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 journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

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
Volume20
Issue number10
DOIs
StatePublished - 1 Oct 2018

Fingerprint

Zellweger Syndrome
Peroxisomes
Metabolomics
Biomarkers
Sphingomyelins
Metabolome
Lysophosphatidylcholines
Metabolic Diseases

Keywords

  • PBD-ZSD
  • metabolomics
  • peroxisome
  • peroxisome biogenesis disorder
  • sphingomyelin

Cite this

Wangler, M. F., Hubert, L., Donti, T. R., Ventura, M. J., Miller, M. J., Braverman, N., ... Elsea, S. H. (2018). A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers. Genetics in Medicine, 20(10), 1274-1283. https://doi.org/10.1038/gim.2017.262
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. ; Elsea, Sarah H. / A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers. In: Genetics in Medicine. 2018 ; Vol. 20, No. 10. pp. 1274-1283.
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abstract = "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",
author = "Wangler, {Michael F.} and Leroy Hubert and Donti, {Taraka R.} and Ventura, {Meredith J.} and Miller, {Marcus J.} and Nancy Braverman and Kelly Gawron and Mousumi Bose and Moser, {Ann B.} and Jones, {Richard O.} and Rizzo, {William B.} and Sutton, {V. Reid} and Qin Sun and Kennedy, {Adam D.} and Elsea, {Sarah H.}",
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Wangler, MF, Hubert, L, Donti, TR, Ventura, MJ, Miller, MJ, Braverman, N, Gawron, K, Bose, M, Moser, AB, Jones, RO, Rizzo, WB, Sutton, VR, Sun, Q, Kennedy, AD & Elsea, SH 2018, 'A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers', Genetics in Medicine, vol. 20, no. 10, pp. 1274-1283. https://doi.org/10.1038/gim.2017.262

A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers. / 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.; Elsea, Sarah H.

In: Genetics in Medicine, Vol. 20, No. 10, 01.10.2018, p. 1274-1283.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers

AU - Wangler, Michael F.

AU - Hubert, Leroy

AU - Donti, Taraka R.

AU - Ventura, Meredith J.

AU - Miller, Marcus J.

AU - Braverman, Nancy

AU - Gawron, Kelly

AU - Bose, Mousumi

AU - Moser, Ann B.

AU - Jones, Richard O.

AU - Rizzo, William B.

AU - Sutton, V. Reid

AU - Sun, Qin

AU - Kennedy, Adam D.

AU - Elsea, Sarah H.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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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Wangler MF, Hubert L, Donti TR, Ventura MJ, Miller MJ, Braverman N et al. A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers. Genetics in Medicine. 2018 Oct 1;20(10):1274-1283. https://doi.org/10.1038/gim.2017.262