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Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

ABSTRACT Malate is an important dicarboxylic acid produced from fumarate in the tricarboxylic acid cycle. Deficiencies of fumarate hydrolase (FH) and malate dehydrogenase (MDH), responsible for malate formation and metabolism, respectively, are known to cause recessive forms of neurodevelopmental disorders (NDDs). The malic enzyme isoforms, malic enzyme 1 (ME1) and 2 (ME2), are required for the conversion of malate to pyruvate. To date, there have been no reports linking deficiency of either malic enzyme isoforms to any Mendelian disease in humans. We report a patient presenting with NDD, subtle dysmorphic features, resolved dilated cardiomyopathy, and mild blood lactate elevation. Whole exome sequencing (WES) revealed a homozygous frameshift variant (c.1379_1380delTT, p.Phe460fs*22) in the malic enzyme 2 (ME2) gene resulting in truncated and unstable ME2 protein in vitro. Subsequent deletion of the yeast ortholog of human ME2 (hME2) resulted in growth arrest, which was rescued by overexpression of hME2, strongly supporting an important role of ME2 in mitochondrial function. Our results also support the pathogenicity and candidacy of the ME2 gene and variant in association with NDD. To our knowledge, this is the first report of a Mendelian human disease resulting from a biallelic variant in the ME encoding gene. Future studies are warranted to confirm ME2‐associated recessive NDD. [ABSTRACT FROM AUTHOR]

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1—a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management. Kleefstra syndrome is a rare neurodevelopmental disorder caused by pathogenic EHMT1 variants affecting multiple organ systems. After almost two decades of research, we describe the current knowledge of EHMT1 variants and their functional consequences, leading to a broad clinical spectrum. Finally, we also obtained important insights into EHMT1 functions. [ABSTRACT FROM AUTHOR]

CTNND2 encodes δ‐catenin, a component of an adherens junction complex, and plays an important role in neuronal structure and function. To date, only heterozygous loss‐of‐function CTNND2 variants have been associated with mild neurodevelopmental delay and behavioral anomalies, a condition, which we named Rauch‐Azzarello syndrome. Here, we report three siblings of a consanguineous family of Syrian descent with a homozygous deletion encompassing the last 19 exons of CTNND2 predicted to disrupt the transcript. All presented with severe neurodevelopmental delay with absent speech, profound motor delay, stereotypic behavior, microcephaly, short stature, muscular hypotonia with lower limb hypertonia, and variable eye anomalies. The parents and the fourth sibling were heterozygous carriers of the deletion and exhibited mild neurodevelopmental impairment resembling that of the previously described heterozygous individuals. The present study unveils a severe manifestation of CTNND2‐associated Rauch‐Azzarello syndrome attributed to biallelic loss‐of‐function aberrations, clinically distinct from the already described mild presentation of heterozygous individuals. Furthermore, we demonstrate novel clinical features in homozygous individuals that have not been reported in heterozygous cases to date. [ABSTRACT FROM AUTHOR]

Background: Neuron navigator 3 (NAV3) is characterized as one of the neuron navigator family (NAV1, NAV2, NAV3) proteins predominantly expressed in the nervous system. The NAV3‐encoded protein comprises a conserved AAA and coiled‐coil domains characteristic of ATPases, which are associated with different cellular activities. Methods: We describe a Saudi proband presenting a complex recessive neurodevelopmental disorder (NDD). Whole exome sequencing (WES) followed by Sanger sequencing, 3D protein modeling and RT‐qPCR was performed. Results: WES revealed a bi‐allelic frameshift variant (c.2604_2605delAG; p.Val870SerfsTer12) in exon 12 of the NAV3 gene. Furthermore, RT‐qPCR revealed a significant decrease in the NAV3 mRNA expression in the patient sample, and 3D protein modeling revealed disruption of the overall secondary structure. Conclusion: For the time, we associate a bi‐allelic variant in the NAV3 gene causing NDD in humans. [ABSTRACT FROM AUTHOR]

Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person's intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD. [ABSTRACT FROM AUTHOR]

Summary: Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

[This corrects the article DOI: 10.3389/fped.2023.1064104.].

IntroductionFragile X syndrome (FXS) is a X-linked neurodevelopmental disorder (NDD). This study aims to investigate the incidence of FXS in Chinese children and analyze the comprehensive clinical characteristics of these FXS children.MethodsChildren diagnosed with idiopathic NDD were recruited between 2016 and 2021 from the department of Child Health Care, Children's Hospital of Fudan University. We combined tetraplet-primed PCR-capillary electrophoresis and whole exome sequencing (WES)/panel or array-based comparative genomic hybridization (array-CGH) to identify the size of the CGG repeats and the mutations or copy number variations (CNVs) in the genome and in FMR1. The clinical features of FXS children were analyzed according to pediatricians' recording, parental questionnaires, the results of examinations and follow-up.ResultsThe incidence of FXS in Chinese children with idiopathic NDD was 2.4% (42/1753) and in those with FXS, 2.38% had a deletion (1/42). Here, we present the clinical characteristics of 36 children with FXS. Overweight was observed in two boys. The average intelligence quotient (IQ)/development quotient (DQ) of all FXS patients was 48. The average ages of meaningful words and walking alone were 2 years and 10 months and 1 year and 7 months, respectively. The most frequent repetitive behavior was stimulated by hyperarousal to sensory stimulation. On social aspects, social withdrawal, social anxiety, and shyness accounted for 75%, 58%, and 56% of the total number of children, respectively. Approximately 60% of FXS children in this cohort were emotionally labile and prone to temper tantrums. Self-injury and aggression toward others could also be observed, at 19% and 28%, respectively. The most frequent behavioral problem was attention-deficit hyperactivity disorder (ADHD) seen in 64% and the most common facial features were a narrow and elongated face and large or prominent ears in 92% of patients.DiscussionScreening of FMR1 full mutation provides the possibility for patients' further medical supports and the clinical features of FXS children obtained in this study will increase the understanding and diagnosis of FXS.

Recently, it has become increasingly clear that there is a bidirectional relationship between sleep/circadian rhythms and neurodegeneration. Knowledge about this topic further improved after the description of the glymphatic system, which is mainly active during sleep. Changes in sleep and circadian rhythms are present not only in overt neurodegenerative diseases but also in their early, prodromal, and preclinical phases, supporting that they precede (and contribute to) the development of neurodegeneration. This narrative review provides a brief overview of sleep and circadian rhythm disruption in neurodegeneration, highlights the bidirectional relationship between sleep changes and neurodegeneration, and addresses future perspectives, in particular, whether sleep changes are able to predict neurodegeneration and the potential sleep actionability to prevent or modulate the development of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Milena Barbosa Porto,1 Geovanna da Mata e Castro,1 Samara Socorro Silva Pereira,2 Elza Maria Gonçalves Santos Uchoa,2 Raffael Zatarin,3 Lysa Bernardes Minasi,1 Aparecido D da Cruz1– 3 1Graduate Program in Genetics, School of Medical and Life Sciences, Pontifical Catholic University of Goiás, Goiânia, GO, Brazil; 2Federal University of Goiás, Graduate Program in Genetics and Molecular Biology, Goiânia, GO, Brazil; 3Clinical Genetics Service, Center for Rehabilitation and Readaptation Dr. Henrique Santillo, State Health Secretary of Goiás, Goiânia, GO, BrazilCorrespondence: Aparecido D da Cruz, Email acruz@pucgoias.edu.brAbstract: Baker-Gordon Syndrome (BAGOS) is a genetically determined 4 (NDD), represented by a phenotypic spectrum of moderate to severe intellectual disability, resulting from mutations in the synaptotagmin 1 (SYT1) gene. Its prevalence is estimated at 1:1,000,000 and the known gene variants have indicated complete penetrance with variable expressivity. SYT1 is a membrane trafficking protein in presynaptic vesicles, which exerts a complex influence on synaptic transmission, with fundamental roles in the release of neurotransmitters and facilitators of endocytosis, impacting both neurotransmission and neuron plasticity. The current case report describes the first Brazilian male patient diagnosed at 17-year-old, and the 39th reported case globally using whole-exome sequencing. A de novo heterozygous missense mutation at chr12q:79448958 (NM_005639.2; c.1103T>C; p.Ile368Thr) in the SYT1 was found and classified as a pathogenic variant. The proband’s clinical phenotype was compatible with BAGOS, involving behavioral changes such as irritability and severe intellectual disability. Knowledge about the mechanism of action and the extent of the genotypic and phenotypic presentations of the mutations in the SYT1 is still unfolding. Thus, we aimed to describe additional genotype–phenotype correlation for BAGOS, contributing to the expansion of the existing knowledge of such a heterogeneous ultra-rare syndrome, and, therefore, improve its diagnostic yield, case management, and therapeutic journey for future patients. Keywords: SYT1, hypotonia, congenital malformations, NDD, WES

Abstract Background Neurodevelopmental disorders (NDDs) are disabilities in brain functioning that cause impairments in cognition, communication, behavior, and sometimes motor skills. The goal of this study was to measure burnout and anxiety among parents of children with neurodevelopmental disorders compared to parents of children with typical development in Saudi Arabia. Results Four hundred twenty-five parents of healthy and parents of children with NDDs, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID), and their parents. Parents of children with NDD had more anxiety and burnout relative to parents of typically developing children, and parents of children with ADHD experienced higher levels of anxiety and depression than parents of children with ASD or ID. Conclusion Parents of children with various neurodevelopmental disorders face a greater degree of psychological distress than parents of typically developing children. Parents of children with NDDs should be provided with interventions and resources to reduce stress and enhance their standard of living.

Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders. [Display omitted] We identified genetic variants of HNRNPC in 13 individuals with intellectual disability and global developmental delay. Through a meta-analysis of multiple cell types, we found that loss of HNRNPC affects alternative splicing, in particular of intellectual disability-associated genes. In vivo assays confirmed that neurodevelopment was affected by aberrant HNRNPC levels. [ABSTRACT FROM AUTHOR]

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A -associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A , a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT- TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5- TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0–24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week–9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A -related autosomal-recessive disease and highlights potential predictors for disease severity and survival. [ABSTRACT FROM AUTHOR]

Background: Neurodevelopmental disorders (NDDs) are disabilities in brain functioning that cause impairments in cognition, communication, behavior, and sometimes motor skills. The goal of this study was to measure burnout and anxiety among parents of children with neurodevelopmental disorders compared to parents of children with typical development in Saudi Arabia. Results: Four hundred twenty-five parents of healthy and parents of children with NDDs, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID), and their parents. Parents of children with NDD had more anxiety and burnout relative to parents of typically developing children, and parents of children with ADHD experienced higher levels of anxiety and depression than parents of children with ASD or ID. Conclusion: Parents of children with various neurodevelopmental disorders face a greater degree of psychological distress than parents of typically developing children. Parents of children with NDDs should be provided with interventions and resources to reduce stress and enhance their standard of living. [ABSTRACT FROM AUTHOR]

Background: Different barriers may hinder children with developmental disabilities (DD) from having a voice in research and clinical interventions concerning fundamentally subjective phenomena, such as participation. It is not well-investigated if video communication tools have the potential to reduce these barriers. Aim: This study investigated the feasibility of administering a self-rating instrument measuring participation, Picture My Participation (PmP), via a video communication tool (Zoom), to children with DD. Materials and methods: PmP was administered to 17 children with DD (mean age 13 years). The pictorial representations of activities and response options in PmP were displayed in a shared PowerPoint presentation, enabling nonverbal responses with the annotate function in Zoom. Child and interviewer perceptions of the interview were measured through questionnaires developed for the purpose. Results: All the children completed the interview. Most PmP questions were answered, and no adverse events were registered. Technical issues could generally be solved. No special training or expensive equipment was needed for the interviews. Conclusion: Interviewer-guided self-ratings of participation and related constructs through video communication may be a feasible procedure to use with children with DD from age 11. Significance: Offering video communication may increase children’s chances to contribute subjective experiences in research and clinical practice. [ABSTRACT FROM AUTHOR]

Recently, it has become increasingly clear that there is a bidirectional relationship between sleep/circadian rhythms and neurodegeneration. Knowledge about this topic further improved after the description of the glymphatic system, which is mainly active during sleep. Changes in sleep and circadian rhythms are present not only in overt neurodegenerative diseases but also in their early, prodromal, and preclinical phases, supporting that they precede (and contribute to) the development of neurodegeneration. This narrative review provides a brief overview of sleep and circadian rhythm disruption in neurodegeneration, highlights the bidirectional relationship between sleep changes and neurodegeneration, and addresses future perspectives, in particular, whether sleep changes are able to predict neurodegeneration and the potential sleep actionability to prevent or modulate the development of neurodegenerative diseases.

BackgroundDifferent barriers may hinder children with developmental disabilities (DD) from having a voice in research and clinical interventions concerning fundamentally subjective phenomena, such as participation. It is not well-investigated if video communication tools have the potential to reduce these barriers.AimThis study investigated the feasibility of administering a self-rating instrument measuring participation, Picture My Participation (PmP), via a video communication tool (Zoom), to children with DD.Materials and methodsPmP was administered to 17 children with DD (mean age 13 years). The pictorial representations of activities and response options in PmP were displayed in a shared PowerPoint presentation, enabling nonverbal responses with the annotate function in Zoom. Child and interviewer perceptions of the interview were measured through questionnaires developed for the purpose.ResultsAll the children completed the interview. Most PmP questions were answered, and no adverse events were registered. Technical issues could generally be solved. No special training or expensive equipment was needed for the interviews.ConclusionInterviewer-guided self-ratings of participation and related constructs through video communication may be a feasible procedure to use with children with DD from age 11.SignificanceOffering video communication may increase children’s chances to contribute subjective experiences in research and clinical practice.

Neurodevelopmental disorders (NDDs) are classified as a group of disorders affecting function and development of the brain and having wide clinical variability. Herein, we describe two affected individuals segregating a recessive NDD. The affected individuals exhibited phenotypes such as global developmental delay (GDD), intellectual disability (ID), microcephaly and speech delay. Whole‐exome sequencing (WES) followed by bidirectional Sanger sequencing techniques identified a homozygous nonsense variant (c.466C > T; p.Gln156*) in the PPFIBP1 gene (NM_003622.4) that segregated with the disease phenotype. Further, to elucidate the effect of the variant on protein structure, 3D protein modelling was performed for the mutant and normal protein that suggested substantial reduction of the mutant protein. Our data support the evidence that PPFIBP1 has a pivotal role in neurodevelopment in humans, and loss‐of‐function variants cause clinically variable neurodevelopmental phenotypes. The present study associated a novel variant in the PPFIBP1 gene that further delineates PPFIBP1‐associated neurodevelopmental disorder. WES revealed a novel homozygous nonsense variant (c.466C > T; p.Gln156*) in the PPFIBP1 gene that segregated perfectly with the disease phenotype and predicted pathogenic referred to various in silico analysis using 3D protein modeling. [ABSTRACT FROM AUTHOR]

Several studies have supported the association between maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of gestation and an increased susceptibility to the development of various psychiatric and neurological disorders, including autism and other neurodevelopmental disorders (NDDs), in the offspring. In the present work, we aimed to provide extensive characterization of the short- and long-term consequences of MIA in the offspring, both at the behavioral and immunological level. To this end, we exposed Wistar rat dams to Lipopolysaccharide and tested the infant, adolescent and adult offspring across several behavioral domains relevant to human psychopathological traits. Furthermore, we also measured plasmatic inflammatory markers both at adolescence and adulthood. Our results support the hypothesis of a deleterious impact of MIA on the neurobehavioral development of the offspring: we found deficits in the communicative, social and cognitive domains, together with stereotypic-like behaviors and an altered inflammatory profile at the systemic level. Although the precise mechanisms underlying the role of neuroinflammatory states in neurodevelopment need to be clarified, this study contributes to a better understanding of the impact of MIA on the risk of developing behavioral deficits and psychiatric illness in the offspring. [ABSTRACT FROM AUTHOR]

Aim: To determine the association of fasting glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) with dyslipidemia in newly diagnosed diabetes (NDD). Method: This collaborative prospective interventional clinical study was carried out by the Biochemistry Department, at the University of Karachi-Pakistan, Baqai Institute of Diabetology and Endocrinology, Karachi-Pakistan and Kansai Electric Power Medical Research Institute, Osaka, Japan. The study duration was from March 2019 to May 2020. Participants were identified on the basis of oral glucose tolerance test (OGTT) results. Of 34 participants, 17 were NDD and 17 were healthy. Demographics and anthropometric details were noted on a predesigned questionnaire. Blood samples were collected at fasting state for plasma glucose, lipid profile, HbA1c, and hormones (GIP and GLP-1). Results: The healthy participants included nine males and eight females, and the NDD participants included ten males and seven females. Mean age was 50.78±2.44 years and BMI was 28.41±0.76 kg/m2. Among healthy participants, both GIP and GLP-1 showed non-significant weak correlation for biochemical parameters. In NDD participants, GIP showed significantly negative moderate correlation with age and non-HDL and positive moderate correlation with LDL only. However, GLP-1 showed significantly positive moderate correlation with total cholesterol (r = 0.564, p = 0.018), LDL (r = 0.498, p = 0.042), HDL (r = 0.50, p = 0.041) and non-HDL (r = 0.503, p = 0.047) in NDD participants. Conclusion: The effect of GIP and GLP-1 measures on dyslipidemia were substantially different among NDD participants in our population. In the NDD group, GLP-1 is significantly moderately associated with dyslipidemia compared to GIP. [ABSTRACT FROM AUTHOR]

Abstract Introduction The current COVID-19 pandemic interferes with family lives across the world, particularly families of children with neurodevelopmental disorders (NDDs) are at a greater risk for being negatively impacted by the pandemic. Together with representatives from this caregiver population the aim was to explore the interference associated with normal family life caused by the COVID-19 pandemic. Method This is a descriptive study using a cross-sectional design. Following a strategic network sampling strategy, a user-developed national survey was completed by a larger sample (N = 1,186) of parents and informal caregivers of children with NDDs. The survey utilized a combination of both closed and open-ended questions, and a logistic regression analysis was carried out to assess the association between family characteristics, characteristics of the child, and COVID-19 related family life interference. Before carrying out the regression an inductive content analysis of the open-ended question on `How has the isolation affected the family´ was carried out to construct the outcome variable. Results The initial analysis indicated that the COVID-19 pandemic induced a shift in everyday family life and a lack of guidance and support related to managing the challenges they were facing. Caregivers who reported that COVID-19 had significantly interfered with their family life, were more likely to report having anxious children, and to have experienced an increased number of conflicts at home. The logistic regression showed that both anxious children and increased conflicts considerably increased the risk for reporting family life interference compared to those that reported no increased conflicts or anxious children. Discussion Considering how the COVID-19 related increased conflicts at home and anxious children threaten the family life of the NDD caregiver population, as an external source of family stress, which might lead to negative impact on their mental and physical well-being, the need for further research in collaboration with user representatives is apparent. Our study suggests that more information should be provided to healthcare providers, social professionals, peers, people with NDDs, and caregivers of people with NDDs about the potential threats that a stressful life event such as the current pandemic can pose to their mental and physical health and their family life.

IntroductionFragile X syndrome (FXS) is a X-linked neurodevelopmental disorder (NDD). This study aims to investigate the incidence of FXS in Chinese children and analyze the comprehensive clinical characteristics of these FXS children.MethodsChildren diagnosed with idiopathic NDD were recruited between 2016 and 2021 from the department of Child Health Care, Children's Hospital of Fudan University. We combined tetraplet-primed PCR-capillary electrophoresis and whole exome sequencing (WES)/panel or array-based comparative genomic hybridization (array-CGH) to identify the size of the CGG repeats and the mutations or copy number variations (CNVs) in the genome and in FMR1. The clinical features of FXS children were analyzed according to pediatricians' recording, parental questionnaires, the results of examinations and follow-up.ResultsThe incidence of FXS in Chinese children with idiopathic NDD was 2.4% (42/1753) and in those with FXS, 2.38% had a deletion (1/42). Here, we present the clinical characteristics of 36 children with FXS. Overweight was observed in two boys. The average intelligence quotient (IQ)/development quotient (DQ) of all FXS patients was 48. The average ages of meaningful words and walking alone were 2 years and 10 months and 1 year and 7 months, respectively. The most frequent repetitive behavior was stimulated by hyperarousal to sensory stimulation. On social aspects, social withdrawal, social anxiety, and shyness accounted for 75%, 58%, and 56% of the total number of children, respectively. Approximately 60% of FXS children in this cohort were emotionally labile and prone to temper tantrums. Self-injury and aggression toward others could also be observed, at 19% and 28%, respectively. The most frequent behavioral problem was attention-deficit hyperactivity disorder (ADHD) seen in 64% and the most common facial features were a narrow and elongated face and large or prominent ears in 92% of patients.DiscussionScreening of FMR1 full mutation provides the possibility for patients' further medical supports and the clinical features of FXS children obtained in this study will increase the understanding and diagnosis of FXS.

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3 , RAB40A , TCEAL4 , TCEAL3 , TCEAL1 , and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving TCEAL1 in seven unrelated families: three hemizygous truncating alleles; one hemizygous missense allele; one heterozygous TCEAL1 full gene deletion; one heterozygous contiguous deletion of TCEAL1 , TCEAL3 , and TCEAL4 ; and one heterozygous frameshift variant allele. Variants were identified through exome or genome sequencing with trio analysis or through chromosomal microarray. Comparison with previously reported Xq22 deletions encompassing TCEAL1 identified a more-defined syndrome consisting of hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features include strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was identified in a male with hypertonia and spasticity without syndromic features. These data provide evidence that TCEAL1 loss of function causes a neurological rare disease trait involving significant neurological impairment with features overlapping the EONDT phenotype in females with the Xq22 deletion. [Display omitted] Applying a gene-first approach and worldwide gene-matching, we identify eight individuals with variants in TCEAL1 , a candidate gene for the early-onset neurological disease trait (EONDT) in females with Xq22.2 deletion. The neurodevelopmental disorder observed overlaps that described in Xq22.2 deletion females, implicating TCEAL1 as the driver gene. [ABSTRACT FROM AUTHOR]

Robotics has made it possible to change and improve many support processes for vulnerable people in different settings. In recent years, its use has been oriented toward supporting therapeutic interventions of neurodevelopmental disorders (NDD), including attention deficit hyperactivity disorder (ADHD). This review of the literature highlights how advances in robotics have evolved in different scenarios of ADHD treatment, its collaboration with other emerging technologies, its results, its limitations, and the research challenges for the future development of robotics in the field of supporting children with ADHD. The authors conducted a literature review based on the location of keywords ‘robotics’ and several NNDs such as ‘ADHD’, ’Autism Spectrum Disorder (ASD)’, ‘cerebral palsy’, and ‘dementia’ in titles, abstracts, and introduction of scientific articles in the Scopus and Web of Science (WoS) database. The reviewed literature was classified according to the type of therapy supported by the robots, the type of robot and the associated technologies. From this analysis, we can solve the research question: Which types of robots have the potential for specific applications in ADHD treatment? Furthermore, this article shows that despite favorable technical results, robotic technologies that support ADHD therapies require significant improvements in terms of scalability, human-machine interaction, and treatment and processing of acquired information to be applied effectively in real-world therapies. The most significant research challenges are proposed to drive research efforts to develop new approaches to enable robotic assistants to participate in ADHD therapies.

WDR45-related neurodevelopmental disorder (NDD) is a clinically-heterogenous congenital disorder of macroautophagy/autophagy. The natural history of this ultra-orphan disease remains incompletely understood, leading to delays in diagnosis and lack of quantifiable outcome measures. In this cross-sectional study, we model quantitative natural history data for WDR45-related NDD using a standardized analysis of 160 published cases, representing the largest cohort to date. The primary outcome of this study was survival. Age at disease onset, diagnostic delay and geographic distribution were quantified as secondary endpoints. Our tertiary aim was to explore and quantify the spectrum of WDR45-related phenotypes. Survival estimations showed low mortality until 39 years of age. Median age at onset was 10 months, with a median diagnostic delay of 6.2 years. Geographic distribution appeared worldwide with clusters in North America, East Asia, Western Europe and the Middle East. The clinical spectrum was highly variable with a bi-phasic evolution characterized by early-onset developmental and epileptic encephalopathy during childhood followed by a progressive dystonia-parkinsonism syndrome along with cognitive decline during early adulthood. Female individuals showed milder disease severity. The majority of pathogenic WDR45 variants were predicted to result in a loss of WDR45 expression, without clear genotype-phenotype associations. Our results provide clinical and epidemiological data that may facilitate an earlier diagnosis, enable anticipatory guidance and counseling of affected families and provide the foundation for endpoints for future interventional trials. Abbreviations: BPAN: beta-propeller protein-associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NDD: neurodevelopmental disorder; NGS: next-generation sequencing; WDR45/WIPI4: WD repeat domain 45 [ABSTRACT FROM AUTHOR]

Background: As transcatheter aortic valve replacement (TAVR) becomes a preferred treatment option for patients with aortic valve stenosis, and demand for TAVR increases, it is imperative that length of stay (LOS) is reduced while maintaining safety and effectiveness. Local Problem: As TAVR procedures have become less invasive and more streamlined, current protocols have not been updated to reflect today's postprocedure requirements. Methods: The next-day discharge (NDD) protocol was established using available literature. A convenience sample was evaluated for NDD protocol inclusion during aortic multidisciplinary team conference using predetermined inclusion and exclusion criteria. Length of stay for NDD protocol participants was compared with LOS from a retrospective convenience sample of patients undergoing TAVR in the time frame mirroring NDD protocol initiation of the year prior. Interventions: Patients meeting inclusion criteria were enrolled in the NDD protocol with a goal of discharge to home on postprocedural day 1 by 2:00 p.m. The NDD protocol included preprocedure expectation setting, prescheduled same-day postprocedure imaging, and discharge priority on postprocedure day 1. Results: There is a significant difference in LOS between the NDD eligible retrospective and prospective groups. The prospective group has a significantly lower LOS than the retrospective group (M = 1.6 vs 2.1, respectively; p = .0454). Conclusions: An NDD protocol can help reduce LOS after TAVR in appropriately selected patients. Further protocol revision will be required to optimize LOS outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The current COVID-19 pandemic interferes with family lives across the world, particularly families of children with neurodevelopmental disorders (NDDs) are at a greater risk for being negatively impacted by the pandemic. Together with representatives from this caregiver population the aim was to explore the interference associated with normal family life caused by the COVID-19 pandemic.Method: This is a descriptive study using a cross-sectional design. Following a strategic network sampling strategy, a user-developed national survey was completed by a larger sample (N = 1,186) of parents and informal caregivers of children with NDDs. The survey utilized a combination of both closed and open-ended questions, and a logistic regression analysis was carried out to assess the association between family characteristics, characteristics of the child, and COVID-19 related family life interference. Before carrying out the regression an inductive content analysis of the open-ended question on `How has the isolation affected the family´ was carried out to construct the outcome variable.Results: The initial analysis indicated that the COVID-19 pandemic induced a shift in everyday family life and a lack of guidance and support related to managing the challenges they were facing. Caregivers who reported that COVID-19 had significantly interfered with their family life, were more likely to report having anxious children, and to have experienced an increased number of conflicts at home. The logistic regression showed that both anxious children and increased conflicts considerably increased the risk for reporting family life interference compared to those that reported no increased conflicts or anxious children.Discussion: Considering how the COVID-19 related increased conflicts at home and anxious children threaten the family life of the NDD caregiver population, as an external source of family stress, which might lead to negative impact on their mental and physical well-being, the need for further research in collaboration with user representatives is apparent. Our study suggests that more information should be provided to healthcare providers, social professionals, peers, people with NDDs, and caregivers of people with NDDs about the potential threats that a stressful life event such as the current pandemic can pose to their mental and physical health and their family life. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cell (iPSC) models of neurodevelopmental disorders (NDDs) have promoted an understanding of commonalities and differences within or across patient populations by revealing the underlying molecular and cellular mechanisms contributing to disease pathology. Here, we focus on developing a human model for PPP2R5D-related NDD, called Jordan syndrome, which has been linked to Early-Onset Parkinson's Disease (EOPD). Here we sought to understand the underlying molecular and cellular phenotypes across multiple cell states and neuronal subtypes in order to gain insight into Jordan syndrome pathology. Our work revealed that iPSC-derived midbrain neurons from Jordan syndrome patients display significant differences in dopamine-associated pathways and neuronal architecture. We then evaluated a CRISPR-based approach for editing heterozygous dominant G-to-A mutations at the transcript level in patient-derived neural stem cells. Our findings show site-directed RNA editing is influenced by sgRNA length and cell type. These studies support the potential for a CRISPR RNA editor system to selectively edit mutant transcripts harboring G-to-A mutations in neural stem cells while providing an alternative editing technology for those suffering from NDDs., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Delay in the diagnosis of neurodevelopmental disorders (NDDs) in toddlers and postnatal depression (PND) is a major public health issue. In both cases, early intervention is crucial but too rarely implemented in practice., Objective: Our goal was to determine if a dedicated mobile app can improve screening of 5 NDDs (autism spectrum disorder [ASD], language delay, dyspraxia, dyslexia, and attention-deficit/hyperactivity disorder [ADHD]) and reduce PND incidence., Methods: We performed an observational, cross-sectional, data-based study in a population of young parents in France with at least 1 child aged <10 years at the time of inclusion and regularly using Malo, an "all-in-one" multidomain digital health record electronic patient-reported outcome (PRO) app for smartphones. We included the first 50,000 users matching the criteria and agreeing to participate between May 1, 2022, and February 8, 2024. Parents received periodic questionnaires assessing skills in neurodevelopment domains via the app. Mothers accessed a support program to prevent PND and were requested to answer regular PND questionnaires. When any PROs matched predefined criteria, an in-app recommendation was sent to book an appointment with a family physician or pediatrician. The main outcomes were the median age of the infant at the time of notification for possible NDD and the incidence of PND detection after childbirth. One secondary outcome was the relevance of the NDD notification by consultation as assessed by health professionals., Results: Among 55,618 children median age 4 months (IQR 9), 439 (0.8%) had at least 1 disorder for which consultation was critically necessary. The median ages of notification for probable ASD, language delay, dyspraxia, dyslexia, and ADHD were 32.5 (IQR 12.8), 16 (IQR 13), 36 (IQR 22.5), 80 (IQR 5), and 61 (IQR 15.5) months, respectively. The rate of probable ADHD, ASD, dyslexia, language delay, and dyspraxia in the population of children of the age included between the detection limits of each alert was 1.48%, 0.21%, 1.52%, 0.91%, and 0.37%, respectively. Sensitivity of alert notifications for suspected NDDs as assessed by the physicians was 78.6% and specificity was 98.2%. Among 8243 mothers who completed a PND questionnaire, highly probable PND was detected in 938 (11.4%), corresponding to a reduction of -31% versus our previous study without a support program. Suspected PND was detected a median 96 days (IQR 86) after childbirth. Among 130 users who filled in the satisfaction survey, 99.2% (129/130) found the app easy to use and 70% (91/130) reported that the app improved follow-up of their child. The app was rated 4.8/5 on Apple's App Store., Conclusions: Algorithm-based early alerts suggesting NDDs were highly specific with good sensitivity as assessed by real-life practitioners. Early detection of 5 NDDs and PNDs was efficient and led to a possible 31% reduction in PND incidence., Trial Registration: ClinicalTrials.gov NCT06301087; https://www.clinicaltrials.gov/study/NCT06301087., (©Fabrice Denis, Florian Le Goff, Madhu Desbois, Agnes Gepner, Guillaume Feliciano, Denise Silber, Jean-David Zeitoun, Guedalia Peretz Assuied. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 18.06.2024.)

Background: Impairing repetitive behaviors are one of the core diagnostic symptoms in autism spectrum disorder and obsessive-compulsive disorder, but they also manifest in attention-deficit/hyperactivity disorder. Although the dorsal striatal circuit has been implicated in repetitive behaviors, extensive heterogeneity in and cross-diagnostic manifestations of these behaviors have suggested phenotypic and likely neurobiological heterogeneity across neurodevelopmental disorders (NDDs)., Methods: Intrinsic dorsal striatal functional connectivity was examined in 3 NDDs (autism spectrum disorder, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder) and typically developing control participants in a large single-cohort sample (N = 412). To learn how diagnostic labels and overlapping behaviors manifest in dorsal striatal functional connectivity measured with functional magnetic resonance imaging, the main and interaction effects of diagnosis and behavior were examined in 8 models (2 seed functional connectivity [caudate and putamen] × 4 sub-behavioral domains [sameness/ritualistic, self-injury, stereotypy, and compulsions])., Results: The obsessive-compulsive disorder group demonstrated distinctive patterns in visual and visuomotor coordination regions compared with the other diagnostic groups. Lower-order repetitive behaviors (self-injury and stereotypy) manifesting across all participants were implicated in regions involved in motor and cognitive control, although the findings did not survive effects of multiple comparisons, suggesting heterogeneity in these behavioral domains. An interaction between self-injurious behavior and an attention-deficit/hyperactivity disorder diagnosis were observed on caudate-cerebellum functional connectivity., Conclusions: These findings confirmed high heterogeneity and overlapping behavioral manifestations in NDDs and their complex underlying neural mechanisms. A call for diagnosis-free symptom measures that can capture not only observable symptoms and severity across NDDs but also the underlying functions and motivations of such behaviors across diagnoses is needed., (Copyright © 2024. Published by Elsevier Inc.)

Neurodevelopmental disorders (NDD) are a group of disorders that include intellectual disability. Although several genes have been implicated in NDD, the molecular mechanisms underlying its pathogenesis remain unclear. Therefore, it is important to develop novel models to analyze the functions of NDD-causing genes in vivo. Recently, rare pathogenic variants of the B-cell lymphoma/leukemia 11A/B (BCL11A/B) gene have been identified in several patients with NDD. Drosophila carries the Chronophage (Cph) gene, which has been predicted to be a homolog of BCL11A/B based on the conservation of the amino acid sequence. In the present study, we investigated whether nervous system-specific knockdown of Cph mimics NDD phenotypes in Drosophila. Nervous system-specific knockdown of Cph induced learning and locomotor defects in larvae and epilepsy-like behaviors in adults. The number of synaptic branches was also elevated in the larval neuromuscular junction without a corresponding increase in the number of boutons. Furthermore, the expression levels of putative target genes that are Drosophila homologs of the mammalian BCL11 target genes were decreased in Cph knockdown flies. These results suggest that Cph knockdown flies are a promising model for investigating the pathology of NDD-induced BCL11A/B dysfunction. [ABSTRACT FROM AUTHOR]

Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3a P900L/+ mouse mimicking a mutation with mild to moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes that may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease. [Display omitted] • DNMT3A mutant phenotypes correlate with epigenomic and transcriptomic disruption • Analyzing multiple DNMT3A mutations reveals core disease-relevant genomic effects • DNMT3A mutants show concordant gene dysregulation with Rett and Sotos syndrome mice Beard et al. characterize a DNMT3A mutant mouse carrying a moderate severity mutation, comparing it with a severe mutation to uncover epigenomic and transcriptional drivers of phenotypic variability. They utilize these mice to identify DNA-methylation-dependent enhancer dysfunction, gene expression changes, and concordant gene dysregulation with other neurodevelopmental disorder models. [ABSTRACT FROM AUTHOR]

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort., Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays., Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD., Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated., Competing Interests: Conflict of Interest Renee Bend and Julie Rath are employees of PreventionGenetics, part of Exact Sciences. Michelle M. Morrow and Francisca Millan are employees of GeneDx, LLC. All other authors declare no conflicts of interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)