Cannabidiol and positive effects on object recognition memory in an in vivo model of Fragile X Syndrome: Obligatory role of hippocampal GPR55 receptors.

Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism. CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.

Mitochondrial dysfunction in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome: prospect use of antioxidants and mitochondrial nutrients.

Fragile X syndrome (FXS) is a genetic disorder characterized by mutation in the FMR1 gene, leading to the absence or reduced levels of fragile X Messenger Ribonucleoprotein 1 (FMRP). This results in neurodevelopmental deficits, including autistic spectrum conditions. On the other hand, Fragile X-associated tremor/ataxia syndrome (FXTAS) is a distinct disorder caused by the premutation in the FMR1 gene. FXTAS is associated with elevated levels of FMR1 mRNA, leading to neurodegenerative manifestations such as tremors and ataxia.Mounting evidence suggests a link between both syndromes and mitochondrial dysfunction (MDF). In this minireview, we critically examine the intricate relationship between FXS, FXTAS, and MDF, focusing on potential therapeutic avenues to counteract or mitigate their adverse effects. Specifically, we explore the role of mitochondrial cofactors and antioxidants, with a particular emphasis on alpha-lipoic acid (ALA), carnitine (CARN) and Coenzyme Q10 (CoQ10). Findings from this review will contribute to a deeper understanding of these disorders and foster novel therapeutic strategies to enhance patient outcomes.

Purinergic Signalling Mediates Aberrant Excitability of Developing Neuronal Circuits in the Fmr1 Knockout Mouse Model.

Neuronal hyperexcitability within developing cortical circuits is a common characteristic of several heritable neurodevelopmental disorders, including Fragile X Syndrome (FXS), intellectual disability and autism spectrum disorders (ASD). While this aberrant circuitry is typically studied from a neuron-centric perspective, glial cells secrete soluble factors that regulate both neurite extension and synaptogenesis during development. The nucleotide-mediated purinergic signalling system is particularly instrumental in facilitating these effects. We recently reported that within a FXS animal model, the Fmr1 KO mouse, the purinergic signalling system is upregulated in cortical astrocytes leading to altered secretion of synaptogenic and plasticity-related proteins. In this study, we examined whether elevated astrocyte purinergic signalling also impacts neuronal morphology and connectivity of Fmr1 KO cortical neurons. Here, we found that conditioned media from primary Fmr1 KO astrocytes was sufficient to enhance neurite extension and complexity of both wildtype and Fmr1 KO neurons to a similar degree as UTP-mediated outgrowth. Significantly enhanced firing was also observed in Fmr1 KO neuron-astrocyte co-cultures grown on microelectrode arrays but was associated with large deficits in firing synchrony. The selective P2Y2 purinergic receptor antagonist AR-C 118925XX effectively normalized much of the aberrant Fmr1 KO activity, designating P2Y2 as a potential therapeutic target in FXS. These results not only demonstrate the importance of astrocyte soluble factors in the development of neural circuitry, but also show that P2Y purinergic receptors play a distinct role in pathological FXS neuronal activity.

Analyzing the Quality of Life in Individuals with Fragile X Syndrome in Relation to Sleep and Mental Health.

The purpose of this paper was to examine the physical, emotional, social and school functioning domains of quality of life of individuals with Fragile X Syndrome, in relation to mental health and sleep patterns to gain a better understanding of how these aspects are affected by the disorder. This study included 119 individuals with Fragile X Syndrome who were given different cognitive examinations by a neuropsychologist or by parent-proxy questionnaires. This study focused on the Pediatric Quality of Life Inventory (PedsQoL), the Anxiety, Depression and Mood Scale (ADAMS), the Children's Sleep Habits Questionnaire (CSHQ), but did include other cognitive tests (Vineland Adaptive Behaviour Scales, Nonverbal IQ, Autism Diagnostic Observation Schedule). We identified significant associations between decreases in emotional, social and school domains of PedsQoL and the ADAMS subtests of Generalized Anxiety, Manic/Hyperactivity and Obsessive/Compulsivity, with the subtest of Depressed Mood having associations with lower physical and emotional domains. We also identified a significant impact between CSHQ subtests of Sleep Anxiety, Night Wakings, Daytime Sleepiness, and Parasomnia with the emotional and school domains of PedsQoL. There were associations connecting school functioning with Bedtime Resistance, and additional associations connecting emotional functioning with Sleep Duration and Sleep Onset Delay. Physical functioning was also associated with Sleep Anxiety. Our study shows how mental health and sleep defects impact improper sleep patterns and mental health which leads to decreases in the quality of life for individuals with FXS, and how it is important to screen for these symptoms in order to alleviate issues.

Phenotypic analysis of multielectrode array EEG biomarkers in developing and adult male Fmr1 KO mice.

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety and social and sensory processing deficits. Recent electroencephalographic (EEG) studies in humans with FXS have identified neural oscillation deficits that include increased resting state gamma power, increased amplitude of auditory evoked potentials, and reduced phase locking of sound-evoked gamma oscillations. Similar EEG phenotypes are present in mouse models of FXS, but very little is known about the development of such abnormal responses. In the current study, we employed a 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in male P21 and P91 WT and Fmr1 KO mice. This led to several novel findings. First, P91, but not P21, Fmr1 KO mice have significantly increased resting EEG power in the low- and high-gamma frequency bands. Second, both P21 and P91 Fmr1 KO mice have markedly attenuated inter-trial phase coherence (ITPC) to spectrotemporally dynamic auditory stimuli as well as to 40 Hz and 80 Hz auditory steady-state response (ASSR) stimuli. This suggests abnormal temporal processing from early development that may lead to abnormal speech and language function in FXS. Third, we found hemispheric asymmetry of fast temporal processing in the mouse auditory cortex in WT but not Fmr1 KO mice. Together, these findings define a set of EEG phenotypes in young and adult mice that can serve as translational targets for genetic and pharmacological manipulation in phenotypic rescue studies.

Conformational and dynamic properties of the KH1 domain of FMRP and its fragile X syndrome linked G266E variant.

The Fragile X messenger ribonucleoprotein (FMRP) is a complex, multi-domain protein involved in interactions with various macromolecules, including proteins and coding/non-coding RNAs. The three KH domains (KH0, KH1 and KH2) within FMRP are recognized for their roles in mRNA binding. In the context of Fragile X syndrome (FXS), over-and-above CGG triplet repeats expansion, three specific point mutations have been identified, each affecting one of the three KH domains (R138QKH0, G266EKH1, and I304NKH2) resulting in the expression of non-functional FMRP. This study aims to elucidate the molecular mechanism underlying the loss of function associated with the G266EKH1 pathological variant. We investigate the conformational and dynamical properties of the isolated KH1 domain and the two KH1 site-directed mutants G266EKH1 and G266AKH1. Employing a combined in vitro and in silico approach, we reveal that the G266EKH1 variant lacks the characteristic features of a folded domain. This observation provides an explanation for functional impairment observed in FMRP carrying the G266E mutation within the KH1 domain, as it renders the domain unable to fold properly. Molecular Dynamics simulations suggest a pivotal role for residue 266 in regulating the structural stability of the KH domains, primarily through stabilizing the α-helices of the domain. Overall, these findings enhance our comprehension of the molecular basis for the dysfunction associated with the G266EKH1 variant in FMRP.

The impact of social-environmental factors on IQ in syndromic intellectual developmental disabilities.

Despite having the same underlying genetic etiology, individuals with the same syndromic form of intellectual developmental disability (IDD) show a large degree of interindividual differences in cognition and IQ. Research indicates that up to 80% of the variation in IQ scores among individuals with syndromic IDDs is attributable to nongenetic effects, including social-environmental factors. In this narrative review, we summarize evidence of the influence that factors related to economic stability (focused on due to its prevalence in existing literature) have on IQ in individuals with syndromic IDDs. We also highlight the pathways through which economic stability is hypothesized to impact cognitive development and drive individual differences in IQ among individuals with syndromic IDDs. We also identify broader social-environmental factors (e.g., social determinants of health) that warrant consideration in future research, but that have not yet been explored in syndromic IDDs. We conclude by making recommendations to address the urgent need for further research into other salient factors associated with heterogeneity in IQ. These recommendations ultimately may shape individual- and community-level interventions and may inform systems-level public policy efforts to promote the cognitive development of and improve the lived experiences of individuals with syndromic IDDs.

Differential cognitive and behavioral development from 6 to 24 months in autism and fragile X syndrome.

BACKGROUND: Specifying early developmental differences among neurodevelopmental disorders with distinct etiologies is critical to improving early identification and tailored intervention during the first years of life. Recent studies have uncovered important differences between infants with fragile X syndrome (FXS) and infants with familial history of autism spectrum disorder who go on to develop autism themselves (FH-ASD), including differences in brain development and behavior. Thus far, there have been no studies longitudinally investigating differential developmental skill profiles in FXS and FH-ASD infants. METHODS: The current study contrasted longitudinal trajectories of verbal (expressive and receptive language) and nonverbal (gross and fine motor, visual reception) skills in FXS and FH-ASD infants, compared to FH infants who did not develop ASD (FH-nonASD) and typically developing controls. RESULTS: Infants with FXS showed delays on a nonverbal composite compared to FH-ASD (as well as FH-nonASD and control) infants as early as 6 months of age. By 12 months an ordinal pattern of scores was established between groups on all domains tested, such that controls > FH-nonASD > FH-ASD > FXS. This pattern persisted through 24 months. Cognitive level differentially influenced developmental trajectories for FXS and FH-ASD. CONCLUSIONS: Our results demonstrate detectable group differences by 6 months between FXS and FH-ASD as well as differential trajectories on each domain throughout infancy. This work further highlights an earlier onset of global cognitive delays in FXS and, conversely, a protracted period of more slowly emerging delays in FH-ASD. Divergent neural and cognitive development in infancy between FXS and FH-ASD contributes to our understanding of important distinctions in the development and behavioral phenotype of these two groups.

Variation of FMRP Expression in Peripheral Blood Mononuclear Cells from Individuals with Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the fragile X messenger ribonucleoprotein 1 (FMR1) gene due to expansion of a 5'-non-coding trinucleotide (CGG) element beyond 200 repeats (full mutation). To better understand the complex relationships among FMR1 allelotype, methylation status, mRNA expression, and FMR1 protein (FMRP) levels, FMRP was quantified in peripheral blood mononuclear cells for a large cohort of FXS (n = 154) and control (n = 139) individuals using time-resolved fluorescence resonance energy transfer. Considerable size and methylation mosaicism were observed among individuals with FXS, with FMRP detected only in the presence of such mosaicism. No sample with a minimum allele size greater than 273 CGG repeats had significant levels of FMRP. Additionally, an association was observed between FMR1 mRNA and FMRP levels in FXS samples, predominantly driven by those with the lowest FMRP values. This study underscores the complexity of FMR1 allelotypes and FMRP expression and prompts a reevaluation of FXS therapies aimed at reactivating large full mutation alleles that are likely not capable of producing sufficient FMRP to improve cognitive function.

Proteomics insights into fragile X syndrome: Unraveling molecular mechanisms and therapeutic avenues.

Fragile X Syndrome (FXS) is a neurodevelopment disorder characterized by cognitive impairment, behavioral challenges, and synaptic abnormalities, with a genetic basis linked to a mutation in the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene that results in a deficiency or absence of its protein product, Fragile X Messenger Ribonucleoprotein (FMRP). In recent years, mass spectrometry (MS) - based proteomics has emerged as a powerful tool to uncover the complex molecular landscape underlying FXS. This review provides a comprehensive overview of the proteomics studies focused on FXS, summarizing key findings with an emphasis on dysregulated proteins associated with FXS. These proteins span a wide range of cellular functions including, but not limited to, synaptic plasticity, RNA translation, and mitochondrial function. The work conducted in these proteomic studies provides a more holistic understanding to the molecular pathways involved in FXS and considerably enhances our knowledge into the synaptic dysfunction seen in FXS.

Unmethylated Mosaic Full Mutation Males without Fragile X Syndrome.

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability (ID) and single gene cause of autism. Although most patients with FXS and the full mutation (FM) have complete methylation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, some have mosaicism in methylation and/or CGG repeat size, and few have completely unmethylated FM alleles. Those with a complete lack of methylation are rare, with little literature about the cognitive and behavioral phenotypes of these individuals. A review of past literature was conducted regarding individuals with unmethylated and mosaic FMR1 FM. We report three patients with an unmethylated FM FMR1 alleles without any behavioral or cognitive deficits. This is an unusual presentation for men with FM as most patients with an unmethylated FM and no behavioral phenotypes do not receive fragile X DNA testing or a diagnosis of FXS. Our cases showed that mosaic males with unmethylated FMR1 FM alleles may lack behavioral phenotypes due to the presence of smaller alleles producing the FMR1 protein (FMRP). However, these individuals could be at a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) due to the increased expression of mRNA, similar to those who only have a premutation.

Visual attention patterns during a gaze following task in neurogenetic syndromes associated with unique profiles of autistic traits: Fragile X and Cornelia de Lange syndromes.

BACKGROUND: Gaze following difficulties are considered an early marker of autism, thought likely to cumulatively impact the development of social cognition, language and social skills. Subtle differences in gaze following abilities may contribute to the diverse range social and communicative autistic characteristics observed across people with genetic syndromes, such as Cornelia de Lange (CdLS) and fragile X (FXS) syndromes. AIMS: To compare profiles of 1) visual attention to the eye region at critical points of the attention direction process, 2) whether children follow the gaze cue to the object, and 3) participant looking time to the target object following the gaze cue between groups and conditions. MATERIALS AND METHODS: Children with CdLS (N = 11) and FXS (N = 8) and autistic (N = 22) and neurotypical (N = 15) children took part in a passive viewing paradigm adapted from Senju and Csibra (2008), in which videos of a central cue (ball/cartoon face/human face) directed attention towards one of two objects. Visual attention patterns were recorded via eye tracking technology. RESULTS: Neurotypical children were used as a reference group against which the autistic, CdLS and FXS groups were compared. Although autistic children looked at the eye region for significantly less time, they looked at the target object as frequently and for a similar duration as neurotypical children. Children with FXS looked at the target as frequently as neurotypical children but looked at it for comparatively less time. Both neurotypical children and children with CdLS frequently looked at the eye region, but children with CdLS were less likely to look at the target than neurotypical children. CONCLUSIONS: Findings provide preliminary evidence of unique patterns of visual attention and gaze following strategies in children with CdLS, children with FXS and autistic children. These unique gaze following patterns may underpin the distinct profiles of social and communication autistic traits observed between these groups.

Parent perspectives following newborn screening resulting in diagnoses of fragile X syndrome or fragile X premutation.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Early Check, a voluntary newborn screening study, screened 18,833 newborns for FXS over ∼3 years. Exploring parental attitudes and perspectives can provide insight to the potential future acceptability of public health screening. METHODS AND PROCEDURES: Mothers of infants who received a screen positive result for FXS (n = 6) or fragile X premutation (FXPM; n = 18) were interviewed about their perceptions and experiences. OUTCOMES AND RESULTS: Mothers of children with FXS described utility in receiving information about their child, particularly to monitor for potential developmental issues and intervene early; overall mothers did not regret participating. Mothers reported various reactions to receiving the FXS or FXPM results including (1) stress and worry; (2) guilt; (3) sadness and disappointment; (4) neutrality, relief, and acceptance; and (5) confusion and uncertainty. CONCLUSIONS AND IMPLICATIONS: Despite initial reactions such as sadness, stress, and worry, mothers found value in learning of their child's presymptomatic diagnosis of FXS, particularly the anticipated long-term benefits of early diagnosis to their child's health and wellbeing. Our results indicate that professionals returning positive newborn screening results should anticipate and prepare for reactions such as parental shock, guilt, sadness, and uncertainty. Genetic counseling and psychosocial support are critical to supporting families.

Developmental associations between motor and communication outcomes in Fragile X syndrome: Variation in the context of co-occurring autism.

LAY ABSTRACT: Fragile X syndrome (FXS), the leading heritable cause of intellectual disability, has a co-occurrence rate of autism spectrum disorder (ASD) estimated at ~60%. Children with FXS experience delayed achievement and slower development of key motor abilities, which happens to an even greater extent for children with both FXS and ASD. A multitude of studies have demonstrated that motor abilities are foundational skills related to later communication outcomes in neurotypical development, as well as in the context of ASD. However, these associations remain unexamined in FXS, or FXS + ASD. In this study, we aimed to determine the associations between early motor skills and their rate of development on communication outcomes in FXS. Furthermore, we investigated whether these associations varied in the context of co-occurring FXS + ASD. Results revealed within-FXS variation in the context of co-occurring ASD between some aspects of motor development and communication outcomes, yet within-FXS consistency between others. Findings provide evidence for variability in developmental processes and outcomes in FXS in the context of co-occurring ASD and offer implications for intervention.

Circuit-based intervention corrects excessive dentate gyrus output in the fragile X mouse model.

Abnormal cellular and circuit excitability is believed to drive many core phenotypes in fragile X syndrome (FXS). The dentate gyrus is a brain area performing critical computations essential for learning and memory. However, little is known about dentate circuit defects and their mechanisms in FXS. Understanding dentate circuit dysfunction in FXS has been complicated by the presence of two types of excitatory neurons, the granule cells and mossy cells. Here we report that loss of FMRP markedly decreased excitability of dentate mossy cells, a change opposite to all other known excitability defects in excitatory neurons in FXS. This mossy cell hypo-excitability is caused by increased Kv7 function in Fmr1 knockout (KO) mice. By reducing the excitatory drive onto local hilar interneurons, hypo-excitability of mossy cells results in increased excitation/inhibition ratio in granule cells and thus paradoxically leads to excessive dentate output. Circuit-wide inhibition of Kv7 channels in Fmr1 KO mice increases inhibitory drive onto granule cells and normalizes the dentate output in response to physiologically relevant theta-gamma coupling stimulation. Our study suggests that circuit-based interventions may provide a promising strategy in this disorder to bypass irreconcilable excitability defects in different cell types and restore their pathophysiological consequences at the circuit level.

Rodents' visual gamma as a biomarker of pathological neural conditions.

Neural gamma oscillations (indicatively 30-100 Hz) are ubiquitous: they are associated with a broad range of functions in multiple cortical areas and across many animal species. Experimental and computational works established gamma rhythms as a global emergent property of neuronal networks generated by the balanced and coordinated interaction of excitation and inhibition. Coherently, gamma activity is strongly influenced by the alterations of synaptic dynamics which are often associated with pathological neural dysfunctions. We argue therefore that these oscillations are an optimal biomarker for probing the mechanism of cortical dysfunctions. Gamma oscillations are also highly sensitive to external stimuli in sensory cortices, especially the primary visual cortex (V1), where the stimulus dependence of gamma oscillations has been thoroughly investigated. Gamma manipulation by visual stimuli tuning is particularly easy in rodents, which have become a standard animal model for investigating the effects of network alterations on gamma oscillations. Overall, gamma in the rodents' visual cortex offers an accessible probe on dysfunctional information processing in pathological conditions. Beyond vision-related dysfunctions, alterations of gamma oscillations in rodents were indeed also reported in neural deficits such as migraine, epilepsy and neurodegenerative or neuropsychiatric conditions such as Alzheimer's, schizophrenia and autism spectrum disorders. Altogether, the connections between visual cortical gamma activity and physio-pathological conditions in rodent models underscore the potential of gamma oscillations as markers of neuronal (dys)functioning.

Variable expression of MECP2, CDKL5, and FMR1 in the human brain: Implications for gene restorative therapies.

MECP2, CDKL5, and FMR1 are three X-linked neurodevelopmental genes associated with Rett, CDKL5-, and fragile-X syndrome, respectively. These syndromes are characterized by distinct constellations of severe cognitive and neurobehavioral anomalies, reflecting the broad but unique expression patterns of each of the genes in the brain. As these disorders are not thought to be neurodegenerative and may be reversible, a major goal has been to restore expression of the functional proteins in the patient's brain. Strategies have included gene therapy, gene editing, and selective Xi-reactivation methodologies. However, tissue penetration and overall delivery to various regions of the brain remain challenging for each strategy. Thus, gaining insights into how much restoration would be required and what regions/cell types in the brain must be targeted for meaningful physiological improvement would be valuable. As a step toward addressing these questions, here we perform a meta-analysis of single-cell transcriptomics data from the human brain across multiple developmental stages, in various brain regions, and in multiple donors. We observe a substantial degree of expression variability for MECP2, CDKL5, and FMR1 not only across cell types but also between donors. The wide range of expression may help define a therapeutic window, with the low end delineating a minimum level required to restore physiological function and the high end informing toxicology margin. Finally, the inter-cellular and inter-individual variability enable identification of co-varying genes and will facilitate future identification of biomarkers.

Sex-specific modulation of early life vocalization and cognition by Fmr1 gene dosage in a mouse model of Fragile X Syndrome.

BACKGROUND: Pup-dam ultrasonic vocalizations (USVs) are essential to cognitive and socio-emotional development. In autism and Fragile X Syndrome (FXS), disruptions in pup-dam USV communication hint at a possible connection between abnormal early developmental USV communication and the later emergence of communication and social deficits. METHODS: Here, we gathered USVs from PND 10 FXS pups during a short period of separation from their mothers, encompassing animals of all possible genotypes and both sexes (i.e., Fmr1-/y vs. Fmr1+/y males and Fmr1+/+, +/-, and -/- females). This allowed comparing the influence of sex and gene dosage on pups' communication capabilities. Leveraging DeepSqueak and analyzing vocal patterns, intricate vocal behaviors such as call structure, duration, frequency modulation, and temporal patterns were examined. Furthermore, homing behavior was assessed as a sensitive indicator of early cognitive development and social discrimination. This behavior relies on the use of olfactory and thermal cues to navigate and search for the maternal or nest odor in the surrounding space. RESULTS: The results show that FMRP-deficient pups of both sexes display an increased inclination to vocalize when separated from their mothers, and this behavior is accompanied by significant sex-specific changes in the main features of their USVs as well as in body weight. Analysis of the vocal repertoire and syntactic usage revealed that Fmr1 gene silencing primarily alters the USVs' qualitative composition in males. Moreover, sex-specific effects of Fmr1 silencing on locomotor activity and homing behavior were observed. FMRP deficiency in females increased activity, reduced nest-reaching time, and extended nest time. In males, it prolonged nest-reaching time and reduced nest time without affecting locomotion. CONCLUSIONS: These findings highlight the interplay between Fmr1 gene dosage and sex in influencing communicative and cognitive skills during infancy.

In this study, we investigated ultrasonic vocalizations (USVs) and homing behavior in a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of autism spectrum disorder (ASD) caused by a mutation of the X-chromosome linked Fmr1 gene. Disruptions in pup-dam USV communication and cognitive skills may be linked to the later emergence of communication and social deficits in ASD. USVs were collected from 10-day-old FXS pups of all possible genotypes and both sexes during a short period of separation from their mothers. We utilized DeepSqueak, an advanced deep learning system, to examine vocal patterns and intricate vocal behaviors, including call structure, duration, frequency modulation, and their temporal patterns. Homing, a sensitive indicator of early cognitive development and social discrimination was assessed at P13. The results showed that FXS pups of both sexes displayed an increased inclination to vocalize when separated from their mothers. Examination of the vocal repertoire and its syntactic usage revealed that the silencing of the Fmr1 gene primarily alters the qualitative composition of ultrasonic communication in males. The sex-specific changes observed in USVs were accompanied by modifications in body weight. Regarding homing behavior, the deficiency of FMRP led to opposite deficits in activity, time to reach the nest, and nesting time depending on sex. Taken together, these findings highlight the interplay between Fmr1 gene dosage and sex in shaping communication and cognition during infancy.

A holistic approach to fragile X syndrome integrated guidance for person-centred care.

BACKGROUND: The Fragile X community has expressed a desire for centralised, national guidelines in the form of integrated guidance for Fragile X Syndrome (FXS). METHODS: This article draws on existing literature reviews, primary research and clinical trials on FXS, a Fragile X Society conference workshop and first-hand experience of clinicians who have worked with those living with FXS over many years. RESULTS: The article scopes proposed integrated guidance over the life course, including appendices of symptoms, comorbidities and referral options for FXS and Fragile X Premutation Associated Conditions. CONCLUSION: Integrated guidance would provide an authoritative source for doctors, health professionals, therapists, care workers, social workers, educators, employers, families and those living with FXS, so that a holistic, person-centred approach can be taken across the United Kingdom to garner the best outcomes for those with FXS.