Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder belonging to the group of vacuolating leukodystrophies. It is characterized by megalencephaly, loss of motor functions, epilepsy, and mild mental decline. In brain biopsies of MLC patients, vacuoles were obse...

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Detalles Bibliográficos
Autores: Bosch, Assumpció, Estévez Povedano, Raúl
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/174669
Acceso en línea:https://hdl.handle.net/2445/174669
Access Level:acceso abierto
Palabra clave:Malalties hereditàries
Malalties del sistema nerviós central
Malalties rares
Genetic diseases
Central nervous system diseases
Rare diseases
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spelling Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for TherapyBosch, AssumpcióEstévez Povedano, RaúlMalalties hereditàriesMalalties del sistema nerviós centralMalalties raresGenetic diseasesCentral nervous system diseasesRare diseasesMegalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder belonging to the group of vacuolating leukodystrophies. It is characterized by megalencephaly, loss of motor functions, epilepsy, and mild mental decline. In brain biopsies of MLC patients, vacuoles were observed in myelin and in astrocytes surrounding blood vessels. It is mainly caused by recessive mutations in MLC1 and HEPACAM (also called GLIALCAM) genes. These disease variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. Besides, dominant mutations in HEPACAM were also identified in a subtype of MLC patients (MLC2B) with a remitting phenotype. MLC1 and GlialCAM proteins form a complex mainly expressed in brain astrocytes at the gliovascular interface and in Bergmann glia at the cerebellum. Both proteins regulate several ion channels and transporters involved in the control of ion and water fluxes in glial cells, either directly influencing their location and function, or indirectly regulating associated signal transduction pathways. However, the MLC1/GLIALCAM complex function and the related pathological mechanisms leading to MLC are still unknown. It has been hypothesized that, in MLC, the role of glial cells in brain ion homeostasis is altered in both physiological and inflammatory conditions. There is no therapy for MLC patients, only supportive treatment. As MLC2B patients show an MLC reversible phenotype, we speculated that the phenotype of MLC1 and MLC2A patients could also be mitigated by the re-introduction of the correct gene even at later stages. To prove this hypothesis, we injected in the cerebellar subarachnoid space of Mlc1 knockout mice an adeno-associated virus (AAV) coding for human MLC1 under the control of the glial-fibrillary acidic protein promoter. MLC1 expression in the cerebellum extremely reduced myelin vacuolation at all ages in a dose-dependent manner. This study could be considered as the first preclinical approach for MLC. We also suggest other potential therapeutic strategies in this review.Frontiers Media SA2021202120212021info:eu-repo/semantics/article13 p.application/pdfhttps://hdl.handle.net/2445/174669Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3389/fncel.2020.627887Frontiers in Cellular Neuroscience, 2021, vol. 14, num. 627887https://doi.org/10.3389/fncel.2020.627887cc by (c) Bosch, Assumpció et al., 2021http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1746692026-05-29T05:05:01Z
dc.title.none.fl_str_mv Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
title Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
spellingShingle Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
Bosch, Assumpció
Malalties hereditàries
Malalties del sistema nerviós central
Malalties rares
Genetic diseases
Central nervous system diseases
Rare diseases
title_short Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
title_full Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
title_fullStr Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
title_full_unstemmed Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
title_sort Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
dc.creator.none.fl_str_mv Bosch, Assumpció
Estévez Povedano, Raúl
author Bosch, Assumpció
author_facet Bosch, Assumpció
Estévez Povedano, Raúl
author_role author
author2 Estévez Povedano, Raúl
author2_role author
dc.subject.none.fl_str_mv Malalties hereditàries
Malalties del sistema nerviós central
Malalties rares
Genetic diseases
Central nervous system diseases
Rare diseases
topic Malalties hereditàries
Malalties del sistema nerviós central
Malalties rares
Genetic diseases
Central nervous system diseases
Rare diseases
description Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder belonging to the group of vacuolating leukodystrophies. It is characterized by megalencephaly, loss of motor functions, epilepsy, and mild mental decline. In brain biopsies of MLC patients, vacuoles were observed in myelin and in astrocytes surrounding blood vessels. It is mainly caused by recessive mutations in MLC1 and HEPACAM (also called GLIALCAM) genes. These disease variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. Besides, dominant mutations in HEPACAM were also identified in a subtype of MLC patients (MLC2B) with a remitting phenotype. MLC1 and GlialCAM proteins form a complex mainly expressed in brain astrocytes at the gliovascular interface and in Bergmann glia at the cerebellum. Both proteins regulate several ion channels and transporters involved in the control of ion and water fluxes in glial cells, either directly influencing their location and function, or indirectly regulating associated signal transduction pathways. However, the MLC1/GLIALCAM complex function and the related pathological mechanisms leading to MLC are still unknown. It has been hypothesized that, in MLC, the role of glial cells in brain ion homeostasis is altered in both physiological and inflammatory conditions. There is no therapy for MLC patients, only supportive treatment. As MLC2B patients show an MLC reversible phenotype, we speculated that the phenotype of MLC1 and MLC2A patients could also be mitigated by the re-introduction of the correct gene even at later stages. To prove this hypothesis, we injected in the cerebellar subarachnoid space of Mlc1 knockout mice an adeno-associated virus (AAV) coding for human MLC1 under the control of the glial-fibrillary acidic protein promoter. MLC1 expression in the cerebellum extremely reduced myelin vacuolation at all ages in a dose-dependent manner. This study could be considered as the first preclinical approach for MLC. We also suggest other potential therapeutic strategies in this review.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/174669
url https://hdl.handle.net/2445/174669
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3389/fncel.2020.627887
Frontiers in Cellular Neuroscience, 2021, vol. 14, num. 627887
https://doi.org/10.3389/fncel.2020.627887
dc.rights.none.fl_str_mv cc by (c) Bosch, Assumpció et al., 2021
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Bosch, Assumpció et al., 2021
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 13 p.
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media SA
publisher.none.fl_str_mv Frontiers Media SA
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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