Genetic heterogeneity in patients with a disorder of peroxisomal β‐oxidation: A complementation study based on pristanic acid β‐oxidation suggesting different enzyme defects

One of the most important functions of peroxisomes concerns the β-oxidation of fatty acids and fatty acid derivatives. Peroxisomes are incapable of oxidizing fatty acids to completion. Instead, fatty acids undergo only a few cycles of β-oxidation in the peroxisome and are then transported to the mitochondrion for complete oxidation to CO2 and H2O. This is true for very long-chain fatty acids like cerotic (C26:0) and lignoceric (C24:0) acid and pristanic acid (2,6,10,14-tetramethylpentadecanoic acid). Another important function of the peroxisomal β-oxidation system concerns its role in bile acid synthesis. Indeed, the CoA esters of diand trihydroxycholestanoic acid which are formed from cholesterol are subjected to β-oxidation in the peroxisome, giving rise to propionyl-CoA and the CoA esters of chenodeoxycholic acid and cholic acid, respectively, which are then conjugated and excreted into bile. The enzymatic organization of the peroxisomal β-oxidation system is as yet incompletely understood. It is clear that there are two acyl-CoA oxidases with specificity for straight-chain (Osumi et al 1980) and branched-chain fatty acyl-CoA esters (Vanhove et al 1993). Until recently it was believed that the subsequent steps are catalysed by one bifunctional protein (Osumi et al 1980) and peroxisomal thiolase (Miyazawa et al 1980), but this view is no longer tenable (see Novikov et al 1994). We have recently found that the bifunctional protein and thiolase as characterized by Hashimoto and coworkers are not involved in pristanic acid β-oxidation. In collaboration with Seedorf and coworkers we have shown that the thiolase encoded by the sterol carrier protein X (SCPx) gene (Seedorf et al 1994) contains 3-ketopristanoyl-CoA thiolase activity, whereas the classical thiolase lacks such activity (Wanders et al 1996). In the last few years an increasing number of patients have been described with a defect J. Inher. Metab. Dis. 20 (1997) 437– 4 4 0 © SSIEM and Kluwer Academic Publishers. Printed in the Netherlands