JIMD Reports (Mar 2022)

Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomics

  • Lucia Laugwitz,
  • Laimdota Zizmare,
  • Vidiyaah Santhanakumaran,
  • Claire Cannet,
  • Judith Böhringer,
  • Jürgen G. Okun,
  • Manfred Spraul,
  • Ingeborg Krägeloh‐Mann,
  • Samuel Groeschel,
  • Christoph Trautwein

DOI
https://doi.org/10.1002/jmd2.12273
Journal volume & issue
Vol. 63, no. 2
pp. 168 – 180

Abstract

Read online

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.

Keywords