A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers

Genet Med. 2018 Oct;20(10):1274-1283. doi: 10.1038/gim.2017.262. Epub 2018 Feb 8.


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.

Keywords: PBD-ZSD; metabolomics; peroxisome; peroxisome biogenesis disorder; sphingomyelin.

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers / blood*
  • Child, Preschool
  • Cohort Studies
  • Female
  • Humans
  • Lysosomal Storage Diseases / blood*
  • Lysosomal Storage Diseases / genetics
  • Lysosomal Storage Diseases / pathology
  • Male
  • Membrane Proteins
  • Metabolomics / methods
  • Peroxisomal Disorders / blood*
  • Peroxisomal Disorders / pathology
  • Sphingomyelins / blood
  • Young Adult
  • Zellweger Syndrome / blood*
  • Zellweger Syndrome / genetics
  • Zellweger Syndrome / pathology


  • Biomarkers
  • Membrane Proteins
  • Sphingomyelins

Supplementary concepts

  • Peroxisome biogenesis disorders