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BACKGROUND: Neurodevelopmental disorders (NDD), such as autism spectrum disorders (ASD) and intellectual disorders (ID), are highly debilitating childhood psychiatric conditions. Genetic factors are recognized as playing a major role in NDD, with a multitude of genes and genomic regions implicated. While the functional validation of NDD-associated genes has predominantly been carried out using mouse models, the significant differences in brain structure and gene function between mice and humans have limited the effectiveness of mouse models in exploring the underlying mechanisms of NDD. Therefore, it is important to establish alternative animal models that are more evolutionarily aligned with humans.
RESULTS: In this study, we employed CRISPR/Cas9 and somatic cell nuclear transplantation technologies to successfully generate a knockout miniature pig model of the MIR137 gene, which encodes the neuropsychiatric disorder-associated microRNA miR-137. The homozygous knockout of MIR137 (MIR137-/-) effectively suppressed the expression of mature miR-137 and led to the birth of stillborn or short-lived piglets. Transcriptomic analysis revealed significant changes in genes associated with neurodevelopment and synaptic signaling in the brains of MIR137-/- miniature pig, mirroring findings from human ASD transcriptomic data. In comparison to miR-137-deficient mouse and human induced pluripotent stem cell (hiPSC)-derived neuron models, the miniature pig model exhibited more consistent changes in critical neuronal genes relevant to humans following the loss of miR-137. Furthermore, a comparative analysis identified differentially expressed genes associated with ASD and ID risk genes in both miniature pig and hiPSC-derived neurons. Notably, human-specific miR-137 targets, such as CAMK2A, known to be linked to cognitive impairments and NDD, exhibited dysregulation in MIR137-/- miniature pigs. These findings suggest that the loss of miR-137 in miniature pigs affects genes crucial for neurodevelopment, potentially contributing to the development of NDD.
CONCLUSIONS: Our study highlights the impact of miR-137 loss on critical genes involved in neurodevelopment and related disorders in MIR137-/- miniature pigs. It establishes the miniature pig model as a valuable tool for investigating neurodevelopmental disorders, providing valuable insights for potential applications in human research.

BACKGROUND: Parents of children with a neurodevelopmental disorder (NDD) experience more stress than parents of typically developing children. In a cocreation process with experts and parents, a low-threshold application that uses exercises based on the principles of positive psychology and mindfulness was developed. This application, called \"Adappt,\" aims at enhancing the ability to adapt of the parents and caregivers of children with NDDs and at supporting their mental health. This protocol describes the evaluation study of the effectiveness of Adappt, its core working mechanisms and user experiences.
METHODS: A pragmatic international multicenter randomized controlled trial will compare the effectiveness of Adappt with a (delayed) waitlist control condition. At least 212 parents or primary caregivers of children younger than 18 years diagnosed with or suspected of a NDD will be randomly assigned to the intervention or waitlist control condition. Participants are excluded if they have severe anxiety or depression levels or are in treatment for mental health issues. Measures will be collected online at baseline, post-intervention (1 month after baseline), and 4 and 7 months after baseline. The primary outcome is the improvement in generic sense of ability to adapt as measured with the Generic Sense of Ability to Adapt Scale (GSAAS; (Front Psychol 14:985408, 2023)) at 4-month follow-up. Secondary outcomes are mental well-being, (parental) distress, and client satisfaction with \"Adappt.\"
CONCLUSIONS: Results of this study will contribute to knowledge on the effectiveness of a low-threshold application for parents of children with a NDD in multiple countries. If the application is found to be effective in improving mental health, recommendations will be made for implementation in health care.
BACKGROUND: This study is registered on clinicaltrials.gov (NCT06248762) on February 8, 2024, and the Open Science Framework ( https://osf.io/5znqv ).

Haploinsufficiency of FOXP1 gene is responsible for a neurodevelopmental disorder presenting with intellectual disability (ID), autism spectrum disorder (ASD), hypotonia, mild dysmorphic features, and multiple congenital anomalies. Joint contractures are not listed as a major feature of FOXP1-related disorder. We report five unrelated individuals, each harboring likely gene disruptive de novo FOXP1 variants or whole gene microdeletion, who showed multiple joint contractures affecting at least two proximal and/or distal joints. Consistent with the phenotype of FOXP1-related disorder, all five patients showed developmental delay with moderate-to-severe speech delay, ID, ASD, and facial dysmorphic features. FOXP1 is implicated in neuronal differentiation and in organizing motor axon projections, thus providing a potential developmental basis for the joint contractures. The combination of joint contractures and neurodevelopmental disorders supports the clinical suspicion of FOXP1-related phenotype.

RASopathies are a group of genetic disorders caused by mutations in genes encoding components and regulators of the RAS/MAPK signaling pathway, resulting in overactivation of signaling. RASopathy patients exhibit distinctive facial features, cardiopathies, growth and skeletal abnormalities, and varying degrees of neurocognitive impairments including neurodevelopmental delay, intellectual disabilities, or attention deficits. At present, it is unclear how RASopathy mutations cause neurocognitive impairment and what their neuron-specific cellular and network phenotypes are. Here, we investigated the effect of RASopathy mutations on the establishment and functional maturation of neuronal networks. We isolated cortical neurons from RASopathy mouse models, cultured them on multielectrode arrays and performed longitudinal recordings of spontaneous activity in developing networks as well as recordings of evoked responses in mature neurons. To facilitate the analysis of large and complex data sets resulting from long-term multielectrode recordings, we developed MATLAB-based tools for data processing, analysis, and statistical evaluation. Longitudinal analysis of spontaneous network activity revealed a convergent developmental phenotype in neurons carrying the gain-of-function Noonan syndrome-related mutations Ptpn11 D61Y and Kras V14l. The phenotype was more pronounced at the earlier time points and faded out over time, suggesting the emergence of compensatory mechanisms during network maturation. Nevertheless, persistent differences in excitatory/inhibitory balance and network excitability were observed in mature networks. This study improves the understanding of the complex relationship between genetic mutations and clinical manifestations in RASopathies by adding insights into functional network processes as an additional piece of the puzzle.

Recently a broad range of phenotypic abnormalities related to the neurodevelopmental and neurodegenerative disorder NEDAMSS (Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures) have been associated with rare single-nucleotide polymorphisms (SNPs) or insertion and deletion variants (Indel) in the intron-less gene IRF2BPL. Up to now, 34 patients have been identified through whole exome sequencing carrying different heterozygous pathogenic variants spanning the intron-less gene from the first polyglutamine tract at the N-terminus to the C3HC4 RING domain of the C-terminus of the protein. As a result, the phenotypic spectrum of the patients is highly heterogeneous and ranges from abnormal neurocognitive development to severe neurodegenerative courses with developmental and seizure-related encephalopathies. While the treatment of IRF2BPL-related disorders has focused on alleviating the patient\'s symptoms by symptomatic multidisciplinary management, there has been no prospect of entirely relieving the symptoms of the individual patients. Yet, the recent advancement of CRISPR-Cas9-derived gene editing tools, leading to the generation of base editors (BEs) and prime editors (PEs), provide an encouraging new therapeutic avenue for treating NEDAMSS and other neurodevelopmental and neurodegenerative diseases, which contain SNPs or smaller Indels in post-mitotic cell populations of the central nervous system, due to its ability to generate site-specific DNA sequence modifications without creating double-stranded breaks, and recruiting the non-homologous DNA end joining repair mechanism.

Syntaxin-binding protein 1 related disorder (STXBP1-RD) is a rare neurologic disorder associated with global neurodevelopmental delay, intellectual disability, early-onset epilepsy, motor abnormalities, and autism. The underlying pathophysiology stems from a de novo mutation in the STXBP1 gene, which codes for the STXBP1 protein. The STXBP1 protein is involved in synaptic vesicle fusion and neurotransmitter release. Pathogenic variants in the STXBP1 gene generally result in haploinsufficiency, an impairment in neurotransmitter release, and subsequent dysfunction in neuronal communication. The STXBP1 Foundation was founded in 2017 to support families of children with STXBP1-RD and accelerate the development of effective therapies and, ultimately, a cure for the disorder. The Foundation initially supported research aimed at better understanding the complex phenotypic presentation of the disease as well as the development of animal and cellular models usable by the research community to more fully characterize STXBP1 function and disease pathogenicity. In 2023, the Foundation embarked on its STXBP1 Fast Forward Strategic Plan, which includes a prospective natural history study and substantive biomarker work to drive forward the development of new precision therapies for STXBP1-RD.
STXBP1: fast-forward to a brighter future STXBP1-related disorder (STXBP1-RD) is a rare and severe brain condition. It causes delays in development, learning problems, seizures starting at an early age, movement challenges, and sometimes autism. The main problem comes from a new mutation in the STXBP1 gene, which makes a protein needed for brain cells to communicate properly. When this gene doesn’t work right, there’s not enough of the protein, leading to trouble with brain cell communication. To help families dealing with this disorder and speed up the search for effective therapies, the STXBP1 Foundation started in 2017. At first, they funded studies to understand the disease better and create models for testing treatments. Then, in 2023, they launched the STXBP1 Fast Forward Strategic Plan. This plan includes studying how the disorder progresses naturally and researching markers that could help develop precise treatments for STXBP1-RD.

Heterozygous mutations in the FOXP1 gene (OMIM#605515) are responsible for a well-characterized neurodevelopmental syndrome known as \"intellectual developmental disorder with language impairment with or without autistic features\" (OMIM#613670) or FOXP1 syndrome for short. The main features of the condition are global developmental delay/intellectual disability; speech impairment in all individuals, regardless of their level of cognitive abilities; behavioral abnormalities; congenital anomalies, including subtle dysmorphic features; and strabismus, brain, cardiac, and urogenital abnormalities. Here, we present two siblings with a de novo heterozygous FOXP1 variant, namely, a four-year-old boy and 14-month-old girl. Both children have significantly delayed early psychomotor development, hypotonia, and very similar, slightly dysmorphic facial features. A lack of expressive speech was the leading symptom in the case of the four-year-old boy. We performed whole-exome sequencing on the male patient, which identified a pathogenic heterozygous c.1541G>A (p.Arg514His) FOXP1 mutation. His sister\'s targeted mutation analysis also showed the same heterozygous FOXP1 variant. Segregation analysis revealed the de novo origin of the mutation, suggesting the presence of parental gonadal mosaicism. To the best of our knowledge, this is the first report of gonadal mosaicism in FOXP1-related neurodevelopmental disorders in the medical literature.

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.
BACKGROUND: ClinicalTrials.gov NCT06301087; https://www.clinicaltrials.gov/study/NCT06301087.

Harel-Yoon syndrome (HAYOS) is a unique neurodevelopmental genetic disorder characterized by hypotonia, spasticity, intellectual disability, hypertrophic cardiomyopathy, and global developmental delay. It primarily results from mutations in the ATAD3A gene, pivotal for mitochondrial function. This report presents a 5-year-old girl with HAYOS harboring a de novo heterozygous variant c.1064G>A; (p.G355D) in ATAD3A. Her clinical profile includes delayed milestones, hypotonia, spastic quadriplegia, and ptosis. Notably, dermatologic anomalies such as hypopigmentation, café au lait macules, and freckling are observed, expanding the known phenotype of HAYOS. The inclusion of dermatologic features challenges our understanding of the syndrome and emphasizes the importance of further research to elucidate the molecular connections between ATAD3A mutations and dermatologic manifestations.