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

doi:10.1038/gim.2017.262

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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 language	English (US)
Pages (from-to)	1274-1283
Number of pages	10
Journal	Genetics in Medicine
Volume	20
Issue number	10
DOIs	https://doi.org/10.1038/gim.2017.262
State	Published - Oct 1 2018

Keywords

PBD-ZSD
metabolomics
peroxisome
peroxisome biogenesis disorder
sphingomyelin

ASJC Scopus subject areas

Genetics(clinical)

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10.1038/gim.2017.262

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Wangler, M. F., Hubert, L., Donti, T. R., Ventura, M. J., Miller, M. J., Braverman, N., Gawron, K., Bose, M., Moser, A. B., Jones, R. O., Rizzo, W. B., Sutton, V. R., Sun, Q., Kennedy, A. D., & 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

@article{affd8040c29d464ba75d390e06f8f9f6,

title = "A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers",

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.}",

note = "Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",

year = "2018",

month = oct,

day = "1",

doi = "10.1038/gim.2017.262",

language = "English (US)",

volume = "20",

pages = "1274--1283",

journal = "Genetics in Medicine",

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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.

KW - PBD-ZSD

KW - metabolomics

KW - peroxisome

KW - peroxisome biogenesis disorder

KW - sphingomyelin

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SN - 1098-3600

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JO - Genetics in Medicine

JF - Genetics in Medicine

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ER -

A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers

Abstract

Keywords

ASJC Scopus subject areas

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