脆弱X症候群

INTRODUCTION: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of fragile X messenger ribonucleoprotein (FMRP) expression and characterized by synaptic dysfunction and cognitive impairment. However, the metabolic and epigenetic mechanisms underlying these abnormalities remain poorly understood. To address this gap, this study investigated the role of hexokinase 2 (HK2) in FXS pathogenesis and explored downstream metabolic and epigenetic mechanisms associated with synaptic dysfunction and cognitive impairment. METHODS: Using an Fmr1 -/Y mouse model, we evaluated HK2 expression and its cell-type specificity in hippocampal neurons. RNA immunoprecipitation (RIP) analysis was performed to examine the association between FMRP and Hk2 mRNA. Genetic knockdown of HK2 was used to assess its effects on neurite outgrowth, synapse density, synaptic transmission, and hippocampal long-term potentiation (LTP). Finally, pharmacological experiments using the HDAC3 inhibitor RGFP966 were performed to examine whether modulation of H3K18la levels contributes to HK2-associated phenotypes. RESULTS: HK2 expression was markedly elevated in hippocampal neurons of Fmr1 -/Y mice. RIP analysis revealed an association between FMRP and Hk2 mRNA, suggesting that HK2 may represent an FMRP-associated transcript. Genetic suppression of HK2 promoted neurite outgrowth, increased synapse density, and improved synaptic transmission and hippocampal long-term potentiation (LTP) in Fmr1 -/Y mice. Mechanistically, HK2 knockdown selectively reduced H3K18la levels without affecting H3K18 acetylation, supporting a role for HK2 in regulating histone lactylation. Consistent with these findings, pharmacological inhibition of HDAC3 with RGFP966 increased H3K18la levels and attenuated the beneficial effects of HK2 suppression on neuronal morphology, synaptic plasticity, and cognitive function. Behavioral analyses demonstrated that modulation of the HK2-H3K18la axis improved spatial learning and memory in Fmr1 -/Y mice. CONCLUSION: Taken together, these findings support a role for the HK2-H3K18la axis in synaptic dysfunction in FXS. Targeting this metabolic-epigenetic axis may provide a potential avenue for future therapeutic exploration in FXS and related neurodevelopment disorders.

Genetic neurodevelopmental disorders (NDDs) encompass a heterogeneous group of conditions characterized by impaired cognitive, behavioral, and neurological development resulting from pathogenic variants affecting brain development and synaptic function. Advances in molecular genetics and next-generation sequencing have significantly expanded the understanding of the genetic architecture underlying disorders such as Rett syndrome (RTT), Fragile X syndrome (FXS), Angelman syndrome (AS), and autism spectrum disorders. Beyond these classical neurodevelopmental disorders, spinal muscular atrophy (SMA) is included as a paradigmatic example of successful RNA-based therapeutic translation. Concurrently, RNA-based therapeutics have emerged as promising precision medicine strategies capable of modulating gene expression at the transcriptional and post-transcriptional levels. These approaches include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), messenger RNA (mRNA) therapies, RNA editing technologies, and splice-modulating agents. Recent clinical successes, particularly in spinal muscular atrophy, have demonstrated the transformative potential of RNA therapeutics in neurological disease. However, substantial challenges remain, including BBB penetration, long-term safety, immune activation, and genotype-specific variability in therapeutic response. This review summarizes current advances in RNA-based therapeutics for genetic NDDs, highlighting molecular mechanisms, disease-specific therapeutic strategies, translational progress, delivery challenges, and future directions. Overall, continued progress will depend on the integration of disease biology, rational RNA therapeutic design, and effective CNS-targeted delivery, supporting the broader implementation of precision RNA medicine for genetic neurodevelopmental disorders.

PURPOSE: Fragile X syndrome (FXS) presents with a variety of behavioral comorbidities. Although multiple publications have reported detailed characterizations for some of them, many gaps of knowledge still remain. Therefore, we characterized the eight most common behavioral comorbidities (i.e., clinician identified behavioral concerns) in children evaluated in specialty FXS clinics. METHODS: We analyzed the pediatric FORWARD clinic-based natural history study database (1,072 males, 338 females), using multiple statistical techniques including chi-square analyses, polychoric and polyserial correlations, and Mann-Whitney tests to determine frequency, co-occurrence, and behavioral scale profiles of children with eight behavioral comorbidities and functional impairment (approximately half of those affected). DSM-5 criteria were only used for autism spectrum disorder (ASD) identification. RESULTS: Attention problems and Anxiety were the two most common and mildest comorbidities, while disruptive behavior (IAAS) . Co-occurrence of impairing behavioral comorbidities were reported for 69% of children, with 39% of them presenting with more than two comorbidities and overall greatest impairment. Comorbidity co-occurrence was influenced by frequency, but strength of association was relatively independent. Strong correlations were found for two distinctive co-occurrences in non-FXS populations: Attention problems-Hyperactivity and Anxiety-Mood disturbances. Although scale scores aligned with other severity parameters, comorbidity-scale correlations reflected relevance of evaluated behaviors. Surprisingly, all behavioral comorbidities were strongly correlated with the Sensory problems scale. CONCLUSION: The reported profiles of impairing behavioral comorbidities could assist clinicians in early identification of behavioral symptoms and in refining their management in children with FXS and, perhaps also, other neurodevelopmental disorders.

Electrical source imaging (ESI) reconstructs where in the brain a scalp EEG signal arises. It is routine in humans but unestablished in the mouse, whose brain is some 3000 times smaller where it is not obvious that a sparse array can separate one region from another. We built an atlas-based ESI pipeline for 30-channel mouse EEG and tested it against simulated dipoles, across 18 combinations of source space, head model and inverse operator, with conductivity and noise sweeps. The best, a region-of-interest source space with an ellipsoid head model and sLORETA, recovered superficial sources to a mean error of 0.93 mm, rising to 5.08 mm at depth. We then applied it to resting EEG from male Fmr1 knockout (n = 18) and wild-type (n = 17) mice. Gamma power was elevated in the knockouts (Low Gamma q = 0.004, standardized mean difference 1.02; High Gamma q = 0.004, 0.67) and localized to six parcels, three of them in both bands. Relative power in Delta, Theta and High Gamma, and both aperiodic parameters, varied by region (q < 0.001 to 0.035). The electrode analysis recovered neither the Delta pattern nor any named structure. The gamma findings survived adjustment for acquisition cohort (p = 0.001 and 0.002). Simulation bounds what the pipeline recovers and which region it assigns activity to, but cannot show that a labeled region is the true source in a live animal. Replication across recording systems, sex, age and injection-naive animals is needed.

Fragile X syndrome (FXS) and tuberous sclerosis complex (TSC) are common monogenic causes of autism spectrum disorder (ASD). FXS arises from FMR1 silencing, while TSC results from mutations in TSC1 or TSC2, both converging on dysregulated ERK and mTORC1 signaling. Animal knockout models suggest opposing effects on synaptic plasticity, with reciprocal compensation in double knockouts (dKO). However, clinical case with dual mutations shows severe neurodevelopmental deficits; here, we explored a human cellular model to dissect the shared and divergent mechanisms. We generated isogenic human pluripotent stem cell (hPSC)-derived models of FMR1KO, TSC2KO, and FMR1/TSC2 dKO neurons. Neuronal transcriptomes were profiled by RNA-seq, integrating ERK, mTOR, FMRP targets, and ASD risk genes. Validation via qPCR of key genes, protein synthesis, proliferation assays, and microelectrode array was performed. The FMR1/TSC2 dKO neural progenitor cells (NPCs) demonstrated high DNA damage response but normalized proliferation. Convergent transcriptomic pathways across FMR1KO, TSC2KO, and dKO neurons included upregulated extracellular matrix and stress responses, and downregulated synaptic and neurotransmission-related pathways. TSC2KO and dKO neurons showed greater similarity transcriptionally and functionally. Translational pathways and global protein synthesis were oppositely regulated in TSC2KO and dKO versus FMR1KO neurons. The dKO neurons showed hyperexcitable network activity, mTOR hyperactivation, with distinct dysregulated FMRP targets and ASD risk gene expression. Unlike mouse models, FMR1/TSC2 dKO hPSC-derived neurons did not show rescue of synaptic gene expression. Rather, dKO neurons predominantly resembled TSC2KO neurons with translational, synaptic, and neurotransmission abnormalities. These findings highlight complex interplay between FMRP and TSC, providing a foundation for future studies of ASD-relevant mechanisms.