X-Linked Adrenoleukodystrophy: Identification of the Primary Defect at the Level of a Deficient Peroxisomal Very Long Chain Fatty Acyl-CoA Synthetase Using a Newly Developed Method for the Isolation of Peroxisomes from Skin Fibroblasts

Abstract

Several types of adrenoleukodystrophy (ALD) differing in age of onset, mode of inheritance and clinical presentation have been described in the literature. The X-linked form of adrenoleukodystrophy, which is the most common, is characterized by demyelination, adrenal sufficiency and the accumulation of very long chain fatty acids, particularly hexacosanoic acid (C_26:0), in tissues and body fluids (Moser et al., 1984). It is now generally accepted that the accumulation of very long chain fatty acids in X-linked ALD is caused by their impaired degradation via the peroxisomal β-oxidation system as first shown by Singh and co-workers in 1981 (see also Rizzo et al., 1984; Singh et al., 1984; Tsuji et al., 1985). Recent studies have shown that the deficient peroxisomal oxidation of very long chain fatty acids in X- linked ALD is not caused by a deficiency of one of the peroxisomal β-oxidation enzymes (acyl-CoA oxidase, bifunctional protein with enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities and 3-oxoacyl-CoA thiolase) since all three enzyme proteins were not only found to be immunologically present as shown by immunoblotting (Wanders et al., 1987) but also functionally active (Hashmi et al., 1986; Wanders et al., 1987). The latter finding led Hashmi and co-workers to suggest that the defect in X-linked ALD is at the level of a deficient activation of very long chain fatty acids to their CoA-esters. However, measurement of this activity in X-linked ALD fibroblasts using tetracosanoic acid (C_24:0) and hexacosanoic acid (C_26:0) as substrates revealed only a partial (about 25%) very long chain acyl-CoA synthetase deficiency (Wanders et al., 1987a).