Cited by 229Genetics and Neurodevelopmental DisordersEpigenetics and DNA MethylationAutism Spectrum Disorder Research

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An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy

Millan, Mark J.·2013·Neuropharmacology

DOI 10.1016/j.neuropharm.2012.11.015

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Abstract

Neurodevelopmental disorders (NDDs) are characterized by aberrant and delayed early-life development of the brain, leading to deficits in language, cognition, motor behaviour and other functional domains, often accompanied by somatic symptoms. Environmental factors like perinatal infection, malnutrition and trauma can increase the risk of the heterogeneous, multifactorial and polygenic disorders, autism and schizophrenia. Conversely, discrete genetic anomalies are involved in Down, Rett and Fragile X syndromes, tuberous sclerosis and neurofibromatosis, the less familiar Phelan-McDermid, Sotos, Kleefstra, Coffin-Lowry and "ATRX" syndromes, and the disorders of imprinting, Angelman and Prader-Willi syndromes. NDDs have been termed "synaptopathies" in reference to structural and functional disturbance of synaptic plasticity, several involve abnormal Ras-Kinase signalling ("rasopathies"), and many are characterized by disrupted cerebral connectivity and an imbalance between excitatory and inhibitory transmission. However, at a different level of integration, NDDs are accompanied by aberrant "epigenetic" regulation of processes critical for normal and orderly development of the brain. Epigenetics refers to potentially-heritable (by mitosis and/or meiosis) mechanisms controlling gene expression without changes in DNA sequence. In certain NDDs, prototypical epigenetic processes of DNA methylation and covalent histone marking are impacted. Conversely, others involve anomalies in chromatin-modelling, mRNA splicing/editing, mRNA translation, ribosome biogenesis and/or the regulatory actions of small nucleolar RNAs and micro-RNAs. Since epigenetic mechanisms are modifiable, this raises the hope of novel therapy, though questions remain concerning efficacy and safety. The above issues are critically surveyed in this review, which advocates a broad-based epigenetic framework for understanding and ultimately treating a diverse assemblage of NDDs ("epigenopathies") lying at the interface of genetic, developmental and environmental processes. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.

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Authors: Millan, M. J.
Corresponding author: Millan, Mark J.
ORCID: Millan, Mark J.
Venue: Neuropharmacology
Publisher: Elsevier BV
Published: 2013-05
Volume: 68
Pages: 2-82
ISSN: 0028-3908 (ISSN-L)
DOI: 10.1016/j.neuropharm.2012.11.015
OpenAlex: W2028188824
Cited by: 229
References: 1,085
Citations by year: 2026: 6 · 2025: 6 · 2024: 7 · 2023: 10 · 2022: 14 · 2021: 12 · 2020: 10 · 2019: 27 · 2018: 18 · 2017: 17 · 2016: 30 · 2015: 17 · 2014: 34 · 2013: 20
FWCI: 2.84
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuropharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords: neurodevelopmental disorders, epigenetics, DNA methylation, histone modifications, chromatin regulation, mRNA splicing, microRNA, small nucleolar RNA, ribosome biogenesis, synaptic plasticity, synaptopathy, RASopathies, excitatory-inhibitory imbalance, autism spectrum disorder, schizophrenia, Down syndrome, Rett syndrome, fragile X syndrome, tuberous sclerosis complex, neurofibromatosis, Phelan-McDermid syndrome, Sotos syndrome, Kleefstra syndrome, Coffin-Lowry syndrome, Angelman syndrome, Prader-Willi syndrome, imprinting disorders, epigenetic therapy
MeSH terms: Autistic Disorder, Central Nervous System Diseases, Humans, Schizophrenia, DNA Methylation, RNA, Untranslated, Epigenesis, Genetic

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An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy

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