Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a multisystemic and heterogeneous disorder caused by the expansion of CTG repeats in the 3’ UTR of the myotonic dystrophy protein kinase (DMPK) gene. There is a congenital form (CDM1) of the disease characterized by severe hypotonia, respiratory insufficiency as we...

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Autores principales:	Thiéry De Serres-Bérard, Marion Pierre, Mohamed Chahine, Jack Puymirat
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Congenital myotonic dystrophy Myotonic dystrophy type 1 Brain development Alternative splicing DMPK MBNL Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/8759f92d2eac44d2beeb669ed7d4ec37
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spelling	oai:doaj.org-article:8759f92d2eac44d2beeb669ed7d4ec372021-11-12T04:26:19ZDeciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy1095-953X10.1016/j.nbd.2021.105532https://doaj.org/article/8759f92d2eac44d2beeb669ed7d4ec372021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121002813https://doaj.org/toc/1095-953XMyotonic dystrophy type 1 (DM1) is a multisystemic and heterogeneous disorder caused by the expansion of CTG repeats in the 3’ UTR of the myotonic dystrophy protein kinase (DMPK) gene. There is a congenital form (CDM1) of the disease characterized by severe hypotonia, respiratory insufficiency as well as developmental delays and intellectual disabilities. CDM1 infants manifest important brain structure abnormalities present from birth while, in contrast, older patients with adult-onset DM1 often present neurodegenerative features and milder progressive cognitive deficits. Promising therapies targeting central molecular mechanisms contributing to the symptoms of adult-onset DM1 are currently in development, but their relevance for treating cognitive impairment in CDM1, which seems to be a partially distinct neurodevelopmental disorder, remain to be elucidated. Here, we provide an update on the clinical presentation of CDM1 and review recent in vitro and in vivo models that have provided meaningful insights on its consequences in development, with a particular focus on the brain. We discuss how enhanced toxic gain-of-function of the mutated DMPK transcripts with larger CUG repeats and the resulting dysregulation of RNA-binding proteins may affect the developing cortex in utero. Because the methylation of CpG islets flanking the trinucleotide repeats has emerged as a strong biomarker of CDM1, we highlight the need to investigate the tissue-specific impacts of these chromatin modifications in the brain. Finally, we outline promising potential therapeutic treatments for CDM1 and propose future in vitro and in vivo models with great potential to shed light on this disease.Thiéry De Serres-BérardMarion PierreMohamed ChahineJack PuymiratElsevierarticleCongenital myotonic dystrophyMyotonic dystrophy type 1Brain developmentAlternative splicingDMPKMBNLNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 160, Iss , Pp 105532- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Congenital myotonic dystrophy Myotonic dystrophy type 1 Brain development Alternative splicing DMPK MBNL Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Congenital myotonic dystrophy Myotonic dystrophy type 1 Brain development Alternative splicing DMPK MBNL Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Thiéry De Serres-Bérard Marion Pierre Mohamed Chahine Jack Puymirat Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy
description	Myotonic dystrophy type 1 (DM1) is a multisystemic and heterogeneous disorder caused by the expansion of CTG repeats in the 3’ UTR of the myotonic dystrophy protein kinase (DMPK) gene. There is a congenital form (CDM1) of the disease characterized by severe hypotonia, respiratory insufficiency as well as developmental delays and intellectual disabilities. CDM1 infants manifest important brain structure abnormalities present from birth while, in contrast, older patients with adult-onset DM1 often present neurodegenerative features and milder progressive cognitive deficits. Promising therapies targeting central molecular mechanisms contributing to the symptoms of adult-onset DM1 are currently in development, but their relevance for treating cognitive impairment in CDM1, which seems to be a partially distinct neurodevelopmental disorder, remain to be elucidated. Here, we provide an update on the clinical presentation of CDM1 and review recent in vitro and in vivo models that have provided meaningful insights on its consequences in development, with a particular focus on the brain. We discuss how enhanced toxic gain-of-function of the mutated DMPK transcripts with larger CUG repeats and the resulting dysregulation of RNA-binding proteins may affect the developing cortex in utero. Because the methylation of CpG islets flanking the trinucleotide repeats has emerged as a strong biomarker of CDM1, we highlight the need to investigate the tissue-specific impacts of these chromatin modifications in the brain. Finally, we outline promising potential therapeutic treatments for CDM1 and propose future in vitro and in vivo models with great potential to shed light on this disease.
format	article
author	Thiéry De Serres-Bérard Marion Pierre Mohamed Chahine Jack Puymirat
author_facet	Thiéry De Serres-Bérard Marion Pierre Mohamed Chahine Jack Puymirat
author_sort	Thiéry De Serres-Bérard
title	Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy
title_short	Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy
title_full	Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy
title_fullStr	Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy
title_full_unstemmed	Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy
title_sort	deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/8759f92d2eac44d2beeb669ed7d4ec37
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Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy

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