Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomics
Abstract Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a deficiency of the arylsulfatase A (ARSA). ARSA deficiency leads to an accumulation of sulfatides primarily in the nervous system ultimately causing demyelination. With evolving therapeutic options, there is an inc...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-03-01
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| Series: | JIMD Reports |
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| Online Access: | https://doi.org/10.1002/jmd2.12273 |
| _version_ | 1818393886381309952 |
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| author | Lucia Laugwitz Laimdota Zizmare Vidiyaah Santhanakumaran Claire Cannet Judith Böhringer Jürgen G. Okun Manfred Spraul Ingeborg Krägeloh‐Mann Samuel Groeschel Christoph Trautwein |
| author_facet | Lucia Laugwitz Laimdota Zizmare Vidiyaah Santhanakumaran Claire Cannet Judith Böhringer Jürgen G. Okun Manfred Spraul Ingeborg Krägeloh‐Mann Samuel Groeschel Christoph Trautwein |
| author_sort | Lucia Laugwitz |
| collection | DOAJ |
| description | Abstract Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a deficiency of the arylsulfatase A (ARSA). ARSA deficiency leads to an accumulation of sulfatides primarily in the nervous system ultimately causing demyelination. With evolving therapeutic options, there is an increasing need for indicators to evaluate disease progression. Here, we report targeted metabolic urine profiling of 56 MLD patients including longitudinal sampling, using 1H (proton) nuclear magnetic resonance (NMR) spectroscopy. 1H‐NMR urine spectra of 119 MLD samples and 323 healthy controls were analyzed by an in vitro diagnostics research (IVDr) tool, covering up to 50 endogenous and 100 disease‐related metabolites on a 600‐MHz IVDr NMR spectrometer. Quantitative data reports were analyzed regarding age of onset, clinical course, and therapeutic intervention. The NMR data reveal metabolome changes consistent with a multiorgan affection in MLD patients in comparison to controls. In the MLD cohort, N‐acetylaspartate (NAA) excretion in urine is elevated. Early onset MLD forms show a different metabolic profile suggesting a metabolic shift toward ketogenesis in comparison to late onset MLD and controls. In samples of juvenile MLD patients who stabilize clinically after hematopoietic stem cell transplantation (HSCT), the macrophage activation marker neopterin is elevated. We were able to identify different metabolic patterns reflecting variable organ disturbances in MLD, including brain and energy metabolism and inflammatory processes. We suggest NAA in urine as a quantitative biomarker for neurodegeneration. Intriguingly, elevated neopterin after HSCT supports the hypothesis that competent donor macrophages are crucial for favorable outcome. |
| first_indexed | 2024-12-14T05:52:26Z |
| format | Article |
| id | doaj.art-0f1efdd0ccc549398ca53844ee8f0043 |
| institution | Directory Open Access Journal |
| issn | 2192-8312 |
| language | English |
| last_indexed | 2024-12-14T05:52:26Z |
| publishDate | 2022-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | JIMD Reports |
| spelling | doaj.art-0f1efdd0ccc549398ca53844ee8f00432022-12-21T23:14:40ZengWileyJIMD Reports2192-83122022-03-0163216818010.1002/jmd2.12273Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomicsLucia Laugwitz0Laimdota Zizmare1Vidiyaah Santhanakumaran2Claire Cannet3Judith Böhringer4Jürgen G. Okun5Manfred Spraul6Ingeborg Krägeloh‐Mann7Samuel Groeschel8Christoph Trautwein9Department of Neuropediatrics, Developmental Neurology and Social Pediatrics University of Tuebingen Tuebingen GermanyWerner Siemens Imaging Center University of Tuebingen Tuebingen GermanyDepartment of Neuropediatrics, Developmental Neurology and Social Pediatrics University of Tuebingen Tuebingen GermanyBruker BioSpin GmbH Ettlingen GermanyDepartment of Neuropediatrics, Developmental Neurology and Social Pediatrics University of Tuebingen Tuebingen GermanyDietmar‐Hopp Metabolic Center Children's Hospital Heidelberg Heidelberg GermanyBruker BioSpin GmbH Ettlingen GermanyDepartment of Neuropediatrics, Developmental Neurology and Social Pediatrics University of Tuebingen Tuebingen GermanyDepartment of Neuropediatrics, Developmental Neurology and Social Pediatrics University of Tuebingen Tuebingen GermanyWerner Siemens Imaging Center University of Tuebingen Tuebingen GermanyAbstract Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a deficiency of the arylsulfatase A (ARSA). ARSA deficiency leads to an accumulation of sulfatides primarily in the nervous system ultimately causing demyelination. With evolving therapeutic options, there is an increasing need for indicators to evaluate disease progression. Here, we report targeted metabolic urine profiling of 56 MLD patients including longitudinal sampling, using 1H (proton) nuclear magnetic resonance (NMR) spectroscopy. 1H‐NMR urine spectra of 119 MLD samples and 323 healthy controls were analyzed by an in vitro diagnostics research (IVDr) tool, covering up to 50 endogenous and 100 disease‐related metabolites on a 600‐MHz IVDr NMR spectrometer. Quantitative data reports were analyzed regarding age of onset, clinical course, and therapeutic intervention. The NMR data reveal metabolome changes consistent with a multiorgan affection in MLD patients in comparison to controls. In the MLD cohort, N‐acetylaspartate (NAA) excretion in urine is elevated. Early onset MLD forms show a different metabolic profile suggesting a metabolic shift toward ketogenesis in comparison to late onset MLD and controls. In samples of juvenile MLD patients who stabilize clinically after hematopoietic stem cell transplantation (HSCT), the macrophage activation marker neopterin is elevated. We were able to identify different metabolic patterns reflecting variable organ disturbances in MLD, including brain and energy metabolism and inflammatory processes. We suggest NAA in urine as a quantitative biomarker for neurodegeneration. Intriguingly, elevated neopterin after HSCT supports the hypothesis that competent donor macrophages are crucial for favorable outcome.https://doi.org/10.1002/jmd2.12273arylsulfatase Ametachromatic leukodystrophyN‐acetylaspartateneopterinnuclear magnetic resonanceurine metabolomics |
| spellingShingle | Lucia Laugwitz Laimdota Zizmare Vidiyaah Santhanakumaran Claire Cannet Judith Böhringer Jürgen G. Okun Manfred Spraul Ingeborg Krägeloh‐Mann Samuel Groeschel Christoph Trautwein Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomics JIMD Reports arylsulfatase A metachromatic leukodystrophy N‐acetylaspartate neopterin nuclear magnetic resonance urine metabolomics |
| title | Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomics |
| title_full | Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomics |
| title_fullStr | Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomics |
| title_full_unstemmed | Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomics |
| title_short | Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomics |
| title_sort | identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative nmr based urinary metabolomics |
| topic | arylsulfatase A metachromatic leukodystrophy N‐acetylaspartate neopterin nuclear magnetic resonance urine metabolomics |
| url | https://doi.org/10.1002/jmd2.12273 |
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