Neurodevelopmental Disorders Research Articles

De novo missense variants of UNC13A are implicated in epileptic encephalopathies and neurodevelopmental disorders

De novo missense variants of UNC13A are implicated in epileptic encephalopathies and neurodevelopmental disorders

Care pathways in childhood neurodevelopmental disorders: Toward greater awareness of KBG syndrome among pediatricians

IntroductionKBG syndrome is an autosomal dominant, polymalformative genetic syndrome that is mainly associated with neurodevelopmental and learning disorders, intellectual disability, behavioral disorders, and epilepsy as well as characteristic dysmorphic features, short stature, and ENT (ear, nose, and throat) abnormalities. However, the diagnostic pathway of these individuals is an element that has not been broadly evaluated. The main aim of this study was therefore to characterize the diagnostic pathway for these individuals, by assessing the different healthcare professionals involved and the main referral elements. MethodThis was a multicenter, retrospective, descriptive study. A cohort of 30 individuals with KBG syndrome who were followed up at Poitiers University Hospital and Bordeaux University Hospital we recruited. ResultsPediatricians were the main healthcare professionals who referred individuals for genetic consultation, and the main reason for referral was an assessment of learning delays or intellectual disability, in association with other abnormalities. ConclusionPediatricians play a crucial role in the diagnostic guidance of individuals with KBG syndrome, and the main reason for referral remains the assessment of a learning delay or intellectual disability. Healthcare professionals must therefore remain attentive to the child's development and the various anomalies associated with it, in particular characteristic dysmorphic features, behavioral disorders, and statural growth.

Debugging neurodevelopment disorders

Gut bacteria are thought to contribute to neurodevelopmental disorders, but whether they are causal or predictive of disease remains unclear. In a prospective longitudinal study of thousands of children, Ahrens etal. generate evidence for the role of the gut microbiome in neurodevelopmental disorders while highlighting important open questions.

Current Perspectives on Attention-deficit Hyperactivity Disorder.

Attention-deficit hyperactivity disorder (ADHD) is a neurobiological and neurodevelopmental disorder with an idiosyncratic genetic base. ADHD presents various characteristics, such as inattention, hyperactivity, and impulsivity. Over the period, ADHD leads to noticeable functional disability. A five- to ten-fold progressed risk of disorder development is observed in the populations with familial history of ADHD. The abnormal structure of the brain in ADHD results in altered neural mechanisms, such as cognition, attention, and memorial function. The mesolimbic, nigrostriatal, and mesocortical pathways in the brain get affected by the deterioration of the levels of dopamine. The hypothesis of dopamine in ADHD and its etiopathology suggests that detained attention and impaired arousal functions are due to reduced levels of dopamine. The quickest way to improve strategical treatment is by clarifying the etiological aspects of ADHD and identifying the underlying mechanisms of pathophysiology, which will assist in exploring the biomarkers for better diagnosis. The implementation of life course theory is a very important research principle announced by Grand Challenges in Global Health Initiative (GCMHI). Long-term research is needed to define the progression of ADHD. Interdisciplinary collaborations promise a great future for research innovations in ADHD.

Mutation of the ALS/FTD-associated RNA-binding protein FUS affects axonal development.

Aberrant condensation and localisation of the RNA-binding protein (RBP) fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Changes in RBP function are commonly associated with changes in axonal cytoskeletal organisation and branching in neurodevelopmental disorders. Here, we asked whether branching defects also occur in vivo in a model of FUS-associated disease. We use two reported Xenopus models of ALS/FTD (of either sex), the ALS-associated mutant FUS(P525L) and a mimic of hypomethylated FUS, FUS(16R). Both mutants strongly reduced axonal complexity in vivo. We also observed an axon looping defect for FUS(P525L) in the target area, which presumably arises due to errors in stop cue signalling. To assess whether loss of axon complexity also had a cue-independent component, we assessed axonal cytoskeletal integrity in vitro Using a novel combination of fluorescence and atomic force microscopy, we found that mutant FUS reduced actin density in the growth cone, altering its mechanical properties. Therefore, FUS mutants may induce defects during early axonal development.Significance statement This study demonstrates that mutation of the ALS/FTD (amyotrophic lateral sclerosis/frontotemporal dementia)-associated RNA-binding protein Fused in Sarcoma (FUS) can result in changes in axonal development. These changes occur both axon-autonomously in cytoskeletal organisation during axon extension and context-dependently during axonal branching. This indicates pre-symptomatic, developmental changes in axonal organisation may occur in familial disease variants.

Cornelia de Lange Spectrum

Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder with multisystemic involvement. The clinical presentation is highly variable, but the classic phenotype, characterized by distinctive craniofacial features, pre- and postnatal growth retardation, extremity reduction defects, hirsutism and intellectual disability can be distinguished from the nonclassic phenotype, which is generally milder and more difficult to diagnose. In addition, the clinical features overlap with those of other neurodevelopmental disorders, so the use of consensus clinical criteria and artificial intelligence tools may be helpful in confirming the diagnosis.Pathogenic variants in NIPBL, which encodes a protein related to the cohesin complex, have been identified in more than 60% of patients, and pathogenic variants in other genes related to this complex in another 15%: SMC1A, SMC3, RAD21, and HDAC8. Technical advances in large-scale sequencing have allowed the description of additional genes (BRD4, ANKRD11, MAU2), but the lack of molecular diagnosis in 15% of individuals and the substantial clinical heterogeneity of the syndrome suggest that other genes and mechanisms may be involved.Although there is no curative treatment, there are symptomatic/palliative treatments that paediatricians should be aware of. The main medical complication in classic SCdL is gastro-esophageal reflux (GER), which should be treated early.

Prématurité moyenne : aspects médicaux et développementaux

Prématurité moyenne : aspects médicaux et développementaux

White Matter Alterations Predict Outcomes of Comprehensive Behavioral Intervention for Tics in Children with Tourette Syndrome: A diffusion MRI study

AimTourette syndrome (TS) is a neurodevelopmental disorder that cause sudden uncontrolled rapid and repeated vocal sounds or movements called tics. Herein, diffusion magnetic resonance imaging (dMRI) connectometry was implemented to evaluate the white matter connectivity differences among TS patients. MethodsA total of 63 TS and 77 typically developed (TD) individuals were enrolled in the present study. dMRI connectometry was utilized to identify differences in connectivity patterns of white matter tracts in TS patients based on quantitative anisotropy (QA). QA was compared between TS and TD patients and correlated with severity scores such as Yale Global Tic Severity Scale (YGTSS) and Premonitory Urge for Tics Scale (PUTS). ResultsHigher white matter connectivity of corpus callosum and bilateral cingulum as well as lower connectivity of corticothalamic and corticostriatal pathways were evident in TS relative to TD. The baseline YGTSS motor, YGTSS total, and PUTS were negatively correlated with corticostriatal pathway, corticothalamic pathway, and bilateral cingulum integrity, respectively. The changes in tic severity scores were also positively correlated with alterations in the white matter integrity of these brain regions following behavioral therapy. ConclusionPatients with TS have several abnormalities in their white matter microstructure particularly in the cortico-striato-thalamo-cortical (CSTC) circuit, correlated with the severity of the disease. Besides, the post-behavioral therapy changes in the white matter integrity of these regions are demonstrated as response predictors.

A global phosphosite-correlated network map of Thousand And One Kinase 1 (TAOK1)

Thousand and one amino acid kinase 1 (TAOK1) is a sterile 20 family Serine/Threonine kinase linked to microtubule dynamics, checkpoint signaling, DNA damage response, and neurological functions. Molecular-level alterations of TAOK1 have been associated with neurodevelopment disorders and cancers. Despite their known involvement in physiological and pathophysiological processes, and as a core member of the hippo signaling pathway, the phosphoregulatory network of TAOK1 has not been visualized. Aimed to explore this network, we first analyzed the predominantly detected and differentially regulated TAOK1 phosphosites in global phosphoproteome datasets across diverse experimental conditions. Based on 709 qualitative and 210 quantitative differential cellular phosphoproteome datasets that were systematically assembled, we identified that phosphorylation at Ser421, Ser9, Ser965, and Ser445 predominantly represented TAOK1 in almost 75% of these datasets. Surprisingly, the functional role of all these phosphosites in TAOK1 remains unexplored. Hence, we employed a robust strategy to extract the phosphosites in proteins that significantly correlated in expression with predominant TAOK1 phosphosites. This led to the first categorization of the phosphosites including those in the currently known and predicted interactors, kinases, and substrates, that positively/negatively correlated with the expression status of each predominant TAOK1 phosphosites. Subsequently, we also analyzed the phosphosites in core proteins of the hippo signaling pathway. Based on the TAOK1 phosphoregulatory network analysis, we inferred the potential role of the predominant TAOK1 phosphosites. Especially, we propose pSer9 as an autophosphorylation and TAOK1 kinase activity-associated phosphosite and pS421, the most frequently detected phosphosite in TAOK1, as a significant regulatory phosphosite involved in the maintenance of genome integrity. Considering that the impact of all phosphosites that predominantly represent each kinase is essential for the efficient interpretation of global phosphoproteome datasets, we believe that the approach undertaken in this study is suitable to be extended to other kinases for accelerated research.

286. The Emergent Transdiagnostic Phenotype of Attention and Executive Function Delay in Neurodevelopmental Conditions

286. The Emergent Transdiagnostic Phenotype of Attention and Executive Function Delay in Neurodevelopmental Conditions

Neurodevelopmental Movement Disorder

Neurodevelopmental Movement Disorder

Abnormalities in pharyngeal arch-derived structures in SATB2-associated syndrome.

SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that Satb2 is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches. Satb2-/- mutant mice exhibit microglossia, a shortened lower jaw, smaller trigeminal ganglia, and larger thyroids. We correlate these findings with the detailed clinical phenotype of four individuals with SAS and remarkable craniofacial phenotypes with one requiring mandibular distraction in childhood. We conclude that the mouse and patient data presented support less well-described phenotypic aspects of SAS including mandibular morphology and thyroid anatomical/functional issues.

MECP2 directly interacts with RNA polymerase II to modulate transcription in human neurons.

Mutations in the methyl-DNA-binding protein MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). How MECP2 contributes to transcriptional regulation in normal and disease states is unresolved; it has been reported to be an activator and a repressor. We describe here the first integrated CUT&Tag, transcriptome, and proteome analyses using human neurons with wild-type (WT) and mutant MECP2 molecules. MECP2 occupies CpG-rich promoter-proximal regions in over four thousand genes in human neurons, including a plethora of autism risk genes, together with RNA polymerase II (RNA Pol II). MECP2 directly interacts with RNA Pol II, and genes occupied by both proteins showed reduced expression in neurons with MECP2 patient mutations. We conclude that MECP2 acts as a positive cofactor for RNA Pol II gene expression at many neuronal genes that harbor CpG islands in promoter-proximal regions and that RTT is due, in part, to the loss of gene activity of these genes in neurons.

EXERCISE IN ADULTS WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER: A SYSTEMATIC REVIEW

INTRODUCTION & AIMS Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders in adults. Stimulant medications are first-line treatments, they have many side effects and do not address common comorbidities such as cardiometabolic disease, depression, and anxiety. Exercise, by contrast, not only improves ADHD symptoms in youth but effectively treats such comorbidities, making it a potentially valuable treatment option. However, exercise efficacy in adults with ADHD has not been systematically reviewed. Therefore, we aimed to summarise the results of acute exercise and training interventions on health-related outcomes for adults with ADHD, including ADHD symptoms, cognitive function, and psychological well-being. METHODS Using PRISMA guidelines, fifteen databases were searched (including grey literature) on 27/08/2020, yielding 22,088 unique publications. Database alerts were created to capture additional studies (n= 2). Screening, data extraction, Risk of Bias and GRADE assessment was conducted by CEHB. RESULTS Seven acute (6 cycling, 1 self-selected, 1 yoga) and 6 training studies (Yoga, Pilates, Kickboxing, Tai Chi, General Coordination, Group Circuit Class, Cycling) were included. Among acute studies, those reporting small-to-moderate improvements in cognitive function were characterised by longer duration exercise (>30 minutes), withholding ADHD medication before exercise, and using cohorts with clinician-confirmed ADHD diagnosis. Among the training studies, only one reported an improvement in cognition following Pilates when compared to an inactive control. It was longer (6 months vs. <8 weeks), prescribed progressive intensity and volume, and had high adherence compared to the non-significant trials. The certainty of evidence was low or very low for all outcomes. CONCLUSIONS Overall, acute exercise may have a small positive effect on cognition in adults with ADHD; however, certainty of the evidence is low. Further research is needed to investigate the impact of different modalities, durations, and intensities of acute exercise and chronic exercise on adult ADHD.

Maternal selenium deficiency during pregnancy in association with autism and ADHD traits in children: the Odense Child Cohort

BackgroundSelenoproteins regulate pathways controlling neurodevelopment, e.g., redox signaling and thyroid hormone metabolism. However, studies investigating maternal selenium in relation to child neurodevelopmental disorders are scarce. Methods719 mother-child pairs from the prospective population-based Odense Child Cohort study in Denmark were included. Three selenium biomarkers, i.e. concentrations of serum selenium, selenoprotein P (SELENOP), and activity of glutathione peroxidase 3 (GPX3), along with serum copper, zinc and iron were measured in early third trimester (at 28.9 +/- 0.8 weeks of pregnancy). ADHD and ASD traits in children were assessed systematically using the established Child Behaviour Checklist at 5 years of age, based on a Danish reference cohort with cut-off at 90th percentile. Multivariable regression models adjusted for biologically relevant confounders were applied. Results155 of 719 (21.6%) children had ASD traits and 59 of 719 (8.2%) children had traits of ADHD at 5 years of age. In crude and adjusted models, all three selenium biomarkers associated inversely with ADHD traits. For ADHD, fully adjusted OR for 10 μg/L increment in selenium was 0.76 (95% CI 0.60, 0.94), for one mg/L increment in SELENOP was 0.73 (0.56, 0.95), and for 10 U/L increment in GPx3 was 0.93 (0.87,1.00). Maternal total selenium was inversely associated with child ASD traits, OR per 10 μg/L increment was 0.85 (0.74, 0,98). SELENOP and GPx3 were not associated with ASD traits. The associations were specific to selenium, as other trace elements such as copper, zinc, or iron were not associated with the outcomes. ConclusionsThe results provide coherent evidence for selenium deficiency as a risk factor for ADHD and ASD traits in an environment with borderline supply, the causality of which should be elucidated in a randomized controlled trial.

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.

Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids

Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.

The protective effects of Ferrostatin-1 against inflammation-induced preterm birth and fetal brain injury

IntroductionRecent studies have suggested the involvement of ferroptosis in preterm birth. Despite compelling evidence, the underlying mechanism remains unknown. This investigation aimed to determine the therapeutic effects of Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, in preterm birth and fetal brain injury. MethodsHuman placenta samples and clinical data of participants were collected to ascertain whether placental ferroptosis was associated with preterm birth. Lipopolysaccharide (LPS)-induced preterm birth mouse model was used to examine the protective effects of Fer-1 on preterm birth. Fetal brain tissues and offspring mice at 5 and 8 weeks were studied to determine the effects of Fer-1 on the cognitive function of offspring. ResultsWe examined the mechanism of spontaneous preterm birth and discovered that placental ferroptosis was associated with preterm birth. Fer-1 inhibited preterm birth by ameliorating placental ferroptosis and maternal inflammation, thus improving LPS-induced intrauterine inflammation to maintain pregnancy. Antenatal administration of Fer-1 prevented LPS-induced fetal brain damage in the acute phase and improved long-term neurodevelopmental impairments by improving placental neuroendocrine signaling and maintaining placental function. ConclusionFer-1 inhibited preterm birth and fetal brain injury by inhibiting maternal inflammation and improving placental function. Our findings provide a novel therapeutic strategy for preterm birth.

Effect of fractional exhaled nitric oxide (FENO)-based asthma management during pregnancy versus usual care on infant development, temperament, sensory function and autism signs.

In this sample, FENO-guided asthma treatment during pregnancy did not improve infant developmental outcomes in the first year of life. ClinicalTrials.gov Identifier: ACTRN12613000202763. • Maternal asthma during pregnancy has been associated with increased rates of neurodevelopmental conditions in offspring, including intellectual disability and autism. • This is the first study to examine how managing asthma during pregnancy via a FENO-guided algorithm or usual care affects infant developmental and behavioural outcomes. While the results of the study showed no impact of the intervention, and therefore do not support the integration of FENO-based management of asthma in antenatal settings for optimal infant development, they do send a positive message about the implications of active asthma management during pregnancy on infant developmental outcomes.

Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. The diagnosis of ASD is currently based on behavior criteria, which overlooks the diversity of genetic, neurophysiological, and clinical manifestations. Failure to acknowledge such heterogeneity has hindered the development of efficient drug treatments for ASD and other NDDs. DEPI (Databased Endophenotyping Patient Identification) is a systems biology, multi-omics, and machine learning-driven platform enabling the identification of subgroups of patients with NDDs and the development of patient-tailored treatments. In this study, we provide evidence for the validation of a first clinically and biologically defined subgroup of patients with ASD identified by DEPI, ASD Phenotype 1 (ASD-Phen1). Among 313 screened patients with idiopathic ASD, the prevalence of ASD-Phen1 was observed to be ~24% in 84 patients who qualified to be enrolled in the study. Metabolic and transcriptomic alterations differentiating patients with ASD-Phen1 were consistent with an over-activation of NF-κB and NRF2 transcription factors, as predicted by DEPI. Finally, the suitability of STP1 combination treatment to revert such observed molecular alterations in patients with ASD-Phen1 was determined. Overall, our results support the development of precision medicine-based treatments for patients diagnosed with ASD.