De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.

We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. In contrast, the CDK19 p.Tyr32His and p.Thr196Ala variants identified in the affected individuals fail to rescue the loss of Cdk8 and behave as null alleles. Additionally, neuronal RNAi-mediated knockdown of Cdk8 in flies results in semi-lethality. The few eclosing flies exhibit severe seizures and a reduced lifespan. Both phenotypes are fully suppressed by moderate expression of the CDK19 reference cDNA but not by expression of the two variants. Finally, loss of Cdk8 causes an obvious loss of boutons and synapses at larval neuromuscular junctions (NMJs). Together, our findings demonstrate that human CDK19 fully replaces the function of Cdk8 in the fly, the human disease-associated CDK19 variants behave as strong loss-of-function variants, and deleterious CDK19 variants underlie a syndromic neurodevelopmental disorder.

Differences in whole-brain metabolism are associated with the expression of genes related to neurovascular unit integrity and synaptic plasticity in temporal lobe epilepsy.

PURPOSE: Temporal lobe epilepsy (TLE) is a common, polygenic epilepsy syndrome that involves glucose hypometabolism in the epileptogenic zone. However, the transcriptional and cellular signatures underlying the metabolism in TLE remain unclear. METHODS: In this retrospective study, 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) scans of TLE patients (n = 104) who underwent anterior temporal lobectomy were consecutively collected between 2016 and 2021. The transcriptional profiles of TLE risk genes across the brain were identified by the gene expression analyses from six TLE patients and twelve postmortem donors (six from the Allen Human Brain Atlas). Integrating the neuroimaging and transcriptomic data, we examined the relationship between the expression of TLE-associated genes and metabolic alterations in TLE. Furthermore, we performed functional enrichment analyses of the genes with higher weight in partial least squares regression using Metascape. RESULTS: A total of 104 patients with TLE (mean age 29 ± 9 years, 50% male) and 30 healthy controls (HCs) (mean age 31 ± 6 years, 53% male) were enrolled. Compared to that of HCs, patients with TLE showed hypometabolism in the temporal lobes and adjacent structures but hypermetabolism in the thalamus and basal ganglia. The cortical map of inter-group differences in cerebral metabolism was spatially correlated with the expression of a weighted combination of genes enriched in ontology terms and pathways related to neurovascular unit (NVU) integrity and synaptic plasticity. DISCUSSION: Our findings, combined with the analysis of neuroimaging and transcriptional data, suggest that genes related to NVU integrity and synaptic plasticity may drive alterations to brain metabolism that mediate the genetic risk of TLE.

Diagnostic value of nerve conduction study in NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND AND AIMS: Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disorder mainly caused by abnormally expanded GGC repeats within the NOTCH2NLC gene. Most patients with NIID show polyneuropathy. Here, we aim to investigate diagnostic electrophysiological markers of NIID. METHODS: In this retrospective dual-center study, we reviewed 96 patients with NOTCH2NLC-related NIID, 94 patients with genetically confirmed Charcot-Marie-Tooth (CMT) disease, and 62 control participants without history of peripheral neuropathy, who underwent nerve conduction studies between 2018 and 2022. RESULTS: Peripheral nerve symptoms were presented by 53.1% of patients with NIID, whereas 97.9% of them showed peripheral neuropathy according to electrophysiological examinations. Patients with NIID were characterized by slight demyelinating sensorimotor polyneuropathy; some patients also showed mild axonal lesions. Motor nerve conduction velocity (MCV) of the median nerve usually exceeded 35 m/s, and were found to be negatively correlated with the GGC repeat sizes. Regarding the electrophysiological differences between muscle weakness type (n = 27) and non-muscle weakness type (n = 69) of NIID, nerve conduction abnormalities were more severe in the muscle weakness type involving both demyelination and axonal impairment. Notably, specific DWI subcortical lace sign was presented in only 33.3% of muscle weakness type, thus it was difficult to differentiate them from CMT. Combining age of onset, distal motor latency, and compound muscle action potential of the median nerve showed the optimal diagnostic performance to distinguish NIID from major CMT (AUC = 0.989, sensitivity = 92.6%, specificity = 97.4%). INTERPRETATION: Peripheral polyneuropathy is common in NIID. Our study suggest that nerve conduction study is useful to discriminate NIID.

DNAH14 variants are associated with neurodevelopmental disorders.

Neurodevelopmental disorders (NDD) are complex and multifaceted diseases involving genetic and environmental sciences. Rapid developments in sequencing techniques have made it possible to identify new disease-causing genes. Our study aimed to identify novel genes associated with NDDs. Trio whole-exome sequencing was performed to evaluate potential NDD variants. We identified three unrelated patients with compound heterozygous DNAH14 variants. The detailed clinical information and genetic results of the recruited patients were obtained and systematically reviewed. Three compound heterozygous DNAH14 variants were identified as follows: c.6100C > T(p.Arg2034Ter) and c.5167A > G(p.Arg1723Gly), c.12640_12641delAA(p.Lys4214Valfs*7) and c.4811T > A(p.Leu1604Gln), andc.7615C > A(p.Pro2539Thr) and c.11578G > A(p.Gly3860Ser), including one nonsense, one frameshift, and four missense variants, which were not existent or with low minor allele frequencies based on the gnomAD database. The missense variants were assumed to be damaging or probably damaging by using multiple bioinformatics tools. Four of these variants were located in the AAA+ ATPase domain, while two were located in the C-terminal domain. Most affected amino acids were highly conserved in various species. A spectrum of neurological and developmental phenotypes was observed, including seizures, global developmental delay, microcephaly, and hypotonia. Thus, our findings indicate that variants of DNAH14 could lead to previously unrecognized NDDs.

Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.

The second DDOST-CDG patient with lactose intolerance, developmental delay, and situs inversus totalis.

Congenital disorders of glycosylation (CDGs) are inherited metabolic diseases affecting protein and lipid glycosylation. DDOST-CDG is a rare, newly identified type of CDGs, with only one case reported so far. In this study, we report a Chinese patient with a homozygous pathogenic variant in DDOST (c.1187G>A) and who presented with feeding difficulty, lactose intolerance, facial dysmorphism, failure to thrive, strabismus, high myopia, astigmatism, hypotonia, developmental delay and situs inversus totalis. Serum transferrin isoelectrofocusing demonstrated defective glycosylation in our patient. This finding further identifies DDOST as a genetic cause of CDGs and expands the clinical phenotype of DDOST-CDG.

A de novo inframe deletion variant in CAPZA2 tentacle domain with global developmental delay and secondary microcephaly.

(A) Sanger sequencing confirmation and family pedigree for the patient. (B) A schematic representation of transcript and translation showing the positions of all CAPZA2 variants identified.

Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND: Abnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China. METHODS: Patients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy. RESULTS: In the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission. CONCLUSIONS: NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

Altered cerebellar-motor loop in benign adult familial myoclonic epilepsy type 1: The structural basis of cortical tremor.

OBJECTIVE: Cortical tremor/myoclonus is the hallmark feature of benign adult familial myoclonic epilepsy (BAFME), the mechanism of which remains elusive. A hypothesis is that a defective control in the preexisting cerebellar-motor loop drives cortical tremor. Meanwhile, the basal ganglia system might also participate in BAFME. This study aimed to discover the structural basis of cortical tremor/myoclonus in BAFME. METHODS: Nineteen patients with BAFME type 1 (BAFME1) and 30 matched healthy controls underwent T1-weighted and diffusion tensor imaging scans. FreeSurfer and spatially unbiased infratentorial template (SUIT) toolboxes were utilized to assess the motor cortex and the cerebellum. Probabilistic tractography was generated for two fibers to test the hypothesis: the dentato-thalamo-(M1) (primary motor cortex) and globus pallidus internus (GPi)-thalamic projections. Average fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) of each tract were extracted. RESULTS: Cerebellar atrophy and dentate nucleus alteration were observed in the patients. In addition, patients with BAFME1 exhibited reduced AD and FA in the left and right dentato-thalamo-M1 nondecussating fibers, respectively false discovery rate (FDR) correction q < .05. Cerebellar projections showed negative correlations with somatosensory-evoked potential P25-N33 amplitude and were independent of disease duration and medication. BAFME1 patients also had increased FA and decreased MD in the left GPi-thalamic projection. Higher FA and lower RD in the right GPi-thalamic projection were also observed (FDR q < .05). SIGNIFICANCE: The present findings support the hypothesis that the cerebello-thalamo-M1 loop might be the structural basis of cortical tremor in BAFME1. The basal ganglia system also participates in BAFME1 and probably serves a regulatory role.

Subcellular-Targeted Near-Infrared-Responsive Nanomedicine with Synergistic Chemo-photothermal Therapy against Multidrug Resistant Cancer.

Multidrug resistance (MDR) is a major obstacle to effective cancer treatment. Therefore, developing effective approaches for overcoming the limitation of MDR in cancer therapy is very essential. Chemotherapy combined with photothermal therapy (PTT) is a potential therapeutic option against MDR. Herein, we developed a subcellular-targeted near-infrared (NIR)-responsive nanomedicine (Fe3O4@PDA-TPP/S2-PEG-hyd-DOX, abbreviated as Fe3O4-ATSPD) as a new photothermal agent with improved photothermal stability and efficiency. This system demonstrates high stability in blood circulation and can be accumulated at the tumor site by magnetic targeting enhanced permeability and retention effect (EPR). Near-infrared (NIR) irradiation at the tumor site generates a photothermal effect from the photosensitizer Fe3O4@PDA, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the conjugated drugs released under low pH condition in endosomes or lysosomes cause nucleus DNA damage and cell apoptosis. This subcellular-targeted NIR-responsive nanomedicine with efficient integration of diagnosis and therapy could significantly enhance MDR cancer treatment by combination of chemotherapy and PTT.

A novel compound heterozygous EPM2A mutation in a Chinese boy with Lafora disease.

EPM2A has been certified as a causative gene in patients with Lafora disease (LD), which is a rare autosomal recessive and severe form of progressive myoclonus epilepsy. LD classically starts in adolescence, characterized by various types of seizure with myoclonic seizure as the main type. Typically within 10 years, intractable seizure attack, rapidly progressing dementia, and a vegetative state were present. LD is particularly frequently found in Mediterranean countries. Here, we report a Chinese family with a novel compound heterozygous mutation in the EPM2A gene, characterized by recurrent vomiting, intractable epilepsy, and progressive cognitive decline.

Common variants of APOE are associated with anti-epileptic drugs resistance in Han Chinese patients.

Purpose/aim of the study: Apolipoprotein E (APOE) has been implicated as one of the susceptibility genes for some subtypes of epilepsy and may be related to anti-epileptic drugs resistance. The purpose of this study was to investigate the possible association between APOE variants and the anti-epileptic drugs resistance in Chinese population. MATERIALS AND METHODS: APOE gene rs429358 and rs7412 variants were genotyped for ϵ2, ϵ3, ϵ4 alleles using amplification refractory mutation system in 480 subjects including 207 anti-epileptic drugs-resistant patients and 273 drug-responsive patients. RESULTS: We found that the frequency of APOE gene rs429358 C allele in the drug resistant patients is higher than that in the drug-responsive patients (14.98% vs. 10.1%, OR = 1.25[1.02 - 1.52], p = 0.017). Moreover, according to the two variants, we analyzed the distributions of -ϵ4 and +ϵ4 alleles of APOE gene and found that there were higher frequencies of +ϵ4 allele in drug-resistant epileptic patients than that in drug-responsive patients (31.8% vs. 13.2%, OR = 1.15[1.05 - 1.25], p = 0.002). CONCLUSIONS: Our study demonstrated that APOE rs429358 variant C allele and ϵ4 allele were associated with the anti-epileptic drugs resistance in Han Chinese patients.

ABCB1, ABCC2, SCN1A, SCN2A, GABRA1 gene polymorphisms and drug resistant epilepsy in the Chinese Han population.

Drug resistance is common in epilepsy despite multiple available medications. Single nucleotide polymorphisms (SNP) may influence drug efficacy in epilepsy. We therefore aimed to clarify the association between polymorphisms of several controversial SNP loci and drug resistance in Chinese Han epilepsy patients from central China. Among all the 391 recruited subjects, 235 and 156 patients were classified into a drug responsive and resistant group, respectively, according to the definition of drug resistance proposed by the International League Against Epilepsy. The candidate SNP loci, including ATP-binding cassette (ABC) subfamily gene ABCB1 rs2032582 and rs1045642; ABC subfamily gene ABCC2 rs717620 and rs2273697; sodium channel subunit gene SCN1A rs3812718, SCN2A rs2304016; γ-amino butyric acid type A (GABAA) receptor subunit subtype gene GABRA1 rs2279020 were genotyped following the Illumina protocols. There were no significant differences in allelic or genotypic frequencies between the drug responsive and resistant patients. The polymorphisms of the above SNP loci may not be associated with drug resistance of epilepsy in the Chinese Han population.

PRRT2 mutations are related to febrile seizures in epileptic patients.

Previous studies reported that the proline-rich transmembrane protein 2 (PRRT2) gene was identified to be related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with PKD, PKD with migraine and benign familial infantile epilepsy (BFIE). The present study explores whether the PRRT2 mutation is a potential cause of febrile seizures, including febrile seizures plus (FS+), generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS); thus, it may provide a new drug target for personalized medicine for febrile seizure patients. We screened PRRT2 exons in a cohort of 136 epileptic patients with febrile seizures, including FS+, GEFS+ and DS. PRRT2 genetic mutations were identified in 25 out of 136 (18.4%) febrile seizures in epileptic patients. Five loss-of-function and coding missense mutations were identified: c.649delC (p.R217Efs*12), c.649_650insC (p.R217Pfs*8), c.412C>G (p.Pro138Ala), c.439G>C (p.Asp147His) and c.623C>A (p.Ser208Tyr). PRRT2 variants were probably involved in the etiology of febrile seizures in epileptic patients.

Machine Learning Predictive Model for Septic Shock in Acute Pancreatitis with Sepsis.

Objective: Acute pancreatitis (AP) progresses to septic shock can be fatal. Early identification of high-risk patients and timely intervention can prevent and interrupt septic shock. By analyzing the clinical characteristics of AP with sepsis, this study uses machine learning (ML) to build a model for early prediction of septic shock within 28 days of admission, which guided emergency physicians in resource allocation and medical decision-making. Methods: This retrospective cohort study collected data from the emergency departments (EDs) of three tertiary care hospitals in China. The dataset was randomly divided into a training dataset (70%) and a testing dataset (30%). Ten ML classifiers were utilized to analyze characteristics of AP with sepsis in the training dataset upon admission. Results were evaluated through cross-validation analysis. The optimal model was then tested on the testing dataset without any parameter modifications. The ML model was evaluated using the receiver operating characteristic curve (ROC) and compared to scoring systems through the DeLong test. Results: A total of 604 AP patients with sepsis were included in this study. The auto-encoder (AE) model based on mean normalization, Pearson correlation coefficient (PCC), and recursive feature elimination (RFE) selection, achieved the highest Area Under the Curve (AUC) on the validation dataset (AUC 0.900, accuracy 0.868), with the AUC of 0.879 and accuracy of 0.790 on the testing dataset. Compared to the Sequential Organ Failure Assessment (AUC 0.741), quick Sequential Organ Failure Assessment (AUC 0.727), Acute Physiology and Chronic Health Evaluation II (AUC 0.778), and Bedside Index of Severity in Acute Pancreatitis (AUC 0.691), the AE model showed superior performance. Conclusion: The AE model outperforms traditional scoring systems in predicting septic shock in AP patients with sepsis within 28 days of admission. This assists emergency physicians in identifying high-risk patients early and making timely medical decisions.

Assessing the impact of industrial intelligence on urban carbon emission performance: Evidence from China.

With the growing emphasis on sustainable development, there has been increasing attention given to measures aimed at promoting environmental improvements and reducing carbon emissions, including the adoption of intelligent industry. Recent studies have analyzed the influence of industrial intelligence on urban carbon emission performance while ignore the spatial spillover effects and lack in-depth discussion of the mechanisms, which reduces the reliability of the assessment of industrial intelligence's impact on carbon emission performance. To address this issue, the paper examines direct effect, spatial spillover effects, and mechanisms, utilizing a balanced panel data from 2008 to 2019 for 238 Chinese cities. The findings reveal that a 1 % improvement in industrial intelligence results in a 2.747 % enhancement of local carbon emission performance. Moreover, through the spatial spillover analysis, we determined that industrial intelligence has a notable negative impact on the carbon emission performance of surrounding areas. The mechanism analysis demonstrated that industrial intelligence affects the carbon emission performance of local and neighboring areas by influencing the agglomeration of productive services. Furthermore, our study illustrates that the industrial intelligence's enhancement effect on carbon emission performance shows more significantly in eastern, resource-dependent, and ordinary prefecture-level cities. Finally, endogeneity and robustness tests conducted yielded consistent conclusions. Our study provides a new perspective on industrial intelligence's carbon reduction effect and contributes to the development of policies related to industrial upgrading and green development.

Th1/Th2 Imbalance in Peripheral Blood Echoes Microglia State Dynamics in CNS During TLE Progression.

Central and systemic inflammation play pivotal roles in epileptogenesis and proepileptogenesis in temporal lobe epilepsy (TLE). The interplay between peripheral CD4+ T cells and central microglia orchestrates the "systemic-central" immune response in TLE. However, the precise molecular mechanisms linking central and systemic inflammation in TLE remain unknown. This preliminary findings revealed an imbalance in Th1/Th2 subsets in the periphery，accompanied by related cytokines release in TLE patients. they proposed that this peripheral Th1/Th2 imbalance may influence central inflammation by mediating microglial state dynamics within epileptic foci and distant brain regions. In Li-pilocarpine-induced TLE rats, a peripheral Th1/Th2 imbalance and observed corresponding central and systemic responses is confirmed. Notably, CD4+ T cells infiltrated through the compromised blood-brain barrierand are spatially close to microglia around epileptic foci. Intravenous depletion and reinfusion of CD4+ T cells modulated microglia state dynamics and altered neuroinflammatory cytokines secretion. Moreover, mRNA sequencing of the human hippocampus identified Notch1 as a key regulator of Th1/Th2 differentiation, CD4+ T cell recruitment to brain infiltration sites, and the regulation of microglial responses, seizure frequency, and cognition. This study underscores the significance of Th1/Th2 imbalance in modulating the "systemic-central" response in TLE, highlighting Notch1 as a potential therapeutic target.

A quantum dot probe conjugated with aß antibody for molecular imaging of Alzheimer's disease in a mouse model.

The treatment of Alzheimer's disease (AD) has been hampered by a lack of sensitive and specific non-invasive diagnostic methods. Quantum dots (QD) are nano-crystals with unique photo-physical properties that bypass some of the limitations of conventional dyes and imaging tools. This study is aimed to evaluate the fluorescence properties of a QD probe conjugated with an anti-Aß antibody (QD-Aß-Ab). Healthy mice and mice bearing mutated human APP695swe and APP717 V-F transgenes received intracerebroventricular injection of the probe for subsequent imaging. Immunohistochemistry revealed that Aß1-42 was distributed in the hippocampus CA1 area in the APP transgenic mice. Fluorescence microscopy demonstrated that fluorescence was mainly observed in the hippocampus area, the cerebral cortex, sagittal septum and striatum of APP transgenic mice. In vivo imaging of mice receiving the QD-Aß-Ab probe showed that healthy mice exhibited a narrow range of fluorescence and lower fluorescence intensity compared with APP transgenic mice. The mean fluorescence intensity of brain tissues of healthy C57BL mice was 12.3784 ± 3.9826, which was significantly lower than that of 10- and 16-month-old APP transgenic mice (45.03 ± 2.66 and 46.69 ± 3.22, respectively; P < 0.05). In this study we present the first direct evidence that QD-Aß-Ab conjugate probes can track in vivo state of Aß accumulation in mice and the findings suggest that such probes may be of potential use for early molecular diagnostic imaging of AD.