Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype

Publication date: 7 January 2020Source: Cell Reports, Volume 30, Issue 1Author(s): Monica Frega, Martijn Selten, Britt Mossink, Jason M. Keller, Katrin Linda, Rebecca Moerschen, Jieqiong Qu, Pierre Koerner, Sophie Jansen, Astrid Oudakker, Tjitske Kleefstra, Hans van Bokhoven, Huiqing Zhou, Dirk Schubert, Nael Nadif KasriSummaryPathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3, or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features of both intellectual disability (ID) and autism spectrum disorder (ASD). To understand how these variants lead to the phenotypic convergence in KSS, we employ a loss-of-function approach to assess neuronal network development at the molecular, single-cell, and network activity level. KSS-gene-deficient neuronal networks all develop into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data reveal distinct regulatory mechanisms, KSS target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network communication, providing insights into the pathophysiology of KSS and phenotypically congruent disorders.Graphical Abstract
Source: Cell Reports - Category: Cytology Source Type: research

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Conclusions Early-onset neurodevelopmental dis orders, particularly with comorbidity, have a far-reaching impact on adult life in terms of SA and DP.byVirtanen M, Lallukka T, Kivim äki M, Alexanderson K, Ervasti J, Mittendorfer-Rutz E. doi:10.5271/sjweh.3885
Source: Scandinavian Journal of Work, Environment and Health - Category: Occupational Health Tags: Original article Source Type: research
Conclusions Early-onset neurodevelopmental disorders, particularly with comorbidity, have a far-reaching impact on adult life in terms of SA and DP. PMID: 32076730 [PubMed - as supplied by publisher]
Source: Scandinavian Journal of Work, Environment and Health - Category: Occupational Health Authors: Tags: Scand J Work Environ Health Source Type: research
Infection by the parasite Toxoplasma, which affects about 33% of world population, is associated with an increased risk of several mental health disorders, the most strongly with schizophrenia. It is unknown whether schizophrenia is associated with this infection the most strongly, or whether this association has just been the most intensively studied for historical reasons. We used the data from 6,367 subjects tested for toxoplasmosis who took part in an internet survey to search for associations of these infections with 24 mental health disorders and evidence of otherwise impaired mental health. The typical symptom assoc...
Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
In conclusion, school-aged children with CP very often screened positive for ASD and/or ADHD. The prevalence of ASD and ADHD is most likely underestimated in children with CP. These screening findings require further investigations.
Source: European Child and Adolescent Psychiatry - Category: Psychiatry Source Type: research
In this report, we describe the prevalence and disease burden of each mental disorder for the states of India, from 1990 to 2017.MethodsWe used all accessible data from multiple sources to estimate the prevalence of mental disorders, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) caused by these disorders for all the states of India from 1990 to 2017, as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We assessed the heterogeneity and time trends of mental disorders across the states of India. We grouped states on the basis of their Socio-demographic Index (SDI), whi...
Source: The Lancet Psychiatry - Category: Psychiatry Source Type: research
Childhood neurodevelopmental disorders include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), communication disorders, learning disabilities, and developmental motor coordination problems, among others (1). These conditions are typically considered to originate early in development, although there have been recent, controversial challenges to this assumption for ADHD (2). Childhood neurodevelopmental disorders, regardless of whether they are defined as diagnostic categories or traits, show strong phenotypic and genetic overlaps with each other (1).
Source: Biological Psychiatry - Category: Psychiatry Authors: Tags: Commentary Source Type: research
Publication date: Available online 12 December 2019Source: Neuroscience &Biobehavioral ReviewsAuthor(s): Naomi Tistarelli, Corrado Fagnani, Miriam Troianiello, Maria Antonietta Stazi, Walter AdrianiAbstractAttention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children worldwide, and also the recognition of its persistence into adulthood is increasing. While ADHD in childhood is highly heritable and mostly driven by familial factors, during adulthood it appears to show a lower heritability, even if there is not total agreement on this yet. This disorder often co-occurs with many othe...
Source: Neuroscience and Biobehavioral Reviews - Category: Neuroscience Source Type: research
Authors: Kurihara M, Ishiura H, Bannai T, Mitsui J, Yoshimura J, Morishita S, Hayashi T, Shimizu J, Toda T, Tsuji S Abstract Heterozygous mutations in KIF1A have been reported to cause syndromic intellectual disability or pure spastic paraplegia. However, their genotype-phenotype correlations have not been fully elucidated. We herein report a man with autism and hyperactivity along with sensory disturbance and spastic paraplegia, carrying a novel de novo mutation in KIF1A (c.37C>T [p.R13C]). Autism and hyperactivity have only previously been reported in a patient with c.38 G>A (R13H) mutation. This case sugge...
Source: Internal Medicine - Category: Internal Medicine Tags: Intern Med Source Type: research
CONCLUSION: To our knowledge, this is the first time that the child-specific health outcomes of preterm birth, low birth weight, asthma, autism spectrum disorder, attention-deficit/hyperactivity disorder, and IQ reduction have been systematically valued and presented in one place. This is an important addition to the body of health-related valuation literature as these outcomes have substantial economic costs that are not considered in most assessments of the benefits of air pollution and climate mitigation policies. In general, however, the available per-case estimates presented here did not incorporate the broad societal...
Source: Environmental Research - Category: Environmental Health Authors: Tags: Environ Res Source Type: research
Publication date: Available online 5 December 2019Source: NeuronAuthor(s): Sehyoun Yoon, Euan Parnell, Maria Kasherman, Marc P. Forrest, Kristoffer Myczek, Susitha Premarathne, Michelle C. Sanchez Vega, Michael Piper, Thomas H.J. Burne, Lachlan A. Jolly, Stephen A. Wood, Peter PenzesSummaryVariants in the ANK3 gene encoding ankyrin-G are associated with neurodevelopmental disorders, including intellectual disability, autism, schizophrenia, and bipolar disorder. However, no upstream regulators of ankyrin-G at synapses are known. Here, we show that ankyrin-G interacts with Usp9X, a neurodevelopmental-disorder-assoc...
Source: Neuron - Category: Neuroscience Source Type: research
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