Abstract X-ALD is a rare disorder caused by impaired b-oxidation of very long chain fatty acids, their accumulation and incorporation in lipids and resulting in pathology, severely impacting central nervous system. Thorough comparative profiling of fatty acids and lipids in different human tissues and biological fluids described in this manuscript has revealed significant differences in composition which explained why blood lipids successfully used as diagnostics biomarkers for X-ALD do not correlate with disease progression and cannot inform on decision making regarding medical intervention. Our data yielded insights in understanding why the metabolic disorder resulting in elevated levels of VLCFAs in all tissues in X-ALD patients causes severe pathology limited to the central nervous system. We then conducted global lipid profiling of cerebrospinal fluid from pediatric patients and using data filtering based on disease progression trend identified new leads for lipid markers with strong disease progression correlations. Data suggests that few associated proteins should be evaluated as potential biomarkers which may be detectable in blood. We also present data from lipids and fatty acids profiling of tissues from X-ALD mouse model and WT mice, and comparison with the profiling data obtained for human tissues. This analysis yielded clues to understanding why the ABCD1 KO mouse model which has the relevant biochemical phenotype, develops only a subtle pathology, while in humans disease manifestation is severe. In the ABCD1 KO mouse longitudinal study reported in this manuscript, we have identified trending lipids which may serve as sensitive biomarkers of fatty acids metabolism modulations.
Kloss et al. (Wed,) studied this question.