New Approaches in Peroxisomal Disorders

Abstract

The peroxisome is a subcellular organelle with important functions in plants and protozoa, which during the last decade has also been shown to have a role in mammalian lipid and amino acid metabolism. These functions include steps in the synthesis of ether lipids and bile acids and fatty acid beta-oxidation, particularly those of very long chain fatty acids. The proposition that the peroxisome carries out significant functions in man is highlighted by the fact that lack of this organelle is associated with severe abnormalities in many human organs. Human peroxisomal disorders are now grouped into three general categories. In the first group, peroxisomes are lacking or reduced in number. This group includes the Zellweger cerebro-hepato-renal syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease and hyperpipecolic acidemia. These patients lack the capacity to synthesize ether lipids and to oxidize very long chain fatty acids or phytanic acid, and they show abnormally high levels of pipecolic acid and bile acid intermediates. These patients rarely survive early childhood, have severe neurological deficits and multiple malformations. A second group includes the 'pseudo-Zellweger' syndrome and the rhizomelic form of chondrodysplasia punctata. Here the peroxisomal structure is intact, but there is deficient function of several peroxisomal enzymes. The third group includes X-linked adrenoleukodystrophy, acatalasemia and 'adult' Refsum's disease. The peroxisomal structure is intact, and the defect in each instance is thought to involve a mutation which affects a single peroxisomal enzyme. Peroxisomal disorders are of current interest because they occur more commonly than had been recognized and show phenotypic and genotypic heterogeneity. Their study provides the opportunity to learn more about the role of the peroxisome in normal brain function and development.