Abstract
X-linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, and is characterized by the accumulation of very long-chain fatty acids in plasma and tissues. Disease-causing mutations are ‘loss of function’ mutations, with no prognostic value with respect to the clinical outcome of an individual. All male patients with ALD develop spinal cord disease and a peripheral neuropathy in adulthood, although age of onset is highly variable. However, the lifetime prevalence to develop progressive white matter lesions, termed cerebral ALD (CALD), is only about 60%. Early identification of transition to CALD is critical since it can be halted by allogeneic hematopoietic stem cell therapy only in an early stage. The primary goal of this study is to identify molecular markers which may be prognostic of cerebral demyelination from a simple blood sample, with the hope that blood-based assays can replace the current protocols for diagnosis. We collected six well-characterized brother pairs affected by ALD and discordant for the presence of CALD and performed multi-omic profiling of blood samples including genome, epigenome, transcriptome, metabolome/lipidome, and proteome profiling. In our analysis we identify discordant genomic alleles present across all families as well as differentially abundant molecular features across the omics technologies. The analysis was focused on univariate modeling to discriminate the two phenotypic groups, but was unable to identify statistically significant candidate molecular markers. Our study highlights the issues caused by a large amount of inter-individual variation, and supports the emerging hypothesis that cerebral demyelination is a complex mix of environmental factors and/or heterogeneous genomic alleles. We confirm previous observations about the role of immune response, specifically auto-immunity and the potential role of PFN1 protein overabundance in CALD in a subset of the families. We envision our methodology as well as dataset has utility to the field for reproducing previous or enabling future modifier investigations.
Highlights
Adrenoleukodystrophy (ALD) is a rare peroxisomal X-linked degenerative disease (MIM 300100), caused by deficiency of the ABC half-transporter encoded by the ABCD1 gene
We applied liquid chromatography mass spectrometry (LCMS) from plasma samples of each of the patients within this cohort as well as matched control samples
We identified differential lipid abundances between ALD samples and control samples, with 139 lipids passing the threshold of p-value < 0.05 (Eq 1, ordinary least squares modeling (OLS)), and 17 lipids remaining significant after multiple testing correction (Bonferroni) (Supplementary Figure S1 and Supplementary Table S1) (Methods)
Summary
Adrenoleukodystrophy (ALD) is a rare peroxisomal X-linked degenerative disease (MIM 300100), caused by deficiency of the ABC half-transporter encoded by the ABCD1 gene. During adulthood virtually all male and, eventually, female patients develop a progressive myelopathy termed adrenomyeloneuropathy (Engelen et al, 2012; Engelen et al, 2014; Huffnagel et al, 2019a). During childhood or sometimes through adulthood male patients can develop cerebral demyelination, termed cerebral ALD (CALD). Untreated CALD is often progressive, but can spontaneously arrest in 10–20% of patients. It causes vegetative state and death 2–3 years after onset, so early identification as well as careful and frequent monitoring of all male ALD patients is necessary. The precise mechanism by which hematopoietic stem cell therapy arrests CALD progression is not clear. The unresolved and unpredictable phenotypic variability of ALD is a crucial roadblock for patient care
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