Neurodevelopmental Anomalies Research Articles

117P Prevalence of neurodevelopmental anomalies in patients with Spinal Muscular Atrophy Type I registered in CUIDAME

117P Prevalence of neurodevelopmental anomalies in patients with Spinal Muscular Atrophy Type I registered in CUIDAME

Molecular mechanisms of human overgrowth and use of omics in its diagnostics: chances and challenges.

Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and or organs. Depending on the underlying physiological pathway affected by pathogenic genetic alterations, overgrowth syndromes are associated with a broad spectrum of neoplasia predisposition, (cardio) vascular and neurodevelopmental anomalies, and dysmorphisms. Pathologic overgrowth may be of prenatal or postnatal onset. It either results from an increased number of cells (intrinsic cellular hyperplasia), hypertrophy of the normal number of cells, an increase in interstitial spaces, or from a combination of all of these. The underlying molecular causes comprise a growing number of genetic alterations affecting skeletal growth and Growth-relevant signaling cascades as major effectors, and they can affect the whole body or parts of it (mosaicism). Furthermore, epigenetic modifications play a critical role in the manifestation of some overgrowth diseases. The diagnosis of overgrowth syndromes as the prerequisite of a personalized clinical management can be challenging, due to their clinical and molecular heterogeneity. Physicians should consider molecular genetic testing as a first diagnostic step in overgrowth syndromes. In particular, the urgent need for a precise diagnosis in tumor predisposition syndromes has to be taken into account as the basis for an early monitoring and therapy. With the (future) implementation of next-generation sequencing approaches and further omic technologies, clinical diagnoses can not only be verified, but they also confirm the clinical and molecular spectrum of overgrowth disorders, including unexpected findings and identification of atypical cases. However, the limitations of the applied assays have to be considered, for each of the disorders of interest, the spectrum of possible types of genomic variants has to be considered as they might require different methodological strategies. Additionally, the integration of artificial intelligence (AI) in diagnostic workflows significantly contribute to the phenotype-driven selection and interpretation of molecular and physiological data.

Altered neuroepithelial morphogenesis and migration defects in iPSC-derived cerebral organoids and 2D neural stem cells in familial bipolar disorder.

Bipolar disorder (BD) is a severe mental illness that can result from neurodevelopmental aberrations, particularly in familial BD, which may include causative genetic variants. In the present study, we derived cortical organoids from BD patients and healthy (control) individuals from a clinically dense family in the Indian population. Our data reveal that the patient organoids show neurodevelopmental anomalies, including organisational, proliferation and migration defects. The BD organoids show a reduction in both the number of neuroepithelial buds/cortical rosettes and the ventricular zone size. Additionally, patient organoids show a lower number of SOX2-positive and EdU-positive cycling progenitors, suggesting a progenitor proliferation defect. Further, the patient neurons show abnormal positioning in the ventricular/intermediate zone of the neuroepithelial bud. Transcriptomic analysis of control and patient organoids supports our cellular topology data and reveals dysregulation of genes crucial for progenitor proliferation and neuronal migration. Lastly, time-lapse imaging of neural stem cells in 2D in vitro cultures reveals abnormal cellular migration in BD samples. Overall, our study pinpoints a cellular and molecular deficit in BD patient-derived organoids and neural stem cell cultures.

Epigenetic Correction and Early Brain Pharmacotherapy in Down Syndrome

Down syndrome (DS) is the most frequent autosomal aneuploidy. It refers to a genetic condition due to the triplication of human chromosome 21 (Hsa21). Disruption of the phenotype is thought to be the result of gene-dosage imbalance. This phenotype is always characterized by neurodevelopmental anomalies. Additionally, persons with DS have higher risks of several medical challenges. These include congenital heart disease, susceptibility to viruses and immune defects, metabolic changes, and hematopoietic abnormalities. In recent years, experimental work has been conducted with the aim of correcting overexpressed genes on chromosome 21 or silencing the extra chromosome 21 to normalize genetic expression. The paper examines the clinical feasibility of these attempts and identifies several caveats. Improving neurogenesis, dendritic density and synaptic connectivity with pharmacological substances is more at hand with the current technical knowledge and legal provisos.

Motion and Form Perception in Childhood-Onset Schizophrenia.

(1) Background: Childhood-onset schizophrenia (COS) is a rare type of psychotic disorder characterized by delusions, hallucinations, grossly disorganized behavior, and poor psychosocial functioning. The etiology of COS is unknown, but neurodevelopmental factors are likely to play a critical role. A potential neurodevelopmental anomaly marker is the dorsal visual system dysfunction, which is implicated in motion perception, spatial functions, and attention. (2) Methods: To elucidate the role of the dorsal visual system in COS, we investigated 21 patients with COS and 21 control participants matched for age, sex, education, IQ, and parental socioeconomic status. Participants completed a motion and form coherence task, during which one assesses an individual's ability to detect the direction of motion within a field of moving elements or dots and to recognize a meaningful form or object from a set of fragmented or disconnected visual elements, respectively. (3) Results: The patients with COS were impaired in both visual tasks compared to the control participants, but the evidence for the deficit was more substantial for motion perception than for form perception (form: BF10 = 27.22; motion: BF10 = 6.97 × 106). (4) Conclusions: These results highlight the importance of dorsal visual stream vulnerability in COS, a potential marker of neurodevelopmental anomalies.

A Vascular-Centric Approach to Autism Spectrum Disorders.

Brain development and function are highly reliant on adequate establishment and maintenance of vascular networks. Early impairments in vascular health can impact brain maturation and energy metabolism, which may lead to neurodevelopmental anomalies. Our recent work not only provides novel insights into the development of cerebrovascular networks but also emphasizes the importance of their well-being for proper brain maturation. In particular, we have demonstrated that endothelial dysfunction in autism spectrum disorders (ASD) mouse models is causally related to altered behavior and brain metabolism. In the prenatal human brain, vascular cells change metabolic states in the second trimester. Such findings highlight the need to identify new cellular and molecular players in neurodevelopmental disorders, raising awareness about the importance of a healthy vasculature for brain development. It is thus essential to shift the mostly neuronal point of view in research on ASD and other neurodevelopmental disorders to also include vascular and metabolic features.

Hydranencephaly: A Case Report

Hydranencephaly is a congenital neurodevelopmental anomaly in which there is an absence of the cerebral hemispheres and intact infratentorial structures. Diagnosis can be made prenatally or postnatally using ultrasound, CT, or MRI. Imaging findings include the presence of primitive brain structures, variable presence of the falx cerebri, and total or near-total absence of the cerebral hemispheres. We reported a case of newborn hydranencephaly in 1 day old neonate with macrocephaly.

Identification of USP9X as a leukemia susceptibility gene

AbstractWe recently reported that children with multiple birth defects have a significantly higher risk of childhood cancer. We performed whole-genome sequencing on a cohort of probands from this study with birth defects and cancer and their parents. Structural variant analysis identified a novel 5 kb de novo heterozygous inframe deletion overlapping the catalytic domain of USP9X in a female proband with multiple birth defects, developmental delay, and B-cell acute lymphoblastic leukemia (B-ALL). Her phenotype was consistent with female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F). Genotype-phenotype analysis including previously reported female probands (n = 42) demonstrated that MRXS99F probands with B-ALL (n = 3) clustered with subjects with loss-of-function (LoF) USP9X variants and multiple anomalies. The cumulative incidence of B-ALL among these female probands (7.1%) was significantly higher than an age- and sex-matched cohort (0.003%) from the Surveillance, Epidemiology, and End Results database (P < .0001, log-rank test). There are no reports of LoF variants in males. Males with hypomorphic missense variants have neurodevelopmental disorders without birth defects or leukemia risk. In contrast, in sporadic B-ALL, somatic LoF USP9X mutations occur in both males and females, and expression levels are comparable in leukemia samples from both sexes (P = .54), with the highest expressors being female patients with extra copies of the X-chromosome. Overall, we describe USP9X as a novel female-specific leukemia predisposition gene associated with multiple congenital, neurodevelopmental anomalies, and B-ALL risk. In contrast, USP9X serves as a tumor suppressor in sporadic pediatric B-ALL in both sexes, with low expression associated with poorer survival in patients with high-risk B-ALL.

Silver Nanoparticles Cause Neural and Vascular Disruption by Affecting Key Neuroactive Ligand-Receptor Interaction and VEGF Signaling Pathways.

Silver nanoparticles (AgNP) are widely used as coating materials. However, the potential risks of AgNP to human health, especially for neural and vascular systems, are still poorly understood. The vascular and neurotoxicity of various concentrations of AgNP in zebrafish were examined using fluorescence microscopy. In addition, Illumina high-throughput global transcriptome analysis was performed to explore the transcriptome profiles of zebrafish embryos after exposure to AgNP. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to elucidate the top 3000 differentially expressed genes (DEGs) between AgNP-exposed and control groups. We systematically investigated the neural and vascular developmental toxicities of AgNP exposure in zebrafish. The results demonstrated that AgNP exposure could cause neurodevelopmental anomalies, including a small-eye phenotype, neuronal morphology defects, and inhibition of athletic abilities. In addition, we found that AgNP exposure induces angiogenesis malformation in zebrafish embryos. Further RNA-seq revealed that DEGs were mainly enriched in the neuroactive ligand-receptor interaction and vascular endothelial growth factor (Vegf) signaling pathways in AgNP-treated zebrafish embryos. Specifically, the mRNA levels of the neuroactive ligand-receptor interaction pathway and Vegf signaling pathway-related genes, including si:ch73-55i23.1, nfatc2a, prkcg, si:ch211-132p1.2, lepa, mchr1b, pla2g4aa, rac1b, p2ry6, adrb2, chrnb1, and chrm1b, were significantly regulated in AgNP-treated zebrafish embryos. Our findings indicate that AgNP exposure transcriptionally induces developmental toxicity in neural and vascular development by disturbing neuroactive ligand-receptor interactions and the Vegf signaling pathway in zebrafish embryos.

Population screening for 15q11-q13 duplications: corroboration of the difference in impact between maternally and paternally inherited alleles.

Maternally inherited 15q11-q13 duplications are generally found to cause more severe neurodevelopmental anomalies compared to paternally inherited duplications. However, this assessment is mainly inferred from the study of patient populations, causing an ascertainment bias towards patients at the more severe end of the phenotypic spectrum. Here, we analyze the low coverage genome-wide cell-free DNA sequencing data obtained from pregnant women during non-invasive prenatal screening (NIPS). We detect 23 15q11-q13 duplications in 333,187 pregnant women (0.0069%), with an approximately equal distribution between maternal and paternal duplications. Maternally inherited duplications are always associated with a clinical phenotype (ranging from learning difficulties to intellectual impairment, epilepsy and psychiatric disorders), while paternal duplications are normal or associated with milder phenotypes (mild learning difficulties and dyslexia). This data corroborates the difference in impact between paternally and maternally inherited 15q11-q13 duplications, contributing to the improvement of genetic counselling. We recommend reporting 15q11-q13 duplications identified during genome-wide NIPS with appropriate genetic counselling for these pregnant women in the interest of both mothers and future children.

Xp22.31 copy number variations in 87 fetuses: refined genotype–phenotype correlations by prenatal and postnatal follow-up

BackgroundXp22.31 deletion and duplication have been described in various studies, but different laboratories interpret pathogenicity differently.ObjectivesOur study aimed to refine the genotype–phenotype associations between Xp22.31 copy number variants in fetuses, with the aim of providing data support to genetic counseling.MethodsWe retrospectively analyzed karyotyping and single nucleotide polymorphism array results from 87 fetuses and their family members. Phenotypic data were obtained through follow-up visits.ResultsThe percentage of fetuses carrying the Xp22.31 deletions (9 females, 12 males) was 24.1% (n = 21), while duplications (38 females, 28 males) accounted for 75.9% (n = 66). Here, we noted that the typical region (from 6.4 to 8.1 Mb, hg19) was detected in the highest ratio, either in the fetuses with deletions (76.2%, 16 of 21) or duplications (69.7%, 46 of 66). In female deletion carriers, termination of pregnancy was chosen for two fetuses, and the remaining seven were born without distinct phenotypic abnormalities. In male deletion carriers, termination of pregnancy was chosen for four fetuses, and the remaining eight of them displayed ichthyosis without neurodevelopmental anomalies. In two of these cases, the chromosomal imbalance was inherited from the maternal grandfathers, who also only had ichthyosis phenotypes. Among the 66 duplication carriers, two cases were lost at follow-up, and pregnancy was terminated for eight cases. There were no other clinical findings in the rest of the 56 fetuses, including two with Xp22.31 tetrasomy, for either male or female carriers.ConclusionOur observations provide support for genetic counseling in male and female carriers of Xp22.31 copy number variants. Most of them are asymptomatic in male deletion carriers, except for skin findings. Our study is consistent with the view that the Xp22.31 duplication may be a benign variant in both sexes.

Cyst of Septum Pellucidum in mental disorders: Schizophrenia and Mental Retardation: Two case reports

IntroductionA septum pellucidum cyst is defined as a fluid collection between the lateral ventricles whose walls have a lateral curvature and are separated by 10 mm or more . Most of these cysts are benign and their clinical significance should be considered as a neurodevelopmental anomaly that may contribute to neuropsychiatric abnormalities . It is often of incidental finding, of little clinical significance. However, an association between this developmental anomaly and a mental disorder, such as schizophrenia and/or intellectual disability, has been reportedObjectivesThe objective of this study is to discuss the relationship between the septum pellucidum cyst and mental disorders, especially schizophrenia and intellectual disability.MethodsWe report in this study two clinical cases, diagnosed with schizophrenia comorbid with intellectual disability and in whom brain imaging has objectified a cyst of the septum pellucidumResultsmultiple cases reports of patients with Schizophrenia and/or mental retardation revealed, on brain imaging, significant abnormalities in midline brain regions such as Septum Pellucidum. It is suggested that CSP, particularly if large, should be considered a developmental anomaly that may contribute to neuropsychiatric abnormalities.ConclusionsWhether the CSP may serve as a risk factor for psychosis or is only a reflection of neuroanatomical changes in individuals with chronic psychotic disorders remains ambiguous. More studies and case reports will be needed to establish the veritable association of CSP and neuropsychiatric disorders in the future, and perhaps to acknowledge the CSP as an early marker and predictor of psychosis.Disclosure of InterestNone Declared

Assessment of Cognitive Abilities and Impact of Parental Intellectual Level in ASD Children

Autism, now called Autism Spectrum Disorder (ASD), includes children with autism, but also those with Asperger's Syndrome and those with Pervasive Developmental Disorder Not Otherwise Specified.&#x0D; In order to learn more about the subject, we were interested in a population of 30 children with ASD aged 10±5 years from the region of Annaba, Algeria, accommodated as half-boarders at the Centre Médico-Pédagogique pour Enfants Handicapés Mentaux. These children are divided by the psychologist of the center into 4 groups according to their degree of impairment (from mild to severe). To classify them, several criteria had to be considered such as the child's comprehension, independence and responsiveness.&#x0D; The study consists of assessing their cognitive abilities on a daily basis and over a period of 20 days. On the other hand, to collect testimonies from parents and the role they can play to help with these neurodevelopmental anomalies.&#x0D; The results reveal impairments in the ability to establish social interactions and to communicate, as well as cognitive abnormalities, in particular reluctance to change and tendencies to repeat behaviour or speech. Some of them, often isolated in their inner world, show particular sensory reactions (auditory, visual, skin...). We also note that the parents' level of education has a strong impact on their position regarding this disorder. That is, the higher it is, the more likely they are to accept their different children.&#x0D; These advances suggest that, for the coming years, ASD in Algeria should occupy a special place in public health policy. It is therefore time to sound the alarm and invest in multidisciplinary research to understand more about its mechanisms but above all to improve its management.

Brain developmental trajectories associated with childhood stuttering persistence and recovery

Stuttering is a neurodevelopmental disorder affecting 5–8 % of preschool-age children, continuing into adulthood in 1 % of the population. The neural mechanisms underlying persistence and recovery from stuttering remain unclear and little information exists on neurodevelopmental anomalies in children who stutter (CWS) during preschool age, when stuttering symptoms typically first emerge. Here we present findings from the largest longitudinal study of childhood stuttering to date, comparing children with persistent stuttering (pCWS) and those who later recovered from stuttering (rCWS) with age-matched fluent peers, to examine the developmental trajectories of both gray matter volume (GMV) and white matter volume (WMV) using voxel-based morphometry. A total of 470 MRI scans were analyzed from 95 CWS (72 pCWS and 23 rCWS) and 95 fluent peers between 3 and 12 years of age. We examined overall group and group by age interactions in GMV and WMV in preschool age (3–5 years old) and school age (6–12 years old) CWS and controls, controlling for sex, IQ, intracranial volume, and socioeconomic status. The results provide broad support for a possible basal ganglia-thalamocortical (BGTC) network deficit starting in the earliest phases of the disorder and point to normalization or compensation of earlier occurring structural changes associated with stuttering recovery.

De novo KCNA6 variants with attenuated KV 1.6 channel deactivation in patients with epilepsy.

Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies. Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage clamp. We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore-lining S6 α-helix of KV 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type KV 1.6 or KV 1.1 subunits. This is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Gross anatomical features of the insular cortex in schizophrenia and schizotypal personality disorder: Potential relationships with vulnerability, illness stages, and clinical subtypes.

Patients with schizophrenia have a higher number of insular gyri; however, it currently remains unclear whether the brain characteristics of patients with schizotypal personality disorder (SPD), a mild form of schizophrenia, are similar. It is also unknown whether insular gross anatomical features are associated with the illness stages and clinical subtypes of schizophrenia. This magnetic resonance imaging study examined gross anatomical variations in the insular cortex of 133 patients with schizophrenia, 47 with SPD, and 88 healthy controls. The relationships between the insular gross anatomy and schizophrenia subgroups (71 first-episode and 58 chronic groups, 38 deficit and 37 non-deficit subtype groups) were also investigated. The number of insular gyri was higher in the schizophrenia and SPD patients than in the controls, where the patients were characterized by well-developed accessory, middle short, and posterior long insular gyri. The insular gross anatomy did not significantly differ between the first-episode and chronic schizophrenia subgroups; however, the relationship between the developed accessory gyrus and more severe positive symptoms was specific to the first-episode group. The prevalence of a right middle short gyrus was higher in the deficit schizophrenia group than in the non-deficit group. These findings suggest that schizophrenia and SPD patients may share an altered insular gross morphology as a vulnerability factor associated with early neurodevelopmental anomalies, which may also contribute to positive symptomatology in the early illness stages and clinical subtypes of schizophrenia.

An X-linked PLXNB3 mutation identified in patients with congenital heart disease with neurodevelopmental disabilities.

Congenital heart disease (CHD) is the most common birth defect and is often accompanied by neurodevelopmental disabilities (NDD) which increase the associated mortality. Plexin families are known to play a key role in the development of heart and the occurrence of neurodevelopmental anomalies. However, there has been no report of PLXNB3 mutation in isolated CHD or CHD with concomitant NDD. We performed whole-exome sequencing (WES) on a proband with CHD with neurodevelopmental anomalies and his family members. Targeted sequencing, conservation analysis, AlphaFold, and PyRosetta were performed to identify more pathogenic mutations of PLXNB3. Scratch wound assay, Ki-67 assessment by flow cytometry, and gene expression analysis of heart development related pathway by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were conducted after 24 h transfection in AC16 and HEK293T to investigate the effect of the target mutation. We identified a pathogenic mutation in the X-linked PLXNB3 gene (c.A4319T p.E1440V). In addition, we found 4 other pathogenic mutations in a cohort of 75 patients with sporadic CHD with NDD. AlphaFold and PyRosetta predicted that these 4 mutations could cause dramatic changes of the PLXNB3 protein structure (root-mean-square deviation score >10 Å). Further functional analysis revealed that this p.E1440V variant inhibits cell migration and proliferation, and affects the activity of key factors in the Notch signaling pathway, myocardial contraction pathway, and neurodevelopmental pathways. These findings suggest that PLXNB3 and the p.E1440V variant may be related to the pathogenesis of CHD associated with NDD.

CYST OF SEPTUM PELLUCIDUM IN MENTAL DISORDERS: SCHIZOPHRENIA AND MENTAL RETARDATION: TWO CASEREPORTS

A septum pellucidum cyst is defined as a fluid collection between the lateral ventricles whose walls have a lateral curvature and are separated by 10 mm or more . Most of these cysts are benign and their clinical significance should be considered as a neurodevelopmental anomaly that may contribute to neuropsychiatric abnormalities . It is often of incidental finding, of little clinical significance. However, an association between this developmental anomaly and a mental disorder, such as schizophrenia and/or intellectual disability, has been reported. We report in this study two clinical cases, diagnosed with schizophrenia comorbid with intellectual disability and in whom brain imaging has objectified a cyst of the septum pellucidum. The objective of this study is to discuss the relationship between the septum pellucidum cyst and mental disorders, especially schizophrenia and intellectual disability.

Commentary: Against the widespread use of other types of PD diagnosis - a commentary on the May 2022 debate (should CAMH professionals be diagnosing personality disorder in adolescence?).

Recent debate papers in Child and Adolescent Mental Health (Debate CAMH, May 2022) advocate a more widespread and appropriate use by CAMH clinicians of borderline personality disorder diagnoses. This paper makes the case against the widespread use of other types of PD diagnosis in children and young people. Nevertheless, it would be of interest to establish to what extent adult PDs have their roots in early neurodevelopmental anomalies, and ascertainment of personality traits can help clarify children's response to environmental or traumatic stresses in those presenting with problems such as at the interface between physical and mental health.

Different maturation patterns for sensorimotor gating and startle habituation deficits in male and female RHA vs RLA rats

Neurodevelopmental anomalies are thought to play a crucial role in the emergence of schizophrenia. The Roman high-avoidance (RHA) rats exhibit impaired prepulse inhibition (PPI), as well as other behavioral and cognitive singularities related to schizophrenia syndromes compared to the Roman low-avoidance (RLA) rats. In the present study, we aimed at elucidating whether PPI deficits in the RHA rats take place during prepubescence, adolescence, or adulthood. Thus, we evaluated the levels of PPI of both strains and both sexes during these three developmental phases. Additionally, we also investigated the onset of startle habituation deficits in the same groups. The results showed that male RHA rats exhibit a clear-cut PPI reduction compared to their RLA counterparts in adulthood. In female RHA rats, we observed lower levels of PPI since adolescence and through adulthood. We also found no differences between PPI percentages among the three ages in RHA male rats. Contrarily, in male RLA rats, PPI levels were increased in adults compared to their adolescent and prepubescent counterparts. Finally, a deficit in startle habituation was observed in adulthood of both male and female RHA rats, although in the latter case the disturbance in startle habituation was more profound. These results further the description of the maturational trajectory of cognitive markers relevant to schizophrenia prodrome and they add face validity to the RHA rats as a model of schizophrenia-relevant phenotypes.