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Brain : a Journal of Neurology Aug 2023Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process...
Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt-Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt-Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt-Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.
Topics: Humans; Animals; Mice; Clemastine; Autism Spectrum Disorder; Pharmaceutical Preparations; Intellectual Disability
PubMed: 37068912
DOI: 10.1093/brain/awad057 -
BMC Psychiatry Aug 2023Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting ~ 2% of children worldwide and is characterized by repetitive, stereotypical behaviours and...
BACKGROUND
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting ~ 2% of children worldwide and is characterized by repetitive, stereotypical behaviours and impaired expressive communication. Cytomegalovirus (CMV) is considered a risk factor for ASD; however, published studies are usually limited by covering too few events and have different conclusions, indicating that the relationship between CMV infection and ASD remains elusive.
METHODS
To investigate the association between CMV infection and ASD, we conducted this 2-sample Mendelian randomization (MR) study using genome-wide association studies (GWAS) summary data from FinnGen and the IEU Open GWAS project.
RESULTS
Our results showed no significant relationship between all 3 CMV infections (unspecified cytomegaloviral diseases, anti-CMV IgG levels, and maternal CMV) and ASD.
CONCLUSIONS
Our results indicate that CMV infection does not significantly increase ASD risk. These results show that the relationship between CMV infection and ASD remains elusive and needs to be further clarified.
Topics: Child; Humans; Autism Spectrum Disorder; Cytomegalovirus; Genome-Wide Association Study; Mendelian Randomization Analysis; Cytomegalovirus Infections
PubMed: 37533011
DOI: 10.1186/s12888-023-05035-w -
Neurobiology of Disease Jul 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial... (Meta-Analysis)
Meta-Analysis
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen's d' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.
Topics: Humans; Autism Spectrum Disorder; Biomarkers; DNA, Mitochondrial; Mitochondria; Mitochondrial Diseases
PubMed: 38703861
DOI: 10.1016/j.nbd.2024.106520 -
Translational Psychiatry Jul 2023Early identification of children on the autism spectrum is crucial for early intervention with long-term positive effects on symptoms and skills. The need for improved...
Early identification of children on the autism spectrum is crucial for early intervention with long-term positive effects on symptoms and skills. The need for improved objective autism detection tools is emphasized by the poor diagnostic power in current tools. Here, we aim to evaluate the classification performance of acoustic features of the voice in children with autism spectrum disorder (ASD) with respect to a heterogeneous control group (composed of neurotypical children, children with Developmental Language Disorder [DLD] and children with sensorineural hearing loss with Cochlear Implant [CI]). This retrospective diagnostic study was conducted at the Child Psychiatry Unit of Tours University Hospital (France). A total of 108 children, including 38 diagnosed with ASD (8.5 ± 0.25 years), 24 typically developing (TD; 8.2 ± 0.32 years) and 46 children with atypical development (DLD and CI; 7.9 ± 0.36 years) were enrolled in our studies. The acoustic properties of speech samples produced by children in the context of a nonword repetition task were measured. We used a Monte Carlo cross-validation with an ROC (Receiving Operator Characteristic) supervised k-Means clustering algorithm to develop a classification model that can differentially classify a child with an unknown disorder. We showed that voice acoustics classified autism diagnosis with an overall accuracy of 91% [CI95%, 90.40%-91.65%] against TD children, and of 85% [CI95%, 84.5%-86.6%] against an heterogenous group of non-autistic children. Accuracy reported here with multivariate analysis combined with Monte Carlo cross-validation is higher than in previous studies. Our findings demonstrate that easy-to-measure voice acoustic parameters could be used as a diagnostic aid tool, specific to ASD.
Topics: Child; Humans; Autism Spectrum Disorder; Retrospective Studies; Autistic Disorder; Acoustics; France
PubMed: 37422467
DOI: 10.1038/s41398-023-02554-8 -
Journal of Attention Disorders Oct 2023The two most prevalent neurodevelopmental disorders-Attention Deficit Hyperactivity Disorder (ADHD) and Autism (ASD)-(ASD/ADHD) strongly impact individuals' functions.... (Review)
Review
BACKGROUND
The two most prevalent neurodevelopmental disorders-Attention Deficit Hyperactivity Disorder (ADHD) and Autism (ASD)-(ASD/ADHD) strongly impact individuals' functions. This is worsened when individuals are undiagnosed and risks such as increased imprisonments, depression or drug misuse are often observed. This systematic review synthesizes the risks associated with late/undiagnosed ASD/ADHD.
METHODS
Four databases were searched (Medline, Scopus, PsychInfor, and Embase). Published studies exploring the impact of undiagnosed ASD/ADHD were included. Exclusion criteria included, lack of diagnosis status, studies not solely on ASD or ADHD, gray literature and studies not in English. The findings were summarize through a narrative synthesis.
RESULTS
Seventeen studies were identified, 14 on ADHD and three on ASD. The narrative synthesis identified three main themes: (1) Health, (2) Offending behavior, and (3) Day-to-day impact. The risks highlighted a significant impact on mental wellbeing and social interactions, higher risks of substance abuse, accidents and offending behavior as well as lower levels of income and education.
DISCUSSION
The findings suggest that undiagnosed ASD/ADHD is linked to many risks and negative outcomes affecting individuals, their families, and the wider society. The restricted number of studies on ASD are a limitation to the generalization of these findings Implications for research and practice are discussed, highlighting the importance of screening and acknowledging the possibility of ASD/ADHD in many settings such as psychiatric and forensic.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Autistic Disorder; Autism Spectrum Disorder; Narration
PubMed: 37341291
DOI: 10.1177/10870547231176862 -
Journal of the Formosan Medical... Nov 2023Neonatal jaundice might result brain insults. Both autistic spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are developmental disorders,...
BACKGROUND/PURPOSE
Neonatal jaundice might result brain insults. Both autistic spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are developmental disorders, which might result from early brain injury at neonatal period. We aimed to explore the association between neonatal jaundice treated with phototherapy and the ASD or ADHD.
METHODS
This retrospective nationwide population cohort study was based on a nationally representative database of Taiwan, and neonates born from 2004 to 2010 were enrolled. All eligible infants were divided into 4 groups, without jaundice, jaundice with no treatment, jaundice with simple phototherapy only and jaundice with intensive phototherapy or blood exchange transfusion (BET). Each infant was follow-up until the date of incident primary outcomes, death, or 7-year-old, whichever occurred first. Primary outcomes were ASD, ADHD. Using cox proportional hazard model to analyze their associations.
RESULTS
In total, 118,222 infants with neonatal jaundice were enrolled, including diagnosed only (7260), simple phototherapy (82,990), intensive phototherapy or BET (27,972 infants). The cumulative incidences of ASD in each group was 0.57%, 0.81%, 0.77%, and 0.83%, respectively. The cumulative incidences of ADHD in each group was 2.83%, 4.04%, 3.52% and 3.48%, respectively. Jaundice groups were significantly associated with ASD, ADHD, or either one, even after all other extraneous maternal and neonatal variables were adjusted. After stratification, the associations were still existed in subgroup with birth weights ≥2500 grams and in male subgroup.
CONCLUSION
Neonatal jaundice correlated with the ASD and ADHD. The associations were significant in infants of both sexes and with birth weights larger than 2500 grams.
Topics: Infant; Infant, Newborn; Female; Humans; Male; Child; Autism Spectrum Disorder; Cohort Studies; Jaundice, Neonatal; Retrospective Studies; Attention Deficit Disorder with Hyperactivity; Birth Weight; Risk Factors; Jaundice
PubMed: 37225632
DOI: 10.1016/j.jfma.2023.05.010 -
Genes Dec 2023Autism spectrum disorder (ASD) is a common neurodevelopmental condition affecting ~1% of people worldwide. Core ASD features present with impaired social communication...
Autism spectrum disorder (ASD) is a common neurodevelopmental condition affecting ~1% of people worldwide. Core ASD features present with impaired social communication abilities, repetitive and stereotyped behaviors, and atypical sensory responses and are often associated with a series of comorbidities. Among these, epilepsy is frequently observed. The co-occurrence of ASD and epilepsy is currently thought to result from common abnormal neurodevelopmental pathways, including an imbalanced excitation/inhibition ratio. However, the pathological mechanisms involved in ASD-epilepsy co-morbidity are still largely unknown. Here, we propose a research protocol aiming to investigate electrophysiological and genetic features in subjects with ASD and epilepsy. This study will include a detailed electroencephalographic (EEG) and blood transcriptomic characterization of subjects with ASD with and without epilepsy. The combined approach of EEG and transcriptomic studies in the same subjects will contribute to a novel stratification paradigm of the heterogeneous ASD population based on quantitative gene expression and neurophysiological biomarkers. In addition, our protocol has the potential to indicate new therapeutic options, thus amending the current condition of absence of data and guidelines for the treatment of ASD with epilepsy.
Topics: Humans; Autism Spectrum Disorder; Epilepsy; Research; Electroencephalography; Gene Expression Profiling
PubMed: 38254951
DOI: 10.3390/genes15010061 -
Frontiers in Immunology 2024Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain...
BACKGROUND
Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain unclear. This study aims to offer deeper insight into causal relationships between circulating inflammatory factors and ASD.
METHODS
Two-sample bidirectional Mendelian randomization (MR) analysis method was used in this study. The genetic variation of 91 circulating inflammatory factors was obtained from the genome-wide association study (GWAS) database of European ancestry. The germline GWAS summary data for ASD were also obtained (18,381 ASD cases and 27,969 controls). Single nucleotide polymorphisms robustly associated with the 91 inflammatory factors were used as instrumental variables. The random-effects inverse-variance weighted method was used as the primary analysis, and the Bonferroni correction for multiple comparisons was applied. Sensitivity tests were carried out to assess the validity of the causal relationship.
RESULTS
The forward MR analysis results suggest that levels of sulfotransferase 1A1, natural killer cell receptor 2B4, T-cell surface glycoprotein CD5, Fms-related tyrosine kinase 3 ligand, and tumor necrosis factor-related apoptosis-inducing ligand are positively associated with the occurrence of ASD, while levels of interleukin-7, interleukin-2 receptor subunit beta, and interleukin-2 are inversely associated with the occurrence of ASD. In addition, matrix metalloproteinase-10, caspase 8, tumor necrosis factor-related activation-induced cytokine, and C-C motif chemokine 19 were considered downstream consequences of ASD.
CONCLUSION
This MR study identified additional inflammatory factors in patients with ASD relative to previous studies, and raised a possibility of ASD-caused immune abnormalities. These identified inflammatory factors may be potential biomarkers of immunologic dysfunction in ASD.
Topics: Humans; Mendelian Randomization Analysis; Autism Spectrum Disorder; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; White People; Biomarkers; Inflammation; Inflammation Mediators; Male; Female; Cytokines; Europe
PubMed: 38742104
DOI: 10.3389/fimmu.2024.1370276 -
Brain and Behavior Jul 2023Sleep abnormalities are highly correlated with neurodevelopmental disorders, such as intellectual disability, attention deficit hyperactivity disorder, and autism...
INTRODUCTION
Sleep abnormalities are highly correlated with neurodevelopmental disorders, such as intellectual disability, attention deficit hyperactivity disorder, and autism spectrum disorders (ASD). The severity of behavioral abnormalities is correlated with the presence of sleep abnormalities. Based on previous research, we investigated that Ctnnd2 gene deletion in mice lead to ASD-like behaviors and cognitive defects. Given the importance of sleep in individuals with ASD, this study aimed to determine the effects of chronic sleep restriction (SR) on wild-type (WT) mice and on Ctnnd2 deletion-induced, neurologically related phenotypes in mice.
METHOD
WT and Ctnnd2 knockout (KO) mice were both subjected to manual SR (5 h per day) for 21 consecutively days separately, then we compared neurologically related phenotypes of WT mice, WT mice subjected to SR, KO mice, and KO mice subjected to SR using a three-chamber assay, direct social interaction test, open-field test, Morris water maze, Golgi staining, and Western blotting.
RESULTS
The effects of SR on WT and KO mice were different. After SR, social ability and cognition were impaired in both WT and KO mice. Repetitive behaviors were increased, and exploration abilities were decreased in KO mice but not in WT mice. Moreover, SR reduced the density and area of mushroom-type dendritic spines in WT rather than KO mice. Finally, the PI3K/Akt-mTOR pathway was found to be involved in the effects induced by SR-impaired phenotypes in WT and KO mice.
CONCLUSION
Overall, results of the present study may have implications for the role of disrupted sleep in patients with CTNND2 gene-related autism and the evolution of neurodevelopmental disorders.
Topics: Animals; Mice; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Mice, Knockout; Phenotype; Phosphatidylinositol 3-Kinases; Sleep
PubMed: 37226399
DOI: 10.1002/brb3.3075 -
EBioMedicine Sep 2023Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as...
BACKGROUND
Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multifaceted ASD phenotypes. In this study, we sought to determine whether plasma metabolite levels could serve as endophenotypes in individuals with ASD and their family members.
METHODS
We employed an untargeted, high-resolution metabolomics platform to analyse 14,342 features across 1099 plasma samples. These samples were collected from probands and their family members participating in the Autism Genetic Resource Exchange (AGRE) (N = 658), compared with neurotypical individuals enrolled in the PrecisionLink Health Discovery (PLHD) program at Boston Children's Hospital (N = 441). We conducted a metabolite quantitative trait loci (mQTL) analysis using whole-genome genotyping data from each cohort in AGRE and PLHD, aiming to prioritize significant mQTL and metabolite pairs that were exclusively observed in AGRE.
FINDINGS
Within the AGRE group, we identified 54 significant associations between genotypes and metabolite levels (P < 5.27 × 10), 44 of which were not observed in the PLHD group. Plasma glutamine levels were found to be associated with variants in the NLGN1 gene, a gene that encodes post-synaptic cell-adhesion molecules in excitatory neurons. This association was not detected in the PLHD group. Notably, a significant negative correlation between plasma glutamine and glutamate levels was observed in the AGRE group, but not in the PLHD group. Furthermore, plasma glutamine levels showed a negative correlation with the severity of restrictive and repetitive behaviours (RRB) in ASD, although no direct association was observed between RRB severity and the NLGN1 genotype.
INTERPRETATION
Our findings suggest that plasma glutamine levels could potentially serve as an endophenotype, thus establishing a link between the genetic risk associated with NLGN1 and the severity of RRB in ASD. This identified association could facilitate the development of novel therapeutic targets, assist in selecting specific cohorts for clinical trials, and provide insights into target symptoms for future ASD treatment strategies.
FUNDING
This work was supported by the National Institute of Health (grant numbers: R01MH107205, U01TR002623, R24OD024622, OT2OD032720, and R01NS129188) and the PrecisionLink Biobank for Health Discovery at Boston Children's Hospital.
Topics: Child; Humans; Autism Spectrum Disorder; Endophenotypes; Genotype; Glutamine; Polymorphism, Single Nucleotide
PubMed: 37544204
DOI: 10.1016/j.ebiom.2023.104746