J Neurodev Disord [JOURNAL]
Sun
200 papers
Current situation and influencing factors of Chinese children's diagnosis delay in autism.
Zhu FL, Ji Y, Wang L … +2 more , Xu M, Zou XB
J Neurodev Disord · 2025 Aug · PMID 40797185 · Full text
BACKGROUND: Although experienced clinicians are capable of diagnosing autism in children before they reach the age of 2, the average age of diagnosis reported internationally is between 4 and 5 years, indicating a signif...
BACKGROUND: Although experienced clinicians are capable of diagnosing autism in children before they reach the age of 2, the average age of diagnosis reported internationally is between 4 and 5 years, indicating a significant delay. This study aimed to determine the factors influencing the diagnostic delay time (DDT) in Chinese autistic children. METHODS: We employed the Cox proportional hazard model to examine the effects of individual, family, sociodemographic, and healthcare system indicators on DDT in 480 Chinese autistic children (age range: 16.10-190.16 months; male-to-female ratio: 5.67:1) recruited from a tertiary hospital between 2021 and 2023. RESULTS: The median DDT was 9.58 months (IQR = 15.01). Independent risk factors for delayed diagnosis included normal language competence (RR = 1.747, p < 0.001), non-core symptoms as first concerns (RR = 1.642, p = 0.013), school attendance (RR = 1.941, p < 0.001), irregular well-child visits (RR = 1.264, p = 0.028), and misdiagnosis history (RR = 0.648, p = 0.001). CONCLUSIONS: Diagnosis delay in Chinese autistic children is heterogeneous. Early monitoring for children with normal language skills and school-aged children, alongside improved healthcare system practices, is critical.
Autism-like phenotype across the lifespan of Shank3B-mutant mice of both sexes.
Szabó J, Filo J, Démuthová R … +4 more , Renczés E, Borbélyová V, Ostatníková D, Celec P
J Neurodev Disord · 2025 Aug · PMID 40753218 · Full text
BACKGROUND: High heritability (80-90%) of the autism spectrum disorder (ASD) and sex-biased incidence (3-4 times more boys than girls) suggest the roles of genetic predisposition and sex in the etiopathogenesis of the di...
BACKGROUND: High heritability (80-90%) of the autism spectrum disorder (ASD) and sex-biased incidence (3-4 times more boys than girls) suggest the roles of genetic predisposition and sex in the etiopathogenesis of the disorder. As ASD is commonly diagnosed in early childhood, most of the research is focused on children, yet animal research predominantly uses adult-aged animals. The effect of aging on the core and secondary ASD symptomatology is understudied, both in patients and animal models of ASD. METHODS: To investigate the effect of aging on sociability, repetitive behavior, exploration, locomotor activity, anxiety-like behavior, and object-avoidance behavior, behavioral phenotyping was conducted in Shank3B (n = 67) and C57BL/6J wild-type (WT, n = 68) mice of both sexes (female n = 70, male n = 65) in adolescence (1-2 months of age, n = 42), adulthood (3-6 months of age, n = 40), and old age (12-18 months of age, n = 53). RESULTS: Social deficits were observed only in old Shank3B males. Anxiety-like behavior peaked in adulthood with Shank3B mice roughly 20% more anxious than controls. Repetitive grooming and object-induced avoidance behavior were twice more prevalent in Shank3B mice consistently across the lifespan. Hypoactivity (20% less distance moved) and reduced exploration (30% less rearing behavior) were recorded in Shank3B mice and were more prevalent in female animals (30% less rearing behavior). Data were analyzed using the Three-way ANOVA (genotype, sex, age), followed by a posthoc Bonferroni correction to compare respective subgroups. CONCLUSIONS: Present study shows that aging affects ASD-like phenotype in the Shank3B-mutant mouse model, even though the effect size seems to be small. The mechanisms underlying these partially sex-specific effects should be the subject of further research with potential translational implications.
Pupil responses to social stimuli are associated with adaptive behaviors across the first 24 months of life.
Grzadzinski R, Carpenter RS, Rutsohn J … +9 more , Jatkar A, Mata K, Bhatt A, Ortiz-Juza MM, Dennehey MR, Gilleskie D, Elison JT, Pégard N, Rodriguez-Romaguera J
J Neurodev Disord · 2025 Aug · PMID 40751179 · Full text
BACKGROUND: Pupil changes in response to well-controlled stimuli can be used to understand processes that regulate attention, learning, and arousal. This study investigates whether pupil dynamics to social stimuli are as...
BACKGROUND: Pupil changes in response to well-controlled stimuli can be used to understand processes that regulate attention, learning, and arousal. This study investigates whether pupil dynamics to social stimuli are associated with concurrent adaptive behavior in typically developing infants. To accomplish this, we developed and assessed pupillary responses to Stimuli for Early Social Arousal and Motivation in Infants (SESAMI). METHODS: A sample of forty-six typically developing children aged six to twenty-four months were exposed to SESAMI. Infants were presented with either dynamic social faces or non-social stimuli that controlled for luminance, motion, and auditory exposure. A multi-level mixed effects model was used to fit pupillary response functions (PRFs) that measure the change in pupil size over time as the infants fixate on either a socially dynamic face or a non-social control. This model produces separate social and non-social PRFs for both the population and each individual. An average individual deviation score from the population PRF was calculated separately for social and non-social trials yielding the pupil response index (PRI). Vineland Adaptive Behavior Scales (VABS) were regressed on social and non-social individual PRIs while controlling for age and average fixation time. We tested whether the social PRI was a statistically significant predictor of adaptive behavior by comparing the model predicted VABS scores with observed scores. RESULTS: An increase in PRI to social stimuli was significantly associated with better adaptive behaviors in typically developing children between 6 and 24 months of age. CONCLUSIONS: SESAMI combined with pupillometry and multi-level mixed effects modeling, provides a novel and scalable framework for quantifying individual differences in pupil changes in response to social stimuli relative to a population-level baseline. By demonstrating that pupil response indices during social fixations predict adaptive behaviors, we lay the foundation to test how these measures may help identify infants with intellectual and developmental disorders.
Patient reported outcomes used in clinical trials and core outcome sets for individuals with genetic intellectual disability: a scoping review.
van Silfhout NY, van Muilekom MM, van Karnebeek CD … +3 more , Daams JG, Haverman L, van Eeghen AM
J Neurodev Disord · 2025 Jul · PMID 40745628 · Full text
BACKGROUND: The impact of genetic intellectual disability (GID) on daily life is significant. To better understand the impact of GID, it is essential to measure relevant patient reported outcomes (PROs). The aim of this...
BACKGROUND: The impact of genetic intellectual disability (GID) on daily life is significant. To better understand the impact of GID, it is essential to measure relevant patient reported outcomes (PROs). The aim of this study is to provide an overview of PROs used for individuals with GID, laying the groundwork for a future generic core PRO set for GID. METHODS: To identify PROs used for individuals with GID, results of two literature reviews were integrated; (1) PROs extracted from a scoping review on outcomes in clinical trials, and (2) PROs identified from a scoping review on core outcome sets (COSs) for specific GIDs through a search in MEDLINE (Ovid), PsycINFO, Embase, and the COMET database. Descriptive analyses were performed. RESULTS: In the first scoping review, 66 different PROs were identified. In the second scoping review, 22 different PROs were identified. After integrating PROs, 18 unique PROs remained, which were classified into a conceptual framework. Most frequently reported PROs were quality of life, perceived health, cognitive functioning, anxiety/stress, and depressive symptoms. CONCLUSION: This study provides an overview of PROs used for individuals with GID. These results will assist in developing a generic core PRO set for GID, to harmonize PROs used in care and research.
Distinct early development trajectories in Nf1 and Tsc2 mouse models of autism.
Ferreira H, Santos S, Martins J … +2 more , Castelo-Branco M, Gonçalves J
J Neurodev Disord · 2025 Jul · PMID 40713507 · Full text
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviors. Males are three times more likely to be diagnosed...
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviors. Males are three times more likely to be diagnosed with ASD than females, and sex-dependent alterations in behavior and communication have been reported both in clinical and animal research. Animal models are useful for understanding ASD-related manifestations and their associated neurobiological mechanisms. However, even though ASD is diagnosed during childhood, relatively few animal studies have focused on neonatal development. METHODS: Here, we performed a detailed analysis of neonatal developmental milestones and maternal separation-induced ultrasonic vocalizations (USVs) in two genetic animal models of ASD, neurofibromatosis type 1 (Nf1) and tuberous sclerosis complex 2 (Tsc2). RESULTS: Nf1 and Tsc2 mice display strikingly distinct developmental profiles regarding motor, strength, and coordination skills. Nf1 mouse pups mostly show genotype-related differences, whereas Tsc2 mouse pups mainly present sexual dimorphisms. Furthermore, we found several differences regarding the number of USVs, frequency modulation, and temporal and spectral profile. Importantly, Nf1 animals tend to present sex- and genotype-dependent differences earlier than the Tsc2 mouse pups, suggesting distinct developmental curves between these two animal models. CONCLUSIONS: This study provides a nuanced understanding of how these two ASD models differ in their developmental trajectories. It underscores the importance of studying sex differences and early-life developmental markers, as these could offer crucial insights into ASD's progression and neurobiology. The distinct profiles of these models may help guide more targeted therapeutic strategies in the future.
Elevated autistic traits and social anxiety, and reduced empathy in adult women with triple X syndrome.
Croyé MA, Freilinger P, Jürgenlimke H … +2 more , Domes G, Meyer J
J Neurodev Disord · 2025 Jul · PMID 40702437 · Full text
BACKGROUND: Triple X syndrome (TXS, 47,XXX) is a sex chromosome aneuploidy affecting females. The condition is associated with cognitive, emotional, and social challenges. While prior research has primarily focused on ch...
BACKGROUND: Triple X syndrome (TXS, 47,XXX) is a sex chromosome aneuploidy affecting females. The condition is associated with cognitive, emotional, and social challenges. While prior research has primarily focused on children, the social and psychological profile of adult women with TXS remains understudied. This study aims to provide a comprehensive assessment of these aspects in adult women with TXS compared to matched controls. METHODS: A cohort of 44 women with TXS (mean age 30.5 years) was compared to 50 age- and education-matched controls (mean age 29.7 years). Standardized assessments measured verbal IQ, psychological distress, chronic stress, emotion regulation, coping mechanisms, social anxiety, empathy, autistic traits, and personality traits. Group comparisons were conducted using ANOVAs and MANOVAs, with additional χ² tests for categorical variables. RESULTS: Depression and trait anxiety did not significantly differ between groups, though both groups exhibited notably high scores. However, a greater number of individuals in the TXS group reported elevated social anxiety and autistic traits, and reduced empathy. Moreover, there were indications of increased self-reported social tensions, personal distress, and somatization within the TXS group. No significant differences were found in personality traits, verbal IQ, chronic stress levels, and emotion regulation. Additionally, TXS participants tended to rely less on the maladaptive coping strategy of alcohol and cigarette consumption. CONCLUSION: Our findings underscore autistic traits, social anxiety, and reduced empathy as significant challenges for adult women with TXS. While cognitive and emotional characteristics were largely comparable to those of age- and education-matched controls, the heightened social difficulties suggest a potential benefit of targeted interventions, such as social skills training, to support affected individuals. Longitudinal studies are essential to understand the long-term progression of these challenges and to develop effective therapeutic strategies.
Brain functional connectivity correlates of autism diagnosis and familial liability in 24-month-olds.
Pruett JR, Todorov AA, Hawks ZW … +27 more , Talovic M, Nishino T, Petersen SE, Davis S, Stahl L, Botteron KN, Constantino JN, Dager SR, Elison JT, Estes AM, Evans AC, Gerig G, Girault JB, Hazlett H, MacIntyre L, Marrus N, McKinstry RC, Pandey J, Schultz RT, Shannon WD, Shen MD, Snyder AZ, Styner M, Wolff JJ, Zwaigenbaum L, Piven J, for the IBIS Network
J Neurodev Disord · 2025 Jul · PMID 40682020 · Full text
BACKGROUND: fcMRI correlates of autism spectrum disorder (ASD) diagnosis and familial liability were studied in 24-month-olds at high (older affected sibling) and low familial likelihood for ASD. METHODS: fcMRI compariso...
BACKGROUND: fcMRI correlates of autism spectrum disorder (ASD) diagnosis and familial liability were studied in 24-month-olds at high (older affected sibling) and low familial likelihood for ASD. METHODS: fcMRI comparisons of high-familial-likelihood (HL) ASD-positive (HLP, N = 23) and ASD-negative (HLN, N = 91), and low-likelihood ASD-negative (LLN, N = 27) 24-month-olds from the Infant Brain Imaging Study (IBIS) Network were conducted, employing object oriented data analysis (OODA), support vector machine (SVM) classification, and network-level fcMRI enrichment analyses. RESULTS: OODA (alpha = 0.0167, 3 comparisons) revealed differences in HLP and LLN fcMRI matrices (p = 0.012), but none for HLP versus HLN (p = 0.047) nor HLN versus LLN (p = 0.225). SVM distinguished HLP from HLN (accuracy = 99%, PPV = 96%, NPV = 100%), based on connectivity involving many networks. SVM accurately classified (non-training) LLN subjects with 100% accuracy. Enrichment analyses identified a cross-group fcMRI difference in the posterior cingulate default mode network 1 (pcDMN1)- temporal default mode network (tDMN) pair (p = 0.0070). Functional connectivity for implicated connections in these networks was consistently lower in HLP and HLN than in LLN (p = 0.0461 and 0.0004). HLP did not differ from HLN (p = 0.2254). Secondary testing showed HL children with low ASD behaviors still differed from LLN (p = 0.0036). CONCLUSIONS: 24-month-old high-familial-likelihood infants show reduced intra-DMN connectivity, a potential neural finding related to familial liability, while widely distributed functional connections correlate with ASD diagnosis.
Identifying compound heterozygous variants in the EEFSEC gene linked to progressive cerebellar atrophy.
Liu Z, He M, Luo X … +7 more , Pan H, Hu J, Wan Z, Peng Y, Luo Y, Wang H, Mao X
J Neurodev Disord · 2025 Jul · PMID 40652205 · Full text
Selenium, an essential micronutrient integrated into selenoproteins as selenocysteine, is fundamental to human health. These selenoproteins are vital for several physiological functions, including maintaining redox balan...
Selenium, an essential micronutrient integrated into selenoproteins as selenocysteine, is fundamental to human health. These selenoproteins are vital for several physiological functions, including maintaining redox balance, safeguarding DNA, and metabolizing thyroid hormones, and are produced via complex pathways involving Sec-tRNA, the SECIS element, and specific proteins such as eEFSec. This study investigates a 4-year-old girl with global developmental delay and cerebellar atrophy, revealing compound heterozygous variants in the EEFSEC gene (p.V488Dfs*113 and p.R443P) through extensive genetic analysis and whole exome sequencing. Both functional prediction tools and structural analysis underscored the detrimental impact of the p.R443P variant. Notably, the patient's plasma exhibited elevated levels of oxidized fatty acid metabolites compared to those in healthy controls, suggesting an impairment in antioxidant mechanisms. This case link a human disease directly to variants in the EEFSEC gene, emphasizing its vital role in cerebellar atrophy and the broader implications for genetic disorders related to defects in selenoprotein synthesis. The results highlight the significance of genetic screening for EEFSEC variants in similar cases, potentially broadening the spectrum of known genetic subtypes associated with selenoprotein translation abnormalities.
Charting the future: current and future directions in translational research for individuals with Down syndrome.
Waugh KA, Wilkins HM, Smith KP … +1 more , Ptomey LT
J Neurodev Disord · 2025 Jul · PMID 40629284 · Full text
The most common genetic cause of intellectual and developmental disability is trisomy of human chromosome 21 (trisomy 21) or Down syndrome. Relative to the general population, individuals with Down syndrome heterogeneous...
The most common genetic cause of intellectual and developmental disability is trisomy of human chromosome 21 (trisomy 21) or Down syndrome. Relative to the general population, individuals with Down syndrome heterogeneously experience atypical morphogenesis, a distinct neurocognitive profile, and a unique spectrum of diverse medical conditions that impact every major organ system. How trisomy 21 results in the highly variable manifestations of Down syndrome remains largely unknown and an active area of heavy investigation with therapeutic implications. For example, common inflammatory and metabolic signatures have begun to emerge across various co-occurring conditions in Down syndrome with assorted impacts on diverse yet intertwined organ systems that could directly or indirectly impact brain health. Here, we review current progress, resources, knowledge gaps, and bottlenecks for precision medicine approaches to promote brain health across the lifespan among individuals with Down syndrome within the larger context of research efforts geared towards our other distinct yet intertwined organ systems. Within this framework, we advocate for interdisciplinary pursuit of systems-level biomarkers to facilitate holistic intervention strategies that precisely benefit individuals with trisomy 21 each experiencing Down syndrome in their own unique way. To this end, we quantitatively assess clinical studies that are actively recruiting participants with Down syndrome and provide historical context through summary figures sourced to user-friendly tables that have been curated from federal websites to empower efficient exploration of research opportunities for interdisciplinary collaborations.
Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder.
Xia D, Xu Y, He Z … +15 more , Chen R, Xiao X, Li X, Deng K, Deng S, Zhang L, Zhang J, Peng X, Meng Z, Wu R, Wang D, Liu Z, Chen H, Li L, Liang L
J Neurodev Disord · 2025 Jul · PMID 40604385 · Full text
ANKRD17 has recently been implicated in intellectual disability (ID) and autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. Using trio whole-exome sequencing (Trio-WES) and chrom...
ANKRD17 has recently been implicated in intellectual disability (ID) and autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. Using trio whole-exome sequencing (Trio-WES) and chromosomal microarray analysis (CMA), we identified two unrelated cases with novel de novo heterozygous ANKRD17 variants. Case 1 describes a fetus with multiple congenital anomalies, where genetic analysis revealed a microdeletion at 4q13.3 truncating the ANKRD17 gene. Case 2 involves a 12-year-old male presenting with mild ID and progressive social impairments, associated with a NM_032217.5: c.1252 C > T (p.Arg418*) variation in ANKRD17. Our study highlighted in mouse models an association between Ankrd17 haploinsufficiency and deficits in social behavior, spatial learning and memory, as well as elevated anxiety. Furthermore, our studies suggest dysregulation of synaptic proteins and mitochondrial function, along with impaired neural circuits following Ankrd17 knockdown. These results expand the genetic and phenotypic spectrum of ANKRD17-related disorders, underscore the critical role of mitochondrial dysfunction in the pathophysiology of ANKRD17-related ID and ASD.
Diffusivity alterations related to cognitive performance and phenylalanine levels in early-treated adults with phenylketonuria.
Pardo J, Capdevila-Lacasa C, Segura B … +6 more , Pané A, Moreno PJ, Garrabou G, Grau-Junyent JM, Junqué C, Consortium PKU.cat
J Neurodev Disord · 2025 Jul · PMID 40604374 · Full text
BACKGROUND: Altered white matter (WM) is consistently reported in patients with phenylketonuria (PKU). However, the knowledge about WM microstructural integrity in early-treated adults with classical PKU and its relation...
BACKGROUND: Altered white matter (WM) is consistently reported in patients with phenylketonuria (PKU). However, the knowledge about WM microstructural integrity in early-treated adults with classical PKU and its relationship with cognition and metabolic parameters is inconclusive. This study aims to explore the cerebral WM microstructural alterations in adult patients with early-treated classical PKU and their association with blood phenylalanine (Phe) levels and neuropsychological performance using whole-brain diffusion tensor imaging (DTI). METHODS: Twenty-nine patients with early-treated classical PKU (mean age = 30.86, SD = 7.74) and 31 healthy controls (mean age = 32.45, SD = 9.40) underwent neuropsychological assessment and MRI. Phe dry blood spot (DBS-Phe) samples, along with venous Phe levels, were collected from the PKU sample to calculate the index of dietary control (IDC). Tract-based spatial statistics (TBSS) of the mean diffusivity (MD), and fractional anisotropy (FA), were carried out with FSL v6.0.4 to assess between-group differences and to explore associations with both cognitive and clinical data. RESULTS: Patients exhibited a widespread white matter tract involvement, with lower MD and higher FA values compared to controls. The most affected tracts were the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus for MD, and the anterior corona radiata, uncinate fasciculus and forceps minor for FA. MD negatively correlated with IDC and venous Phe levels, whereas FA negatively correlated with full-scale intelligence quotient (FSIQ) (p-value ≤0.05 FWE-corrected). CONCLUSIONS: Microstructural WM alterations were present in adults with early-treated classical PKU, and these abnormalities were related to global intelligence and metabolic control markers. Although our results suggest the importance of proper disease management, further studies are needed to determine its long-term relevance.
Pathways to autism diagnosis in adulthood.
Dufour I, Chiu Y, Brodeur S … +6 more , Courteau M, Courteau J, Dubé É, Lesage A, Fombonne É, Couture M
J Neurodev Disord · 2025 Jul · PMID 40596839 · Full text
BACKGROUND: This study explored Trajectories of Diagnoses (TDs) preceding a first diagnosis of autism in adulthood. METHODS: This retrospective cohort study used health administrative data from Quebec, Canada, and includ...
BACKGROUND: This study explored Trajectories of Diagnoses (TDs) preceding a first diagnosis of autism in adulthood. METHODS: This retrospective cohort study used health administrative data from Quebec, Canada, and included all adults with a first recorded diagnosis of autism between 2012 and 2017. A TDs was defined as a succession of medical records of psychiatric and/or neurodevelopmental conditions over time. These TDs were retrospectively analyzed from 2002 to 2017, using a state sequence analysis of diagnoses, in order: Autism, Intellectual or developmental disabilities (IDDs), Schizophrenia spectrum disorder (SSD), Bipolar Disorder (BD), Depressive Disorder (DD), Anxiety Disorder (AD), Attention-deficit/hyperactivity disorder (ADHD), and Other psychiatric and/or neurodevelopmental conditions. RESULTS: The cohort included 2799 adults with a first recorded diagnosis of autism between 2012 and 2017. Several psychiatric and/or neurodevelopmental conditions were recorded since 2002, including AD (77.5%), DD (58.0%), SSD (49.4%), BD (48.3%), and IDDs (33.2%). Results revealed 5 distinct types of TDs. Types 1 (63.8%), 2 (17.6%) and 3 (6%) represented individuals in younger age groups with similar characteristics but with very different sequences of diagnoses, characterized by mixed diagnoses in type 1, SSD and AD in Type 2, and IDDs, DD, AD, and ADHD in type 3. Types 4 and 5 (9.0% and 3.6%), representing middle-aged/older groups, displayed distinctive TDs associated with high healthcare use, almost entirely associated with SSD (Type 4) and BD (Type 5). CONCLUSION: This study proposes a complementary examination of the multiple pathways to diagnosis experienced by adults, highlighting the need to address differential diagnosis and co-occurring psychiatric and neurodevelopmental conditions.
Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD.
Zhong Y, Baum LW, Tubbs JD … +11 more , Ye R, Chen LH, Wu T, Hung SF, Tang CP, Ho TP, Moyzis R, Swanson J, Lee CC, Sham PC, Leung PWL
J Neurodev Disord · 2025 Jun · PMID 40542392 · Full text
OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with a significant genetic component. The latest genome-wide association study (GWAS) meta-analysis of ADHD identified 27 w...
OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with a significant genetic component. The latest genome-wide association study (GWAS) meta-analysis of ADHD identified 27 whole-genome significant risk loci in the European population. However, genetic risk factors for ADHD are less well-characterized in the Asian population, especially for low-frequency / rare variants. METHODS: In this study, we aimed to investigate the contributions of both common and low-frequency / rare variants to ADHD in a Hong Kong sample. Our sample comprised 279 cases and 432 controls who underwent genotyping using the Illumina Infinium Global Screening Array. We employed various analytical methods at different levels, while also leveraging multi-omics data and large-scale summary statistics to comprehensively analyze the genetic basis of ADHD. RESULTS: We identified 41 potential genomic risk loci with a suggestive association (p < 1e), pointing to 111 candidate risk genes, which were enriched for genes differentially expressed during late infancy brain development. Furthermore, tissue enrichment analysis implicated the involvement of the cerebellum. At the polygenic level, we also discovered a strong genetic correlation with resting-state functional MRI connectivity of the cerebellum involved in the attention/central executive and subcortical-cerebellum networks. In addition, an accumulation of ADHD common-variant risks found in European ancestry samples was found to be significantly associated with ADHD in the current study. In low-frequency / rare variant analyses, we discovered the correlations between ADHD and collapsing effects of rare damaging variants in TEP1, MTMR10, DBH, TBCC, and ANO1. Based on biological and functional profiles of the potential risk genes and gene sets, both common and low-frequency / rare variant analyses demonstrated that ADHD genetic risk was associated with immune processes. CONCLUSIONS: These findings re-validate the abnormal development of the neural system in ADHD and extend the existing neuro-dysfunction hypothesis to a multi-system perspective. The current study identified convergent risk factors from common and low-frequency / rare variants, which implicates vulnerability in late-infancy brain development, affecting especially the cerebellum, and the involvement of immune processes.
Developmental milestones and cognitive trajectories in school-aged children with 16p11.2 deletion.
Verbesselt J, Breckpot J, Zink I … +1 more , Swillen A
J Neurodev Disord · 2025 Jun · PMID 40537766 · Full text
BACKGROUND: 16p11.2 deletion syndrome (16p11.2DS) is a recurrent CNV that occurs de novo in approximately 70% of cases and confers risk for neurodevelopmental disorders, including intellectual disability (ID) and autism...
BACKGROUND: 16p11.2 deletion syndrome (16p11.2DS) is a recurrent CNV that occurs de novo in approximately 70% of cases and confers risk for neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorders (ASD). The current study focusses on developmental milestones, cognitive profiles and longitudinal cognitive trajectories. METHODS: In-person assessments, digital medical records and parental interviews on developmental history of 24 children (5-16 years) with a confirmed BP4-BP5 16p11.2DS were reviewed and analysed for developmental milestones (motor, language, continence). Standardised intelligence tests were administered in all children, and longitudinal IQ-data were available for a subgroup (79%, 19/24). RESULTS: Motor, language, and continence milestones were delayed. Average IQ was in the borderline range (IQ 71) with 46% (11/24) having borderline IQ (IQ 70-84). Both intra- and interindividual variability were found across the five cognitive domains with significant discrepancies between verbal and non-verbal skills in 55% (11/20). Longitudinal IQ-data indicate that school-aged children with 16p11.2DS perform statistically significantly lower at the second time point (p < 0.001) with 58% showing a growing into deficit trajectory. CONCLUSION: Delayed motor, language and continence milestones are common in 16p11.2DS carriers. School-aged children with 16p11.2DS show increasing cognitive impairments over time, pointing to the need for early diagnosis, regular cognitive follow-up and individualised intervention. The high prevalence of disharmonic IQ-profiles highlights the importance of expanding the focus beyond full-scale IQ (FSIQ) outcomes. Future studies in larger cohorts including carrier relatives are needed to gain more insight into the penetrance and phenotypic variability of 16p11.2DS.
Enhancing the discriminatory power of polygenic scores for ADHD and autism in clinical and non-clinical samples.
Li JJ, He Q, Dorn S … +2 more , Wang Z, Lu Q
J Neurodev Disord · 2025 Jun · PMID 40490728 · Full text
BACKGROUND: Polygenic scores (PGS) are widely used in psychiatric genetic associations studies due to their predictive power for focal outcomes. However, they lack discriminatory power, in part due to the high degree of...
BACKGROUND: Polygenic scores (PGS) are widely used in psychiatric genetic associations studies due to their predictive power for focal outcomes. However, they lack discriminatory power, in part due to the high degree of genetic overlap between psychiatric disorders. The lack of prediction specificity limits the clinical utility of psychiatric PGS, particularly for diagnostic applications. The goal of the study was to enhance the discriminatory power of psychiatric PGS for two highly comorbid and genetically correlated neurodevelopmental disorders in ADHD and autism spectrum disorder (ASD). METHODS: Genomic structural equation modeling (GenomicSEM) was used to generate novel PGS for ADHD and ASD by accounting for the genetic overlap between these disorders (and eight others) to achieve greater discriminatory power in non-focal outcome predictions. PGS associations were tested in two large independent samples - the Philadelphia Neurodevelopmental Cohort (N = 4,789) and the Simons Foundation Powering Autism Research for Knowledge (SPARK) ASD and sibling controls (N = 5,045) cohort. RESULTS: PGS from GenomicSEM achieved superior discriminatory power in terms of showing significantly attenuated associations with non-focal outcomes relative to traditionally computed PGS for these disorders. Additionally, genetic correlations between GenomicSEM PGS for ASD and ADHD were significantly attenuated in cross-trait associations with other psychiatric disorders and outcomes. CONCLUSIONS: Psychiatric PGS associations are likely inflated by the high degree of genetic overlap between the psychiatric disorders. Methods such as GenomicSEM can be used to refine PGS signals to be more disorder-specific, thereby enhancing their discriminatory power for future diagnostic applications.
Neural excitation/inhibition imbalance and neurodevelopmental pathology in human copy number variant syndromes: a systematic review.
Sylvester AL, Hensenne E, Ivanov D … +4 more , Poser BA, Linden DEJ, van Amelsvoort T, Vingerhoets C
J Neurodev Disord · 2025 Jun · PMID 40490701 · Full text
Cumulative evidence suggests neurodevelopmental disorders are closely related. The risk of these disorders is increased by a series of copy number variant syndromes - phenotypically heterogeneous genetic disorders, prese...
Cumulative evidence suggests neurodevelopmental disorders are closely related. The risk of these disorders is increased by a series of copy number variant syndromes - phenotypically heterogeneous genetic disorders, present in a minority of the population. Recent models suggest that a disruption in the balance between excitatory and inhibitory neural activity may contribute to the aetiology of neurodevelopmental disorders, and may be additionally disturbed in copy number variant syndromes. In this systematic review, the databases PubMed, Embase, and Scopus were searched for studies of excitation/inhibition imbalance in relation to neurodevelopmental disorders in human copy number variant samples. A total of 53 studies were included, representing a variety of copy number variants and research methodologies. The resulting data suggests excitation/inhibition balance is indeed disrupted in different copy number variant populations, providing insight into a putative mechanism of both idiopathic and genetic neurodevelopmental disorders. However, the high level of heterogeneity in the data set, alongside emerging techniques for excitation/inhibition assessment, prompts further investigation of this field.
Acceptability and safety of a probiotic beverage supplementation (Bio-K +) and feasibility of the proposed protocol in children with a diagnosis of autism spectrum disorder.
Gaougaou G, Zahra R, Morel S … +11 more , Bélanger V, Knoth IS, Cousineau D, D'Arc BF, Grzywacz K, Rousseau G, Déziel E, Godbout R, Lippé S, Millette M, Marcil V
J Neurodev Disord · 2025 May · PMID 40413384 · Full text
BACKGROUND: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders defined by stereotyped behavior and challenges in social communication and social interaction. ASD is associated with various comorbid...
BACKGROUND: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders defined by stereotyped behavior and challenges in social communication and social interaction. ASD is associated with various comorbidities, including anxiety, gastrointestinal (GI) symptoms and sleep disorders. Evidence supports an association between intestinal dysbiosis and the severity of ASD-related symptoms. Probiotic intake was suggested to restore microbial homeostasis and decrease neurobehavioral, GI and sleep symptoms in individuals diagnosed with autism. METHODS: This study aims to evaluate the acceptability and safety of a Bio-K + probiotics beverage in autistic children aged 4 to 11 years and the feasibility of the proposed research protocol to measure its impact on behaviors and comorbidities. The 30-week study consisted of daily supplementation with Bio-K + probiotics for 14 weeks. Acceptability and safety were monitored throughout the study. Feasibility was assessed by comparing recruitment and completion rates to pre-established thresholds. Preliminary impact of supplementation on behaviors (Autism Treatment Evaluation Checklist (ATEC) score), GI symptoms and sleep disorders was evaluated. RESULTS: Of the 23 children recruited (mean age 6.7 ± 2.2 years, 70% males), 65% had GI problems and 91% had sleep disorders. Probiotic supplementation was accepted by all participants and no product-related adverse event was reported. Feasibility rates exceeded pre-established thresholds for almost all study outcomes including recruitment rate, compliance, electroencephalography, actigraphy and completion of questionnaires. Preliminary data suggest an improvement in behaviors associated with autism assessed with the total ATEC score, and in GI symptoms and sleep disorders. CONCLUSION: This study demonstrates probiotic beverage acceptability and safety and protocol feasibility in autistic children. To further support our data, a double-blinded placebo-controlled study is needed to determine its efficacy.
Remote EEG acquisition in Angelman syndrome using PANDABox-EEG.
Gálvez-Ortega K, Harold R, Neo WS … +6 more , Hoilett OS, Borosh AM, Friesen-Haarer A, Gombas S, Foti D, Kelleher B
J Neurodev Disord · 2025 May · PMID 40413379 · Full text
OBJECTIVE: We describe the development and validation of PANDABox-EEG, a novel protocol for remote EEG assessment with no on-site technician, tailored for Angelman syndrome (AS). We argue that this protocol is reliable,...
OBJECTIVE: We describe the development and validation of PANDABox-EEG, a novel protocol for remote EEG assessment with no on-site technician, tailored for Angelman syndrome (AS). We argue that this protocol is reliable, valid, and widely acceptable for use in families affected by Angelman syndrome. BACKGROUND: AS is a rare neurogenetic condition characterized by developmental delays, sleep problems, seizures, and a happy demeanor. People with AS are frequently monitored via EEG to inform clinical care, and EEG-measured delta activity has been proposed as a reliable biomarker to monitor treatment effectiveness. Traditional EEG assessments pose logistical and financial burdens for families due to the need to travel to a medical center to complete assessments. Telehealth methods, however, offer a pathway forward. METHODS: PANDABox-EEG was developed through multidisciplinary collaboration with psychologists, psychophysiologists, engineers, and special-education scholars, incorporating caregiver feedback and user-centered design principles. It pairs PANDABox, a telehealth platform for biobehavioral assessment in rare disorders, with a dry electrode EEG system. Twenty-eight participants (7 AS, 7 siblings, 14 caregivers) completed three 5-min EEG sessions each over the course of a week. Caregivers were asked to provide feedback on acceptability of the design, and EEG data was quantified and assessed for metrics of reliability and validity. RESULTS: PANDABox-EEG demonstrated high feasibility and acceptability, with 91% of caregivers reporting strong satisfaction assessment comfort. EEG data quality was promising, with high internal consistency (split-half reliability range for children with AS: r = .96-.98) and test-retest reliability for delta power among (test-retest reliability range for children with AS: ρ = .88-.96). Finally, we successfully detected the characteristic increased delta power in AS (effect size between AS and non-AS siblings: d = 1.56-2.85) and its association with age (effect size between non-AS siblings and caregivers: d = 2.19-2.72). CONCLUSION: PANDABox-EEG provides a feasible, cost-effective, and reliable method for remote EEG assessment in AS. Its high caregiver satisfaction and ability to capture relevant neurophysiological markers suggest potential for broader application. With further validation, PANDABox-EEG can enhance accessibility and inclusivity, benefiting clinical management and research in AS and other clinical populations in need of frequent EEG monitoring by eliminating the need to travel.
Contribution of families using the GenIDA database to the description of MED13L syndrome and literature review.
Caumes R, Burger P, Mandel JL … +3 more , Béhal H, Ghoumid J, Smol T
J Neurodev Disord · 2025 May · PMID 40389839 · Full text
The GenIDA project aims to improve the understanding and management of rare genetic forms of intellectual disability by fostering collaboration among patients, caregivers, healthcare professionals, and research professio...
The GenIDA project aims to improve the understanding and management of rare genetic forms of intellectual disability by fostering collaboration among patients, caregivers, healthcare professionals, and research professionals. Clinical data is provided by patients' families via a structured questionnaire to identify medically relevant insights and better understand the natural history of rare diseases. This study focused on MED13L syndrome, analyzing data from 41 patients in the GenIDA database and comparing it with 102 cases from the scientific literature and 6 new descriptions of patients from our medical center.The GenIDA series confirmed the key features of MED13L syndrome, including global developmental delay, poor speech, intellectual disability, and cardiac defects (OMIM #616789), at frequencies similar to those reported in the literature. The GenIDA series identified a higher prevalence of visual impairment (76%) and highlighted under-recognized musculoskeletal issues, such as foot deformities, which had previously received little attention. This study highlights the value of family-reported data in describing the full phenotype of rare syndromes. A comprehensive review of published cases showed that patients with missense variants have more severe impairments, including increased cardiac defects, global developmental delay, and a higher incidence of epilepsy, than patients with premature truncated variants.These findings highlight the importance of family involvement in rare disease research and the need for further studies to explore genotype-phenotype correlations to improve patient care and outcomes.
Acute administration of lovastatin had no pronounced effect on motor abilities, motor coordination, gait nor simple cognition in a mouse model of Angelman syndrome.
Fenton TA, Petkova SP, Adhikari A … +1 more , Silverman JL
J Neurodev Disord · 2025 May · PMID 40382580 · Full text
Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs) and intellectua...
Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs) and intellectual disabilities (IDs). One NDD, associated with ASD and ID, is Angelman Syndrome (AS). AS is a rare genetic NDD for which there is currently no cure nor effective therapeutics. The genetic cause is known to be the loss of expression from the maternal allele of ubiquitin protein ligase E3A (UBE3A). The Ube3a maternal deletion mouse model of AS reliably demonstrates behavioral phenotypes of relevance to AS and therefore offers a suitable in vivo system in which to test potential therapeutics, with construct and face validity. Successes in reducing hyperexcitability and epileptogenesis have been reported in an AS model following acute treatment with lovastatin, an ERK inhibitor by reducing seizure threshold and percentage of mice exhibiting seizures. Since there has been literature reporting disruption of the ERK signaling pathway in AS, we chose to evaluate the effects of acute lovastatin administration in a tailored set of translationally relevant behavioral assays in a mouse model of AS. Unexpectedly, deleterious effects of sedation were observed in wildtype (WT), age matched littermate control mice and despite a baseline hypolocomotive phenotype in AS mice, even further reductions in exploratory activity, were observed post-acute lovastatin treatment. Limitations of this work include that chronic lower dose regimens, more akin to drug administration in humans were beyond the scope of this work, and may have produced a more favorable impact of lovastatin administration over single acute high doses. In addition, lovastatin's effects were not assessed in younger subjects, since our study focused exclusively on adult functional outcomes. Metrics of gait, as well as motor coordination and motor learning in rotarod, previously observed to be impaired in AS mice, were not improved by lovastatin treatment. Finally, cognition by novel object recognition task was worsened in WT controls and not improved in AS, following lovastatin administration. In conclusion, lovastatin did not indicate any major improvement to AS symptoms, and in fact, worsened behavioral outcomes in the WT control groups. Therefore, despite its attractive low toxicity, immediate availability, and low cost of the drug, further investigation for clinical study is unwarranted given the results presented herein.
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