A Metabolomic Map of Zellweger Spectrum Disorders Reveals Novel Disease Biomarkers
Purpose: Peroxisome biogenesis disorders–Zellweger spectrum disorders (PBD-ZSD) are metabolic diseases with multisystem manifestations. Individuals with PBD-ZSD exhibit impaired peroxisomal biochemical functions and have abnormal levels of peroxisomal metabolites, but the broader metabolic impact of peroxisomal dysfunction and the utility of metabolomic methods is unknown. Methods: We studied 19 individuals with clinically and molecularly characterized PBD-ZSD. We performed both quantitative peroxisomal biochemical diagnostic studies in parallel with untargeted small molecule metabolomic profiling in plasma samples with detection of >650 named compounds. Results: The cohort represented intermediate to mild PBD-ZSD subjects with peroxisomal biochemical alterations on targeted analysis. Untargeted metabolomic profiling of these samples revealed elevations in pipecolic acid and long-chain lysophosphatidylcholines, as well as an unanticipated reduction in multiple sphingomyelin species. These sphingomyelin reductions observed were consistent across the PBD-ZSD samples and were rare in a population of >1,000 clinical samples. Interestingly, the pattern or “PBD-ZSD metabolome” was more pronounced in younger subjects suggesting studies earlier in life reveal larger biochemical changes. Conclusion: Untargeted metabolomics is effective in detecting mild to intermediate cases of PBD-ZSD. Surprisingly, dramatic reductions in plasma sphingomyelin are a consistent feature of the PBD-ZSD metabolome. The use of metabolomics in PBD-ZSD can provide insight into novel biomarkers of disease.
MSU Digital Commons Citation
Wangler, Michael F.; Hubert, Leroy; Donti, Taraka R.; Ventura, Meredith J.; Miller, Marcus J.; Braverman, Nancy; Gawron, Kelly; Bose, Mousumi; Moser, Ann B.; Jones, Richard O.; Rizzo, William B.; Sutton, V. Reid; Sun, Qin; Kennedy, Adam D.; and Elsea, Sarah H., "A Metabolomic Map of Zellweger Spectrum Disorders Reveals Novel Disease Biomarkers" (2018). Department of Nutrition and Food Studies Scholarship and Creative Works. 18.