ALD liver, although the thiolase appeared to be in precursor form (2-3 kDa larger than the mature
enzyme) in neonatal ALD. Unlike either neonatal ALD or
Zellweger syndrome, all three peroxisomal beta-oxidation
enzymes were present in X-linked ALD liver. Despite the absence in neonatal ALD liver of bifunctional
enzyme protein, its
mRNA was detected by
RNA blot analysis in fibroblasts from these patients. These observations suggest that lack of bifunctional
enzyme protein in neonatal ALD results from either abnormal translation of the
mRNA or degradation of the
enzyme prior to its entry into peroxisomes.