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Ann Clin Transl Neurol. 2020 Jan 22. doi: 10.1002/acn3.50975. [Epub ahead of print]

Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction.

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Department of Child Neurology, Center for Childhood White Matter Diseases, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, Amsterdam, The Netherlands.
Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Axonal Signaling, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
Cell Biology Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
Pediatric Blood and Marrow Transplantation Program, Princess Maxima Center, Utrecht, The Netherlands.
Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms University, Bonn, Germany.



In metachromatic leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted metachromatic leukodystrophy patients.


Autopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) metachromatic leukodystrophy patients, and two age-matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t-test, linear regression or the nonparametric Mann-Whitney U-test was performed to evaluate differences between the transplanted, nontransplanted, and control group.


In brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti-inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in metachromatic leukodystrophy, we detected no enzymatic cross-correction to resident astrocytes and oligodendrocytes.


In conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross-correction of oligo- and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.

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