Neurodevelopmental Disorders Research Articles

Progressive Myoclonus Epilepsy and Beyond: Systematic Review of SEMA6B-Related Disorders.

Progressive myoclonus epilepsy (PME) is a rare, clinically and genetically heterogeneous epilepsy syndrome, and pathogenic variants in the SEMA6B gene have recently been reported to be among the causes of PME. Cases with pathogenic variants in the SEMA6B gene are extremely rare, only a limited number of cases have been reported in the literature. In this systematic review, we aimed to present a summary of a PME case in which a heterozygous nonsense variant of c.2086C>T p.(Gln696*) in the SEMA6B gene was detected in the etiology and other cases with SEMA6B pathogenic variant in the literature. Except our case, 35 cases from 12 studies were included. The main clinical findings of this patients were cognitive problems, seizures, gait and speech disturbances, and cognitive and/or motor regression, and they had a wide spectrum of severity. Response to antiseizure medications was also highly variable, almost half of the patients had pharmacoresistant seizures. Patients were divided into four different phenotypic groups according to their clinical presentations: PME (18/36), developmental and epileptic encephalopathy (DEE) (13/36), neurodevelopmental disorder (NDD) (4/36), and epilepsy (1/36), respectively. In conclusion, although SEMA6B has been associated with PME, it may actually cause a much broader phenotypic spectrum. Due to their extreme rarity, our knowledge of SEMA6B-related disorders is limited. As with all other rare diseases, each new SEMA6B-related disorder case of could contribute to a better understanding of the disease. And a better understanding of the disease may allow the development of specific treatment options in the future.

Primary cilia shape postnatal astrocyte development through Sonic Hedgehog signaling.

Primary cilia function as specialized signaling centers that regulate many cellular processes including neuron and glia development. Astrocytes possess cilia, but the function of cilia in astrocyte development remains largely unexplored. Critically, dysfunction of either astrocytes or cilia contributes to molecular changes observed in neurodevelopmental disorders. Here, we show that a sub-population of developing astrocytes in the prefrontal cortex are ciliated. This population corresponds to proliferating astrocytes and largely expresses the ciliary protein ARL13B. Genetic ablation of astrocyte cilia in vivo at two distinct stages of astrocyte development results in changes to Sonic Hedgehog (Shh) transcriptional targets. We show that Shh activity is decreased in immature and mature astrocytes upon loss of cilia. Furthermore, loss of cilia in immature astrocytes results in decreased astrocyte proliferation and loss of cilia in mature astrocytes causes enlarged astrocyte morphology. Together, these results indicate that astrocytes require cilia for Shh signaling throughout development and uncover functions for astrocyte cilia in regulating astrocyte proliferation and maturation. This expands our fundamental knowledge of astrocyte development and cilia function to advance our understanding of neurodevelopmental disorders.

Multiclass classification of Autism Spectrum Disorder, attention deficit hyperactivity disorder, and typically developed individuals using fMRI functional connectivity analysis.

Neurodevelopmental conditions, such as Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), present unique challenges due to overlapping symptoms, making an accurate diagnosis and targeted intervention difficult. Our study employs advanced machine learning techniques to analyze functional magnetic resonance imaging (fMRI) data from individuals with ASD, ADHD, and typically developed (TD) controls, totaling 120 subjects in the study. Leveraging multiclass classification (ML) algorithms, we achieve superior accuracy in distinguishing between ASD, ADHD, and TD groups, surpassing existing benchmarks with an area under the ROC curve near 98%. Our analysis reveals distinct neural signatures associated with ASD and ADHD: individuals with ADHD exhibit altered connectivity patterns of regions involved in attention and impulse control, whereas those with ASD show disruptions in brain regions critical for social and cognitive functions. The observed connectivity patterns, on which the ML classification rests, agree with established diagnostic approaches based on clinical symptoms. Furthermore, complex network analyses highlight differences in brain network integration and segregation among the three groups. Our findings pave the way for refined, ML-enhanced diagnostics in accordance with established practices, offering a promising avenue for developing trustworthy clinical decision-support systems.

Language Profiles of School-Age Children With 16p11.2 Copy Number Variants in a Clinically Ascertained Cohort.

Individuals with proximal 16p11.2 copy number variants (CNVs), either deletions (16p11.2DS) or duplications (16p11.2Dup), are predisposed to neurodevelopmental difficulties and disorders, such as language disorders, intellectual disability, and autism spectrum disorder. The purpose of the current study was to characterize language profiles of school-age children with proximal 16p11.2 CNVs, in relation to the normative sample and unaffected siblings of children with 16p11.2DS. Standardized language tests were conducted in 33 school-age children with BP4-BP5 16p11.2 CNVs and eight unaffected siblings of children with 16p11.2DS to evaluate language production and comprehension skills across various language domains. A standardized intelligence test was also administered, and parents completed a standardized questionnaire to assess autistic traits. Language profiles were compared across 16p11.2 CNVs and intrafamilial pairs. The influence of nonverbal intelligence and autistic traits on language outcomes was investigated. No significant differences were found between children with 16p11.2DS and those with 16p11.2Dup, although both groups exhibited significantly poorer language skills compared to the normative sample and unaffected siblings of children with 16p11.2DS. Severe language deficits were identified in 70% of individuals with 16p11.2 CNVs across all language subdomains, with significantly better receptive vocabulary skills than overall receptive language abilities. In children with 16p11.2DS, expressive language deficits were more pronounced than receptive deficits. In contrast, only in children with 16p11.2Dup did nonverbal intelligence influence their language outcomes. The current study contributes to the deeper understanding of language profiles in 16p11.2 CNVs in a clinically ascertained cohort, indicating generalized deficits across multiple language domains, rather than a syndrome-specific pattern targeting specific subdomains. The findings underscore the importance of early diagnosis, targeted therapy, and monitoring of language skills in children with 16p11.2 CNVs. https://doi.org/10.23641/asha.27228702.

Embryonic 6:2 Fluorotelomer Alcohol Exposure Disrupts the Blood‒Brain Barrier by Causing Endothelial‒to‒Mesenchymal Transition in the Male Mice.

6:2 Fluorotelomer alcohol (6:2 FTOH) is a raw material used in the manufacture of short-chain poly- and perfluoroalkyl substances. Our previous study revealed that gestational exposure to 6:2 FTOH can impair blood‒brain barrier (BBB) function in offspring, accompanied by anxiety-like behavior and learning memory deficits. The aim of this study was to further investigate the specific mechanism by which maternal exposure to 6:2 FTOH resulted in impaired BBB function in offspring mice. Pregnant mice were orally administered different doses of 6:2 FTOH (0, 5, 25, and 125mg/kg/day) from gestation day 8.5 until delivery. These results confirmed that maternal 6:2 FTOH exposure impaired BBB function and disrupted the brain immune microenvironment. Subsequent investigations revealed that endothelial-to-mesenchymal transition (EndMT) in the cerebral microvascular endothelium of offspring may be the mechanism mediating functional disruption of the BBB. Mechanistic studies revealed that exposure to 6:2 FTOH upregulated ETS proto-oncogene 1 (ETS1) expression via the tumor necrosis factor-α/extracellular signal-regulated kinase 1/2 signaling pathway, which mediated disturbances in energy metabolism, leading to impaired actin dynamics and subsequently triggering the EndMT phenotype. This is the first finding indicating that gestational 6:2 FTOH exposure caused functional impairment of the BBB through ETS1-mediated EndMT in cerebral microvascular endothelial cells, potentially providing novel insight into the environmental origins of neurodevelopmental disorders.

Unraveling the relative abundance of psychobiotic bacteria in children with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits. Accumulated evidence has shown a link between alterations in the composition of gut microbiota and both neurobehavioural and gastrointestinal symptoms in children with ASD which are related to the genera Lactobacillus and Bifidobacterium. These genera have been recently categorized as “psychobiotics”. Moreover, this study aimed to compare the relative abundance of psychobiotics (L. plantarum, L. reuteri, and B. longum) to the total gut microbiome in typically developing (TD) children and those with ASD in order to correlate the distribution of psychobiotic with the severity and sensory impairments in autism. The ASD children were assessed using the Childhood Autism Rating Scale (CARS), while sensory impairments were evaluated using the Short Sensory Profile (SSP). Furthermore, the gut microbiome was analyzed using the quantitative real-time PCR. The study revealed a statistically significant increase in the relative abundance of L. reuteri and L. plantarum in the TD group in comparison to ASD children. Regarding the SSP total score of ASD children, a statistically significant negative correlation was found between both Lactobacillus and L. plantarum with the under-responsive subscale. For the Autism Treatment Evaluation Checklist (ATEC) score, B. longum and Lactobacillus showed a significant positive correlation with Health/Physical/Behaviour.

Most babies born at a French hospital before 26 weeks survived with good outcomes.

The aim of this French study was to determine the neonatal morbidity, mortality and neurodevelopmental outcomes when infants born at the limit of viability reached 2 years of corrected age. We then compared the results with national and international cohorts. This study focused on 294 French infants born from 22 to 25 weeks of gestation in a single tertiary perinatal centre from January 2010 to December 2019. We used data on neonatal mortality and morbidity to calculate the survival rates of infants without moderate to severe neurodevelopmental and sensory deficits at 2 years of corrected age. These outcomes were compared with data from contemporary epidemiological studies of similar populations. Nearly two-thirds (60.5%) of the infants survived to discharge, with varying rates based on their gestational ages, and 57.3% had no severe neonatal morbidity. The vast majority (90.4%) of the 166 alive and available at 2 years of corrected age were free of moderate to severe neurodevelopmental impairment. Our survival rates exceeded a national French cohort study, but were closely aligned with international cohorts. These findings highlight the importance of incorporating local data into ethical decision-making about life-saving treatment for infants at the limit of viability.

Transcriptomic analysis of rat prefrontal cortex following chronic stress induced by social isolation – Relevance to psychiatric and neurodevelopmental illness, and implications for treatment

Social isolation is an established risk factor for psychiatric illness, and became increasingly topical with the spread of SARS-CoV-2. We used RNA sequencing (RNA-Seq) to enable unbiased assessment of transcriptomic changes within the prefrontal cortex (PFC) of isolation-reared rats. To provide insight into the relevance of this manipulation for studying human illness, we compared differentially expressed genes (DEGs) and enriched biological functions against datasets involving post-mortem frontal cortical tissue from patients with psychiatric and neurodevelopmental illnesses. Sixteen male Sprague-Dawley rats were reared in groups of four or individually from weaning on postnatal day (PND) 22–24 until PFC tissue collection for RNA-Seq (PND64-66). We identified a total of 183 DEGs in isolates, of which 128 mirrored those in PFC tissue from patients with stress-related mental illnesses and/or neurodevelopmental conditions featuring social deficits. Seventy-one encode proteins classed as druggable by the gene-drug interaction database. Interestingly there are antagonists or inhibitors for the products of three of these up-regulated DEGs (Hrh3, Snca and Sod1) and agonists or activators for products of six of these down-regulated DEGs (Chrm4, Klf2, Lrrk2, Nr4a1, Nr4a3 and Prkca). Some have already undergone pre-clinical and clinical evaluation, and studies with the remainder may be warranted. Changes to Hrh3, Sod1, Chrm4, Lrrk2, Nr4a1 and Prkca were replicated in an independent cohort of sixteen male Sprague-Dawley rats via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings support the continued use of post-weaning isolation rearing to investigate the neurobiology of stress-related disorders and evaluate therapeutic targets.

Subclinical rhythmic EEG discharge of adults (SREDA) in pediatric population: A case series with systematic review of the literature.

Subclinical rhythmic electrographic discharge of adults (SREDA) is one of the rarest and most challenging non-epileptic electroencephalographic variants. Although the pathogenesis of this activity is unclear, an association with vascular insufficiency and cerebral hypoxia has been proposed. SREDA usually occurs in adulthood, but there are few reports in the pediatric population. We performed a systematic review of the literature, confirming the rarity of this condition in children, and added 5 more subjects. We report on a total of 16 children with SREDA. Sufficient data are available for 15 patients. The mean age at first detection of SREDA was 11.5 years. We observed that 67% (10/15) of the subjects had previous seizures: 80% (8/10) of them had an epilepsy diagnosis and 38% (3/8) had generalized epilepsy. Moreover, 8 of 13 subjects whose medical history was available (61%) had a neurodevelopmental disorder. From an electroencephalographic point of view, we noted a prevalence of bilateral SREDA with atypical localization and abrupt onset and end. Since SREDA can be incorrectly interpreted as an epileptic discharge, with possible therapeutic implications, it is important to consider its possible occurrence also in pediatric patients, perhaps more frequently in those with neurodevelopmental disorders.

The Need for Speed; Investigating Channelopathy-Associated Epilepsy Using High Throughput Electrophysiological Approaches

Pathogenic variants in genes encoding ion channels are frequently discovered in monogenic disorders associated with epilepsy and neurodevelopmental disorders. This review covers advances in the use of automated patch clamp recording for determining the functional consequences of epilepsy-associated ion channel variants and the use of induced pluripotent stem cell (iPSC) derived neurons for in-depth investigations of the physiological consequences of such variants. The combination of these advanced technologies was a focus of the recently completed NINDS-funded Channelopathy-associated Epilepsy Research Center without Walls.

Patterns of Brain Maturation in Autism and Their Molecular Associations

In the neurotypical brain, regions develop in coordinated patterns, providing a fundamental scaffold for brain function and behavior. Whether altered patterns contribute to clinical profiles in neurodevelopmental conditions, including autism, remains unclear. To examine if, in autism, brain regions develop differently in relation to each other and how these differences are associated with molecular/genomic mechanisms and symptomatology. This study was an analysis of one the largest deep-phenotyped, case-control, longitudinal (2 assessments separated by approximately 12-24 months) structural magnetic resonance imaging and cognitive-behavioral autism datasets (EU-AIMS Longitudinal European Autism Project [LEAP]; study dates, February 2014-November 2017) and an out-of-sample validation in the Brain Development Imaging Study (BrainMapASD) independent cohort. Analyses were performed during the 2022 to 2023 period. This multicenter study included autistic and neurotypical children, adolescents, and adults. Autistic participants were included if they had an existing autism diagnosis (DSM-IV/International Statistical Classification of Diseases and Related Health Problems, Tenth Revision or DSM-5 criteria). Autistic participants with co-occurring psychiatric conditions (except psychosis/bipolar disorder) and those taking regular medications were included. Neuroanatomy of neurotypical and autistic participants. Intraindividual changes in surface area and cortical thickness over time, analyzed via surface-based morphometrics. A total of 386 individuals in the LEAP cohort (6-31 years at first visit; 214 autistic individuals, mean [SD] age, 17.3 [5.4] years; 154 male [72.0%] and 172 neurotypical individuals, mean [SD] age, 16.35 [5.7] years; 108 male [62.8%]) and 146 individuals in the BrainMapASD cohort (11-18 years at first visit; 49 autistic individuals, mean [SD] age, 14.31 [2.4] years; 42 male [85.7%] and 97 neurotypical individuals, mean [SD] age, 14.10 [2.5] years; 58 male [59.8%]). Maturational between-group differences in cortical thickness and surface area were established that were mostly driven by sensorimotor regions (eg, across features, absolute loadings for early visual cortex ranged from 0.07 to 0.11, whereas absolute loadings for dorsolateral prefrontal cortex ranged from 0.005 to 0.06). Neurodevelopmental differences were transcriptomically enriched for genes expressed in several cell types and during various neurodevelopmental stages, and autism candidate genes (eg, downregulated genes in autism, including those regulating synaptic transmission; enrichment odds ratio =3.7; P =2.6 × -10). A more neurotypical, less autismlike maturational profile was associated with fewer social difficulties and more typical sensory processing (false discovery rate P <.05; Pearson r ≥0.17). Results were replicated in the independently collected BrainMapASD cohort. Results of this case-control study suggest that the coordinated development of brain regions was altered in autism, involved a complex interplay of temporally sensitive molecular mechanisms, and may be associated with both lower-order (eg, sensory) and higher-order (eg, social) clinical features of autism. Thus, examining maturational patterns may provide an analytic framework to study the neurobiological origins of clinical profiles in neurodevelopmental/mental health conditions.

The clinical and genetic spectrum of paediatric speech and language disorders.

Speech and language disorders are known to have a substantial genetic contribution. Although frequently examined as components of other conditions, research on the genetic basis of linguistic differences as separate phenotypic subgroups has been limited so far. Here, we performed an in-depth characterization of speech and language disorders in 52 143 individuals, reconstructing clinical histories using a large-scale data-mining approach of the electronic medical records from an entire large paediatric healthcare network. The reported frequency of these disorders was the highest between 2 and 5 years old and spanned a spectrum of 26 broad speech and language diagnoses. We used natural language processing to assess the degree to which clinical diagnoses in full-text notes were reflected in ICD-10 diagnosis codes. We found that aphasia and speech apraxia could be retrieved easily through ICD-10 diagnosis codes, whereas stuttering as a speech phenotype was coded in only 12% of individuals through appropriate ICD-10 codes. We found significant comorbidity of speech and language disorders in neurodevelopmental conditions (30.31%) and, to a lesser degree, with epilepsies (6.07%) and movement disorders (2.05%). The most common genetic disorders retrievable in our analysis of electronic medical records were STXBP1 (n = 21), PTEN (n = 20) and CACNA1A (n = 18). When assessing associations of genetic diagnoses with specific linguistic phenotypes, we observed associations of STXBP1 and aphasia (P = 8.57 × 10-7, 95% confidence interval = 18.62-130.39) and MYO7A with speech and language development delay attributable to hearing loss (P = 1.24 × 10-5, 95% confidence interval = 17.46-infinity). Finally, in a sub-cohort of 726 individuals with whole-exome sequencing data, we identified an enrichment of rare variants in neuronal receptor pathways, in addition to associations of UQCRC1 and KIF17 with expressive aphasia, MROH8 and BCHE with poor speech, and USP37, SLC22A9 and UMODL1 with aphasia. In summary, our study outlines the landscape of paediatric speech and language disorders, confirming the phenotypic complexity of linguistic traits and novel genotype-phenotype associations. Subgroups of paediatric speech and language disorders differ significantly with respect to the composition of monogenic aetiologies.

Efficacy of Nonpharmacological Treatment in Children and Adolescent with Tic Disorder: A Systematic Review

Tic disorders (TDs) are neurodevelopmental conditions which affect 0.3–0.9% of individuals aged &lt; 18 years. Although tics often improve or resolve spontaneously over time, treatment is often recommended. Pharmacological approaches are widely used as primary interventions. However, their side effects encouraged the development and the interest in nonpharmacological approaches, whose efficacy in pediatric populations remains poorly understood. This systematic review aimed to evaluate the efficacy of nonpharmacological treatments for children and adolescents with TDs. A literature review was performed using PubMed, EBSCOhost, and JABA databases up to 16 May 2024. Eligible articles were randomized controlled trials, written in English and published in peer-reviewed journals, investigating the efficacy of nonpharmacological treatments in pediatric populations diagnosed with TDs. Significant evidence supported the efficacy of behavioral interventions such as the Comprehensive Behavioral Intervention for Tics (CBIT), its reduced version the Habit Reversal Therapy (HRT), and the Exposure and Relapse Prevention (ERP) in reducing tics and tic-related impairment among young people, as assessed through the Yale Global Tic Severity Scale. Behavioral interventions were generally effective in reducing tics, although some studies reported higher effects on motor tics when compared to vocal tics. High level of efficacy was observed for both face-to-face and online treatments. While future studies are needed to improve treatment effects, especially on vocal tics, as well as to have a better understanding of treatment components and modalities, taken together, the present findings support the use of nonpharmacological intervention for TDs in youth.

ZMYND11 Functions in Bimodal Regulation of Latent Genes and Brain-like Splicing to Safeguard Corticogenesis.

Despite the litany of pathogenic variants linked to neurodevelopmental disorders (NDD) including autism (ASD) and intellectual disability 1,2 , our understanding of the underlying mechanisms caused by risk genes remain unclear. Here, we leveraged a human pluripotent stem cell model to uncover the neurodevelopmental consequences of mutations in ZMYND11 , a newly implicated risk gene 3,4 . ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor 5,6 . Our findings reveal that ZMYND11-deficient cortical neural stem cells showed upregulation of latent developmental pathways, impairing progenitor and neuron production. In addition to its role on histones, ZMYND11 controls a brain-specific isoform switch involving the splicing regulator RBFOX2. Extending our findings to other chromatin-related ASD risk factors revealed similar developmental pathway activation and splicing dysregulation, partially rescuable through ZMYND11's regulatory functions.

RettDb: the Rett syndrome omics database to navigate the Rett syndrome genomic landscape.

Rett syndrome (RTT) is a neurodevelopmental disorder occurring almost exclusively in females and leading to a variety of impairments and disabilities from mild to severe. In >95% cases, RTT is due to mutations in the X-linked gene MECP2, but the molecular mechanisms determining RTT are unknown at present, and the complexity of the system is challenging. To facilitate and provide guidance to the unraveling of those mechanisms, we developed a database resource for the visualization and analysis of the genomic landscape in the context of wild-type or mutated Mecp2 gene in the mouse model. Our resource allows for the exploration of differential dynamics of gene expression and the prediction of new potential MECP2 target genes to decipher the RTT disorder molecular mechanisms. Database URL: https://biomedinfo.di.unipi.it/rett-database/.

Maternal e-cigarette exposure alters DNA methylome, site-specific CpG and CH methylation, and transcriptomic signatures in the neonatal brain

Maternal use of e-cigarette (e-cig) aerosols poses significant risks to fetal brain development, potentially increasing susceptibility to neurodevelopmental disorders in later life. However, the underlying mechanisms remain incompletely understood. This study aimed to understand the effects of fetal e-cig exposure on DNA methylome and transcriptomic changes in the neonatal brain. Pregnant rats were exposed to e-cig aerosols, and neonatal brains (5 males and 5 females/group) from both control and e-cig-exposed groups were used for experimental analysis. Results indicated that prenatal e-cig exposure altered site-specific DNA methylation patterns at both CpG and CH (non-CpG) sites, predominantly in intergenic and intronic regions, with sex dimorphism in methylation and gene expression changes. Gene ontology analysis revealed that e-cig exposure not only affected neuron projection development and axonogenesis but also altered pathways related to neurodegeneration and long-term depression. These findings provide novel insights into the dynamic changes of CpG and CH methylation induced by e-cig exposure, underscoring the susceptibility of the developing brain to maternal e-cig exposure and its potential implications for developmental disorders and neurodegenerative diseases later in life.

Postnatal dysregulation of androgens in extremely preterm male infants

Abstract Context Neurodevelopmental impairments are common among survivors of extremely preterm birth, particularly in males. Hyperactivation of the hypothalamic-pituitary-gonadal (HPG) axis has been suggested as an underlying cause, but this has been poorly investigated. Objective Establish levels and temporal changes in circulating androgens in extremely preterm infant males. Design and Participants Observational cohort study analyzing cord blood serum (n=25) and postnatal plasma (n=13) collected from day 0 until week 11 from infant males born at 22.8-27.9 weeks gestational age. Main outcome measures Testosterone and dihydrotestosterone (DHT) were determined using gas-chromatography mass-spectrometry, sex hormone-binding globulin (SHBG) with ELISA, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) with Luminex xMAP multiplex assay. Results Testosterone and DHT levels were higher on day 0 (median 4.27 and 0.30 ng/ml) than in cord blood (0.15 and 0.01 ng/ml), p&amp;lt;0.001 for both. Levels of the hormones then declined rapidly until day 5 (median 0.16 and 0.12 ng/ml), then remained relatively constant throughout the study period. Median levels of testosterone and DHT across the whole study period were approximately 6-fold higher compared to reported in utero levels. FSH and LH showed similar postnatal patterns as the androgens. SHBG steadily increased over time, and as a result, the fraction of bioavailable testosterone declined with infant postnatal age. Conclusions The HPG axis is activated immediately after birth in extremely preterm infant males resulting in an androgen pulse occurring several months earlier than during a normal pregnancy. The long-term implications of high androgen exposure during a sensitive neurodevelopmental period warrant further studies.

Neuroradiologic, clinic and genetic characterization of cerebellar heterotopia: a pediatric multicentric study.

Background and purpose:Cerebellar heterotopia (CH) is a neuroradiological abnormality poorly reported and investigated in the literature. It can be observed as an isolated finding, but it has been mainly reported in the context of cerebellar dysgenesis and in syndromic conditions. The aim of this study is to provide a comprehensive neuroradiological, clinical, and genetic characterization of a cohort of pediatric patients with cerebellar heterotopia.Materials and methods:Patients with a diagnosis of CH were systematically selected from the neuroimaging databases of the four Italian Centers participating in this retrospective study. For each patient, information regarding demographic, clinical, genetic and neuroradiological data were collected.Results:Thirty-two pediatric patients were recruited and subdivided into two groups: patients with isolated CH and/or cerebellar malformations (n= 18) and patients with CH associated with cerebral malformations (n=14). Isolated CH consistently showed a peripheral subcortical localization in the inferior portion of cerebellar hemispheres, with either unilateral or bilateral distribution. Ten patients belonging to the second group had a diagnosis of CHARGE syndrome, and their nodules of CH were mainly but not exclusively bilateral, symmetric, located in the peripheral subcortical zone and in the inferior portion of the cerebellar hemispheres; the remaining 4 patients of the second group, showed either bilateral or unilateral CH, located in both peripheral cortex and deep white matter and in the superior and inferior portions of cerebellum. Patients with isolated CH showed high prevalence of language development delay; neurodevelopmental disorders were the most represented clinical diagnoses. Recurring features were behavioral problems and motor difficulties. A conclusive genetic diagnosis was found in 18/32 patients.Conclusions:We found distinctive neuroradiological patterns of CH. Genetic results raise the possibility of a correlation between cerebellar morphological and functional developmental disruption, underscoring the importance of CH detection and reporting to orient the diagnostic path.Abbreviations CH Cerebellar heterotopia; MRI Magnetic resonance imaging; CC Corpus callosum; ASD autism spectrum disorder; IVH inferior vermian hypoplasia.

Expanded phenotypic spectrum in MODY 5 patients with 17q12 deletion syndrome: experience from an Indian tertiary care hospital.

To study the clinical and genotypic spectrum of patients with HNF-1ß deletions (MODY 5) at a tertiary care hospital. This study included four patients from the Department of Endocrinology at Sher-i-Kashmir Institute of Medical Sciences Srinagar with a strong clinical suspicion of MODY 5. Genetic analysis, including a monogenic gene panel comprising 78 genes associated with MODY and other similar forms of monogenic diabetes, was done. Dosage analysis of HNF 1B by Multiplex Ligand-dependent Probe Amplification (MLPA) was performed. The mean age of patients was 22.25 years with a male-to-female ratio of 3:1. Associated phenotypic features included neurodevelopmental disorder in all four patients, insulin resistance in two patients (2/4) and alopecia in three patients (3/4). One patient had clinical and biochemical hyperandrogenism. All patients had renal malformations, and one patient had a Mullerian anomaly. Family history was present in 1 patient. All patients had pancreatic abnormalities, the most common type being dorsal agenesis of the pancreas (3/4), followed by annular pancreas (1/4). All patients had a genetic deletion of the gene HNF1B on chromosome 17 with a deletion interval of (?_37686431)_(37745059_?), (?_37687281)-(37744884_?), comprising exons 1 to 9. It is imperative to maintain a high index of suspicion for MODY 5 in patients presenting with renal anomalies and diabetes, even in the absence of a family history. Early identification allows for screening family members and ensures a comprehensive approach to identifying and managing other abnormalities in these patients.

Professor Alessandro Zuddas' Impact and Legacy: The Influential Networking and Human Connection Skills of a Passionate Scientist, Clinical Academic, and Pioneer in Child and Adolescent Psychopharmacology.

Professor Alessandro Zuddas, from the University of Cagliari (Italy), passed away prematurely in July 2022. As a prominent figure in child and adolescent neuropsychiatry, he substantially influenced the fields of neurodevelopmental disorders and neuropsychopharmacology both nationally and internationally. Professor Zuddas was a renowned expert in basic and clinical research in child and adolescent psychopharmacology, an enlightened and stimulating educator, and a mentor to many students, residents, and senior colleagues. With his enthusiasm and unique ability to network, he contributed enormously to trace a path in the field that we continue to follow. His name will remain in the textbooks and articles he authored. Here, as colleagues and friends who had the honor to work with him, we provide our personal views of Alessandro's impact and legacy, which go far beyond his publications.