TY - JOUR
T1 - Neurodegenerative disease after hematopoietic stem cell transplantation in metachromatic leukodystrophy
AU - Al-Saady, Murtadha
AU - Beerepoot, Shanice
AU - Plug, Bonnie C.
AU - Breur, Marjolein
AU - Galabova, Hristina
AU - Pouwels, Petra J. W.
AU - Boelens, Jaap-Jan
AU - Lindemans, Caroline
AU - van Hasselt, Peter M.
AU - Matzner, Ulrich
AU - Vanderver, Adeline
AU - Bugiani, Marianna
AU - van der Knaap, Marjo S.
AU - Wolf, Nicole I.
N1 - Funding Information: We are grateful to the MLD patients and their families for their participation in this study. Part of this study was funded by the Dutch Brain Foundation (Hersenstichting; grant WS2015-02). We also thank the European Leukodystrophy Association (ELA) for their organization of MLD brainstorming meetings, which helped us shape this work. Prof. Dr. Volkmar Gieselmann is also owed thanks for supplying our laboratory with the necessary antibodies and for his helpful comments reviewing the manuscript. Amsterdam Leukodystrophy Center and the affiliated authors are members of the European Reference Network for Rare Neurological Disorders (ERN-RND), project ID 739510. Funding Information: We are grateful to the MLD patients and their families for their participation in this study. Part of this study was funded by the Dutch Brain Foundation (Hersenstichting; grant WS2015‐02). We also thank the European Leukodystrophy Association (ELA) for their organization of MLD brainstorming meetings, which helped us shape this work. Prof. Dr. Volkmar Gieselmann is also owed thanks for supplying our laboratory with the necessary antibodies and for his helpful comments reviewing the manuscript. Publisher Copyright: © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2023/7
Y1 - 2023/7
N2 - Objective: Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post-treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology. Methods: Three metachromatic leukodystrophy patients treated with hematopoietic stem cell transplantation with a progressive clinical course despite stable white matter pathology were clinically and radiologically analyzed. Longitudinal volumetric MRI was used to quantify atrophy. We also examined histopathology in three other patients deceased after treatment and compared them with six untreated patients. Results: The three clinically progressive patients developed cognitive and motor deterioration after transplantation, despite stable mild white matter abnormalities on MRI. Volumetric MRI identified cerebral and thalamus atrophy in these patients, and cerebellar atrophy in two. Histopathology showed that in brain tissue of transplanted patients, arylsulfatase A expressing macrophages were clearly present in the white matter, but absent in the cortex. Arylsulfatase A expression within patient thalamic neurons was lower than in controls, the same was found in transplanted patients. Interpretation: Neurological deterioration may occur after hematopoietic stem cell transplantation in metachromatic leukodystrophy despite successfully treated leukodystrophy. MRI shows gray matter atrophy, and histological data demonstrate absence of donor cells in gray matter structures. These findings point to a clinically relevant gray matter component of metachromatic leukodystrophy, which does not seem sufficiently affected by transplantation.
AB - Objective: Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post-treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology. Methods: Three metachromatic leukodystrophy patients treated with hematopoietic stem cell transplantation with a progressive clinical course despite stable white matter pathology were clinically and radiologically analyzed. Longitudinal volumetric MRI was used to quantify atrophy. We also examined histopathology in three other patients deceased after treatment and compared them with six untreated patients. Results: The three clinically progressive patients developed cognitive and motor deterioration after transplantation, despite stable mild white matter abnormalities on MRI. Volumetric MRI identified cerebral and thalamus atrophy in these patients, and cerebellar atrophy in two. Histopathology showed that in brain tissue of transplanted patients, arylsulfatase A expressing macrophages were clearly present in the white matter, but absent in the cortex. Arylsulfatase A expression within patient thalamic neurons was lower than in controls, the same was found in transplanted patients. Interpretation: Neurological deterioration may occur after hematopoietic stem cell transplantation in metachromatic leukodystrophy despite successfully treated leukodystrophy. MRI shows gray matter atrophy, and histological data demonstrate absence of donor cells in gray matter structures. These findings point to a clinically relevant gray matter component of metachromatic leukodystrophy, which does not seem sufficiently affected by transplantation.
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U2 - https://doi.org/10.1002/acn3.51796
DO - https://doi.org/10.1002/acn3.51796
M3 - Article
C2 - 37212343
SN - 2328-9503
VL - 10
SP - 1146
EP - 1159
JO - Annals of clinical and translational neurology
JF - Annals of clinical and translational neurology
IS - 7
ER -