Michael F Wangler1,2,3,4, Leroy Hubert5, Taraka R Donti5, Meredith J Ventura6, Marcus J Miller5, Nancy Braverman7, Kelly Gawron8, Mousumi Bose8, Ann B Moser9, Richard O Jones9, William B Rizzo10, V Reid Sutton5, Qin Sun5, Adam D Kennedy11, Sarah H Elsea12. 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. michael.wangler@bcm.edu. 2. Texas Children's Hospital, Houston, Texas, USA. michael.wangler@bcm.edu. 3. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. michael.wangler@bcm.edu. 4. Developmental Biology Program, Baylor College of Medicine, Houston, Texas, USA. michael.wangler@bcm.edu. 5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. 6. School of Medicine, Baylor College of Medicine, Houston, Texas, USA. 7. Research Institute of the McGill University Health Center, Montreal, Quebec, Canada. 8. Department of Nutrition and Food Studies, Montclair State University, Montclair, New Jersey, USA. 9. Division of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. 10. University of Nebraska Medical Center, Omaha, Nebraska, USA. 11. Metabolon, Morrisville, North Carolina, USA. 12. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. elsea@bcm.edu.
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.
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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