scholarly journals Reflections on the genetics-first approach to advancements in molecular genetic and neurobiological research on neurodevelopmental disorders

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Anne B. Arnett ◽  
Tianyun Wang ◽  
Evan E. Eichler ◽  
Raphael A. Bernier
Keyword(s):  
Neurodevelopmental Disorders ◽  
Protein Function ◽  
Single Gene ◽  
Expression Patterns ◽  
Molecular Genetic ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Main Body ◽  
Gene Characterization ◽  
The Impact

Abstract Background Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are common diagnoses with highly heterogeneous phenotypes and etiology. The genetics-first approach to research on NDDs has led to the identification of hundreds of genes conferring risk for ASD, ID, and related symptoms. Main body Although relatively few individuals with NDDs share likely gene-disruptive (LGD) mutations in the same gene, characterization of overlapping functions, protein networks, and temporospatial expression patterns among these genes has led to increased understanding of the neurobiological etiology of NDDs. This shift in focus away from single genes and toward broader gene–brain–behavior pathways has been accelerated by the development of publicly available transcriptomic databases, cell type-specific research methods, and sequencing of non-coding genomic regions. Conclusions The genetics-first approach to research on NDDs has advanced the identification of critical protein function pathways and temporospatial expression patterns, expanding the impact of this research beyond individuals with single-gene mutations to the broader population of patients with NDDs.

scholarly journals Low Birth Weight Prevalence in Children Diagnosed with Neurodevelopmental Disorders in Dubai

2021 ◽  
Vol 8 ◽  
pp. 2333794X2110317
Author(s):  
Faisal A. Nawaz ◽  
Meshal A. Sultan
Keyword(s):  
Risk Factors ◽  
Birth Weight ◽  
Mental Disorders ◽  
Low Birth Weight ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
High Birth Weight ◽  
Perinatal Risk Factors ◽  
Perinatal Risk ◽  
The Impact

The aim of this study is to evaluate the prevalence of low birth weight and other perinatal risk factors in children diagnosed with neurodevelopmental disorders. This is one of the first studies in the Arabian Gulf region focused on the contribution of these factors toward the development of various disorders such as attention-deficit/hyperactivity disorder, autism spectrum disorder, and other mental disorders. This descriptive study was based on qualitative data analysis. We reviewed retrospective information from the electronic medical records of 692 patients in Dubai, United Arab Emirates. The prevalence of low birth weight in children with mental disorders was significantly higher as compared to the general population (16% vs 6% respectively). Furthermore, other risk factors, including high birth weight and preterm birth were noted to have a significant association with neurodevelopmental disorders. Future research on the impact of perinatal risk factors will contribute to advancement of early intervention guidelines.

scholarly journals Mutations in neuroligin-3 in male mice impact behavioral flexibility but not relational memory in a touchscreen test of visual transitive inference

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Rebecca H. C. Norris ◽  
Leonid Churilov ◽  
Anthony J. Hannan ◽  
Jess Nithianantharajah
Keyword(s):  
Neurodevelopmental Disorders ◽  
Reaction Times ◽  
Gene Mutations ◽  
Behavioral Flexibility ◽  
Cognitive Disorders ◽  
Autism Spectrum ◽  
Transitive Inference ◽  
Relational Memory ◽  
Response Latencies ◽  
Inference Test

AbstractCognitive dysfunction including disrupted behavioral flexibility is central to neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). A cognitive measure that assesses relational memory, and the ability to flexibly assimilate and transfer learned information is transitive inference. Transitive inference is highly conserved across vertebrates and disrupted in cognitive disorders. Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility. We first refined a rodent touchscreen assay to measure visual transitive inference, then assessed two mouse models of Nlgn3 dysfunction (Nlgn3−/y and Nlgn3R451C). Deep analysis of touchscreen behavioral data at a trial level established we could measure trajectories in flexible responding and changes in processing speed as cognitive load increased. We show that gene mutations in Nlgn3 do not disrupt relational memory, but significantly impact flexible responding. Our study presents the first analysis of reaction times in a rodent transitive inference test, highlighting response latencies from the touchscreen system are useful indicators of processing demands or decision-making processes. These findings expand our understanding of how dysfunction of key components of synaptic signaling complexes impact distinct cognitive processes disrupted in neurodevelopmental disorders, and advance our approaches for dissecting rodent behavioral assays to provide greater insights into clinically relevant cognitive symptoms.

scholarly journals Parent mediated intervention programmes for children and adolescents with neurodevelopmental disorders in South Asia: A systematic review

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247432
Author(s):  
Kamrun Nahar Koly ◽  
Susanne P. Martin-Herz ◽  
Md. Saimul Islam ◽  
Nusrat Sharmin ◽  
Hannah Blencowe ◽  
...  
Keyword(s):  
Systematic Review ◽  
Children And Adolescents ◽  
South Asia ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Learning Ability ◽  
Child Interaction ◽  
Parent Child Interaction ◽  
The Impact ◽  
Parent Child

Objective Parent-mediated programmes have been found to be cost effective for addressing the needs of the children and adolescents with Neurodevelopmental Disorders (NDD) in high-income countries. We explored the impact of parent-mediated intervention programmes in South Asia, where the burden of NDD is high. Methods A systematic review was conducted using the following databases; PUBMED, MEDLINE, PsycINFO, Google Scholar and Web of Science. Predefined MeSH terms were used, and articles were included if published prior to January 2020. Two independent researchers screened the articles and reviewed data. Outcomes measures The review included studies that targeted children and adolescents between 1 and 18 years of age diagnosed with any of four specific NDDs that are commonly reported in South Asia; Autism Spectrum Disorder (ASD), Intellectual Disability (ID), Attention Deficit Hyperactivity Disorder (ADHD) and Cerebral Palsy (CP). Studies that reported on parent or child outcomes, parent-child interaction, parent knowledge of NDDs, or child activities of daily living were included for full text review. Results A total of 1585 research articles were retrieved and 23 studies met inclusion criteria, including 9 Randomized Controlled Trials and 14 pre-post intervention studies. Of these, seventeen studies reported effectiveness, and six studies reported feasibility and acceptability of the parent-mediated interventions. Three studies demonstrated improved parent-child interaction, three studies demonstrated improved child communication initiations, five studies reported improved social and communication skills in children, four studies demonstrated improved parental knowledge about how to teach their children, and four studies reported improved motor and cognitive skills, social skills, language development, learning ability, or academic performance in children. Conclusion This systematic review of 23 studies demonstrated improvements in parent and child skills following parent-mediated intervention in South Asia. Additional evaluations of locally customized parent-mediated programmes are needed to support development of feasible interventions for South Asian countries.

scholarly journals Translational animal models of autism and neurodevelopmental disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 293-305 ◽  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Homologous Genes ◽  
Biological Outcomes

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.

Elucidation of Abnormal Extracellular Regulated Kinase (ERK) Signaling and Associations with Syndromic and Non-syndromic Autism

2020 ◽  
Vol 21 ◽  
Author(s):  
Aarti Tiwari ◽  
Saloni Rahi ◽  
Sidharth Mehan
Keyword(s):  
Autism Spectrum Disorder ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Erk Signaling ◽  
Erk Pathway ◽  
Signaling Mechanism ◽  
Syndromic Autism

Abstract: Autism is a highly inherited and extremely complex disorder in which results from various cases indicate chro-mosome anomalies, unusual single-gene mutations, and multiplicative effects of particular gene variants, characterized pri-marily by impaired speech and social interaction and restricted behavior. The precise etiology of Autism Spectrum Disorder (ASD) is currently unclear. The extracellular signal-regulated kinase (ERK) signaling mechanism affects neurogenesis and neuronal plasticity during the development of the central nervous mechanism. In this regard, the pathway of ERK has re-cently gained significant interest in the pathogenesis of ASD. The mutation occurs in a few ERK components. Besides, the ERK pathway dysfunction lies in the upstream of modified translation and contributes to synapse pathology in syndromic types of autism. In this review, we highlight the ERK pathway as a target for neurodevelopmental disorder autism. In addi-tion, we summarize the regulation of the ERK pathway with ERK inhibitors in neurological disorders. In conclusion, a better understanding of the ERK signaling pathway provides a range of therapeutic options for autism spectrum disorder

A method to delineate de novo missense variants across pathways prioritizes genes linked to autism

2021 ◽  
Vol 13 (594) ◽  
pp. eabc1739
Author(s):  
Amanda Koire ◽  
Panagiotis Katsonis ◽  
Young Won Kim ◽  
Christie Buchovecky ◽  
Stephen J. Wilson ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Protein Function ◽  
De Novo ◽  
Autism Spectrum ◽  
Homologous Gene ◽  
Fitness Effect ◽  
Missense Variants ◽  
Whole Exome ◽  
New Gene ◽  
The Impact

Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method to de novo missense variants in whole-exome sequences of individuals with autism spectrum disorder (ASD) to unravel genes and pathways connected to ASD. Evolutionary action predicts the impact of missense variants on protein function by measuring the fitness effect based on phylogenetic distances and substitution odds in homologous gene sequences. By examining de novo missense variants in 2384 individuals with ASD (probands) compared to matched siblings without ASD, we found missense variants in 398 genes representing 23 pathways that were biased toward higher evolutionary action scores than expected by random chance; these pathways were involved in axonogenesis, synaptic transmission, and neurodevelopment. The predicted fitness impact of de novo and inherited missense variants in candidate genes correlated with the IQ of individuals with ASD, even for new gene candidates. Taking an evolutionary action method, we detected those missense variants most likely to contribute to ASD pathogenesis and elucidated their phenotypic impact. This approach could be applied to integrate missense variants across a patient cohort to identify genes contributing to a shared phenotype in other complex diseases.

scholarly journals mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex

2021 ◽  
Vol 22 (11) ◽  
pp. 6034
Author(s):  
Martin Schüle ◽  
Tamer Butto ◽  
Sri Dewi ◽  
Laura Schlichtholz ◽  
Susanne Strand ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Neurodevelopmental Disorders ◽  
Cholesterol Biosynthesis ◽  
Single Gene ◽  
Autism Spectrum ◽  
Altered Expression ◽  
Mtorc1 Signaling ◽  
Mtor Activity

Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders (ASD) to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy, and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1, and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels, pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.

scholarly journals Hypertensive disorders of pregnancy and risk of neurodevelopmental disorders in the offspring: a systematic review and meta-analysis protocol

BMJ Open ◽  
2017 ◽  
Vol 7 (10) ◽  
pp. e018313 ◽  
Author(s):  
Gillian M Maher ◽  
Gerard W O’Keeffe ◽  
Louise C Kenny ◽  
Patricia M Kearney ◽  
Ted G Dinan ◽  
...  
Keyword(s):  
Systematic Review ◽  
Neurodevelopmental Disorders ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Chronic Hypertension ◽  
Hypertensive Disorders Of Pregnancy ◽  
Hypertensive Disorders ◽  
Increased Risk ◽  
Meta Analyses ◽  
The Impact

IntroductionHypertensive disorders of pregnancy (HDPs), that is chronic hypertension, gestational hypertension, pre-eclampsia (de novo or superimposed on chronic hypertension) and white coat hypertension, affect approximately 5%–15% of pregnancies. HDP exposure has been linked to an increased risk of autism spectrum disorder, attention deficit/hyperactivity disorder and other neurodevelopmental disorders in children. However, findings are inconsistent, and a clear consensus on the impact of HDPs on the risk of neurodevelopmental disorders is needed. Therefore, we aim to synthesise the published literature on the relationship between HDPs and the risk of neurodevelopmental disorders in the form of a systematic review and meta-analysis.Methods and analysisWe will include cohort, case–control and cross-sectional studies in which diagnosis of an HDP was reported, and neurodevelopmental disorders were the outcome of interest based on a preprepared protocol. A systematic search of PubMed, CINAHL, Embase, PsycINFO and Web of Science will be conducted in accordance with a detailed search strategy. Two authors will independently review the titles and abstracts of all studies, perform data extraction using a standardised data collection form and assess study quality using a bias classification tool. Meta-analyses will be performed to calculate overall pooled estimates using the generic inverse variance method. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses.Ethics and disseminationThis proposed systematic review and meta-analysis is based on published data, therefore, does not require ethics approval. Findings will be presented at scientific conferences and disseminated through publication in a peer-reviewed journal.RegistrationCRD42017068258.

scholarly journals Medical teachers’ opinions about students with neurodevelopmental disorders and their management

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Eloi Magnin ◽  
Ilham Ryff ◽  
Thierry Moulin
Keyword(s):  
Neurodevelopmental Disorders ◽  
Ethical Issues ◽  
Autism Spectrum ◽  
Free Text ◽  
Cross Sectional ◽  
Vas Score ◽  
Quantitative Descriptive ◽  
Attention Deficit Hyperactivity Disorders ◽  
The Impact ◽  
Medical Teachers

Abstract Background Some students have neurodevelopmental disorders that might affect their academic and professional careers if they are not identified and addressed by specific pedagogic adaptations. The objective of this work was to describe medical teachers’ opinions of students with neurodevelopmental disorders and their management of these students. Methods An anonymous cross-sectional electronic survey was performed to describe medical teachers’ opinions about the impact of neurodevelopmental disorders on the student’s life and on the medical teachers’ management. aThe survey was created, including visual analogic scales and free text, to assess teachers’ opinions from identification and assessment of neurodevelopemental burden on students and teachers, to their own knowledge about neurodevelopemental disorders and the specific pedagogic management available. The survey was sent to 175 medical teachers in 2019, of whom 67 responded. Quantitative descriptive statistics and qualitative analysis of free text were reported. Results Many medical teachers report having encountered students who might have had neurodevelopmental disorders (dyspraxia 33%; dyslexia 46%; autism spectrum disorders 68%; attention deficit hyperactivity disorders 75%). Impact on students and on teachers was considered as important (mean VAS score for impact over 60/100 for all syndromes except for dyspraxia). Medical teachers’ self-reported knowledge about neurodevelopmental disorders (mean VAS score 43.9/100) and available pedagogical adaptations (mean VAS score 19.0/100) was limited. The teachers were concerned about ethical issues (mean VAS score 72.2/100) but were interested in receiving specialized training (mean VAS score 64.4/100). Conclusion Medical teachers feel unprepared to manage students with neurodevelopmental disorders. They would be interested in specific training and procedures about the pedagogic management of these students.

scholarly journals Duplication of chromosome 16p13.11-p12.3 with different expressions in the same family

2021 ◽  
Vol 24 (1) ◽  
pp. 89-94
Author(s):  
N Pop-Jordanova ◽  
T Zorcec ◽  
E Sukarova-Angelovska
Keyword(s):  
Neurodevelopmental Disorders ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Comparative Genomic ◽  
Incomplete Penetrance ◽  
Typical Development ◽  
Small Children ◽  
Neurodevelopmental Delay ◽  
Chromosomal Duplication ◽  
Older Siblings

Abstract The knowledge about genetic involvement in neurodevelopmental disorders, and especially in autism, is currently rising. To date, more than 100 gene mutations related to autistic syndromes have been described. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited. Recently, array comparative genomic hybridization (aCGH) has identified sub microscopic deletions and duplications as a common cause of mental retardation and autism. In this article we report the occurrence of the same genetic finding (chromosome 16p13.11-p12.3 duplication) in a family with four small children, where two older siblings manifested a global neurodevelopmental delay associated with an autism spectrum disorder (ASD), but younger twin brothers with the same mutation, have typical development. Genetic analysis showed that the chromosomal duplication was inherited from the father, in which phenotype and functioning are quite typical. As is known, the duplication can pass from parents to children. The 16p13.11 micro duplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance.

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