Fragile X Research Articles (Page 1)

BackgroundFragile X syndrome (FXS) is the most common inherited intellectual disability, caused by the loss of fragile X mental retardation protein (FMRP), which regulates neuronal signaling and plasticity. FXS patients and Fmr1 knockout (KO) mice exhibit sensory hypersensitivity, hyperarousal, and hippocampus-dependent learning deficits. Dysregulated metabotropic glutamate receptor (mGluR) and muscarinic acetylcholine receptor (mAChR) signaling, along with reduced kainate receptor (KAR) function, have been implicated in FXS pathophysiology. Activation of these signaling pathways induce gamma-frequency network oscillations hippocampal slices in vitro. However, their specific contribution to aberrant gamma oscillations in FXS remains unclear.MethodsWe recorded local field potential (LFP) gamma oscillations in vitro in hippocampal CA3 from wild-type (WT) and Fmr1 KO mice. Oscillations were induced pharmacologically using carbachol (CCh), the group I mGluR agonist dihydroxyphenylglycine (DHPG), or kainate (KA). In addition, we quantified synaptic protein expression of mAChR M1, mGluR1, mGluR5, GluK1, and GluK2-receptors involved in gamma oscillation generation under these conditions.ResultsFmr1 KO slices exhibited increased integrated gamma power (20–80 Hz) in response to DHPG and CCh, suggesting higher network synchronization through mGluR and mAChR pathways. In contrast, KA-induced oscillations showed reduced synchrony and gamma peak power, indicating disrupted network coordination. Aberrant spiking activity during both CCh- and KA-induced oscillations further supports impaired temporal coordination in Fmr1 KO mice. These physiological changes were only partially reflected by altered expression of the corresponding receptor proteins.LimitationsIn the current study, we found aberrant gamma oscillation power in in vitro hippocampal slices of Fmr1 KO mice. It remains to be determined whether these oscillatory changes extend to pharmacologically induced gamma oscillations in cortical slice preparations in vitro.ConclusionsOur findings demonstrate that hippocampal gamma oscillations are differentially affected by distinct neuromodulatory pathways in Fmr1 KO mice. Enhanced responsiveness to cholinergic and mGluR activation and reduced coherence of KA-induced rhythms suggest that multiple dysregulated mechanisms contribute to gamma oscillopathies in FXS.Supplementary informationThe online version contains supplementary material available at 10.1186/s13229-025-00687-9.

Abstract It has been suggested that mentalizing abilities underlie the distinct profiles of autism characteristics observed between Cornelia de Lange (CdLS) and fragile X syndromes (FXS) and autistic people without a genetic syndrome. However, traditional explicit mentalizing tasks have high language demands that may mask true mentalizing abilities in these populations. We compared performance on traditional explicit tasks and an implicit anticipatory looking mentalizing task in children with CdLS (N = 9), boys with FXS (N = 9), autistic (N = 22) and neurotypical (N = 34) children. The groups showed divergent patterns of performance. Neurotypical children had higher explicit mentalizing scores than all other groups. However, neurotypical, FXS and CdLS groups showed better implicit mentalizing performance than autistic children. Both chronological age and receptive language ability correlated with explicit mentalizing scores in neurotypical children. In autistic children, there was an association between explicit mentalizing score and receptive language ability but not chronological age. Explicit mentalizing score was not associated with receptive language ability or chronological age in the CdLS and FXS groups. Neither chronological age nor receptive language ability correlated with implicit mentalizing task performance in any group. Findings suggest that explicit tasks may mask true mentalizing abilities in autistic children, children with CdLS and children with FXS.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and single-gene cause of autism. The Stanford-Binet, Fifth Edition (SB-5) is commonly used to assess IQ in FXS. It is not known if the SB-5 routing form's abbreviated IQ (ABIQ) score accurately estimates full-scale IQ (FSIQ), limiting data-informed decision-making when choosing between an abbreviated or full SB-5 battery. 198 participants with FXS (143 males) aged 4 to 47 years of age completed the full SB-5. We calculated differences between abbreviated and full-scale estimates of IQ and assessed the extent to which the agreement between ABIQ and FSIQ varied as a function of age, routing subtest scatter, and FSIQ. The abbreviated SB-5 battery over-estimated FSIQ in most school-age children (< 11 years), and under-estimated FSIQ in adolescents and adults. This under-estimate of FSIQ was larger when there was a greater discrepancy (scatter) between the two routing subtests that comprise ABIQ and in individuals with FSIQ < 68. Clinicians and researchers should consider administering the full SB-5 battery to individuals with FXS when possible. If only an abbreviated estimate of IQ is available, ABIQ should be interpreted with caution based on our findings of over- or under-estimation occurring across development. Large discrepancies between verbal and nonverbal skills as well as greater severity of ID should both serve as cues to administer the full battery to avoid under-estimating cognitive skills that are otherwise only captured by FSIQ.

Fragile X syndrome (FXS) presents with variable cognitive and neurobehavioral abnormalities. We recently reported clinically relevant behavioral subtypes in children with FXS based on a latent class analysis (LCA), which suggested an association between level of intellectual disability (ID) and frequency of co-occurring behavioral conditions. The present study further investigated ID-behavioral comorbidity associations in the same subject sample. We analyzed the large (1,072 males, 338 females) pediatric FORWARD clinic-based natural history study database, using multiple statistical techniques including chi-square analyses, polyserial correlations, regression analyses, and LCA. We demonstrated that frequency of irritability/agitation, aggression, and self-injury (IAAS), autism spectrum disorder (ASD), hypersensitivity and, to lesser extent, perseverative behavior (OCD-like) are a function of ID level across the range of FXS clinical severity. With exception of IAAS, these associations were further supported by correlations between ID levels and scales shown to represent the aforementioned behavioral comorbidities. The ID-behavioral comorbidity associations reported here could help in the identification and management of problematic behaviors in individuals with FXS and other ID-associated disorders.

Rationale:Fragile X-associated tremor/ataxia syndrome (FXTAS), presenting with cognitive impairment as the initial symptom, is rare. This report emphasizes the need to consider FXTAS diagnosis in cases of early onset cognitive impairment in an aging population.Patient concerns:A 57-year-old male with FXTAS was initially misdiagnosed with neuronal intranuclear inclusion disease, whose first manifestation was cognitive impairment. Testing showed a verbal IQ of 74, a performance IQ of 73, and a full scale of IQ 71, and a Clinical Memory Quotient of 74. Furthermore, his Mini-Mental State Examination score of 23 reflected a decline in short-term memory. Following reevaluation of imaging, identified T2-fluid attenuation inversion recovery hyperintensity at the cerebellar peduncles, and further investigation of the family history revealing a 7-year-old grandson with fragile X syndrome (FXS), repeat genetic testing of the patient demonstrated 121 CGG repeats in the FMR1 gene, confirming the diagnosis of FXTAS.Diagnoses:FXTAS.Interventions:The patient was treated with donepezil and simvastatin daily and alcohol consumption was restricted.Outcomes:After 1 year, the patient showed partial improvements in memory, with his Mini-Mental State Examination score rising to 27, allowing him to resume employment as a community security guard.Lessons:Due to the highly variable clinical presentation of FXS within families, clinicians should always consider fragile X testing and detailed family history when middle-aged and elderly males exhibit unexplained cognitive impairment or tremors. With the acceleration of aging in society, this case underscores the importance of multigenerational genetic screening for maternal grandparents, particularly males, in FXS families and prioritizing follow-up monitoring.

Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism-like behaviors. Glutamatergic mGluR5 receptors and matrix metalloproteinase-9 (MMP-9) are therapeutic targets to treat FXS, but clinical trials targeting each of these pathways have not been successful. Here, we tested if the electroencephalography (EEG) phenotypes associated with FXS are reversed with a novel combination of treatments affecting the two pathways. Fmr1 knockout (KO) mice were given 10 days of CTEP (mGluR5 antagonist) alone or in combination with minocycline (MMP-9 inhibitor). EEG was recorded during resting (no acoustic stimulation) and during sound presentations (to produce sound-evoked EEG) at 1 day and 10 days after the beginning of treatment administration to test acute effects and potential tachyphylaxis. In pre-treatment WT and KO mice comparisons, we replicated previously published Fmr1 KO mouse EEG phenotypes including elevated power in the resting gamma band, elevated single trial power, and reduced phase-locking to spectrotemporally dynamic auditory stimuli. We found that CTEP treatment alone did not show any benefit compared to vehicle in Fmr1 KO mice after either 1 or 10 days of treatment. CTEP + minocycline reduced resting gamma band power in the Fmr1 KO mice to a greater extent than vehicle at both treatment time points. There were no effects on sound-evoked responses. These data suggest that combined CTEP and minocycline treatment alters resting EEG measures while each treatment administered separately does not yield similar changes. High power in broadband gamma frequency correlates with irritability, stereotyped behaviors, and hyperactivity in FXS patients, suggesting a combination of drugs that reduce mGluR5 and MMP-9 activity may be beneficial in FXS.

Background: Fragile X Syndrome (FXS) is the most common monogenic cause of autism spectrum disorders, and is characterized by the excessive immature excitatory synapses in cortical neurons, leading to excitatory/inhibitory imbalance and core autistic behaviors. This synaptic pathology has been attributed to dysregulated levels of synaptic proteins, including CYFIP2: a key regulator of synaptic structure and plasticity. However, the mechanism underlying the increased CYFIP2 protein level in FXS neurons remains unclear. Neurons abundantly secrete extracellular vesicles (EVs) enriched with bioactive cargos (proteins and miRNAs). Objectives: the goal of this research is to identify whether EV-dependent secretion plays important roles in regulating the intracellular CYFIP2 protein level in WT and FXS neurons. Methods and Results: our proteomic analysis reveals that CYFIP2 protein is packaged in EVs released by mouse cortical neurons. Pharmacological and genetic blockades of neuronal EV release significantly elevated intracellular CYFIP2 levels by 78 ± 14% and 168 ± 39%, respectively. Glutamate-evoked EV release significantly reduced the CYFIP2 level by 24 ± 2%. Neurons from Fmr1 KO mice, an FXS model, secreted significantly less EVs (46 ± 5%) than the wild type, and showed significantly elevated CYFIP2 (by 155 ± 31%). Evoking EV release in FXS neurons significantly lowered the intracellular CYFIP2 (by 53 ± 6%). Conclusions: these findings identify an EV-secretion-dependent mechanism that controls neuronal CYFIP2 level, implicating EV-mediated export in the regulation of synaptic protein homeostasis, synaptic remodeling, and FXS-associated synaptic deficits.

Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism spectrum disorder; however, the molecular function of FMRP remains uncertain. Here, using cell lines and fibroblasts and induced pluripotent stem cell-derived neurons from healthy individuals and patients with FXS, we showed that FMRP regulates collided ribosomes by recruiting activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor to collided ribosomes, and either positively or negatively regulating translation, depending on transcript context. Disease-associated ASCC3 variants that perturbed ASCC3-FMRP interaction were also found to be defective in ribosome association and handling of collided ribosomes. In cells of a patient with FXS and the Fmr1 KO mouse model, ASCC3 abundance was reduced, and overexpression of ASCC3 in the brains of fetal Fmr1 KO mice promoted neuronal migration. In addition, CRISPR-mediated activation of ASCC3 by lateral ventricular injection of adeno-associated virus (AAV) ameliorated synaptic defects and improved locomotor activity, cognitive deficits, obsessive-compulsive-like behavior, and social interaction deficits after 1 month in 2-month-old Fmr1 KO mice compared with untreated Fmr1 KO controls. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and demonstrated proof of concept that targeting RQC may offer alternative treatment strategies for FXS.

Individuals with Fragile X syndrome (FXS) manifest clinical impairments in several domains. Previous research has shown that auditory evoked potentials (AEPs), measured using electroencephalogram (EEG), are altered in FXS, but the associations between these alterations and the symptoms observed in FXS have not been thoroughly investigated. The aim of this study was to compare AEP markers between individuals with FXS and neurotypical (NT) controls, with the main purpose of exploring how these markers are related to various clinical symptoms present in FXS. A passive auditory oddball paradigm was presented. P1, N1, P2, N2, P3 and mismatch negativity (MMN) amplitudes and latencies were compared between 41 children and adults with FXS and 46 age-matched NT controls. Amplitudes and latencies, as well as habituation and change detection effects were compared between the groups using mixed design ANOVAs. Pearson correlations were then performed to explore associations between AEP markers and symptoms in the FXS group. Our results showed that FXS participants had increased N1, P2 and MMN amplitudes and latencies, as well as lack of habituation and change detection effects compared to NT controls. Our correlational analyses revealed several associations between AEPs and phenotypic manifestations; notably, associations between exaggerated N1 and P2 amplitudes and more severe autistic and ADHD symptoms. These findings confirm that abnormalities of the N1 and P2 components are robust biomarkers of altered sensory processing in FXS and suggest that these alterations may present a dose-response relation to clinical impairments in FXS.

ABSTRACT The Fragile X Messenger Ribonucleoprotein (FMRP) is a selective RNA-binding protein that localizes to the cytoplasm and the nucleus. The loss of FMRP results in Fragile X Syndrome (FXS), an autism spectrum disorder. FMRP interacts with ribosomes and regulates the translation of mRNAs essential for neuronal development and synaptic plasticity. However, the biochemical nature of this translation regulation is unknown. Here, we report that a potential feature of FMRP-mediated translation regulation during neuronal differentiation is the modulation of 2’-O-methylation of ribosomal RNA. 2’O-methylation, facilitated by C/D box snoRNAs in the nucleus, is a major epitranscriptome mark on rRNA, essential for ribosome assembly and function. We found that FMRP influences a distinct rRNA 2’O-Methylation pattern across neuronal differentiation. We show that in H9 ESCs, FMRP interacts with a selected set of C/D box snoRNA in the nucleus, resulting in the generation of ribosomes with a distinct pattern of rRNA 2’O-Methylation. This epitranscriptome pattern on rRNA undergoes a significant change during the differentiation of ESCs to neuronal precursors and cortical neurons. ESCs exhibit substantial levels of hypomethylated residues on rRNA, which progressively decrease in neuronal precursors and post-mitotic cortical neurons. This reduction correlates with changes in global protein synthesis across different stages of differentiation. Importantly, this stepwise change in the 2’O-methylation pattern during neuronal differentiation is altered in the absence of FMRP, which could impact neuronal development and contribute to dysregulated protein synthesis observed in Fragile X Syndrome.

Glycogen-synthase-kinase-3β (GSK-3β) and microtubule dynamics are implicated in Fragile X syndrome (FXS). We examined behaviors and hippocampal α-tubulin post-translational modifications (PTMs) in Fmr1-KO male mice without and with chronic administration of the GSK-3β inhibitors SB216763 (30 mg/kg, i.p.) and AF3581 (10 mg/kg, i.p.). Fmr1-KO male mice and wild-type (WT) were evaluated in the open field, marble-burying, elevated-plus-maze (EPM), novel-object-recognition (NOR) and three-chamber sociability test (3-CST); acetylated α-tubulin (Acet/Total-Tub) and tyrosinated/detyrosinated α-tubulin (Tyr/Glu-Tub) ratios were then analyzed. Fmr1-KO male showed hyperactivity, excessive marble burying and impaired NOR; Acet/Total-Tub was elevated and Tyr/Glu-Tub reduced vs. WT, indicating reduced microtubule dynamics. In a mixed-sex cohort bred female WT displayed lower Acet/Total-Tub and increased Tyr/Glu-Tub vs. male WT. The Fmr1-KO-associated decrease in Tyr/Glu-Tub was consistent across sexes. FMRP and synaptic markers were also analyzed in this cohort, spinophilin was found increased in both male and female Fmr1-KO. Fmr1-heterozygous females showed no molecular alterations, supporting the protective role of FMRP. Fmr1-KO male mice received vehicle or GSK-3β inhibitors and were tested in behavioral assays followed by α-tubulin PTMs analysis. Daily vehicle injections appeared to abolish baseline differences in hyperactivity, marble burying and α-tubulin PTMs. Under these conditions both inhibitors reduced marble burying. SB216763 normalized social discrimination in 3-CST, while AF3581 only produced a non-significant positive trend. Neither compound altered α-tubulin PTMs. These results show that GSK-3β inhibition has anti-perseverative and pro-social effects in Fmr1-KO male mice. However, behavioral and molecular endpoints, such as α-tubulin PTMs, appear to be sensitive to both genetic background and experimental procedures.

Fragile X syndrome (FXS) is characterized by cortical hyperexcitability, a core neurophysiological feature that contributes to sensory hypersensitivity, cognitive dysfunction, and other disabling symptoms. This disruption in excitatory-inhibitory balance is a key pharmacological target, yet reliable biomarkers to quantify it noninvasively remain limited. Spectral slope, derived from the aperiodic component of the EEG power spectrum, has emerged as a potential index of cortical excitability. Here, we evaluated spectral slope and theta-alpha peak frequency in individuals with FXS to assess their utility as candidate neurophysiological biomarkers. Five minutes of resting state EEG data were collected from 70 subjects with FXS (mean age 20.5 ± 10 years; 32 females) and 71 age-matched controls (mean age 22.2 ± 10.7 years; 30 females). The Spectral Parameterization toolbox (SpecParam) was used to separate periodic and aperiodic components of the source localized power spectra and characterize aperiodic slope and theta-alpha peak frequency. Statistical modeling of aperiodic slope revealed a significant two-way interaction between sex and diagnostic group, but no interaction with brain lobe. Among males, the aperiodic slope was significantly decreased in FXS, indicating greater cortical excitability, compared to typically developing controls (TDC), whereas no difference was observed between FXS and TDC females. For peak alpha frequency, statistical modeling identified significant two-way interactions between sex and diagnostic group, and between brain lobe and diagnostic group, but no significant three-way interaction. This study is limited by the absence of non-invasive measures of cortical fragile X mental retardation protein (FMRP). Additionally, participants were not stratified by mosaic status and FMRP levels were not quantified, which could affect variability and interpretation. Compared to traditional band-limited power measures, aperiodic slope provides a more direct and validated index of excitation-inhibition balance. Our findings of reduced aperiodic slope in male subjects with FXS align with preclinical circuit-level evidence of increased excitability in FXS and are consistent with previous findings of reduced individual alpha peak frequency, supporting with thalamocortical dysrhythmia models of FXS. Importantly, aperiodic slope measurements can be applied directly to various modalities of local field potential data, enabling more robust cross-species and translational comparisons.

Fragile X syndrome (FXS) is the most prevalent inherited form of intellectual disability (ID) and the primary monogenic cause of autism spectrum disorder (ASD) worldwide. The disorder arises from a CGG trinucleotide expansion of more than 200 repeats, known as a full mutation (FM) that occurs in the fragile X messenger ribonucleoprotein 1 (FMR1) gene locus at Xq27.3. This expansion induces hypermethylation of the gene's promoter region, leading to epigenetic silencing and a consequent reduction in the expression of the FMR1 (FMRP)-a protein critical for synaptic plasticity and maturation. While the genetic basis of FXS is well established, further clarification is needed to understand how variations in the FMR1 gene lead to divergent clinical outcomes. This systematic review explores the differences in clinical features, genetic variations and molecular mechanisms between individuals with a FM, clinically diagnosed with FXS and premutation (PM) carriers with fragile X premutation-associated conditions (FXPAC), with a focus on implications for improving support for individuals with ID and their families. Three databases (PubMed, Web of Science and Scopus) were systematically searched, guided by a variety of keywords, to identify qualitative, empirical research about clinical, genetic and molecular differences between FM and PM carriers. A total of 62 articles were examined, and 44 were included in the review. The information is presented in the following categories: clinical features, genetic variations, molecular mechanisms, diagnostics and treatments. Three primary themes are discussed: (1) variability in clinical manifestations, (2) genetic insights and diagnostic advancements and (3) current and emerging management strategies. Research gaps are also highlighted along with perspectives and implications for further research. The identification and treatment of FXS and FXPAC remains a major public health and clinical concern. This systematic literature review provides a more robust understanding of FXS and the clinical, genetic and molecular distinctions between FM and PM carriers. Despite growing knowledge of the condition, significant efforts are still required to refine diagnostic tools, develop targeted interventions and support individuals and families affected by FXS.

Clinical Utility and Performance of Methylation-Specific Triplet-Primed PCR for Fragile X syndrome diagnosis.

BackgroundFragile X syndrome (FXS) is a rare, genetically based neurodevelopmental disorder characterized by intellectual disability. While previous research has largely focused on its genetic mechanisms, the role of metabolism and the gut microbiome in FXS remains underexplored. This study aimed to investigate age-related metabolic differences in the gut flora and serum metabolites of children with FXS and their associations with clinical behavioral outcomes.MethodsA total of 32 children with FXS under 18 years were enrolled and divided into two age groups: younger (3–8 years) and older (8–18 years). Intestinal microbiota composition was analyzed using 16S rDNA gene sequencing, and serum metabolite profiles were assessed via ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Spearman correlation analysis was used to assess associations among gut flora, serum metabolites, and scores from the Social Responsiveness Scale (SRS) and Child Behavior Checklist (CBCL).ResultsSignificant differences in gut bacterial genera and 1,352 serum metabolites were observed between the age groups. The older group exhibited higher levels of phospholipids, steroids, and peptides, and enrichment in the steroid hormone biosynthesis pathway. Several metabolites were significantly correlated with SRS and CBCL scores, indicating potential links between metabolic changes and behavioral symptoms.ConclusionAge-associated metabolic and gut microbiota alterations in FXS may contribute to variations in clinical presentation. These findings suggest a metabolic basis for FXS and provide a foundation for future research into microbiome-targeted interventions in FXS management.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is highly comorbid with autism spectrum disorders and can cause abnormal social behaviors. The CA2 subregion of the hippocampus is essential for social memory processing and social recognition. A social interaction induces changes in CA2 neuronal firing; however, it is unknown whether these changes are impaired in FXS models. Here, we examined CA2 activity in a rat model of Fragile X Syndrome (Fmr1 knockout rats). In Fmr1 knockout rats, we observed impaired CA2 cell responses to social stimuli, despite similar social behaviors. Further, in CA2 of Fmr1 knockout rats, we found reduced expression of oxytocin receptors and impaired whole cell responses to oxytocin. Together, these results raise the possibility that abnormal CA2 activity contributes to impaired social behavior in FXS and may suggest novel treatment targets for FXS patients.

Dysregulated spine morphology is a common feature in the pathology of many neurodevelopmental and neuropsychiatric disorders. Overabundant immature dendritic spines in the hippocampus are causally related to cognitive deficits of Fragile X syndrome (FXS), the most common form of heritable intellectual disability. Recent findings from us and others indicate autophagy plays important roles in synaptic stability and morphology, and autophagy is downregulated in FXS neurons. However, the mechanism remains unclear. In this study, we identified that activated autophagy degrades the eukaryotic initiation factor 4G1 (eIF4G1) and postsynaptic density protein-95 (PSD-95) in hippocampal neurons of Fmr1 KO mice and FXS neurons from patients, which subsequently corrected the dysregulated postsynaptic organization and actin assembly, the critical processes determining synaptic maturation and density. Centrally activating autophagy in hippocampus degrades eIF4G1 and PSD-95, restores actin dynamics, and improves cognition of Fmr1 KO mice. In human neurons derived from patients diagnosed with both FXS and intellectual disability, activating autophagy corrected the aberrant actin assembly. Thus, our findings revealed a previously unappreciated mechanism through which autophagy affects actin assembly and synaptic organization, suggesting a critical role of autophagy in regulating structural synaptic plasticity in healthy and diseased conditions.

Fragile X syndrome (FXS), a leading inherited cause of intellectual disability and autism, is frequently accompanied by sleep and circadian rhythm disturbances. In this study, we comprehensively characterized these disruptions and evaluated the therapeutic potential of a circadian-based intervention in the fragile X mental retardation 1 (Fmr1) knockout (KO) mouse. The Fmr1 KO mice exhibited fragmented sleep, impaired locomotor rhythmicity, and attenuated behavioral responses to light, linked to an abnormal retinal innervation and reduction of light-evoked neuronal activation in the suprachiasmatic nucleus. Behavioral testing revealed significant deficits in social memory and increased repetitive behaviors in the mutants, which correlated with sleep fragmentation. Remarkably, a scheduled feeding paradigm (6 hr feeding/18 hr fasting) significantly enhanced circadian rhythmicity, consolidated sleep, and improved social deficits and repetitive behaviors in the Fmr1 KO mice. This intervention also normalized the elevated levels of some pro-inflammatory cytokines, including IL-12 and IFN-γ, in the mutants' blood, suggesting that its benefits extend to inflammatory pathways. These findings highlight the interplay between circadian disruption, behavior and an inflammatory response in FXS, and provide compelling evidence that time-restricted feeding may serve as a promising non-pharmacological approach for improving core symptoms in neurodevelopmental disorders.

BACKGROUND: FXTAS Syndrome (Fragile X-Associated Tremor/Ataxia Syndrome) is a neurodegenerative disease with late onset, which manifests in men and women carrying the mutation in the FMR1 gene, located in the X-chromosome. The disease manifests with high phenotypic variability (tremor, cerebellar ataxia, parkinsonism, oculomotor disorders, cognitive and mental disorders). Due to the insufficient awareness among the physicians on this disease, FXTAS Syndrome patients often get incorrect diagnosis (essential tremor, Parkinson disease, multisystem atrophy, spinocerebellar ataxia etc.). CLINICAL CASE DESCRIPTION: The case presented is the patient aged 68 years with a severe past medical history (ischemic heart disease, post-infarction cardiosclerosis with the formation of post-infarction aneurism, arterial hypertension, pulmonary tuberculosis, chronic obstructive pulmonary disease, type 2 diabetes), in which the FXTAS Syndrome has first manifested with tremors, impaired coordination of motions, balance problems, cognitive disorders and affective disorders. The disease was confirmed by the genetic test (in the FMR1 gene, 96 CGG repeats were found). The patient’s daughter was examined with detecting the premutation of the FMR1 gene, while the grandson has a Martin-Bell syndrome. CONCLUSION: Neurologists and specialists of adjacent fields should keep in mind the FXTAS Syndrome (Fragile X-Associated Tremor/Ataxia Syndrome) and, in case of the patient having the corresponding symptoms, should rule out this rare neurodegenerative disease by arranging the genetic testing to reveal the mutation in the FMR1 gene.

The neurodevelopmental disorder fragile X syndrome (FXS) results from hypermethylation of the FMR1 gene, which prevents production of the FMRP protein. FMRP modulates the expression and function of a variety of proteins, including voltage-gated ion channels, such as hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, which are integral to rhythmic activity in thalamic structures. Thalamocortical pathology, particularly involving the mediodorsal thalamus (MD), has been implicated in neurodevelopmental disorders such as FXS. MD connectivity with the medial prefrontal cortex (mPFC) is integral to executive functions such as working memory and social behaviours that are disrupted in FXS. We used a combination of retrograde labelling and ex vivo brain slice whole-cell electrophysiology in 40 wild-type and 42 Fmr1 knockout male mice to investigate how a lack of Fmr1 affects intrinsic cellular properties in lateral (MD-L) and medial (MD-M) MD neurons that project to the mPFC (MD→mPFC neurons). In MD-L neurons, Fmr1 knockout decreased the HCN-mediated membrane properties voltage sag and membrane after-hyperpolarization. We also identified a delay in rebound spike timing in both complex bursts and low-threshold spikes. In Fmr1 knockout mice, reduced HCN channel activity in MD-L→mPFC neurons impaired both the timing and the magnitude of HCN-mediated membrane potential regulation. Changes in response timing might adversely affect rhythm propagation in Fmr1 KO thalamocortical circuitry. MD thalamic neurons are crucial for maintaining rhythmic activity involved in cognitive and affective functions. Understanding specific mechanisms of thalamocortical circuit activity might lead to therapeutic interventions for individuals with FXS and other conditions characterized by thalamic dysrhythmia.