Complex Neurodevelopmental Disorder Research Articles

Association Between Respiratory Infections and Risk of Autism Spectrum Disorder

Abstract: Autism Spectrum Disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder. Its incidence has dramatically risen during the last few decades. ASD is a multifactorial disorder. In addition to genetic factors, the environment plays a key role during critical periods of neurodevelopment. The prenatal environment, as well as perinatal and postnatal exposures to infection and inflammation, are increasingly identified as potential risk factors for autism and can influence development and increase neurodevelopmental disorders. Immune dysfunction and dysregulation are considered an important factor contributing to the pathogenesis of autism and may influence the course and severity of the disease. This study aims to analyze the data available in the scientific literature regarding the correlation between respiratory infections and autism.

Prader-Willi Syndrome: guidance for children and transition into adulthood.

Prader Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability, and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.

Antioxidants, Hormetic Nutrition, and Autism.

Autism spectrum disorder (ASD) includes a heterogeneous group of complex neurodevelopmental disorders characterized by atypical behaviors with two core pathological manifestations: deficits in social interaction/communication and repetitive behaviors, which are associated with disturbed redox homeostasis. Modulation of cellular resilience mechanisms induced by low levels of stressors represents a novel approach for the development of therapeutic strategies, and in this context, neuroprotective effects of a wide range of polyphenol compounds have been demonstrated in several in vitro and in vivo studies and thoroughly reviewed. Mushrooms have been used in traditional medicine for many years and have been associated with a long list of therapeutic properties, including antitumor, immunomodulatory, antioxidant, antiviral, antibacterial, and hepatoprotective effects. Our recent studies have strikingly indicated the presence of polyphenols in nutritional mushrooms and demonstrated their protective effects in different models of neurodegenerative disorders in humans and rats. Although their therapeutic effects are exerted through multiple mechanisms, increasing attention is focusing on their capacity to induce endogenous defense systems by modulating cellular signaling processes such as nuclear factor erythroid 2 related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) pathways. Here we discuss the protective role of hormesis and its modulation by hormetic nutrients in ASD.

Case report: Early use of whole exome sequencing unveils HNRNPU-related neurodevelopmental disorder and answers additional clinical questions through reanalysis

This case report chronicles the diagnostic odyssey and resolution of a 27-year-old female with a complex neurodevelopmental disorder (NDD) using Whole Exome Sequencing (WES). The patient presented to a precision medicine clinic with multiple diagnoses including intellectual disability, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), tics, seizures, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although this patient previously had chromosomal microarray and several single-gene tests, the underlying cause of this patient’s symptoms remained elusive. WES revealed a pathogenic missense mutation in the HNRNPU gene, associated with HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) and developmental and epileptic encephalopathy-54 (DEE54, OMIM: # 617391). Following this diagnoses, other treating clinicians identified additional indications for genetic testing, however, as the WES data was readily available, the clinical team was able to re-analyze the WES data to address their inquiries without requiring additional tests. This emphasizes the pivotal role of WES in expediting diagnoses, reducing costs, and providing ongoing clinical utility throughout a patient’s life. Accessible WES data in primary care settings can enhance patient care by informing future genetic inquiries, enhancing coordination of care, and facilitating precision medicine interventions, thereby mitigating the burden on families and the healthcare system.

Neuregulin 2 Is a Candidate Gene for Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with heterogeneous and complex genetic underpinnings. Our previous microarray gene expression profiling identified significantly different neuregulin-2 gene (NRG2) expression between ASD patients and controls. Thus, we aimed to clarify whether NRG2 is a candidate gene associated with ASD. The study consisted of two stages. First, we used real-time quantitative PCR in 20 ASDs and 20 controls to confirm the microarray gene expression profiling results. The average NRG2 gene expression level in patients with ASD (3.23 ± 2.80) was significantly lower than that in the controls (9.27 ± 4.78, p < 0.001). Next, we conducted resequencing of all the exons of NRG2 in a sample of 349 individuals with ASD, aiming to identify variants of the NRG2 associated with ASD. We identified three variants, including two single nucleotide variants (SNVs), IVS3 + 13A > G (rs889022) and IVS10 + 32T > A (rs182642591), and one small deletion at exon 11 of NRG2 (delGCCCGG, rs933769137). Using data from the Taiwan Biobank as the controls, we found no significant differences in allele frequencies of rs889022 and rs182642591 between two groups. However, there is a significant difference in the genotype and allele frequency distribution of rs933769137 between ASDs and controls (p < 0.0001). The small deletion is located in the EGF-like domain at the C-terminal of the NRG2 precursor protein. Our findings suggest that NRG2 might be a susceptibility gene for ASD.

Low-frequency repetitive transcranial magnetic stimulation alleviates abnormal behavior in valproic acid rat model of autism through rescuing synaptic plasticity and inhibiting neuroinflammation

Autism is a complex neurodevelopmental disorder with no effective treatment available currently. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a promising neuromodulation technique to treat autism. However, the mechanism how rTMS works remains unclear, which restrict the clinical application of magnetic stimulation in the autism treatment. In this study, we investigated the effect of low-frequency rTMS on the autistic-like symptoms and explored if this neuroprotective effect was associated with synaptic plasticity and neuroinflammation in the hippocampus. A rat model of autism was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats and male offspring were treated with 1 Hz rTMS daily for two weeks continuously. Behavior tests were performed to identify behavioral abnormality. Synaptic plasticity was measured by in vivo electrophysiological recording and Golgi-Cox staining. Synapse and inflammation associated proteins were detected by immunofluorescence and Western blot analyses. Results showed prenatal VPA-exposed rats exhibited autistic-like and anxiety-like behaviors, and cognitive impairment. Synaptic plasticity deficits and the abnormality expression of synapse-associated proteins were found in the hippocampus of prenatal VPA-exposed rats. Prenatal VPA exposure increased the level of inflammation cytokines and promoted the excessive activation of microglia. rTMS significantly alleviated the prenatal VPA-induced abnormalities including behavioral and synaptic plasticity deficits, and excessive neuroinflammation. TMS maybe a potential strategy for autism therapy via rescuing synaptic plasticity and inhibiting neuroinflammation.

Early pyridoxine administration rescues autism-like behavior in the BTBR T+tf/J autistic model

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social impairment and repetitive, stereotyped behaviors. An imbalanced oxidative stress status and neuroinflammation are involved in ASD development. In this study, we investigated the effects of pyridoxine, a form of vitamin B6 with potent anti-oxidant and anti-inflammatory features, on autism-like behavior in BTBR T + ltpr3tf/J (BTBR) mice, a model of autism. Mice received pyridoxine from postnatal days 7 to 14. Behavioral tests were conducted on 8-week-old male mice, and the inflammatory status and oxidative stress levels were also assessed in the mouse hippocampus. Postnatal pyridoxine treatment significantly improved social deficits, stereotyped behaviors, and cognitive deficits in BTBR mice. In addition, pyridoxine treatment alleviated neuroinflammation in the hippocampus manifested by reduced Iba1+ microglia and inflammatory factors, such as interleukin-1β (IL-1β), IL-6, TNF-α, and NF-κB. Further, pyridoxine-treated BTBR mice had elevated Nrf2 and HO-1 in the hippocampus. Postnatal pyridoxine administration might improve autistic-like behaviors in BTBR mice via attenuating oxidative stress and neuroinflammation in the hippocampus.

Research on multi‐center assisted diagnosis of ASD based on multimodal feature fusion

AbstractAutism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder, and structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) provide information about brain structure and function, aiding in objective ASD diagnosis. However, existing ASD classification methods face challenges such as sample scarcity, inter‐imaging center variations, insufficient single‐modality information, and inconsistent feature dimensions. This study introduced a method based on the Local Global Multimodal Domain Adaptation (LGMDA)‐Sparse Adaptive Prior Coupled Dictionary Learning (SACDL) framework. Initially, the LGMDA method was introduced to achieve multi‐source DA. By minimizing differences between different data domains while maximizing inter‐class differences within the same domain, it expands the sample size of multi‐modal data, addressing the issues of sample scarcity and heterogeneity in ASD data. Subsequently, the SACDL method was employed for multimodal fusion. It initialized dictionaries using the ATGP algorithm, combined sMRI and fMRI data for dictionary learning, adaptively adjusted sparsity parameters, and integrated ASD phenotype data for constrained optimization. It enables joint learning of shared and modality‐specific features, balancing differences in feature dimensions. Experimental results show that this model effectively utilizes multi‐center, multi‐modal information to achieve better auxiliary diagnosis than single‐modal small samples. This method has the potential to provide effective solutions for ASD multi‐source and multi‐modal classification problems, which are significant for ASD research and clinical diagnosis.

A SYSTEMIC REVIEW ON THE MANAGEMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER IN CHILDREN

ADHD, a tantalising neurodevelopmental disorder documented in the DSM-5, fascinates with its distinctive characteristics: persistent inattention and hyperactivity. Beyond the surface, it intertwines with cognitive, social, and behavioural domains and affects 5.29% globally. Ayurvedic hints like Mano Vibhrama and Raja-Tama guna alignment illuminate a path, offering tridosha-shaman therapy, Medhya rasayana, and Panchakarma. A fusion of modern understanding and ancient wisdom paves the way for unravelling ADHD's enigma, promising novel solutions. This study aims to systematically review the management of attention deficit hyperactivity disorder in Ayurveda. To conduct this study, Ayurveda research articles were obtained from PubMed, Google Scholar and AYUSH portal. A total of 40 studies were obtained, which underwent further screening processes to achieve the quality of inclusion criteria. A total of 14 articles were selected from different publications of the review. Out of 14 articles obtained, 7 studies (n=14) exclusively focused on shaman chikitsa with different single drugs and various drug formulations, 06 studies (n=14) focused on shaman and Panchakarma therapy, which includes shirodhara, abhyanga, matra basti, kashaya basti and nasya, 1 study (n=14) emphasised the importance of Panchakarma. Out of 14 clinical studies, 6 showed highly significant results, 1 showed comparatively insignificant results, and 7 showed moderately significant results. This study combines Ayurvedic insights with modern ADHD research, providing a promising opportunity for integrative treatment approaches. Further investigation of this intersection could reveal new dimensions in the fight against this complex neurodevelopmental disorder.

Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder

BackgroundSuccinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy.MethodsSSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy.ResultsThe 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4–14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder’s clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation.ConclusionsFindings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy.

Exploring the Neurogenetic Landscape of Autism Spectrum Disorder: The Role of Brain-Derived Neurotrophic Factor (BDNF) Gene in the Complex Web of Neurodevelopment

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with varied manifestations including altered metabolic profiles. Recent research highlights the potential role of Brain-Derived Neurotrophic Factor (BDNF), a hormone derived from adipose tissue, in the pathology of ASD. BDNF levels are reportedly correlated with the severity of autism symptoms, suggesting a link between metabolic dysfunction and the disorder. Objective: This study aims to deepen the understanding of BDNF levels in individuals with ASD and to explore the implications for diagnosis, treatment, and management of the disorder. It seeks to elucidate the relationship between low BDNF levels and increased autism severity, and to identify potential therapeutic interventions targeting BDNF dysregulation. Methods: EDTA blood samples (5ml each) from 140 participants (108 with ASD and 32 healthy controls) were collected across various hospitals in Karachi. Plasma serum levels of BDNF were analyzed following a six-month follow-up. A comprehensive statistical analysis was performed, focusing on the relationship between BDNF levels and autism severity, and evaluating diagnostic and therapeutic implications of BDNF dysregulation. Results: Analysis revealed that lower BDNF serum levels were consistently associated with higher autism severity. Specifically, 60-70% of participants with ASD scored below 8 on the Mini-Mental State Examination (MMSE), indicating significant cognitive impairment. The statistical significance of these findings was confirmed with p-values <0.05. Conclusion: The study confirms that low BDNF levels are significantly associated with greater severity of autism symptoms, underscoring the importance of metabolic factors in the pathogenesis of ASD. BDNF stands out as a potential biomarker for early ASD diagnosis and personalized treatment strategies. Future Prospects: Future research should aim to delineate the mechanistic relationship between BDNF dysregulation and ASD pathology. Longitudinal studies are needed to assess the long-term effects of BDNF modulation on ASD outcomes and to validate its effectiveness as both a diagnostic and prognostic marker.

Immediate effect of physical activity on the autonomic nervous system in individuals with autism spectrum disorders of different age groups: a randomised trial

BackgroundAutism spectrum disorder (ASD) is one of the most complex neurodevelopmental disorders. It affects almost all human physiological systems. Individuals with ASD often display dysregulation in their autonomic nervous system...

"Therapeutic potential of licorice extract in a prenatal valproic acid model of autism spectrum disorder in Wistar rats: Neurobehavioral and neurobiochemical insights"

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), impose significant burdens on society due to their genetic and clinical complexity. We explored the therapeutic potential of Glycyrrhiza glabra (licorice) extract in a prenatal valproic acid (VPA) model of ASD. Neurobehavioral parameters encompassing social interaction, locomotor activity, repetitive behaviour, anxiety-related behaviour, and learning and memory were assessed in Wistar rat offspring. Licorice extract administration at 150 mg/kg and 300 mg/kg was initiated from postnatal day 21, emulating the developmental stage of early childhood. The study incorporated a controlled group, a VPA-induced ASD group, and groups treated with two different doses of licorice extract and Risperidone.Results revealed that licorice extract, particularly at 300 mg/kg, exhibited remarkable potential in restoring social interaction deficits, enhancing locomotor activity, attenuating repetitive behaviour, and mitigating anxiety-related behaviour-like behaviours. Furthermore, licorice extract displayed cognitive benefits, as evidenced by the discrimination index enhancement in object recognition memory. Importantly, licorice extract demonstrated modulatory effects on neuroinflammation and oxidative stress, evident through suppressed interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels, as well as reduced thiobarbaturic acid reactive substances (TBARS) in the brain.These findings underscore the promising neuroprotective properties of Glycyrrhiza glabra extract against prenatal VPA-induced ASD-like behaviours. The elucidation of licorice's multifaceted impact on behaviour, cognition, and neurobiochemical markers offers a potential avenue for future therapeutic interventions for ASD, meriting further investigation in clinical contexts. This study contributes to the expanding knowledge of natural compounds in ameliorating complex neurodevelopmental disorders and highlights the necessity of multi-faceted approaches to address their intricate etiology and manifestation.

Uncinate fasciculus microstructural organisation and emotion recognition in schizophrenia: controlling for hit rate bias.

Schizophrenia (SCZ) is a complex neurodevelopmental disorder characterised by functional and structural brain dysconnectivity and disturbances in perception, cognition, emotion, and social functioning. In the present study, we investigated whether the microstructural organisation of the uncinate fasciculus (UF) was associated with emotion recognition (ER) performance. Additionally, we investigated the usefulness of an unbiased hit rate (UHR) score to control for response biases (i.e., participant guessing) during an emotion recognition task (ERT). Fifty-eight individuals diagnosed with SCZ were included. The CANTAB ERT was used to measure social cognition. Specific ROI manual tract segmentation was completed using ExploreDTI and followed the protocol previously outlined by Coad et al. (2020). We found that the microstructural organisation of the UF was significantly correlated with physical neglect and ER outcomes. Furthermore, we found that the UHR score was more sensitive to ERT subscale emotion items than the standard HR score. Finally, given the association between childhood trauma (in particular childhood neglect) and social cognition in SCZ, a mediation analysis found evidence that microstructural alterations of the UF mediated an association between childhood trauma and social cognitive performance. The mediating role of microstructural alterations in the UF on the association between childhood trauma and social cognitive performance suggests that early life adversity impacts both brain development and social cognitive outcomes for people with SCZ. Limitations of the present study include the restricted ability of the tensor model to correctly assess multi-directionality at regions where fibre populations intersect.

Age at autism spectrum disorder diagnosis and its association with child and family characteristics in a tertiary care hospital in Malaysia.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Despite the absence of a cure, early diagnosis and intensive early intervention can improve the outcomes. However, little is known about the median age at ASD diagnosis in Malaysia or the child/family characteristics associated with early diagnosis. Therefore, this study aimed to determine the median age at ASD diagnosis among Malaysian children presenting to the country's largest public tertiary neurodevelopmental center and to investigate the possible demographic, child, and family characteristics associated with an early age at diagnosis. Data were collected between February 2017 and February 2019 from a database maintained by the child development unit of the country's largest publicly funded tertiary hospital, containing data from an ethnically diverse population. Among Malaysian children attending the clinic, the median age at ASD diagnosis was 48 months. Early autism diagnosis (<36 months of age) was associated with increased severity of social communication and interaction impairments, coexisting intellectual impairment, children from high socioeconomic status families, and children who receive joint care from their families and a maid or babysitter. The study findings highlight the socioeconomic inequalities in the country, a lack of parental awareness of early ASD signs, and the presence of cultural influences on the age at diagnosis of ASD.

The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism spectrum disorder

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by deficient social communication and interaction together with restricted, stereotyped behaviors. Currently approved treatments relieve comorbidities rather than core symptoms. Since excitation/inhibition balance and synaptic plasticity are disrupted in ASD, molecules targeting excitatory synaptic transmission appear as highly promising candidates to treat this pathology. Among glutamatergic receptors, the NMDA receptor has received particular attention through the last decade to develop novel allosteric modulators. Here, we show that positive NMDA receptor modulation by zelquistinel, a spirocyclic β-lactam platform chemical, relieves core symptoms in two genetic and one environmental mouse models of ASD. A single oral dose of zelquistinel rescued, in a dose-response manner, social deficits and stereotypic behavior in Shank3Δex13-16−/− mice while chronic intraperitoneal administration promoted a long-lasting relief of such autistic-like features in these mice. Subchronic oral mid-dose zelquistinel treatment demonstrated durable effects in Shank3Δex13-16−/−, Fmr1−/− and in utero valproate-exposed mice. Carry-over effects were best maintained in the Fmr1 null mouse model, with social parameters being still fully recovered two weeks after treatment withdrawal. Among recently developed NMDA receptor subunit modulators, zelquistinel displays a promising therapeutic potential to relieve core symptoms in ASD patients, with oral bioavailability and long-lasting effects boding well for clinical applications. Efficacy in three mouse models with different etiologies supports high translational value. Further, this compound represents an innovative pharmacological tool to investigate plasticity mechanisms underlying behavioral deficits in animal models of ASD.

Evaluation of an Integrated Fluency and Acceptance and Commitment Therapy Intervention for Adolescents and Adults Who Stutter.

Developmental stuttering is a complex and multifaceted neurodevelopmental disorder that may cause pervasive negative consequences for adults who stutter (AWS). Historically, intervention for AWS has primarily addressed speech fluency, with less focus on the covert psychosocial aspects of the disorder. The purpose of this article is to report on a feasibility trial evaluating a novel integrated intervention that combines traditional stuttering management techniques with Acceptance and Commitment Therapy (ACT) for AWS. Twenty-nine AWS participated in the feasibility trial. All participants successfully completed a combined fluency and ACT intervention, titled the fluency and Acceptance and Commitment Therapy for Stuttering (fACTS) Program. As this was a feasibility study, no control group was included. Intervention was administered by two certified practicing speech-language pathologists, over eight 60- to 90-min sessions. Generalized linear mixed modeling was used to determine change from pre- to post-intervention and follow-up. Significant pre- and post-intervention improvements in self-efficacy, psychosocial functioning, and psychological flexibility were observed, along with significant reductions in observable stuttering behaviors (i.e., stuttered speech frequency). Intervention gains for all variables of interest were maintained 3 and 6 months post-intervention. The fACTS Program was created to be a holistic and flexible intervention to promote self-efficacy beliefs and address stuttering-related psychosocial impacts and speech fluency goals of AWS. Preliminary results indicated positive improvement in all psychosocial outcomes (i.e., self-efficacy, psychosocial impact, and psychological flexibility) and observable speech fluency following completion of the program. Future clinical trials of the fACTS Program with an included control group will further investigate the mechanisms of change for the positive effects observed.

Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment

We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37–38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37–38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.

Identification and Analysis of ZIC-Related Genes in Cerebellum of Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with significant genetic heterogeneity. The ZIC gene family can regulate neurodevelopment, especially in the cerebellum, and has been implicated in ASD-like behaviors in mice. We performed bioinformatic analysis to identify the ZIC gene family in the ASD cerebellum. We explored the roles of ZIC family genes in ASD by investigating (i) the association of ZIC genes with ASD risk genes from the Simons Foundation Autism Research Initiative (SFARI) database and ZIC genes in the brain regions of the Human Protein Atlas (HPA) database; (ii) co-expressed gene networks of genes positively and negatively correlated with ZIC1, ZIC2, and ZIC3, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and receiver operating characteristic (ROC) curve analysis of genes in these networks; and (iii) the relationship between ZIC1, ZIC2, ZIC3, and their related genes with cerebellar immune cells and stromal cells in ASD patients. (i) ZIC1, ZIC2, and ZIC3 were associated with neurodevelopmental disorders and risk genes related to ASD in the human cerebellum and (ii) ZIC1, ZIC2, and ZIC3 were highly expressed in the cerebellum, which may play a pathogenic role by affecting neuronal development and the cerebellar internal environment in patients with ASD, including immune cells, astrocytes, and endothelial cells. (iii) OLFM3, SLC27A4, GRB2, TMED1, NR2F1, and STRBP are closely related to ZIC1, ZIC2, and ZIC3 in ASD cerebellum and have good diagnostic accuracy. (iv) ASD mice in the maternal immune activation model demonstrated that Zic3 and Nr2f1 levels were decreased in the immune-activated cerebellum. Our study supports the role of ZIC1, ZIC2, and ZIC3 in ASD pathogenesis and provides potential targets for early and accurate prediction of ASD.

Temperament Traits in Pediatric Obsessive-Compulsive Disorder in Relation to Tourette Syndrome and Attention-Deficit Hyperactivity Disorder

Introduction: Pediatric obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS) are often concurrent. This study explores the temperament profile of complex OCD phenotypes. Methods: A clinical registry recorded demographic data, psychiatric diagnoses, and temperament traits, including novelty seeking (exploratory behaviors), harm avoidance (fear of uncertainty), reward dependence (sentimentality), and persistence (perseverance). Temperament data were accrued from the Junior Temperament and Character Inventory (JTCI). Participants were divided into (1) OCD only; (2) OCD+ADHD or TS; and (3) OCD+ADHD+TS to compare temperament. Results: Participants include 126 youths with OCD (61.9% male, 88.9% white) between the ages 6 and 18 years (12.7 ± 3.1). Among the three groups, the complex neurodevelopmental disorder group OCD+ADHD+TS expresses the highest novelty seeking and lowest persistence. Harm avoidance is increased in all groups compared to reference controls, irrespective of concurrent ADHD or TS. For the OCD+ADHD+TS group, contamination and washing symptoms have higher novelty seeking (p < 0.01), while counting and ordering have lower novelty seeking (p < 0.05). Harm avoidance is increased with aggressive, somatic, and checking symptoms in OCD only (p < 0.01), while persistence is increased with repeating and counting symptoms in the comorbid groups (OCD+ADHD or TS, OCD+ADHD+TS). Discussion/Conclusion: The complex subtype, OCD+ADHD+TS, is associated with high novelty seeking and low persistence, while high harm avoidance is linked to pediatric OCD irrespective of ADHD or TS co-occurrence. In sum, pediatric OCD with ADHD and TS confers a unique temperament profile, further refining complex phenotypes of pediatric OCD for future research.