A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers

Michael F. Wangler, Leroy Hubert, Taraka R. Donti, Meredith J. Ventura, Marcus J. Miller, Nancy Braverman, Kelly Gawron, Mousumi Bose, Ann B. Moser, Richard O. Jones, William B. Rizzo, V. Reid Sutton, Qin Sun, Adam D. Kennedy, Sarah H. Elsea

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

Original languageEnglish
Pages (from-to)1274-1283
Number of pages10
JournalGenetics in Medicine
Issue number10
StatePublished - 1 Oct 2018


  • metabolomics
  • peroxisome
  • peroxisome biogenesis disorder
  • sphingomyelin


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