Biochemical and cell biological aspects of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy is a devastating peroxisomal disorder with only limited options for treatment. Recent findings however have pointed towards fatty acid elongation as a possible target for therapeutic intervention of X-ALD. Chapter 2 describes how bezafibrate reduces VLCFA levels in X-ALD fibroblasts by inhibiting fatty acid chain elongation. Based on these results, an open-label pilot study was performed to evaluate the effect of bezafibrate on VLCFA accumulation in blood cells of AMN patients. Unfortunately, bezafibrate failed to lower VLCFA levels in blood cells of X-ALD patients. Most likely this is attributable to its inability to reach adequate drug levels in vivo. In chapter 3 the kinetic characteristics of ELOVL1 and further investigation of the effect of fibrates on fatty acid chain elongation are described. This revealed that bezafibrate had the strongest effect in intact cells while the CoA-ester of gemfibrozil was the strongest inhibitor of VLCFA elongation activity in vitro. The CoA esters of bezafibrate and gemfibrozil inhibit chain elongation by specifically inhibiting the first step of the elongation system, catalyzed by ELOVL1.
Correct diagnosis of patients is a major focus of the Laboratory Genetic Metabolic Diseases. In chapter 4 a method is reported to resolve the pathogenicity of novel ABCD1 variants of unknown significance. Correct diagnosis is of importance to all X-ALD patients as it will help in the identification of present and future health issues and allows for the correct counseling on the reproductive risk of the disease. Chapter 5 is focused on the intracellular metabolism of a range of fatty acids and the role of peroxisomes therein. To this end the differences in de novo fatty acid metabolism between control, ABCD1 deficient, ABCD3 deficient and PBD cell lines were studied. Furthermore, the effects of mitochondrial deficiencies on peroxisomal metabolism were investigated. Finally, studies were done to resolve how PBD and ABCD1 deficiency change the fatty acid composition of different lipid species. In chapter 6 a summary is given of the main findings of this thesis work followed by a discussion of the results obtained plus future perspectives.