Molecular Insights into Neurological Regression with a Focus on Rett Syndrome-A Narrative Review

Abstract

Rett syndrome (RTT) is a multisystem neurological disorder. Pathogenic changes in the MECP2 gene that codes for methyl-CpG-binding protein 2 (MeCP2) in RTT lead to a loss of previously established motor and cognitive skills. Unravelling the mechanisms of neurological regression in RTT is complex, due to multiple components of the neural epigenome being affected. Most evidence has primarily focused on deciphering the complexity of transcriptional machinery at the molecular level. Little attention has been paid to how epigenetic changes across the neural epigenome in RTT lead to neurological regression. In this narrative review, we examine how pathogenic changes in MECP2 can disrupt the balance of the RTT neural epigenome and lead to neurological regression. Environmental and genetic factors can disturb the balance of the neural epigenome in RTT, modifying the onset of neurological regression. Methylation changes across the RTT neural epigenome and the consequent genotoxic stress cause neurons to regress into a senescent state. These changes influence the brain as it matures and lead to the emergence of specific symptoms at different developmental periods. Future work could focus on epidrugs or epi-editing approaches that may theoretically help to restore the epigenetic imbalance and thereby minimise the impact of genotoxic stress on the RTT neural epigenome.

Keywords: Rett syndrome; epigenome; methylation; neurological regression.

Figure 1

Epigenetics and onset of neurological disease. To maintain normal brain function, methylated DNA can influence DNA’s higher-order structure, i.e., chromatin packaging. When DNA methylation is not impaired, the kinetics of gene transcription can operate normally. However, disrupted DNA methylation alters the kinetics of gene transcription, changing the rates of different transcriptional mechanisms. A pathogenic/likely pathogenic change in the methyl-CpG-binding protein 2 (MECP2) gene results in a failure of MeCP2 to recruit co-repressors, resulting in an open chromatin configuration. For simplicity, the recruitment of co-repressors and transcription repression are shown. However, other kinetics of transcription could also be altered. Methylation impairment, in turn, leads to the manifestation of different neurological disorders. The impact of these disorders is far-reaching and has a significant biological (severity of the disease), ecological (burden on healthcare systems), psychological (mental health) and social (social support) impact. This figure was created using images from BioRender (https://biorender.com/).

Figure 2

Narrative literature review flow chart.

Figure 3

Contributing factors in neurological regression. Different factors can precipitate neurological regression. Pre/perinatal complications such as hypoxia at birth can activate pathways involving hypoxia-inducible factors (HIF 1 alpha and beta). Prolonged stimulation of these pathways can alter gene expression through hypoxia-responsive elements (HREs) and lead to neuronal cell death. The onset of regression may also be associated with epilepsy, as observed in some individuals with MECP2 duplication syndrome. Infections of the brain can lead to changes in brain homeostasis. Infectious agents may lead to changes in brain development and longer-term neurological sequelae in the foetal brain. Neuroimmune dysfunction can lead to increases in pro-inflammatory cytokines, and the resulting cytokine storm can affect a variety of neuro-immune signalling cascades. These changes can lead to aberrant microglial activation, neurological deterioration and behavioural abnormalities. Deficiency in folate leads to remethylation disorders. Severe folate deficiency in childhood can lead to hyperhomocysteinemia, characterised by failure to thrive, developmental delay and epilepsy. This figure was created using images from BioRender (https://biorender.com/).

Figure 4

Expression levels of MeCP2. A diagram of MeCP2 expression levels across the lifespan. Expression levels of MeCP2 increase during the embryonic and post-natal period when neurogenesis and differentiation have been completed. Levels coincide with neuronal maturation and dendritic branching and stabilize at 10 years of age, at which point it maintains the functioning of mature neurons. In most cases of Rett syndrome (RTT), pathogenic/likely pathogenic variants in MECP2 lead to volumetric reductions in brain size. Compared to neurotypical individuals, the effect size of volume reduction in RTT was the largest in the putamen, hippocampus and corpus callosum. Neuronal morphology is altered in RTT with less pronounced dendritic trees and fewer branches. This change leads to impairments in neuronal branching and synaptic connections. This figure was created using images from BioRender (https://biorender.com/).

Figure 5

Adverse epigenomic events lead to neurological regression in Rett syndrome. The MeCP2 protein has varied roles across the genome. Pathogenic/likely pathogenic changes in MECP2 can lead to widespread adverse epigenomic changes. Distinct parts of the brain could have region-specific methylation signatures and be more sensitive to these changes than others. Because MeCP2 expression coincides with brain maturation, the spinal cord and brainstem could be affected before other regions. Aberrant MeCP2 expression in the brainstem may, therefore, reflect the symptoms of autonomic dysregulation typically seen in RTT. The adverse impact of mutated MeCP2 across the epigenome is too little initially, as apparent symptoms do not appear. However, it is likely that during these initial stages, the neural epigenome is modified (for example, a decrease in histone H3 acetylation), leading to subtle prodromal changes. As adverse events accumulate across the epigenome, the build-up of genotoxic stress causes neurons to enter a senescent state, leading to neurological regression. Epigenetic stability is region-specific. The anecdotal cases of late-onset regression in RTT imply that other factors could be in play to counteract the accumulation of deleterious events across the epigenome and the emergence of early-onset regression typically seen in RTT. This figure was created using images from BioRender (https://biorender.com/).