Multi-Omic Approach to Identify Phenotypic Modifiers Underlying Cerebral Demyelination in X-Linked Adrenoleukodystrophy

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

Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need

“…Considering the important role of glycosphingolipids in the nervous system, it will be interesting to see whether this finding can be replicated in a larger cohort. Richmond et al employed a lipidomics strategy using plasma samples of six well-characterized brother pairs affected by ALD and discordant for the presence of cerebral ALD [ 50 ]. The study was unable to separate cerebral ALD and non-cerebral ALD using principal component analysis which indicated very similar lipid profiles of these two groups and no statistically significant lipid marker was identified that could discriminate between cerebral ALD and non-cerebral ALD patients.…”

Evolution of adrenoleukodystrophy model systems

“…1,2 Moreover, given that monozygotic twins can have a disconcordant disease course, a combination of rare genetic modifiers, epigenetic, and environmental factors have been hypothesized to impact the disease outcome. 3,4 The complex clinical presentation and the absence of a genotype-phenotype correlation are complicating our understanding of the disease.…”

Dosage Compensation in Females with X-Linked Metabolic Disorders

“…Schilder described several case reports with cerebral lesions accompanied by acute inflammatory changes. Since then, all symptoms analogous to those mentioned by Schilder have been called “Schilder’s disease” [ 162 ]. Even today, determining the actual number of cases still remains a problematic issue, mainly due to the lack of uniform diagnostic criteria.…”

“…Diagnosis is made on the basis of serum VLCFA levels and genetic testing [ 164 ]. The most common forms of X-ALD are CALD and AMN, found in populations around the world [ 162 ]. CALD only affects boys, usually between 5–14 years.…”