Therapeutic Advances in Autism and Other Neurodevelopmental Disorders.
Ontology highlight
ABSTRACT:
SUBMITTER: Neul JL
PROVIDER: S-EPMC4489958 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epigenetic marks are modifications of DNA and histones. They are considered to be permanent within a single cell during development, and are heritable across cell division. Programming of neurons through epigenetic mechanisms is believed to be critical in neural development. Disruption or alteration in this process causes an array of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Recent studies have provided evidence for an altered epigenetic landscape in ASDs and demonstrated the central role of epigenetic mechanisms in their pathogenesis. Many of the genes linked to the ASDs encode proteins that are involved in transcriptional regulation and chromatin remodeling. In this review we highlight selected neurodevelopmental disorders in which epigenetic dysregulation plays an important role. These include Rett syndrome, fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, and Kabuki syndrome. For each of these disorders, we discuss how advances in our understanding of epigenetic mechanisms may lead to novel therapeutic approaches.
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Project description:Alterations in social cognition (SC) are hypothesized to underlie social communication and interaction challenges in autism spectrum disorder (ASD). The aetiological underpinnings driving this association remain unclear. We examined SC in 196 twins with ASD, other neurodevelopmental disorders or typical development using the naturalistic Movie for the Assessment of Social Cognition. Autism and its severity were assessed with the Autism Diagnostic Observation Schedule-2, and autistic traits with the Social Responsiveness Scale-2. Using within twin-pair regression models, controlling for age, sex, IQ, and unmeasured familial confounders such as genetic background and shared-environment, SC correlated with ASD diagnosis, autism severity, and autistic traits. Our findings highlight the importance of SC alterations in autism and suggest a non-shared environmental impact on the association.
| S-EPMC6606667 | biostudies-other
Project description:Autism spectrum disorders (ASDs) are a spectrum of neurodevelopmental disorders characterized by impaired social interaction and communication, as well as stereotyped and repetitive behaviors. ASDs affect nearly 2% of the United States child population and the worldwide prevalence has dramatically increased in recent years. The etiology is not clear but ASD is thought to be caused by a combination of intrinsic and extrinsic factors. Circadian rhythms are the ∼24 h rhythms driven by the endogenous biological clock, and they are found in a variety of physiological processes. Growing evidence from basic and clinical studies suggest that the dysfunction of the circadian timing system may be associated with ASD and its pathogenesis. Here we review the findings that link circadian dysfunctions to ASD in both experimental and clinical studies. We first introduce the organization of the circadian system and ASD. Next, we review physiological indicators of circadian rhythms that are found disrupted in ASD individuals, including sleep-wake cycles, melatonin, cortisol, and serotonin. Finally, we review evidence in epidemiology, human genetics, and biochemistry that indicates underlying associations between circadian regulation and the pathogenesis of ASD. In conclusion, we propose that understanding the functional importance of the circadian clock in normal and aberrant neurodevelopmental processes may provide a novel perspective to tackle ASD, and clinical treatments for ASD individuals should comprise an integrative approach considering the dynamics of daily rhythms in physical, mental, and social processes.
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Project description:Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder characterised by motor and vocal tics. Despite decades of research, the aetiology of TS has remained elusive. Recent successes in gene discovery backed by rapidly advancing genomic technologies have given us new insights into the genetic basis of the disorder, but the growing collection of rare and disparate findings have added confusion and complexity to the attempts to translate these findings into neurobiological mechanisms resulting in symptom genesis. In this review, we explore a previously unrecognised genetic link between TS and a competing series of trans-synaptic complexes (neurexins (NRXNs), neuroligins (NLGNs), leucine-rich repeat transmembrane proteins (LRRTMs), leucine rich repeat neuronals (LRRNs) and cerebellin precursor 2 (CBLN2)) that links it with autism spectrum disorder through neurodevelopmental pathways. The emergent neuropathogenetic model integrates all five genes so far found to be uniquely disrupted in TS into a single pathogenetic chain of events described in context with clinical and research implications.
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Project description:The growth arrest and DNA damage inducible protein 45 (GADD45) family comprises stress-induced nuclear proteins that interact with DNA demethylases to facilitate DNA demethylation, thereby regulating diverse cellular processes including oxidative stress, DNA damage repair, apoptosis, proliferation, differentiation, inflammation, and neuroplasticity by modulating the expression patterns of specific genes. Widely expressed in the central nervous system, the GADD45 family plays a pivotal role in various neurological disorders, rendering it a potential therapeutic target for central nervous system diseases. This review presented a comprehensive overview of the expression patterns and potential mechanisms of action associated with each member of GADD45 family (GADD45α, GADD45β, and GADD45γ) in neurodevelopmental, neurodegenerative, and neuropsychiatric disorders, while also explored strategies to harness these mechanisms for intervention and treatment. Future research should prioritize the development of effective modulators targeting the GADD45 family for clinical trials aimed at treating central nervous system diseases.
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Project description:Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.
| S-EPMC3915351 | biostudies-literature
Project description:BackgroundMaternal diabetes has been associated with a risk of neurodevelopmental disorders (NDDs) in offspring, though the common co-occurrence of autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID) is rarely considered, nor is the potential for confounding by shared familial factors (e.g. genetics).MethodsThis population-based cohort study used data from Psychiatry Sweden, a linkage of Swedish national registers, to follow 2 369 680 individuals born from 1987 to 2010. We used population-averaged logit models to examine the association between exposure to maternal type 1 diabetes mellitus (T1DM), pre-gestational type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), and odds of NDDs in offspring. Subgroup analysis was then performed to investigate the timings of GDM diagnosis during pregnancy and its effect on the odds of NDDs in offspring. We compared these results to models considering paternal lifetime T1DM and T2DM as exposures.ResultsOverall, 45 678 individuals (1.93%) were diagnosed with ASD, 20 823 (0.88%) with ID and 102 018 (4.31%) with ADHD. All types of maternal diabetes were associated with odds of NDDs, with T2DM most strongly associated with any diagnosis of ASD (odds ratioadjusted 1.37, 95% confidence interval 1.03-1.84), ID (2.09, 1.53-2.87) and ADHD (1.43, 1.16-1.77). Considering common co-morbid groups, the associations were strongest between maternal diabetes and diagnostic combinations that included ID. Paternal T1DM and T2DM diagnoses were also associated with offspring NDDs, but these associations were weaker than those with maternal diabetes. Diagnosis of GDM between 27 and 30 weeks of gestation was generally associated with the greatest risk of NDDs in offspring, with the strongest associations for outcomes that included ID.ConclusionThe association of maternal diabetes with NDDs in offspring varies depending on the co-morbid presentation of the NDDs, with the greatest odds associated with outcomes that included ID. Results of paternal-comparison studies suggest that the above associations are likely to be partly confounded by shared familial factors, such as genetic liability.
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Project description:Many children with autism and other neurodevelopmental disorders undergo expensive, time-consuming behavioral interventions that often yield only modest improvements. The development of adjunctive interventions that can increase the benefit of rehabilitation therapies is essential in order to improve the lives of individuals with neurodevelopmental disorders.Vagus nerve stimulation (VNS) is an FDA approved therapy that is safe and effective in reducing seizure frequency and duration in individuals with epilepsy. Individuals with neurodevelopmental disorders often exhibit decreased vagal tone, and studies indicate that VNS can be used to overcome an insufficient vagal response. Multiple studies have also documented significant improvements in quality of life after VNS therapy in individuals with neurodevelopmental disorders. Moreover, recent findings indicate that VNS significantly enhances the benefits of rehabilitative training in animal models and patients, leading to greater recovery in a variety of neurological diseases. Here, we review these findings and provide a discussion of how VNS paired with rehabilitation may yield benefits in the context of neurodevelopmental disorders.VNS paired with behavioral therapy may represent a potential new approach to enhance rehabilitation that could significantly improve the outcomes of individuals with neurodevelopmental disorders.
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Project description:Neurodevelopmental disorders (NDDs) are characterized by a wide range of symptoms including delayed speech, intellectual disability, motor dysfunction, social deficits, breathing problems, structural abnormalities, and epilepsy. Unfortunately, current treatment strategies are limited and innovative new approaches are sorely needed to address these complex diseases. The metabotropic glutamate receptors are a class of G protein-coupled receptors that act to modulate neurotransmission across many brain structures. They have shown great promise as drug targets for numerous neurological and psychiatric diseases. Moreover, the development of subtype-selective allosteric modulators has allowed detailed studies of each receptor subtype. Here, we focus on the metabotropic glutamate receptor 7 (mGlu7) as a potential therapeutic target for NDDs. mGlu7 is expressed widely throughout the brain in regions that correspond to the symptom domains listed above and has established roles in synaptic physiology and behavior. Single nucleotide polymorphisms and mutations in the GRM7 gene have been associated with idiopathic autism and other NDDs in patients. In rodent models, existing literature suggests that decreased mGlu7 expression and/or function may lead to symptoms that overlap with those of NDDs. Furthermore, potentiation of mGlu7 activity has shown efficacy in a mouse model of Rett syndrome. In this review, we summarize current findings that provide rationale for the continued development of mGlu7 modulators as potential therapeutics.
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