神経細胞移動異常症

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a severe neurological disorder with complex pathogenesis. The role of telomere-associated genes in HIE remains unclear. This study aims to investigate their alterations and mechanisms to provide new therapeutic insights. METHODS: Telomere-associated differentially expressed genes (Telomere-DEGs) were identified from neonatal mouse HIE transcriptome datasets (GSE23317, GSE144456) in GEO. GO and KEGG enrichment analyses were performed. A protein-protein interaction network was constructed using STRING, and the best Telomere-DEGs (BTDGs) were identified via CytoHubba, followed by validation in GSE144456. Immune infiltration was assessed with CIBERSORT. Potential drugs targeting BTDGs were predicted using DGIdb. HT22 cell OGD/R and neonatal mouse HIE models were established. qRT-PCR, Western blot, immunofluorescence, flow cytometry, ROS detection, and CCK-8 assays were used to validate BTDG expression and explore the regulatory role of the SOCS3/NF-κB axis in telomere dysfunction and oxidative stress. RESULTS: Eighteen HIE-related Telomere-DEGs were identified, with ten defined as BTDGs. Enrichment analyses revealed involvement in glial cell regulation, inflammation, and immune cell migration. Immune infiltration analysis showed significantly increased infiltration of Th1 and mature dendritic cells in the HIE group. BTDG expression was positively associated with neutrophil infiltration, negatively correlated with M1 macrophage infiltration, and positively correlated with M2 macrophage infiltration. Drug prediction identified 19 FDA-approved drugs targeting BTDGs, including Phenobarbital, Baclofen, and Bromocriptine. In vivo, SOCS3 and Ccl4 mRNA and protein were significantly upregulated in the HIE mouse hippocampus. In vitro, OGD/R upregulated SOCS3 in HT22 cells, accompanied by decreased TRF2, increased γ-H2AX and ROS, and reduced cell viability. SOCS3 knockdown inhibited NF-κB activation, upregulated TRF2, reduced γ-H2AX and ROS, and decreased apoptosis, which were reversed by the NF-κB activator PMA. CONCLUSION: The study systematically identified Telomere-DEGs in neonatal HIE, characterized the disease's inflammatory immune microenvironment, and predicted potential targeted therapeutic agents. SOCS3 upregulation in HIE was confirmed both in vivo and in vitro. In vitro mechanistic studies suggest that SOCS3 aggravates telomere damage and oxidative stress through NF-κB activation, leading to neuronal injury, thus providing experimental evidence for HIE mechanism research and targeted therapy.

The objective was to identify risk factors for long-term sequelae in children with congenital cytomegalovirus (cCMV) infection and to develop a prognostic scoring system (cCMVnet score) to support individualized management. This retrospective study was conducted within the prospective European Registry of Children with cCMV and included 570 children born between 2011 and 2024 in 11 countries. Eligible participants had confirmed cCMV, early cranial ultrasound and brain MRI (≤ 90 days of life), and at least six months of follow-up. The primary outcome was sequelae, defined as sensorineural hearing loss (SNHL), motor impairment, epilepsy, or visual impairment. Predictors were identified using multivariable logistic regression with Elastic-Net selection, followed by development and internal validation of the score. Overall, 63.2% were symptomatic at birth and 28.9% developed sequelae, mainly SNHL (24.7%), motor impairment (8.2%), epilepsy (4.0%), and visual impairment (2.6%). Splenomegaly, severity of hearing loss and neuroimaging abnormalities (white matter changes, calcifications, ventriculomegaly, and cortical malformations/migration abnormalities) were significant predictors. The cCMVnet score showed strong discrimination (AUC 0.872). At a 2.99 point cut-off, sensitivity was 81.3%, specificity 85.3%, and negative predictive value 90.6%.Conclusions: The cCMVnet score enables accurate risk stratification beyond symptomatic status integrating clinical, audiological, and neuroimaging findings. External validation is needed before widespread implementation.

The development and maintenance of the nervous system depend on a tightly regulated intracellular transport network in which kinesin superfamily (KIF) motor proteins drive microtubule-based delivery of synaptic vesicle precursors, organelles, mRNAs, and signaling components along axons and dendrites. Disruption of this machinery underlies a clinically heterogeneous spectrum of neurodevelopmental disorders (NDDs), including intellectual disability, epilepsy, autism spectrum disorder, microcephaly, malformations of cortical development, spasticity, and axonal neuropathy. Here, we synthesize current knowledge on how kinesin dysfunction shapes neurodevelopment. We outline the physiological roles of kinesins in neuronal polarity, organelle and mitochondrial positioning, synaptogenesis, and progenitor division, and survey principal disease-associated genes, including KIF1A, KIF5A, KIF7, KIF11, KIF2A, KIF5C, and emerging members such as KIF14, KIF15, and KIF16B. We detail how distinct pathogenic mechanisms, such as loss of motility, impaired cargo coupling, motor hyperactivity, mitotic spindle defects, and disrupted ciliary signaling, converge on shared cellular endpoints, and how tubulin isotypes and posttranslational modifications further modulate motor output. In this review, we discuss translational implications, including variant-resolved diagnosis and precision strategies to restore transport, dampen pathological hyperactivity, or stabilize the microtubule track. Collectively, these advances reframe kinesinopathies as mechanistically stratified disorders of neuronal transport.

Mirror movements (MMs) are involuntary movements on one side of the body that mimic voluntary movements on the opposite side. Schizencephaly is an uncommon congenital neuronal migration disorder characterised by the presence of a trans-mantle column of heterotopic grey matter, with or without a full-thickness cleft filled with cerebrospinal fluid, which links the pial surface of the cerebral hemisphere with the ependymal surface of the lateral ventricle. We report a case of a 13-year-old child with unilateral schizencephaly who presented with MMs. Transcranial magnetic stimulation was used to understand the neurophysiology of MMs. Single-pulse and paired-pulse stimulation were done. The silent period was shortened with absent short-interval intracortical inhibition and reduced intracortical facilitation. This suggests reduced GABAergic and glutamatergic transmission in the brain. These altered neurophysiological parameters, along with motor cortex re-organisation, may account for MMs in our case.

Congenital microcephaly and lissencephaly spectrum disorders are characterized by disrupted neuronal proliferation and migration, often driven by underlying genetic variants. Here, we identified and characterized of a novel gene (Tetratricopeptide Repeat Domain 14, TTC14) and its homozygous missense variant (c.89 A > G; p.His30Arg (p.H30R)) in a female proband presenting with microcephaly, epileptic spasms, global developmental delay, and neuroimaging features of simplified gyral pattern, focal pachygyria, and corpus callosum thinning. Trio-based whole exome sequencing revealed this variant to be rare and autosomal recessively inherited from both asymptomatic parents. Structural modeling demonstrated that H30 lies at the start of an α-helical region and is evolutionarily conserved. The p.His30Arg substitution caused significant steric clashes and disrupted local folding. Interaction network analysis and molecular dynamics simulations confirmed structural destabilization, increased conformational flexibility, and loss of stability in the mutant protein. While mRNA and protein levels remained unaltered, the TTC14-p.His30Arg protein mislocalized from the nucleus to the cytosol and formed aggregates. Functionally, proband fibroblasts exhibited increased cell death and altered cell cycle progression. TTC14 interacts with RNA splicing and mRNA processing proteins, and gene ontology analysis implicated it in RNA binding and spliceosomal complex assembly in key brain regions including the cerebral cortex, hippocampus, and white matter. These findings collectively suggest that TTC14 plays a crucial role in RNA metabolism during neurodevelopment, and that the p.His30Arg variant impairs its function, possibly leading to a neurodevelopmental disorder within the lissencephaly spectrum. This study identifies TTC14 as a likely pathogenic candidate gene in cortical malformation syndromes.