There is significant heterogeneity in clinical presentations, brain-imaging findings, and genetic underpinnings of autism. Autism traits, particularly social affect and joint attention, and related domains of adaptive functioning and cognitive development, are key characteristics in determining autism “profiles”. This study aimed to understand such baseline profiles in preschool autistic children receiving early intervention (age range, 2–7 years old; sample size N = 67). We also examined the association between phenotypic pre-intervention characteristics and response to intervention using Early Start Denver Model (ESDM). Baseline characteristics prior to receiving early intervention demonstrated a link between eye tracking measure of joint attention, namely better gaze accuracy, and clinical profile of autism traits, particularly better social affect/social overtures and adaptive functioning. Further, better receptive and expressive language, visual reception and fine motor skills, and higher development quotients on a visual processing task, were found to be associated with more accurate eye movements on a joint attention task. Predictors of improvement in autistic traits post-intervention included higher age at entry to intervention and baseline developmental functioning. Specifically, social affect was found to change in the same direction as cognitive functioning post-ESDM intervention, especially with regard to visual reception, fine motor and receptive language skills. The findings also suggest that better social affect and joint attention, characterised by better social overtures and maintenance of attention, are predictive of more accurate eye gaze in a social exercise, thereby making these potential intervention targets in early intervention.
Establishing evidence of content validity, or how well a measure reflects the intended outcome, is essential for developing or selecting assessment tools that support individualized care and research in clinical populations like Down syndrome (DS). This study aimed to examine caregiver-reported relevance of a widely used measure of executive function in school-aged youth with DS, the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Parent Form. Specifically, this study focused on one aspect of content validity, relevance to the target population, which has yet to be systematically evaluated in DS. This study integrated data from two online studies of youth with DS. After completing the BRIEF-2, caregivers were asked forced-choice questions about the relevance of the measure to their child with DS, as well as an open-text question about their response strategy for items they deemed not relevant. Caregivers of 281 youth with DS between the ages of 6–18 years (M = 12.7, SD = 3.4) reported on the relevance of the BRIEF-2 for their child. Just under half (46.3
Cerebral palsy (CP) is a neurodevelopmental disorder with a significant male predisposition, yet the underlying genetic mechanisms driving this sex-specific risk remain poorly understood. Given the hemizygous state of X-linked variants in males, we hypothesized that X-chromosomal genetic variations may contribute to CP susceptibility in male patients. We performed an X-chromosome-wide association study (XWAS) using whole-exome sequencing (WES) data from 1,076 male CP patients and 1,057 healthy male controls of Chinese ancestry. Quality control, principal component analysis (PCA), and logistic regression were applied to identify risk loci for CP. Six candidate single nucleotide variants (SNVs) in UTP14A were genotyped via MassARRAY, and haplotype analysis was conducted using SHEsis. We identified a significant association between the intronic variant rs2281277 in UTP14A and CP (P = 1.38E-05, FDR q-value = 0.0465, OR = 0.644). In addition to the lead SNV rs2281277, five other SNVs in UTP14A also showed a suggestive association with CP, including rs141750783, rs61318448, rs2273021, rs2281278, and rs111975985. Haplotype analysis further revealed a risk haplotype (CGTATC) defined by these six SNVs, which was associated with a 53.1
Auditory processing (AP) is a fundamental function in speech signal processing. The ability to process speech signals in noisy environments is commonly used to assess AP capabilities. Research on the AP characteristics in Chinese children remains scarce, and the relationship between AP and language/cognitive development has not been explored. This study investigated the AP performance of children with developmental language disorder (DLD) in daily life and under the standardized speech-in-noise (SIN) comprehension paradigm. Using functional Near-Infrared Spectroscopy (fNIRS) to monitor brain activation in real-time during noisy environments, the study analyzed the functional modes of targeted brain regions in Chinese DLD children under noisy environments, while also exploring the relationships between AP behaviors, brain activation patterns, and cognition. This cross-sectional study enrolled 34 Chinese preschool children with DLD and 43 age- and gender-matched typically developing (TD) children. Parents completed basic demographic information, the Preschool Auditory Processing Assessment Scale (PAPAS), and the Behavior Rating Scale of Executive Function-Preschool Version (BRIEF-P). A self-developed SIN comprehension paradigm adapted for Chinese preschool children with DLD was utilized, and fNIRS was employed to record brain activation patterns while the children performed the SIN comprehension task. 1) AP Behavior: The DLD group scored higher than TD group on all dimensions of the PAPAS (P < 0.05); main effects of the group (F = 54.303, P < 0.001) and listening condition (F = 11.83, P = 0.001) were significant for the accuracy (ACC). 2) Brain activation characteristics during the SIN comprehension task: The DLD group showed significantly lower activation than the TD group in the left dorsolateral prefrontal cortex (DLPFC), left Broca’s area, bilateral superior temporal gyrus and middle temporal gyrus (STG and MTG), and right Wernicke’s area (P-corrected < 0.05). 3) The AP total scores, auditory decoding scores, and hyperactivity impulse dimension scores of both groups of children were negatively correlated with the scores on each dimension of the DREAM-C and the WPPSI-IV/WISC-IV (P-corrected < 0.05); the scores on each PAPAS dimension were positively correlated with the scores on each dimension of BRIEF-P (P-corrected < 0.05). 4) The activation levels in the left DLPFC, left Broca’s area, right Wernicke’s area, and bilateral STG and MTG in both groups of children were positively correlated with all dimensions of the DREAM-C (P-corrected < 0.05). The activation levels in the left DLPFC, left Broca’s area, right Wernicke’s area, and right STG and MTG were positively correlated with the full-scale intelligence quotient and verbal comprehension index scores (P-corrected < 0.05). Children with DLD may exhibit AP abnormalities as early as the preschool years, as reflected by poorer performance on AP tasks and atypical cortical activation patterns.
With the advent of exome sequencing, a growing number of children are being identified with de novo loss-of-function mutations in the dynamin 1-like (DNM1L) gene, which encodes the large GTPase essential for mitochondrial fission, dynamin-related protein 1 (DRP1). Mutations in DRP1 result in severe neurodevelopmental phenotypes, such as developmental delay, optic atrophy, and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in different domains of DRP1 uniquely disrupt cortical development and synaptic maturation. We leveraged the power of human induced pluripotent stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model early stages of cortical development in vitro. High-resolution time-lapse imaging of transport in neuronal projections revealed mutation-specific changes in mitochondrial motility of severely hyperfused mitochondrial structures. Transcriptional profiling of mutant DRP1 cortical neurons during maturation also implicated mutation-dependent alterations in synaptic development and gene expression of calcium-regulatory genes. Disruptions in calcium dynamics were confirmed using live functional recordings of 65–200 days in vitro (DIV) mutant DRP1 cortical neurons. These findings strongly suggest that altered mitochondrial morphology in DRP1 mutant neurons leads to pathogenic dysregulation of synaptic development and activity.
Abstract Background Epilepsy and Autism Spectrum Disorder (ASD) frequently co-occur, yet the prevalence and factors associated with epilepsy within autistic individuals remain insufficiently defined. This study aimed to determine the prevalence of epilepsy and examine demographic, developmental, and medical correlates in a large cohort of autistic individuals in Qatar. Methods We conducted a cross-sectional analysis of 1,257 autistic individuals recruited through clinical and research channels in Qatar. Bivariate and multivariable logistic regression analyses were used to identify factors associated with epilepsy, with false discovery rate correction applied for multiple comparisons. Results Epilepsy was identified in 10.7% of the cohort, with affected individuals being significantly older (7.33 years) than those without epilepsy (6.59 years, p = 0.003). Factors associated with epilepsy included developmental delays—particularly in motor milestones such as delayed sitting (aOR = 2.954, p < 0.001) and walking (aOR = 3.289, p < 0.001)—and perinatal complications such as hypoxia (aOR = 3.188, p = 0.015). Behavioral features, including sleep disturbances (aOR = 5.167, p < 0.001) and anxiety (aOR = 2.334, p < 0.001), were also significantly associated. Conclusion These findings highlight the complex interplay between developmental, behavioral, and perinatal factors associated with epilepsy within this cohort of autistic individuals and underscore the importance of systematic monitoring and multidisciplinary management to optimize outcomes in this cohort.
Abstract Background Children born very preterm (VPT) have greater executive function (EF) challenges and internalizing, inattention, and social communication-interaction differences (the Preterm Behavioral Phenotype [PBP]) than full-term (FT) children. EF and PBP outcomes for VPT children with white matter injury (WMI) are less well understood. Furthermore, the extent that EF challenges serve as a neurocognitive mechanism for the PBP is unknown. Methods As part of a longitudinal study, 123 VPT infants (≤ 30 weeks gestation) were recruited from a level-III neonatal intensive care unit and underwent developmental follow-up at ages 5 and 9–10 years. Forty-four VPT infants had high-grade WMI. Seventy-nine FT control children were also included. At the 5 and 9–10 year follow-up, children completed EF tasks tapping short-term/working memory, inhibitory control, and flexibility/shifting, which were combined into an EF composite at each timepoint. Parents and children also completed measures assessing children’s attention-deficit/ hyperactivity, internalizing/anxiety, and social communication-interaction outcomes to generate parent- and child-informant PBP composites at age 9–10 years. Serial mediation analysis examined EF at ages 5 and 9–10 years as serial mediators linking VPT birth and WMI with the PBP, adjusted for covariate factors. Results VPT and WMI children demonstrated lower EF abilities at both timepoints compared to FT children ( p ≤.02). VPT and WMI children obtained higher child-informant PBP composite scores ( p <.001) as well as parent- and child-informant social communication-interaction and ADHD-inattentive problem ratings ( p ≤.03) at age 9–10 years. Lower EF at both timepoints correlated with higher parent- and child-informant PBP ratings ( r -0.2 to -0.45, p <.05). Serial mediation analysis showed that EF development from age 5 to 9–10 years (proportion mediated 3–5%) as well as EF at age 9–10 years (proportion mediated 16–43%) partially mediated associations linking VPT birth and WMI with PBP outcomes. Conclusions VPT and WMI children had greater EF and PBP challenges compared to FT children, with WMI children at greatest risk. Disrupted EF development, at least in part, contributed to the PBP. Findings suggest that VPT and WMI children are in need of early and ongoing EF supports, and that EF training interventions may improve mental health outcomes in this population.
Abstract Background The Early Start Denver Model (ESDM) is a naturalistic developmental behavioral intervention (NDBI) widely used to support early development in young autistic children. This study examines early developmental trajectories associated with different styles and intensities of ESDM-based intervention compared with community Therapy as Usual (TAU) over a 6-month period. It also explores predictors of individual language development based on the intervention style. Methods A total of 112 autistic children participated in the study and were assessed longitudinally while receiving either higher (6 h a week) or lower (3 h a week) intensity ESDM, or TAU at higher (6 h a week) intensity ( N = 29, 32, and 51 participants in each group, respectively). Results The primary findings show that children receiving higher-intensity ESDM exhibited steeper developmental trajectories than children receiving TAU in all the developmental areas such as Language, Personal-Social skills, Performance, Eye-Hand coordination and the General score. Notably, lower-intensity ESDM was associated with steeper developmental gains in individual general development, language, personal social skills, and performance when compared to TAU at double the intensity. Additionally, secondary results indicate that language developmental trajectories are influenced by different factors in the ESDM and TAU groups, with social domain and adaptive behaviors predicting language progress in the ESDM group and baseline cognitive skills predicting language development in the TAU group. Conclusions This study provides observational evidence that different intervention models and intensities may be associated with different short-term developmental trajectories in community settings, particularly where only limited weekly intervention hours are feasible. These findings may help inform service planning in low-resource contexts, while requiring replication in more controlled designs. Trial registration Clinical Trial ID: NCT06494605.
Abstract Genetically defined neurodevelopmental syndromes provide a framework for examining constraints on language development. This study compared language performance in children and adolescents with 22q11.2 deletion syndrome (22q11.2DS; n = 40) and Down syndrome (DS; n = 40), matched for age and nonverbal cognitive ability, aged 6–16 years. Standardized assessments included the Clinical Evaluation of Language Fundamentals (CELF-5) and the BLOC-C to evaluate multiple receptive and expressive language domains. Group differences, effect sizes, and associations with age were analyzed to characterize syndrome-specific profiles. Children with 22q11.2DS demonstrated relatively stronger receptive vocabulary and syntax alongside weaker morphosyntactic and pragmatic skills, with vocabulary showing moderate positive associations with age. In contrast, the DS group exhibited generally lower performance across domains, with pronounced difficulties in morphosyntax and limited age-related gains. These findings highlight differences in overall level of performance and relative strengths within a globally impaired profile across syndromes and emphasize the value of multi-dimensional assessment in capturing both age-related patterns and vulnerabilities.
Phelan-McDermid syndrome (PMS) is caused in the majority of cases by the loss or mutation of one allele of the SHANK3 gene, located in human chr 22q13.33. PMS displays large interindividual differences in clinical severity and longitudinal trajectory. Other genes located in this chromosomal region are known to contribute to the clinical phenotype (CELSR1, TCF20) in patients with larger deletions. The aim of this study is to identify clinically-relevant phenotypic features significantly influenced by the size of chromosome 22q terminal deletion and to identify new potential candidate genes likely to be involved in these phenotypic effects. Genotype–phenotype correlations were investigated in 63 PMS patients directly ascertained by deep clinical phenotyping and determination of deletion size (Agilent CGH-array 180K or 400K). Patients were partitioned into eleven categories, based on deletion size (Mb). Phenotypic variables significantly influenced by deletion size were initially detected by exact χ2 (10,000 iterations) and Kendall’s Tau. Candidate genes were then sought using: (a) ROC curves for binary dichotomous variables; (b) best separation threshold for quantitative variables. Phenotypic variables significantly associated with chromosome 22q deletion size in our sample include: expressive language (p < 0.001); motor development timing (p < 0.001); gait (p < 0.001); muscle strength (p < 0.01); social cognition, encompassing eye contact, exchange gesture, and joint attention (p < 0.001—< 0.05); infectious diseases coincident with the onset of behavioral manifestations (p < 0.001); brain structural abnormalities on MRI (p < 0.001); dysmorphisms (p < 0.001); renal and urinary malformations (p < 0.01); comorbid lifelong bipolar disorder (p < 0.05). The best separation thresholds for many of these variables were located within or nearby genes playing important morphogenetic (PLXNB2, TAFA5) or neurodevelopmental roles (BRD1, TBC1D22A, ATXN10 and/or FBLN1). For renal malformations, the two best thresholds point toward one long non-coding RNA and a cluster of antisense RNAs. The genes identified in this study appear as strong candidates to contribute to the PMS phenotype, by conferring an additional layer of abnormal neurodevelopment and impaired morphogenesis to the disruptive effects produced by SHANK3 haploinsufficiency.
Abstract Background Maternal depression during pregnancy has been associated with increased risk of offspring autism spectrum disorder (ASD) – a highly heritable neurodevelopmental disorder. However, no study to date has taken into account maternal ASD traits in the association between maternal prenatal depression and child ASD. Methods This study utilized data from the Environmental Influences on Child Health Outcomes (ECHO) consortium—a large, national prospective longitudinal study—to examine maternal ASD traits as a covariate and moderator in the association between maternal prenatal depression and child ASD traits. Participants were 645 mother–child dyads. Mothers self-reported prenatal depressive symptoms and ASD traits. Child ASD traits were rated by parents using the Social Responsiveness Scale and Child Behavior Checklist. Maternal depression and child ASD diagnoses were either parent-reported or from medical record review. Results We found that both maternal prenatal depressive symptoms and depression diagnoses predicted child ASD traits (β’s > .04, p ’s < .003). These associations remained significant after accounting for maternal ASD traits for the CBCL only (β’s > .42, p ’s < .001). Maternal prenatal depression did not predict child ASD diagnoses. Maternal ASD traits predicted child ASD traits and diagnoses (β’s > .06, p ’s < .001). Maternal ASD traits did not moderate the association between maternal prenatal depression and child ASD traits. Conclusion Providers might consider early screening for ASD in children of mothers with a history of elevated depressive symptoms during pregnancy.
Abstract Background Individuals with fragile X syndrome (FXS) and Down syndrome (DS) have significant and pervasive challenges in language (and more specifically grammar) and executive functions (EFs). While these aspects of development are linked in autism and developmental language disorder, there has not been an investigation into this in FXS and DS. Thus, the purpose of this study was: 1) to evaluate the feasibility of experimental tasks for language and EFs, 2) to test if there are differences in language and EFs in DS and FXS, and 3) to test if EFs are related to grammatical abilities in DS and FXS within and between groups. Methods Participants included 21 boys with FXS and 25 participants with DS (n = 9 females) between 9–17 years of age; groups were matched on chronological age (variance ratio = 1.13; d = 0.04, p = 0.897) and were similar on nonverbal IQ and vocabulary. Participants completed lab-based assessments including standardized assessments of nonverbal IQ and vocabulary, experimental measures of grammar (i.e., grammatical judgment and sentence imitation), three experimental executive function tasks, and a parent report of executive functions. Results While there were participants who could not complete the tasks, overall the feasibility was high (72–91% participants completed the tasks). Wilcoxon rank-sum tests revealed no significant group differences in experimental grammar or EF tasks. In contrast, large differences emerged on parent-reported EFs, with greater impairment in FXS for shifting and inhibition. We used generalized linear regression models with Gaussian and binomial distributions to examine the relationships between EFs and grammatical abilities. We found that only working memory significantly predicted grammatical judgment. Conclusions Participants with DS and FXS showed similar grammatical production and comprehension skills, contrasting with prior studies that relied on standardized testing and found more impaired production skills for children and adolescents with DS. Our sentence imitation task highlighted expressive grammar skills in DS, while grammaticality judgment posed challenges as a measure of grammar comprehension. Feasbility was good for all tasks, but there was a range, and younger participants in particular seemed to struggle with some of the tasks. The contrast in group differences between experimental and parent-reports of EFs calls into question whether the two measure EFs in a similar manner. Lastly, our study suggests that the language–EF relationships in intellectual disabilities may diverge from patterns documented in neurotypical development and language impairment without intellectual disability.
Abstract Purpose Asian populations are among the fastest-growing ethnic groups in Aotearoa New Zealand (NZ), yet little is known about the prevalence of neurodevelopmental conditions (NDCs) within these communities. The study compared the prevalence and age of diagnosis of NDCs (Attention Deficit Hyperactivity Disorder [ADHD], autism, communication and language disabilities [CLDs], intellectual disability [ID], motor disabilities [MDs], and specific learning disabilities [SLDs]) between NZ-born Asian and non-Asian populations, and differences across Asian subgroups. Methods A national cross-sectional analysis was conducted using linked administrative microdata from the Integrated Data Infrastructure, covering the 2021/22 estimated resident population aged 0–24 years (N = 1,334,247). Following adjustment for socioeconomic factors, standardized NDC rates were calculated for Asian and non-Asian populations and Asian subgroups (Indian, Chinese, Southeast Asian, and Other Asian). Results Lower standardized rates of NDCs were identified among Asian (2.85%, 95% CI [2.77, 2.94]) compared to non-Asian (4.52%, 95% CI [4.49, 4.56]) participants. Most notably, rates of ADHD (1.1%, 95% CI [1.05, 1.16] vs. 2.94%, 95% CI [2.91, 2.97]) and ID (0.34%, 95% CI [0.31, 0.38] vs. 0.58%, 95% CI [0.57, 0.60]) were significantly lower among Asian participants. Among Asian sub-groups, rates of NDCs were lowest for Chinese children, with particularly low rates of Autism, MDs and SLDs. Conclusion Findings highlight substantial differences in NDC rates between NZ-born Asian and non-Asian ethnicities, suggesting that socioeconomic context, cultural perceptions, and diagnostic pathways may influence identification patterns across and between Asian subgroups. Culturally responsive approaches are critical for equitable NDC identification and support.
3q29 deletion (3q29Del) syndrome is caused by a 1.6 Mb copy number variant (CNV) located near the telomeric end of the long arm of the third human chromosome. Hemizygosity of this set of 22 protein-coding genes significantly increases risk for schizophrenia and autism spectrum disorders among other neurodevelopmental conditions, but it is not known which genes in this CNV interval are responsible for these phenotypes. We have evaluated existing literature and public genomic resources for this set of genes, categorizing them based on known cellular functions and assessed their potential as phenotypic drivers. We provide a comprehensive, synthetic review of the essential known functions of 3q29 deleted genes, and how multiple 3q29-encoded proteins may functionally interact. Our analysis reveals that ubiquitination/SUMOylation stands out among processes potentially compromised due to compound haploinsufficiency of four 3q29Del genes (UBXN7, FBXO45, RNF168, SENP5). The available genomic evidence indicates that no single gene in the 3q29 locus is solely responsible for the neurodevelopmental phenotypes of 3q29Del syndrome. Overall, we propose that functional, expression, and gene constraint evidence supports six genes (TFRC, UBXN7, FBXO45, PAK2, NCBP2, DLG1) as the most likely phenotypic drivers in 3q29Del syndrome. Haploinsufficiency of these proteins would likely disrupt metabolic, synaptic, and signaling mechanisms in developing and mature neurons, which collectively may impair neural circuit differentiation and function.
Abstract Background Life expectancy for individuals with Down syndrome (DS) has significantly increased, primarily due to medical advances. While DS is considered a genetically determined form of Alzheimer’s disease (DS-AD), with neuropathological markers evident by age 40, the onset of clinical dementia varies. Modifiable risk factors are thought to contribute meaningfully to dementia risk in the general population. Advances in intervention studies in the general population suggest cognitive decline can be reduced through multimodal lifestyle interventions, however no large-scale multimodal studies have been conducted in the DS population. Search strategy A comprehensive search was conducted across five electronic databases—Medline, EMBASE, CINAHL, Web of Science, and ASSIA to identify studies that examined the relationship between lifestyle interventions and cognitive outcomes in adults with DS. The search combined database-specific controlled language with keywords related to exercise, diet, social activities, cardiovascular health, and brain stimulation. Studies included were peer-reviewed original research articles focusing on adults with DS and reported on cognitive outcomes or AD-related biomarkers. Results The search yielded 24,774 articles, with 16,868 remaining after duplicates were removed. A total of 44 articles met inclusion criteria across the domains of exercise, diet, cardiovascular health, social connectedness, and cognitive stimulation. Most studies focused on exercise, indicating some cognitive benefits, particularly in executive functions and working memory, though results were inconsistent, and many suggested the necessity of high adherence to intervention protocols. No studies were found that examined the direct impact of diet on cognition in DS. Findings on cognitive stimulation, cardiovascular health and social connectedness suggested potential but inconclusive benefits for cognitive function. Conclusions This review underscores the significant gaps in research regarding non-pharmacological interventions for DS-AD. It highlights the need for tailored, well-structured studies to better understand and leverage potential cognitive benefits of lifestyle interventions in the DS population. Implementing such interventions early in life and before significant disease progression may help maintain quality of life and independence among individuals with DS. Future research should focus on comprehensive, multi-domain interventions to ascertain their efficacy and optimal application.
Background Rett Syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Despite its monogenic nature, the molecular events contributing to RTT pathogenesis are not fully elucidated. Methods We applied a multi-omics approach to comprehensively analyse the spatiotemporal gene and protein expression patterns in MeCP2-mutant (RTT) and isogenic control (IC) forebrain organoids. Dorsal and ventral forebrain organoids were cultured for 75 days using patient-derived RTT and IC hiPSC lines. Transcriptomics and proteomics profiles were characterized at days 0, 13, 40, and 75, corresponding to distinct neurodevelopmental phases. Results The spatiotemporal transcriptomic analysis revealed alterations in GABAergic signaling at the latest neurodevelopmental stages, while changes in neuronal development, DNA-associated processes, and post-transcriptional regulation were found to occur across different stages. These changes were also observed at the protein level and in independent validation datasets. Notably, differentially expressed lncRNA genes such as MIR137HG and PWRN1 may act as regulators of these affected processes. Moreover, our results provide systematic evidence for the involvement of imprinted genes in RTT pathology. Conclusions Together, our study lays the foundation for future studies to functionally validate the significance of the identified processes and molecular targets in RTT pathogenesis, and to assess their value as therapeutic targets.
Abstract The cerebellum contributes to the control of movement, language, and sociability. Purkinje cells, the main output neurons of the cerebellar cortex, are reduced in cerebellar malformations (CMs) and in autism spectrum disorder (ASD). Thus, CMs may increase the risk for ASD. We conducted a meta-analysis to determine the prevalence of ASD in individuals with CMs. We searched PubMed, Embase, and APA PsycINFO for studies assessing ASD in patients with radiologically confirmed CMs. We evaluated risk of bias using Joanna Briggs Institute Checklists. Finally, we extracted data to calculate ASD prevalence and assess variation across CM subtypes. From 1,564 screened articles, 32 studies met inclusion criteria, encompassing 1,032 individuals with CMs. ASD prevalence was 31.2%, significantly higher than the general population rate (1 in 31). High heterogeneity was observed (I² = 72.3%; p < 0.0001). Vermis and cerebellar hypoplasia reliably contributed to the high ASD prevalence. Many studies had small sample sizes and used different metrics to diagnose autism. ASD is more common in individuals with CMs, especially vermis malformations, than in the general population. Early neurodevelopmental monitoring may benefit those with prenatally diagnosed CMs.
BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disease that severely impacts a person’s health and daily living, requiring lifelong specialist care. This places substantial demands on caregivers, leading to a decline in physical and mental health, financial strain, and reduced quality of life. This study examines the association between a diagnostic journey in Angelman syndrome and parents’ quality of life. METHODS: A self-administered, anonymous, computer-assisted online survey of 120 caregivers was conducted between March and August 2024. The Polish version of the WHO Quality of Life-BREF and the Consumer Financial Protection Bureau Financial Well-Being Scale were used. The collected information was imported into JASP 0.18.3. RESULTS: 54.2% of caregivers experienced difficulties in obtaining timely diagnoses, 51.6% reported receiving misdiagnoses, and 87.4% consulted several specialists before the correct diagnosis was confirmed. Many caregivers believed that a delayed diagnosis harmed their children’s health (31.7%) and resulted in unwarranted or inappropriate hospitalizations (18.3%), medical procedures (26.7%), and medications (16.7%). Caregivers struggled to access genetic counselling and psychological support. AS caregivers had lower quality of life scores compared to the national average across all domains, including social relationships (85.8%), physical health (80.8%), environmental (72.5%), and psychological (61.7%). Caregivers’ quality of life was associated with economic stability, gender, and the timing of diagnosis. CONCLUSION: There is a need for better access to genetic testing, a holistic healthcare approach, and comprehensive support services for caregivers, as well as reliable information, psychological support, financial assistance, and social services.
Methylenetetrahydrofolate‐reductase (MTHFR) is a critical enzyme in folate-dependent one-carbon metabolism. While MTHFR polymorphisms have been linked to sensorineural hearing loss and neurodevelopmental disorders in humans, the translation of early-life metabolic stress into long-term sensory processing and perceptual consequences has remained unclear. Here, we combined neonatal ultrasonic vocalization analysis, adult auditory-brainstem recordings, two-photon calcium imaging of the auditory cortex, and high-resolution psychophysics to map the effects of partial Mthfr deficiency across different developmental stages. MTHFR-deficient pups produced calls with lower onset frequencies and altered temporal structure. In adulthood, MTHFR-deficient mice exhibited elevated auditory brainstem response thresholds and reduced wave I amplitudes, indicating reduced cochlear output. Despite robust cortical tone responses, two-photon imaging revealed significantly broadened frequency–response areas, and a trained cortical activity decoder showed selectively reduced separability for closely spaced tones. Guided by these neural findings, behavioral testing revealed intact discrimination for widely separated tones but impaired performance near the perceptual boundary, indicating reduced fine spectral acuity. Together, these findings outline a developmental trajectory in which early metabolic stress impairs peripheral encoding, central gain compensates for the loss of sensitivity, and perceptual precision is ultimately compromised, highlighting one-carbon dysregulation as a modifiable contributor to auditory dysfunction.
Abstract Background Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by distinct eating behaviors that evolve from early feeding difficulties to later hyperphagia. Early brain abnormalities remain poorly understood, with no data on brain perfusion during infancy. This study investigated early brain perfusion and functional connectivity in infants with PWS and their associations with feeding and social functioning. Method Twenty-seven infants (mean age 3 months) were included in this prospective study. Thirteen genetically confirmed PWS infants (mean age 2.7 ± 1.2 months) underwent 3T multimodal MRI combined with structural imaging, arterial spin labeling (ASL) to quantify cerebral blood flow (CBF) at rest, and resting-state functional MRI to assess functional connectivity. Oral-motor and social functioning were evaluated via the Neonatal Oral-Motor Assessment Scale (NOMAS) and Coding Interactive Behavior (CIB) scale. Group differences in CBF between PWS infants and 14 age-matched controls (mean age 3.5 ± 1.1 months) were investigated via whole-brain voxelwise analysis and linear regression, controlling for age and sex (p ≤ 0.05, FWE-corrected). Within the PWS group, associations between imaging and clinical data were analyzed via age-adjusted linear regressions, corrected for multiple comparisons using the false discovery rate procedure. Results Compared with controls, infants with PWS presented significantly increased CBF in the insula-superior temporal region, striatum-pallidum, and anterior cingulate cortex (p(FWE) ≤ 0.05). Within the PWS group, the anterior cingulate CBF was significantly associated with oral-motor performance (p(FDR) = 0.04) and birth weight (p(FDR) = 0.03). The functional connectivity between the insula-temporal region and the striatum pallidum was significantly associated with unacylated ghrelin levels (p(FDR) = 0.04), whereas the interhemispheric striatum-pallidum functional connectivity was significantly associated with social functioning (p(FDR) = 0.01). Conclusions This multimodal MRI study identified early brain hyperperfusion in infants with PWS, preceding the onset of hallmark symptoms. Perfusion in the anterior cingulate cortex is related to early feeding and growth, and functional connectivity within the insular and striatal regions is linked to social and metabolic measures, suggesting that these associations develop early in life. These findings provide a basis for future longitudinal studies to clarify how early patterns of brain function are related to developmental outcomes.
