Journal
GENETICS IN MEDICINE
Volume 20, Issue 10, Pages 1274-1283Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2017.262
Keywords
metabolomics; peroxisome; PBD-ZSD; peroxisome biogenesis disorder; sphingomyelin
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Funding
- NIGMS NIH HHS [T32 GM007526] Funding Source: Medline
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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.
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