J Neurodev Disord [JOURNAL]
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200 papers
The effectiveness of transcranial electrical stimulation in individuals with specific learning disorder (SLD): systematic review and transfer analysis.
Nejati V, Ghafuri F, Hosseini K … +1 more , Behroozmand R
J Neurodev Disord · 2025 Nov · PMID 41193951 · Full text
This comprehensive review aimed to investigate the transferability of transcranial electrical Stimulation (tES) interventions in individuals with specific learning disabilities (SLD) based on the FIELD model, encompassin...
This comprehensive review aimed to investigate the transferability of transcranial electrical Stimulation (tES) interventions in individuals with specific learning disabilities (SLD) based on the FIELD model, encompassing function, implements, ecology, level, and durability. A systematic search of electronic databases yielded a total of 13 eligible studies, 11 transcranial direct current stimulation (tDCS), 1 transcranial random noise stimulation (tRNS), and 1 transcranial alternating current stimulation (tACS), encompass 286 individuals with SLD, for inclusion. The overall effect size analysis revealed positive transfer effects in all domains of FIELD, indicating the potential effectiveness of non-invasive brain stimulations (NIBS) interventions in enhancing various aspects of learning and behavior in individuals with SLD. The subgroup analysis further underscored the positive impact of age, dose, and concurrent intervention on transferability. In conclusion, this study contributes valuable insights into the transferability of tES interventions and holds promise for improving learning and behavioral outcomes in individuals with SLD.
Development of the Angelman syndrome video assessment: quantifying meaningful change.
Sheehy KA, Leffler MG, Woods RJ … +13 more , Komorowski R, Crean R, Zigler CK, Duis J, Boorom O, Brady N, DeValk L, Harris N, Sapp A, Woeber C, Sadhwani A, Tan WH, ASVA Delphi Panelists
J Neurodev Disord · 2025 Nov · PMID 41184737 · Full text
BACKGROUND: The Angelman Syndrome Video Assessment (ASVA) is a clinician-reported outcome measure that was developed to assess the functional ability of individuals with Angelman Syndrome (AS) in a familiar environment....
BACKGROUND: The Angelman Syndrome Video Assessment (ASVA) is a clinician-reported outcome measure that was developed to assess the functional ability of individuals with Angelman Syndrome (AS) in a familiar environment. Through standardized tasks and associated scorecards, clinicians assess four meaningful domains of functioning: communication, activities of daily living (ADLs, which include fine motor skills), gross motor, and external direction (i.e., the ability to follow directions) via scorecards with pre-established criteria. The aim of this project was to develop and refine the scorecards using a rigorous process in partnership with caregivers, clinicians, and researchers in the AS community. METHODS: The Scorecard development process included four phases: (1) video source material study, (2) identification of initial scoring criteria, (3) scorecard drafts, and (4) two (Caregiver and Clinician panel and PT panel) two-round modified Delphi processes to reach consensus. All phases were conducted remotely except for Round 2 of the Caregiver and Clinician Delphi Panel, which was conducted in person. Votes were held for each scoring criterion and consensus was defined as ≥ 70% agreement. RESULTS: In the communication, ADLs, and external direction domains, scorecard criteria reached 80 to 100% agreement among caregivers (n = 8) and clinicians (n = 2), resulting in a total of 218 scoring criteria and levels across 10 tasks. In the gross motor domain, scorecard criteria reached 100% agreement among physical therapists (n = 8) with a total of 347 scoring criteria and levels across 8 tasks. CONCLUSIONS: The ASVA was developed with insights from the AS community, including caregivers of individuals with AS, clinicians, and researchers. The ASVA is a novel, disease-specific, clinician-reported outcome measure that uses standardized video capture and scorecards that were developed through a rigorous process, resulting in well-developed criteria to quantify meaningful changes of function in individuals with AS in communication, ADLs, gross motor function, and external direction.
Longitudinal characterization of clinical, developmental, and behavioral phenotypes in 101 children and adults with FOXG1 syndrome.
Brimble E, Ventola P, Blomenberg E … +7 more , Frahlich K, Kuhathaas K, Hart CE, Bahi-Buisson N, Olson HE, Marsh ED, Ayalon G
J Neurodev Disord · 2025 Oct · PMID 41136907 · Full text
BACKGROUND: FOXG1 syndrome is a severe genetic neurodevelopmental disorder characterized by intellectual and developmental disabilities (IDD), postnatal microcephaly, epilepsy, and movement disorder. With the advent of m...
BACKGROUND: FOXG1 syndrome is a severe genetic neurodevelopmental disorder characterized by intellectual and developmental disabilities (IDD), postnatal microcephaly, epilepsy, and movement disorder. With the advent of molecular therapies, establishing the natural history of FOXG1 syndrome is critical to enable clinical trial readiness. However, traditional study designs are challenging to implement for rare disorders without significant burden to participants. METHODS: The study population included 101 children and adults with (likely) pathogenic variants in or involving FOXG1 (ages 0.4 - 34.8 years). Participant medical records underwent systematic annotation and harmonization of recorded clinical phenotypes, interventions, and outcomes through use of a patient-centric real-world data (RWD) platform. Retrospective medical record data were paired with prospective administration of validated measures of development and behavior, including the Vineland-3, the Aberrant Behavior Checklist, and the Children’s Sleep Habits Questionnaire. Descriptive and inferential statistics were employed to characterize longitudinal phenotypes and to explore genotype-phenotype correlations. RESULTS: Through systematic evaluation of 101 people with FOXG1 syndrome, we generated a robust dataset encompassing >40,000 annotated clinical terminology concepts that represent >770 cumulative patient data years. Core clinical phenotypes include IDD, gastrointestinal disorders, strabismus, epilepsy, movement disorders, and sleep problems. The FOXG1 syndrome behavioral phenotype is characterized by irritability, including aggressive behaviors, stereotypies, social withdrawal, and lethargy; in those with missense variants, features of autism spectrum disorders are also reported. Data derived from both medical records and validated measures confirm and expand upon previously described genotype-phenotype correlations, whereby truncating variants are associated with greater limitations across motor and communication domains, as well as increased frequency of core FOXG1 syndrome phenotypes. Further, individuals with truncating variants had higher scores on a composite measure of FOXG1 syndrome severity, which persists when modeled longitudinally. Employing the same composite measure, we demonstrate that FOXG1 syndrome is a static encephalopathy without evidence of neurodegeneration. CONCLUSIONS: By combining retrospective RWD with prospective survey administration in a large sample population, we establish the natural history of FOXG1 syndrome and highlight candidate clinical endpoints for use in clinical trials, including quantitative evaluations of communication and movement disorders.
Functional connectivity patterns differ as a function of co-occurring attentional problems in preschoolers with autism.
Boxberger A, Chen B, Olson L … +5 more , Cordova M, Mahmalji J, Rios A, Linke AC, Fishman I
J Neurodev Disord · 2025 Oct · PMID 41131500 · Full text
BACKGROUND: Symptoms of attention-deficit/hyperactivity disorder (ADHD) are common in children with autism spectrum disorder (ASD), and are associated with greater developmental challenges, poorer clinical outcomes, and...
BACKGROUND: Symptoms of attention-deficit/hyperactivity disorder (ADHD) are common in children with autism spectrum disorder (ASD), and are associated with greater developmental challenges, poorer clinical outcomes, and alterations in functional connectivity (FC) of the brain. However, despite the consensus that ASD and other neurodevelopmental conditions emerge early in life, little is known about the trajectories of brain and behavioral development during the first years of life in children with ASD and co-occurring attention problems (AP). METHODS: In a sample of 122 young children (ages 1.5-5 years) with and without ASD, we examined whether toddlers and preschoolers with ASD and co-occurring AP already differ from peers with ASD without co-occurring AP on adaptive and developmental skills, ASD symptoms, and FC of the frontoparietal and salience networks, which have been previously linked to ADHD symptoms in older children with ASD and ADHD. RESULTS: Results of general linear model analyses revealed lower developmental and adaptive skills across multiple domains in children with ASD and elevated AP compared with their peers with lower AP, despite equivalent levels of ASD symptoms. Further, children with ASD and elevated AP showed reduced FC within the frontoparietal network (p = .027), between the frontoparietal and language networks (p = .004), and the frontoparietal and default mode networks (p = .046) in comparison to their peers with lower AP. No group differences in FC of the salience network were observed (all p > .05). CONCLUSIONS: These findings provide evidence that neurodevelopmental and behavioral differences in children with ASD and co-occurring AP emerge very early in life, before a reliable diagnosis of ADHD is typically made. Specifically, these results demonstrate that early inattention symptoms are associated with unique connectivity patterns in executive circuitry as early as the first years of life in toddlers and preschoolers with ASD, likely contributing to the phenotypic and neural heterogeneity recognized in autism. Thus, our results underscore the importance of considering co-occurring conditions early in developmental research and clinical care, as further understanding these trajectories can inform early interventions during the critical time period when they have the greatest potential for positive impact.
Evidence of neurocognitive and resting state functional connectivity differences in carriers of NRXN1 deletions.
Fitzgerald J, Molloy CJ, Dinneen T … +10 more , Feerick NE, O'Sullivan M, O'Conaill R, Al-Shehhi M, Reilly R, Lynch SA, Heron EA, Kelly C, Shen S, Gallagher L
J Neurodev Disord · 2025 Oct · PMID 41094379 · Full text
BACKGROUND: NRXN1 deletion (NRXN1 del) is a rare copy number variant associated with several neurodevelopmental, neuropsychiatric, and cognitive outcomes. The NRXN1 gene encodes for a pre-synaptic cell adhesion molecule...
BACKGROUND: NRXN1 deletion (NRXN1 del) is a rare copy number variant associated with several neurodevelopmental, neuropsychiatric, and cognitive outcomes. The NRXN1 gene encodes for a pre-synaptic cell adhesion molecule that is important for synapse formation, regulation and neurotransmission. We used a gene-first approach to investigate neurocognitive and brain phenotypes in NRXN1 del carriers. METHODS: Forty-two participants (21 NRXN1 del carriers and 21 neurotypical age and sex-matched comparisons) completed IQ assessments, and a neurocognitive battery, including, executive function, attention, and social cognition tasks. Magnetic resonance imaging (MRI) data, including T1-weighted anatomical scans, resting state functional MRI and diffusion tensor imaging, were acquired in 36 participants (17 NRXN1 del carriers and 19 comparisons). RESULTS: NRXN1 del carriers had lower mean IQ and poorer spatial working memory performance compared to comparisons (p ≤ 0.05). Neuroimaging results revealed group differences in visual and ventral attention resting state networks (p < 0.05). Network-based statistical analysis showed a significant effect of group status for 28/115 connections, with poorer segregation between visual and default networks in NRXN1 del carriers relative to comparisons. No differences in brain structural volume or cortical thickness, or diffusion measures of white matter structural architecture were observed between groups. CONCLUSIONS: This exploratory study provides evidence for neurocognitive impacts and brain functional differences related to underlying synaptic mechanisms. Brain functional differences in NRXN1 del carriers may support altered excitation/inhibition dynamics within the brain. Gene-first approaches may establish brain-based translational markers to identify neurobiologically informed subgroups within neurodevelopmental and neuropsychiatric conditions, and ultimately transdiagnostic therapeutic strategies.
Clinical determinants of psychiatric care in genetic neurodevelopmental disorders: a cross-sectional analysis.
Adams DJ, Klomhaus AM, Wong NR … +7 more , Schneider BN, DiStefano C, Mehta S, Wilson RB, Martinez-Agosto JA, Jeste SS, Besterman AD
J Neurodev Disord · 2025 Oct · PMID 41057772 · Full text
BACKGROUND: This study aims to identify clinical and developmental factors associated with psychotropic medication exposure and subspecialty psychiatric service utilization among patients with genetic neurodevelopmental...
BACKGROUND: This study aims to identify clinical and developmental factors associated with psychotropic medication exposure and subspecialty psychiatric service utilization among patients with genetic neurodevelopmental disorders (GNDDs). METHODS: We conducted a retrospective analysis of 316 patients from the Care and Research in Neurogenetics (CARING) Clinic at the University of California, Los Angeles (UCLA). We assessed the association between neurodevelopmental and psychiatric diagnoses, behavioral histories, family history, and service utilization with two outcomes: (1) the number of psychotropic medication classes trialed before clinic intake and (2) whether the patient was evaluated by a CARING psychiatrist. Poisson and logistic regression models were used to evaluate associations while adjusting for demographic and clinical covariates. RESULTS: Individuals with more severe behavioral disturbances had higher psychiatric service needs, while intellectual disability was associated with greater psychotropic medication exposure but not increased psychiatric consultation, possibly due to prior community-based care. The presence of a pathogenic/likely pathogenic genetic variant was not associated with either outcome, suggesting that genetic diagnosis alone does not predict psychiatric needs. Instead, behavioral comorbidities, not genetic status, were the primary drivers of psychotropic use and psychiatric referrals. A history of developmental delay was negatively associated with psychiatric consultation, and mediation analyses indicated that early intervention services partly explained this relationship. Additionally, patients receiving behavioral therapies had higher psychotropic exposure, reflecting greater clinical complexity and frequent use of multimodal treatment strategies. CONCLUSIONS: Our findings suggest that psychiatric needs in GNDDs are more closely tied to behavioral comorbidities than to genetic diagnosis status, reinforcing the importance of symptom-driven psychiatric evaluation. The observed relationship between early developmental interventions and psychiatric service utilization warrants further longitudinal investigation. These results highlight opportunities to optimize psychiatric care pathways through early screening, integrated behavioral and pharmacologic interventions, and targeted resource allocation for individuals with neurodevelopmental disorders.
The neurodevelopmental spectrum of CASK-related disorder.
Martin J, Mavrogalou-Foti A, Eck J … +2 more , Hattersley L, Baker K
J Neurodev Disord · 2025 Oct · PMID 41039189 · Full text
BACKGROUND: Pathogenic CASK variants are associated with neurodevelopmental disorders of variable severity including X-linked intellectual disability (XLID) and microcephaly with pontocerebellar hypoplasia (MICPCH). Alth...
BACKGROUND: Pathogenic CASK variants are associated with neurodevelopmental disorders of variable severity including X-linked intellectual disability (XLID) and microcephaly with pontocerebellar hypoplasia (MICPCH). Although the number of diagnosed cases is rising, current understanding of the CASK-related neurodevelopmental spectrum is limited. Here, we systematically review the published characteristics of individuals with CASK-related disorder, and compare these to a more recently-diagnosed group. We provide quantitative information about the ranges of adaptive abilities, motor function, visual function and social-emotional-behavioural characteristics, and explore within-group associations. METHODS: One hundred and fifty-one individuals with CASK variants were identified in published literature. Thirty-one children and young people with CASK variants were recruited to the UK-based Brain and Behaviour in Neurodevelopmental disorders of Genetic Origin (BINGO) project. BINGO-participating caregivers completed a bespoke medical history questionnaire and battery of standardised neurodevelopmental measures. RESULTS: Comparing the recently diagnosed BINGO CASK-related disorder group to previously reported individuals, we found consistent prevalence of tone abnormalities, sensorineural hearing loss and epilepsy, but lower prevalence of severe/profound ID, MICPCH, optic atrophy and nystagmus. Areas of frequent difficulty not highlighted in previous reports include sleep difficulties and cerebral visual impairment (CVI). Neurodevelopmental characteristics were highly variable within the BINGO CASK-related disorder group, and group-wide patterns were similar to those observed in other rare genetic conditions. Within the BINGO CASK-related group, epilepsy is significantly associated with ID severity, after controlling for age. Sub-groups with MICPCH or microcephaly only have equivalent ranges of adaptive function, but MICPCH may be associated with more severe motor difficulties. CONCLUSION: The spectrum of neurodevelopmental characteristics associated with CASK-related disorder appears to be broadening with increased access to genome-wide diagnostic testing. Further studies are needed to elucidate the relationships between CASK variants, structural brain development, epilepsy, and neurodevelopmental characteristics.
Courtship and distress ultrasonic vocalizations are altered in a mouse model of Angelman syndrome.
Guoynes CD, Pavalko G, Sidorov MS
J Neurodev Disord · 2025 Oct · PMID 41034775 · Full text
BACKGROUND: Angelman syndrome (AS) is a single-gene neurodevelopmental disorder caused by loss of function of the maternal copy of the UBE3A gene. Nearly all individuals with AS lack speech, resulting in major impacts on...
BACKGROUND: Angelman syndrome (AS) is a single-gene neurodevelopmental disorder caused by loss of function of the maternal copy of the UBE3A gene. Nearly all individuals with AS lack speech, resulting in major impacts on daily life for patients and caregivers. To evaluate new therapies for AS, it is crucial to have a mouse model that characterizes meaningful clinical features. Vocalizations are used in many contexts in mice, including pup retrieval, social interactions, courtship, and distress. Previous work in the Ube3am−/p+ mouse model of AS found abnormalities in the number of ultrasonic vocalizations (USVs) mice produced during pup isolation and same-sex social interactions. Here, we evaluated Ube3am−/p+ vocalizations during courtship and distress. Quantifying USVs in these contexts enables comparison of USVs in social (courtship) and non-social (distress) settings. In addition, we assessed the utility of incorporating USV testing into existing Ube3am−/p+ mouse behavioral assessments used to evaluate potential AS treatments. METHODS: We used multiple behavioral paradigms to evaluate courtship vocalizations and tail suspension tests to evaluate distress vocalizations in adult wild-type (WT) and Ube3am−/p+ littermates, and quantified USV properties using the program DeepSqueak. A subset of mice also performed an established Ube3am−/p+ behavioral battery that included rotarod, open field, marble burying, and nest building. We used principal component analysis to evaluate the value of USV testing in this cohort in the context of other behaviors. RESULTS: In both social courtship and nonsocial distress behavioral paradigms, Ube3am−/p+ mice made fewer USVs compared to WT mice. Spectral properties of USVs were abnormal in Ube3am−/p+ mice on courtship tests but mostly typical on distress tests. Including USVs in the Ube3am−/p+ mouse behavior battery increased the distance between Ube3am−/p+ and WT clusters in principal component space. CONCLUSIONS: Ube3am−/p+ mice have disrupted USV production in social and nonsocial contexts. Spectral properties of USVs are most impacted in the social courtship context. Adding USVs to the Ube3am−/p+ behavior battery may improve sensitivity to detect group differences and changes in communication.
The association between infant EEG aperiodic exponent and the trajectory of restricted and repetitive behaviors for toddlers with and without autism.
Chung H, Job Said A, Tager-Flusberg H … +2 more , Nelson CA, Wilkinson CL
J Neurodev Disord · 2025 Sep · PMID 41023786 · Full text
BACKGROUND: Restricted and repetitive behaviors (RRB) are core features of autism but are also observed in typical development. Our understanding of the neural underpinnings of RRBs is limited. Given that excitation-inhi...
BACKGROUND: Restricted and repetitive behaviors (RRB) are core features of autism but are also observed in typical development. Our understanding of the neural underpinnings of RRBs is limited. Given that excitation-inhibition (E/I) balance may underlie RRBs, we aimed to evaluate the relationship between aperiodic exponent (as a proxy of E/I balance) and changes in RRBs over time in infants with and without elevated likelihood of autism. METHODS: Resting-state EEG data were collected from 12-to-14-month-old infants and aperiodic exponent was calculated. Parent-reported RRBs were obtained using the Repetitive Behavior Scale-Revised questionnaire to measure the severity and change in RRBs from 12-to-36 months. Multiple linear regressions were conducted to assess relationships between aperiodic and change in RRBs. RESULTS: Marginal effects analysis of linear regressions revealed significant associations such that lower aperiodic exponent was associated with elevated RRBs reported over time across the whole sample ([Formula: see text]=0.31, β= -0.21, p = 0.01), which was more prominently observed in the infants who later received an autism diagnosis (δy/δx = -15.57, p < .001). CONCLUSIONS: Results suggest that early EEG aperiodic activity may serve as a potential correlate of increased manifestation of RRBs. Longitudinal studies are needed to elucidate whether the early trajectory of aperiodic activity in development influences the severity of RRBs in childhood.
Patient reported outcomes that matter to individuals with (genetic) intellectual disabilities: a qualitative study.
van Silfhout NY, van Muilekom MM, van Karnebeek CD … +2 more , Haverman L, van Eeghen AM
J Neurodev Disord · 2025 Sep · PMID 41023671 · Full text
BACKGROUND: To improve the quality of care and the impact of interventions for individuals with (genetic) intellectual disabilities ((G)ID), it is essential to identify and measure relevant patient reported outcomes (PRO...
BACKGROUND: To improve the quality of care and the impact of interventions for individuals with (genetic) intellectual disabilities ((G)ID), it is essential to identify and measure relevant patient reported outcomes (PROs), which represent patient perspective on their health and functioning. Currently, various, and potentially irrelevant PROs are being measured for individuals with (G)ID. The aim of this study is to identify relevant PROs from the perspective of different stakeholders, as one of the first steps towards development of a meaningful PRO set for children and adults with (G)ID. METHODS: A qualitative study was performed using focus groups and interviews with individuals with (G)ID, caregivers, healthcare professionals (HCPs) and European patient representatives. A focus group- and interview guide was developed including two themes: the impact of (G)ID on daily life and important topics to discuss with HCPs. Data collection took place until data sufficiency was reached. All sessions were recorded and transcribed verbatim. Transcripts were analysed by three researchers using a thematic analysis approach. PROs were classified and conceptualized (i.e., describing the content of each PRO in detail) within a conceptual framework. RESULTS: Ten focus groups and 13 interviews were conducted with a total of 51 participants. In total, seven adolescents and 10 adults with (G)ID, 12 caregivers, 13 multidisciplinary HCPs and nine European patient representatives participated. Data sufficiency was reached. PROs reported by participants were related to all health domains including physical, mental, and social functioning. Themes related to the negative impact of (G)ID were prioritized for discussion during consultations. CONCLUSIONS: This study sheds light on relevant PROs for individuals with (G)ID, marking one of the first steps in developing a meaningful PRO set for (G)ID. Once established, this set will inform care, research agendas, policymaking, and the development of a generic patient reported outcome measure (PROM) set for (G)ID, improving care quality and research impact for this complex and vulnerable population.
MED13L-related disorder characterized by severe motor speech impairment.
Mitchel MW, Turner S, Walsh LK … +3 more , Torene RI, Myers SM, Taylor CM
J Neurodev Disord · 2025 Sep · PMID 40993520 · Full text
BACKGROUND: MED13L-related disorder is associated with intellectual disability, motor delay, and speech deficits. Previous studies have focused on broad clinical descriptions of individuals, but limited information regar...
BACKGROUND: MED13L-related disorder is associated with intellectual disability, motor delay, and speech deficits. Previous studies have focused on broad clinical descriptions of individuals, but limited information regarding specific speech diagnoses and results of direct testing has been published to date. We conducted deep phenotyping to characterize the speech, language, motor, cognitive, and adaptive phenotypes of individuals with MED13L-related disorder. METHODS: In this cross-sectional study, we administered standardized articulation, language, motor, and cognitive testing to 17 children and adolescents (mean age 9y 9m; SD 4y 5m; range 4y 2m to 19y 7m). In-person testing was supplemented with broad developmental, medical, and behavioral information collected virtually from a cohort of 67 individuals. RESULTS: All individuals who completed in-person articulation testing met diagnostic criteria for speech apraxia, dysarthria, or both. Language impairment was present in all of the in-person cohort and reported for almost all (97%) of the virtual cohort. Those who were able to complete motor testing demonstrated significant deficits in visual motor integration (mean 57.08, SD 9.26). Full scale IQs fell in the borderline to intellectual disability range, consistent with reported cognitive impairment in 97% of the virtual cohort. Notable medical features included hypotonia (83%), vision problems (72%), recurrent otitis media (58%), gastrointestinal problems (57%), and seizures (31%). CONCLUSIONS: MED13L-related disorder is characterized by a high rate of motor speech disorders that occur in the context of globally impaired motor, language, and cognitive skills. Children would benefit from early referrals to speech therapy to assess their speech, language, and support needs.
Preliminary perspectives on gene therapy in fragile X syndrome: a caregiver view.
Eley SEA, Weissgold S, Stanfield AC
J Neurodev Disord · 2025 Sep · PMID 40890602 · Full text
BACKGROUND: There have been increasing numbers of clinical trials of medications for fragile X syndrome (FXS) in recent years, many targeted at proposed underlying cellular or circuit based mechanisms. As yet none of the...
BACKGROUND: There have been increasing numbers of clinical trials of medications for fragile X syndrome (FXS) in recent years, many targeted at proposed underlying cellular or circuit based mechanisms. As yet none of these have led to widespread changes in clinical practice. Genetic therapies represent a different therapeutic approach, which aim to address the genetic mechanisms by which FXS arises. Although not yet moving into human studies in FXS, this is an area of increasing research importance in neurodevelopmental conditions more broadly. It is important that families affected by FXS get the chance to give their views about future genetic therapies, given the potential controversies around genetic therapies. METHODS: We developed a questionnaire to capture caregiver views around gene therapy in FXS. The questionnaire was developed alongside a group of parents / caregivers of a child with FXS to ensure the language used was appropriate and that it would allow a variety of views to be captured. The questionnaire contained questions around current knowledge of gene therapy, what families think of gene therapy and their views on gene therapy trials taking place. Responses were analysed by thematic analysis carried out by two of the authors with data from the questionnaires being grouped into themes and subthemes. RESULTS: The questionnaire was completed by 195 individuals who are parents of, or who care for, someone with FXS. Respondents were primarily from the UK (60.5%) and the Americas (22.1%). The majority of dependants were male (86%). Responses showed a strong interest from the Fragile X community in gene therapy trials taking place, with themes emerging around quality of life, outcomes and feelings. Hope for positive change was balanced against caution about unintended consequences, the newness of the treatment and tolerability. CONCLUSION: Overall, caregivers felt hopeful, excited and interested in the prospect of gene therapy potentially providing a new treatment option, but there was some trepidation about the potential effects. Taking caregiver views into account will help inform decisions around the development and testing of any future genetic interventions.
Learning impairments in Fmr1mice on an audio-visual temporal pattern discrimination task.
Mol W, Post S, Lee M … +3 more , Thapa R, Erickson M, Goel A
J Neurodev Disord · 2025 Aug · PMID 40883686 · Full text
Estimating time and making predictions is integral to our experience of the world. Given the importance of timing to most behaviors, disruptions in temporal processing and timed performance are reported in a number of ne...
Estimating time and making predictions is integral to our experience of the world. Given the importance of timing to most behaviors, disruptions in temporal processing and timed performance are reported in a number of neuropsychiatric disorders such as Schizophrenia, Autism Spectrum Disorder (ASD), Fragile X Syndrome (FXS), and Attention-deficit Hyperactivity Disorder (ADHD). Symptoms that implicitly include disruption in timing are atypical turn-taking during social interactions, unusual verbal intonations, poor reading, speech and language skills, inattention, delays in learning, and difficulties making predictions. Currently, there are no viable treatments for these symptoms, the reason being the underlying neural dysfunction that contributes to timing deficits in neuropsychiatric disorders is unknown. To address this unknown, we have designed a novel Temporal Pattern Sensory Discrimination Task (TPSD) for awake-behaving mice. Stimuli consist of paired audiovisual stimuli that differ in duration. Compared to Wild-Type (WT) mice, Fmr1 mice, a well-established mouse model of FXS, showed significant impairment in learning the TPSD task, as evidenced by reduced discriminability indices and atypical licking patterns. Often sensory information is multimodal and, indeed, studies show that learning in humans and rodents improves with multimodal stimuli than with unimodal stimuli. To test how the multimodal nature of stimuli impacted performance of Fmr1 mice, following training on the audiovisual stimuli, we tested mice on audio-only or visual-only stimuli. While WT mice showed significant disruption in performance when tested on unimodal stimuli, Fmr1 mice displayed equivalent performance on visual-only stimuli when compared to the multimodal task. Our novel task captures timing difficulties and multisensory integration issues in Fmr1 mice and provides an assay to examine the associated neural dysfunction.
Face perception, attention, and memory as predictors of social change in autistic children.
Webb SJ, Kwan B, Bernier R … +15 more , Charwarska K, Dawson G, Dziura J, Faja S, Hellmann G, Jeste S, Kleinhans N, Levin A, Naples A, Sabatos-DeVito M, Şentürk D, Shic F, Sugar C, McPartland JC, Autism Biomarkers Consortium for Clinical Trials
J Neurodev Disord · 2025 Aug · PMID 40885894 · Full text
OBJECTIVE: Social perception and attention markers have been identified that, on average, differentiate autistic from non-autistic children. However, little is known about how these markers predict behavior over time at...
OBJECTIVE: Social perception and attention markers have been identified that, on average, differentiate autistic from non-autistic children. However, little is known about how these markers predict behavior over time at both short and long time intervals. METHODS: We conducted a large multisite, naturalistic study of 6- to 11-year-old children diagnosed with ASD (n = 214). We evaluated three markers of social processing: social perception via the ERP N170 Latency to Upright Faces; social attention via the Eye Tracking (ET) OMI (Oculomotor Index of Gaze to Human Faces) that captures percent looking to faces from three tasks; and social cognition via the NEPSY Face Memory task. Each was evaluated in predicting social ability and autistic social behaviors derived from parental interviews and questionnaires about child behavior at + 6 months (T3) and + 4 years (T4). RESULTS: Adjusting for baseline performance, time between measurements, age, and sex, our results suggest differential prognostic relations for each of the markers. The ERP N170 Latency to Upright Faces showed limited prognostic relations, with a significant relation to short term changes in face memory. The ET OMI was related to face memory over both short and long term. Both the ET OMI and Face Memory predicted long-term autistic social behavior scores. CONCLUSIONS: In the context of a large-scale, rigorous evaluation of candidate markers for use in future clinical trials, our primary markers had significant but small-effect prognostic capability. The ET OMI and Face Memory showed significant long-term predictive relations, with increased visual attention to faces and better face memory at baseline related to increased social approach and decreased autistic social behaviors 4 years later.
eIF5A and hypusination-related disorders: literature review and case report of DOHH-related encephalopathy.
Beltrán-Corbellini Á, Valls-Carbó A, Toledano R … +3 more , García-Morales I, Sánchez-Miranda Román I, Gil-Nagel A
J Neurodev Disord · 2025 Aug · PMID 40883692 · Full text
BACKGROUND: Eukaryotic initiation factor 5 A (eIF5A) and hypusination-related disorders (eIF5A-HRD) are recently described diseases caused by pathogenic heterozygous variants in the translation factor EIF5A or biallelic...
BACKGROUND: Eukaryotic initiation factor 5 A (eIF5A) and hypusination-related disorders (eIF5A-HRD) are recently described diseases caused by pathogenic heterozygous variants in the translation factor EIF5A or biallelic variants in the two enzymes involved in the post-translational synthesis of hypusine in the eIF5A precursor, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), necessary for its activation. We review the current knowledge regarding eIF5A-HRD, and report the case of the sixth and oldest known patient with DOHH-related disorder (DOHH-D), aiming to expand and discuss the molecular basis and the general and epilepsy phenotypes of this group of diseases. RESULTS: Literature review yielded one paper describing 7 individuals with eIF5A-related disorders (eIF5A-D), one reporting 5 subjects with DHPS-related disorders (DHPS-D) and one characterizing 5 individuals with DOHH-D. Main phenotypic features consisted of prenatal issues, hypotonia, dysmorphisms, microcephaly, moderate-severe neurodevelopmental disorders/intellectual disability and behavioral disorders. We report the case of a 24-years-old male with DOHH-D manifesting as Dravet-like syndrome. He displays microcephaly and neurodevelopmental delay with attention deficit with hyperactivity disorder, along with a happy demeanor. Basic language skills and ambulation capacity with crouch gait are preserved. Onset of epilepsy was at 8 months with refractory temperature-triggered hemiclonic seizures and status epilepticus, followed by nocturnal tonic-clonic seizures from adolescence. Fenfluramine was the most effective approach, reducing seizure intensity, duration and frequency, and contributing to cognitive and behavior improvements. No patient with eIF5A-D presented seizures. Taking our patient into account, 4/5 and 4/6 reported individuals with DHPS-D and DOHH-D, respectively, presented epilepsy. Seven out of 8 epilepsy patients debuted between 2 and 5 years, most of them presented developmental and epileptic encephalopathies or generalized epilepsies (5/8 with temperature or infection-triggered seizures), and 4/8 were refractory. We hypothesize that dysregulation of IQSEC2 and SHANK3, among other genes, might contribute to the eIF5A-HRD phenotype. CONCLUSIONS: eIF5A-HRD are recently described entities displaying neurodevelopmental disorders and microcephaly, and reported patients are scarce. More than 70% of DHPS-D and DOHH-D patients present epilepsy, 63% of them with temperature-triggered seizures. Valproic acid or fenfluramine may be effective. Rare homozygous or compound heterozygous missense variants in these genes should be screened in patients with encephalopathy and temperature-triggered seizures.
Phenotypic variation in neural sensory processing by deletion size, age, and sex in Phelan-McDermid syndrome.
Smith MR, Berry-Kravis E, Thaliath A … +12 more , Isenstein EL, Durkin AR, Foss-Feig J, Siper PM, Nelson CA, Baczewski L, Levin AR, Powell CM, Pulver SL, Mosconi MW, Kolevzon A, Ethridge LE
J Neurodev Disord · 2025 Aug · PMID 40855273 · Full text
BACKGROUND: Phelan-McDermid Syndrome (PMS) is a rare genetic condition characterized by deletion or mutation of region 22q13.3, which includes the SHANK3 gene. Clinical descriptions of this population include severely im...
BACKGROUND: Phelan-McDermid Syndrome (PMS) is a rare genetic condition characterized by deletion or mutation of region 22q13.3, which includes the SHANK3 gene. Clinical descriptions of this population include severely impaired or absent expressive language, mildly dysmorphic features, neonatal hypotonia, developmental delays, intellectual impairments, and autistic-like traits including abnormal reactivity to sensory stimuli. Electroencephalography (EEG) has shown promise as a tool for identifying neurophysiological abnormalities in neurodevelopmental disorders. However, few EEG studies focused on sensory processing have been performed on this population. Thus, this study focuses on comparisons of event-related potential (ERP), event-related spectral perturbation (ERSP), and inter-trial coherence (ITC) between PMS and typically developing (TD) individuals in a standard auditory gating task measuring attenuation of neural activity to repetitive auditory stimuli. METHODS: A total of 37 participants, 21 PMS (12 females, age range 8-18.6 years) and 16 TD individuals (8 females, age range 8.2-15.3 years) were included. Analysis consisted of a series of general linear models using a regional (frontal) and global (whole-head) approach to characterize neural activity between PMS and TD participants by age, sex, and group. RESULTS: Most notably, individuals with PMS had delayed or low amplitude P50, N1, and P2 responses in frontal and whole-head analyses as well as poor frontal phase-locking to auditory stimuli for alpha, beta and gamma ITC, indicating impaired processing of stimulus properties. Additionally, individuals with PMS differed from TD by age in delta, theta, and alpha power, as well as frontal beta-gamma ITC, suggesting different developmental trajectories for individuals with PMS. Within PMS, larger deletion sizes were associated with increased auditory processing abnormalities for frontal P50 as well as whole-head P50 and N1. LIMITATIONS: This is one of the largest EEG studies of PMS. However, PMS is a rare genetic condition, and our small sample has limited statistical power for subgroup comparisons. Findings should be considered exploratory. CONCLUSIONS: Results suggest that participants with PMS exhibit auditory processing abnormalities with complex variation by deletion-size, age, and sex with congruency to impaired early recognition (P50), feature processing (N1), information integration (delta, theta), sensory processing and auditory inhibition (alpha), and inhibitory modulation of repeated auditory stimuli (beta, gamma). Findings may provide valuable insight into clinical characterization of sensory and speech behaviors in future studies.
Biomarker development in Sturge-Weber syndrome.
Gupta SS, Joslyn KE, McKenney KD … +1 more , Comi AM
J Neurodev Disord · 2025 Aug · PMID 40851064 · Full text
Sturge-Weber Syndrome (SWS) is a congenital neurovascular disorder caused by a somatic mosaic mutation in the R183Q GNAQ gene and characterized by capillary-venous malformations of the brain, skin, and eyes. Clinical man...
Sturge-Weber Syndrome (SWS) is a congenital neurovascular disorder caused by a somatic mosaic mutation in the R183Q GNAQ gene and characterized by capillary-venous malformations of the brain, skin, and eyes. Clinical manifestations include facial port-wine birthmark, glaucoma, seizures, headache or migraine, hemiparesis, stroke or stroke-like episodes, developmental delay, behavioral problems, and hormonal deficiencies. SWS requires careful monitoring, management, and early identification to improve outcome and prevent neurological deterioration. Over the last 25 years, biomarkers have been developed to improve early diagnosis and prognosis and allow for the monitoring of clinical status and treatment response. Importantly, advancements in biomarker research may enable presymptomatic treatment for infants with SWS. This review summarizes current, ongoing, and potential future SWS biomarker studies. These biomarkers, in combination with clinical data, offer a rich source of data for rare disease research leveraging machine learning in future research.
An epigenome-wide association study in the case-control study to explore early development identifies differential DNA methylation near ZFP57 as associated with autistic traits.
Howerton EM, Morrill V, Schrott R … +13 more , Daniels J, Song AY, Benke K, Volk H, Farzadegan H, Anido Alexander A, Tapia AL, Dichter GS, Croen LA, Wiggins L, Wojcik G, Fallin MD, Ladd-Acosta C
J Neurodev Disord · 2025 Aug · PMID 40819066 · Full text
BACKGROUND: Quantitative measures of autism spectrum disorder (ASD)-related traits can provide insight into trait presentation across the population. Previous studies have identified epigenomic variation associated with...
BACKGROUND: Quantitative measures of autism spectrum disorder (ASD)-related traits can provide insight into trait presentation across the population. Previous studies have identified epigenomic variation associated with ASD diagnosis, but few have evaluated quantitative traits. We sought to identify DNA methylation patterns in child blood associated with Social Responsiveness Scale score, Second Edition (SRS). METHODS: We conducted an epigenome-wide association study of SRS in child blood at approximately age 5 in the Study to Explore Early Development, a case-control study of ASD in the United States. We measured DNA methylation using the Illumina 450K array with 857 samples in our analysis after quality control. We performed regression of the M-value to identify single sites or differentially methylated regions (DMRs) associated with SRS scores, adjusting for sources of biological and technical variation. We examined methylation quantitative trait loci and conducted gene-ontology-term pathway analyses for regions of interest. RESULTS: We identified a region about 3.5 kb upstream of ZFP57 on chromosome 6 as differentially methylated (family-wise error rate [fwer] < 0.1) by continuous SRS T-score in the full sample (N = 857; fwer = 0.074) and among ASD cases only (N = 390; fwer = 0.021). ZFP57 encodes a transcription factor involved in imprinting regulation and maintenance, and this DMR has been previously associated with ASD in brain and buccal samples. CONCLUSIONS: Blood DNA methylation near ZFP57 was associated (fwer < 0.1) with SRS in the full population sample and appears to be largely driven by trait heterogeneity within the autism case group. Our results indicate DNA methylation associations with ASD quantitative traits are observable in a population and provide insights into specific biologic changes related to autism trait heterogeneity.
Challenges with shifting, regardless of disengagement: attention mechanisms and eye movements in Williams syndrome.
Hallman A, Willfors C, Fawcett C … +3 more , Frick MA, Nordgren A, Kleberg JL
J Neurodev Disord · 2025 Aug · PMID 40804613 · Full text
BACKGROUND: People with Williams syndrome (WS) face challenges in various areas of cognitive processing, including attention. Previous studies suggest that these challenges are particularly pronounced when disengagement...
BACKGROUND: People with Williams syndrome (WS) face challenges in various areas of cognitive processing, including attention. Previous studies suggest that these challenges are particularly pronounced when disengagement of attention from a previously attended stimulus is required, as compared to shifting attention without the need to disengage. Difficulties with attention could in turn be implicated in several of the behavioral characteristics of WS. Here, disengagement and shifting of visual attention, together with pupil dilation, were independently assessed in one of the largest eye-tracking studies of WS to date. METHODS: We investigated shifting, disengagement, and the effects of auditory alerting cues on pupil dilation in WS individuals (n = 45, age range = 9–58 years), non-WS individuals with intellectual disability (ID) (n = 36, age range = 6–59 years), and typically developed (TD) infants (n = 32, age range = 6–7 months), children and adults (n = 31, age range = 9–60 years), using a modified gap-overlap task. Data were analyzed using linear mixed-effect models (LMMs). RESULTS: Individuals with WS were less likely to shift their attention to upcoming targets than TD individuals (all ages), but more likely than the ID group to do so. When they did shift attention, participants with WS and ID were slower to initiate a gaze shift than TD participants regardless of whether disengagement was needed. In the WS group, failure to shift attention was strongly predicted by higher arousal (pupil dilation), which was induced by auditory alerting cues. CONCLUSIONS: Contrasting with previous theories of attention in WS, we found no evidence for a specific challenge in disengaging attention. Instead, our results point to a more general challenge in shifting attention. Reduced attention shifting in WS may be partly explained by atypical arousal regulation. These results contribute to our understanding of the WS phenotype.
Objective diagnosis of attention-deficit/hyperactivity disorder by using load cell movement analysis under a smart chair in a simulated classroom: influence of sex and age.
Ouyang CS, Wu RC, Chiu YH … +2 more , Yang RC, Lin LC
J Neurodev Disord · 2025 Aug · PMID 40797295 · Full text
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children, typically characterized by persistent patterns of inattention or hyperactivity-impulsivity. Its diagnosis r...
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children, typically characterized by persistent patterns of inattention or hyperactivity-impulsivity. Its diagnosis relies on criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and is primarily based on subjective observations and information provided by parents and teachers. Despite the availability of assessment tools such as the Swanson, Nolan, and Pelham questionnaire, diagnosing ADHD in children remains challenging. Such scales predominantly offer subjective insights into the disorder. Therefore, in this study, we developed an objective method that employs load cells for the objective diagnosis of ADHD. METHODS: A simulated classroom environment was constructed to replicate a real-world setting. The setup included a desk, chair, and large screen. Load cells, which deform under applied force, were integrated into the four legs of the chair to capture movement data. This study involved 30 children with ADHD (14 boys and 16 girls; mean age: 8 years and 1 month ± 1 year and 10 months) and 30 age- and sex-matched children without ADHD (mean age: 8 years and 3 months ± 1 year and 10 months). Participants were instructed to sit on the chair and watch an age-appropriate educational video on mathematics. Movement data, captured through the load cells, were analyzed to calculate the average trajectory length (ATL) as a measure of activity. For participants with ADHD, SNAP-IV questionnaires were completed by parents and teachers. RESULTS: The ATL values for the ADHD and non-ADHD groups were 0.0378 ± 0.0191 and 0.0157 ± 0.0119 (p < 0.0001), respectively. In the ADHD group, boys exhibited a higher ATL (0.0443 ± 0.0100) than girls (0.0303 ± 0.0228; p = 0.0432). The SNAP-IV scores assigned by parents and teachers for participants with ADHD were 33.14 ± 13.75 and 30.95 ± 14.32, respectively. Decision tree classifiers incorporating sex as a variable demonstrated robust performance, achieving an accuracy of 90.67%, sensitivity of 92.33%, specificity of 89.00%, and area under the curve of 91.06%. CONCLUSION: The smart chair equipped with load cells is an interesting development in progress tool for the objective diagnosis of ADHD and can aid clinical physicians in making decisions regarding ADHD evaluation.
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