Factors associated with social participation among children with fragile X syndrome.

Neurodevelopmental disorders (NDDs), including Autism Spectrum Disorder (ASD), Fragile X syndrome (FXS), and Rett Syndrome (RTT), share impairments in cognitive and behavioral functioning and may involve an altered excitatory/inhibitory balance modulated by the endocannabinoid system. This systematic review evaluated the safety and efficacy of cannabinoid-based products (CBPs) in these pediatric NDDs. We conducted a systematic review according to Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) 2020, including randomized and nonrandomized studies of patients under 18 years treated with cannabidiol (CBD), cannabidivarin (CBDV), tetrahydrocannabinol (THC), or their combinations. Outcomes were adverse events (AEs) and treatment discontinuation, seizure reduction, and behavioral and cognitive changes. Study quality and certainty of evidence were assessed using design-specific risk-of-bias tools and the GRADE approach. Seventeen studies (two randomized controlled trials, observational studies, and case series) met the inclusion criteria. Across diagnoses, CBPs were generally associated with mild-to-moderate AEs and low discontinuation rates. Descriptive pooled proportions suggested behavioral improvements in ASD and FXS and seizure reduction in RTT, with exploratory analyses indicating differential effects of CBD versus CBD + THC on behavioral and cognitive outcomes in ASD. CBPs may offer potential benefits for selected behavioral symptoms and comorbid epilepsy in pediatric NDDs, but current evidence is insufficient to support routine clinical use. High-quality randomized controlled trials with standardized outcome measures and long-term follow-up are needed to clarify efficacy, safety, and syndrome-specific effects.

The elusive folding mechanism of KH1 domain of Fragile X Messenger Ribonucleoprotein 1.

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, and is frequently accompanied by seizures. Early-life treatment with the hormone oxytocin (OXT) improves social behavior and cognitive function in rodent models of autism with intellectual disability, including FXS, but potential OXT treatment effects on seizure susceptibility have not been evaluated. Here we tested, in both sexes, if intranasal OXT (iOXT) or saline (iSAL) during the second postnatal week reduces audiogenic seizures (AGS) in the Fmr1 -Knockout (KO) mouse model of FXS. OXT given daily from postnatal day (P) 7 to P13 significantly reduced the incidence and severity of AGS and the latency to seize in adult male Fmr1 -KOs. Female KOs exhibited less severe seizures that were unaffected by treatment. Wild type mice did not exhibit AGS independent of treatment. To test if antiepileptic effects of iOXT are age-dependent, a separate cohort received iOXT daily from P30 to P36. Male KOs receiving later treatments exhibited robust seizures that were comparable between OXT- and SAL-treatment groups, suggesting that OXT's enduring antiepileptic effects are confined to early postnatal treatments. Tests of acute OXT effects in adulthood demonstrated an attenuation of male Fmr1 -KO AGS at testing 30-60 min and 1 day post-treatment but these effects were not evident 15 days later. These findings reveal marked sex differences in the propensity for audiogenic seizures in Fmr1 -KO mice and demonstrate that early-life OXT treatment mitigates seizure susceptibility in males FXS model mice.

Fragile X syndrome (FXS), the most common monogenic neurodevelopmental disorder associated with autism and intellectual disability, results from the loss of expression of the X-linked FMR1 gene. Synaptic and circuit-level abnormalities in the brain are well documented in FXS and extensively studied in the Fmr1 KO mouse model. In CA1 hippocampal neurons, functional, molecular, and structural synaptic changes have been described, yet the canonical form of Hebbian CA1 long-term potentiation (LTP) remains intact in Fmr1 KO mice. Here we examined whether state-dependent synaptic plasticity in CA1, in which prior "priming" activity modulates subsequent synaptic plasticity, was altered in male Fmr1 KO mice. We found that NMDA receptor activation prior to LTP induction produced metaplastic inhibition of LTP, which was exaggerated in Fmr1 KO mice. This effect was mediated by the activity of small conductance calcium-activated potassium (SK) channels which was enhanced after NMDA priming and dampened dendritic excitability. Blocking SK channels during NMDA-primed LTP induction eliminated the abnormal metaplasticity in Fmr1 KO slices, implicating altered SK activity in the exaggerated LTP inhibition in Fmr1 KO mice. These finding reveal a disrupted functional coupling between NMDA receptors and SK channels in Fmr1 KO mice, altering the impact of priming on LTP expression in the CA1. Altered metaplasticity may represent a neural correlate of impaired hippocampal function in Fmr1 KO mice and potentially contribute to clinical manifestations in FXS individuals.

Alternative splicing plays a crucial role in the development and progression of hepatocellular carcinoma (HCC), yet the underlying regulatory mechanisms and therapeutic potential remain largely unexplored. Here, we identified the RNA-binding protein FMR1 autosomal homolog 1 (FXR1) as a key driver of HCC pathogenesis through the regulation of alternative splicing. FXR1 was highly expressed in HCC tissues, and its elevated expression was associated with a poor prognosis. Mechanistically, high FXR1 induced the retention of exon 6 in mitogen-activated protein kinase-activated protein kinase 5 (MK5), generating a long, kinase-competent isoform (termed MK5-L). This isoform acted as an important oncogenic factor for HCC progression by phosphorylating GSK3β and subsequently activating the Wnt/β-catenin pathway. Functional studies showed that the FXR1/MK5-L axis is critical for HCC cell proliferation and metastasis, both invivo and invitro. Importantly, therapeutic intervention using an FXR1-targeting antisense oligonucleotide (ASO) effectively suppresses tumor progression and metastasis in preclinical models by shifting splicing toward the inactive MK5-S isoform. Overall, our study unveils a novel splicing-mediated oncogenic pathway and establishes FXR1 and its downstream target MK5-L as promising prognostic biomarkers and therapeutic targets for HCC.

Proficient sensory processing affords adaptive responses required for daily functioning. Sensory processing differences are common across neurodevelopmental disabilities (NDDs), including autism and fragile X syndrome (FXS), and, in some cases, associated with challenging behaviors. Although sensory processing differences are common in both autism and FXS, little is known about possible variation as a function of genetic etiology, or autism classification. This study characterized sensory processing features and examined associations between these features and challenging behavior in 102 male participants—non-syndromic autism (n = 37), FXS-only (n = 15), FXS + ASD (n = 20), and neurotypical (NT) children (n = 30). Autistic children demonstrated the highest levels of sensory processing differences; however, nuanced group differences were also identified. The autistic groups (autism and FXS + ASD) were similar on hypo-responsivity and sensory seeking, and the FXS groups (FXS-only and FXS + ASD) were similar on hyper-responsivity and sensory seeking. Within-group associations between sensory differences and challenging behavior were relatively similar across groups. Findings have implications for potential etiological mechanisms of sensory processing differences and associated functional consequences. Implications for diagnostic specificity and intervention are discussed.Lay Sensory processing differences are common in neurodevelopmental disabilities such as autism and fragile X syndrome (FXS). Sensory differences include extreme sensitivity to sensory experiences (hyper-responsivity), decreased sensitivity to sensory experiences (hypo-responsivity), and seeking out sensory experiences to an unexpected degree (sensory seeking). While more is known about sensory differences and challenging behaviors in autism, less is known about these patterns in children with FXS. This study examined the profiles of sensory processing differences and patterns of association between types of sensory response and challenging behavior in males between 24 and 69 months of age with FXS with and without co-occurring autism compared with young autistic males. Participant’s parents filled out questionnaires about sensory responses and challenging behaviors. Results showed that sensory hyper-responsivity is likely part of the broader behavioral profile of FXS, whereas hypo-responsivity is more indicative of autism. In addition, results demonstrated comparable associations between types of atypical sensory processing and ratings of challenging behaviors across groups. These findings contribute to our understanding of the similarities and differences between autism and FXS and have important implications for targeted assessment and intervention practices.

Boys with fragile X syndrome (FXS) have relative weakness in morphosyntax, specifically finiteness markers. However, most research has focused on grammatical production as compared to receptive grammatical judgment. Thus, the current study examined both grammatical production and judgment through pattern analysis and individual differences. Thirty-three boys with FXS aged 9-18 years completed the third-person singular, BE/DO, and grammatical judgment probes from the Test of Early Grammatical Impairment. Unscorable responses were categorized and coded. To compare grammatical judgment to grammatical production, participants were categorized using a median split approach. Grammatical production and grammatical judgment performance showed variability across participants, with mean scores below ceiling in both domains. Comparison of production and judgment revealed substantial heterogeneity. Specifically, over half of the participants demonstrated discrepant performance between the grammatical production and judgment domains, whereas the remaining participants showed consistent performance across both domains. Differences in grammatical profiles were not explained by chronological age or nonverbal cognitive ability. Findings revealed persistent difficulties in the grammatical production and judgment of finiteness marking (particularly BE forms) and highlighted the heterogeneity of linguistic profiles. These findings emphasize the importance of comprehensively assessing both grammatical production and judgment skills to inform intervention approaches in FXS.

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. Participants included 21 boys with FXS and 25 participants with DS (n = 9 females) between 9-17years 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. 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. 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.

Translatome profiling reveals opposing alterations in inhibitory and excitatory neurons of fragile X mice and identifies EPAC2 as a therapeutic target.

Fragile X Syndrome (FXS) is an inherited cause of intellectual disability and autism, arising from silencing of the Fmr1 gene and loss of Fragile X Messenger Ribonucleoprotein 1 (FMRP). FMRP is an RNA-binding protein critically involved in neurodevelopmental processes, including neurogenesis. We examined the proliferation and maturation of adult-born dentate granule cells (abDGCs) and glial populations in Fmr1 knockout (KO) and wild-type (WT) mice at 4, 12, and 24 weeks of age under control and early-life stress (ELS) conditions. Based on prior findings, we hypothesized that KO mice would exhibit increased neurogenesis and atypical responses to ELS compared with WT mice. Using immunohistochemistry, we quantified multiple stages of neurogenesis in the dentate gyrus, including proliferating (Ki67+), immature (doublecortin [DCX]+), and apoptotic (cleaved caspase-3 [CC3]+) cells. We also assessed glia using Iba1 (microglia) and GFAP (astrocytes) immunoreactivity. KO mice displayed significantly increased Ki67+ proliferating and reduced CC3+ apoptotic cells across ages, accompanied by increased Iba1+ and GFAP+ glial densities. However, KO mice exhibited fewer DCX+ neuroblasts at later time points. When reared in ELS conditions, KO mice show blunted or no changes in neurogenesis and glial populations relative to WT mice reared in ELS conditions or KO mice in control conditions. These results indicate that FMRP loss disrupts hippocampal neurogenesis by increasing cell proliferation while limiting neuronal maturation and expanding glial populations. Moreover, the absence of neurogenic and glial responses to ELS in KO mice highlights a gene–environment interaction that may influence FXS-related neuropathology by limiting the adaptive capacity of the hippocampal neurogenic niche.

Fragile X syndrome (FXS) lacks FDA-approved treatments despite various small molecules contributing to phenotypic rescue in the FMR1 knockout (KO) mouse model. Translation from the mouse model has been hampered by phenotypic heterogeneity that contributes to participation barriers among participants who are most affected and may be unable to regularly visit the research laboratory. The current study utilized a crossover design to test the acute neural and behavioral effects of a single 10mg dose of gaboxadol and the reliability of electroencephalography (EEG) and behavioral data collected in participant homes compared to the clinic. Ten adult males with full mutation FXS completed four blinded dosing visits (two placebo, two gaboxadol), with two occurring in-home and two in-lab. Pre- and post-dose assessments included resting high-density EEG, an auditory chirp paradigm, RBANS List Learning, and NIH Toolbox Cognition Battery subtests. No serious adverse events were reported. Compared with placebo, gaboxadol increased theta and alpha band power, with no interaction between collection environment (home vs. lab). Additionally, gaboxadol increased the proportion of electrodes with detectable low-frequency peaks and slowed the peak frequency. There were no effects on auditory-evoked measures or NIH Toolbox, with only a marginal effect on RBANS List Learning. An analysis of pre-dose EEG found reliability estimates across testing locations for all tested resting power and behavioral measures that were similar to in-lab reliability estimates found in the literature. Single-dose gaboxadol augmented theta and alpha power in FXS during resting EEG, similar to previous findings in the typically developing population and in the FMR1 KO, without normalizing gamma abnormalities, altering auditory-evoked responses, or contributing to behavioral change. These results did not significantly differ between the home and lab settings, supporting the feasibility of in-home data collection for clinical trials in FXS, including those that use complex measures such as EEG as endpoints. clinicaltrials.gov, NCT06334419, Registration Date: March 8, 2024.

Electroencephalography signals in a female Fragile X Syndrome mouse model.

An estimated 30%-50% of male individuals with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD), indicating phenotypic overlap but potentially distinct neurobiology. Here, we aimed to characterize shared and divergent cortical features between FXS and ASD. High-resolution, motion-corrected quantitative MRI was used to compare cortical morphometry and relaxometry in 61 male participants (9-18 years) with FXS or ASD. To increase power, ASD participants were pooled from multiple MPnRAGE studies and harmonized across protocols using ComBat. Cortical thickness and R1 (longitudinal relaxation rate; proxy for myelination) were computed across the cerebral cortex. Relative to ASD, FXS exhibited greater cortical thickness predominantly in early sensory cortices implicated in low-level visual and auditory processing spanning occipital, parietal, and temporal regions. No significant group differences in R1 were found. Thicker cortex in FXS within primary and early associative sensory areas suggests divergent early sensory processing mechanisms between FXS and ASD. Characterizing different neuroanatomical features between the two disorders provides a grounding to develop more disorder-specific interventions despite similar behavioral difficulties. Future work should test developmental trajectories, include females and comorbidities, and link imaging markers to individual sensory/clinical profiles to inform and improve personalized therapies and interventions.

Investigate transient, non-averaged electroencephalography (EEG) signals in the gamma frequency band during an auditory chirp paradigm in individuals with FragileXsyndrome (FXS), a population characterized by elevated background gamma power, and to assess their relationship with clinical features. Source-localized EEG responses to auditory chirp stimulus were studied in 36 individuals with FXS and 39 typically developing controls (TDC). Transient high-power gamma-band events were extracted using a thresholding approach. Gamma event properties were compared between groups and correlated with mean EEG features and clinical measures. In male FXS subjects, gamma event peak power was increased in the temporal source and lacked correlation with inter-trial coherence (ITC). Event rate, duration, and frequency span were similar between groups. Event peak power was positively correlated with obsessive and stereotyped behavior scales. Peak power of transient gamma events during auditory response is tonically elevated, dissociated from phase synchronization, and associated with neuropsychiatric features in FXS. Identifying a tonic elevation of gamma event peak power in FXS during auditory processing suggests altered neural circuit mechanisms underlying aberrant gamma activity. This provides a more direct basis for understanding auditory hypersensitivity, fostering opportunities for back translation and targeted treatment development.

Contribution of astrocytic calcium signaling to auditory hypersensitivity in a mouse model of fragile X syndrome.

Deficits in episodic memory are a debilitating feature of Fragile X syndrome (FXS) and other congenital autism spectrum disorders (ASDs). There is evidence that oxytocin (OXT) treatments can improve sociability in persons with ASD and related animal models, encouraging the idea that benefits might extend to cognitive function. We tested this possibility in male FXS model, Fmr1-knockout (KO) mice. Intranasal treatments with OXT or saline were given daily during the second or fifth postnatal week, and effects on social behavior, spatial and episodic memory, and hippocampal synaptic plasticity were assessed in adulthood. Saline-treated Fmr1-KOs exhibited profound deficits in social recognition, object location memory, what-when-where components of episodic memory and long-term potentiation (LTP) in both the CA3-CA1 and lateral perforant path (LPP) systems; NMDAR-mediated components of LPP responses were also impaired. OXT treatments during the second week postnatal normalized all of these functions in Fmr1-KOs assessed in adulthood; this included restoration of initial stages of CA3-CA1 LTP and granule cell NMDAR-mediated currents. In hippocampal slices from naïve adult male Fmr1-KO mice, bath-applied OXT treatment restored LTP in CA1 but not the LPP, indicating pathway-specific effects. Intranasal OXT treatments during the 5th week postnatal did not have enduring effects in either genotype. The present evidence that early OXT treatment corrects a broad range of cognitive and synaptic plasticity deficits in Fmr1-KO mice identifies a clinically plausible strategy for normalizing hippocampal function in ASD and FXS, and highlights the presence of a critical developmental window for effective intervention.

Fragile X syndrome (FXS) is a monogenic X-linked cause of intellectual disability and autism. Individuals with FXS often have high levels of anxiety and sometimes display challenging behaviours. Autonomic dysfunction has been suggested to be one physiological mechanism that may contribute to these. Therefore, the objective of this review is to systematically examine existing evidence on autonomic function in FXS. An electronic literature search was conducted on OVID platforms (Medline, Embase and PsycINFO) and Web of Knowledge databases for references published before 22 April 2025, which physiologically measured autonomic function in FXS. A preregistered search strategy was designed to gather literature on the autonomic nervous system in FXS. A total of 1426 articles were identified, and 28 studies met the inclusion criteria. Samples comprised individuals across the lifespan (ages < 1-71 years), with most studies utilising a case control design to examine indices of autonomic function; 75% of studies found a between-group difference in autonomic function metrics. Of these studies, hyperarousal in the FXS group was present in 86% (N = 18) of studies. Although some studies reported associations of autonomic function with clinical characteristics, findings varied considerably between studies. There was some evidence of potential differences between genders, although more research in female populations is required. Of the 28 included studies, 64% (N = 18) further examined links between autonomic function and clinical characteristics associated with FXS, demonstrating links between relevant clinical symptoms, that is, autistic traits and hyperarousal, as well as potential gender differences in autonomic function. The findings demonstrate evidence for autonomic hyperarousal as a clinical phenotype in FXS across the lifespan. Future work is required to define whether overactivation of the sympathetic nervous system, as indicated by hyperarousal in FXS, can be linked to clinical symptoms. Variations in sample demographics as well as in methodological approaches to measuring autonomic function both hinder accurate comparison of the results from included studies.

Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with molecular, neuroanatomical, and behavioral changes. In FXS, astrocytes express dysregulated gene and protein networks, thereforeidentifying upstream pathways mediating astrocyte changes may provide a point of intervention. We focus on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, finding that this lessens audiogenic seizure severity in male FXS mice. We performed in vivo transcriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted and membrane proteins in FXS astrocytes, with these alterations mitigated when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses in the FXS auditory cortex. Our findings show that astrocytes contribute to some FXS mouse molecular and functional phenotypes, and targeting astrocyte BMP signaling improves some FXS symptoms.

STUDY QUESTIONDoes FMR1 repeat length confer clinically meaningful predictive value for premature ovarian insufficiency (POI)?SUMMARY ANSWERFMR1 repeat length increases POI risk from ∼36 repeats onward but has limited diagnostic utility compared with a polygenic score for menopause timing.WHAT IS KNOWN ALREADYFMR1 premutation carriers (≥55 repeats) are reported to have high risk of Fragile-X Associated Primary Ovarian Insufficiency (FXPOI), but prior studies were small and highly ascertained.STUDY DESIGN, SIZE, DURATIONCross-sectional analysis of ∼92 000 women from the UK Biobank with genetic and health data.PARTICIPANTS/MATERIALS, SETTING, METHODSFemale UK Biobank participants were genotyped for FMR1 repeat length. Associations with self-reported POI, age at menopause, and other reproductive phenotypes were analysed in women. FMR1 protein levels were measured, and genome-wide analyses were conducted to identify potential genetic modifiers.MAIN RESULTS AND THE ROLE OF CHANCEOf 518 female premutation carriers with available age at natural menopause, only 6.9% reported POI. Elevated POI risk was observed starting at 36 repeats, increasing continuously with repeat length, but no threshold showed strong predictive power (maximum AUC 0.60 vs AUC 0.64 for polygenic score). No association was found between repeat length and FMR1 protein levels, consistent with an RNA gain-of-function toxicity mechanism. RAD52 was identified as a potential genetic modifier.LARGE SCALE DATAUK Biobank resource (https://www.ukbiobank.ac.uk).LIMITATIONS, REASONS FOR CAUTIONPOI was self-reported rather than clinically confirmed. Analyses could not assess AGG interruptions, mosaicism, or X-inactivation. Genetic modifiers require replication. Findings are limited to a single population dataset.WIDER IMPLICATIONS OF THE FINDINGSThese results challenge the utility of the FXPOI disease category, suggest limited diagnostic value of clinical FMR1 premutation testing for POI, and highlight alternative mechanisms and potential modifiers such as RAD52.STUDY FUNDING/COMPETING INTEREST(S)This work was conducted using the UK Biobank resource (application 9905). This work was funded by the Medical Research Council (unit programs: MC_UU_12015/2, MC_UU_00006/2) and Wellcome (Discovery award 302536/Z/23/Z). The sponsors had no role in the study design, collection, analysis, or interpretation of the data, the writing of the manuscript or the decision to submit it for publication. J.R.B.P. and A.M. have engaged in paid consultancy for Ovartix Ltd.TRIAL REGISTRATION NUMBERN/A.