Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy.
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ABSTRACT:
SUBMITTER: Negraes PD
PROVIDER: S-EPMC8531162 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeRecent quantitative neuroimaging studies of childhood absence epilepsy (CAE) have identified various structural abnormalities that might be involved in the onset of absence seizure and associated cognitive and behavioral functions. However, the neuroanatomical alterations specific to CAE remain unclear, and so this study investigated the regional alterations of brain structures associated with newly diagnosed CAE.MethodsSurface and volumetric magnetic resonance imaging data of patients with newly diagnosed CAE (n=18) and age-matched healthy controls (n=18) were analyzed using Free-Surfer software. A group comparison using analysis of covariance was performed with significance criteria of p<0.05 and p<0.01 in global and regional analyses, respectively.ResultsCompared with control subjects, the patients with CAE had smaller total and regional volumes of cortical gray-matter (GM) in the right rostral middle frontal, right lateral orbitofrontal, and left rostral middle frontal regions, as well as in the right precentral, right superior, middle, left middle, and inferior temporal gyri. The cortex in the right posterior cingulate gyrus and left medial occipital region was significantly thicker in patients with CAE than in controls.ConclusionsPatients with CAE showed a reduced bilateral frontotemporal cortical GM volume and an increased posterior medial cortical thickness, which are associated with the default mode network. These structural changes can be suggested as the neural basis of the absence seizures and neuropsychiatric comorbidities in CAE.
| S-EPMC7541981 | biostudies-literature
Project description:Diagnostic yield of epilepsy panel testing of patients with seizure onset within the first year of life
| PRJEB26566 | ENA
Project description:Degeneration of the substantia innominata (SI) is significantly correlated with cognitive performance in Parkinson's disease (PD). We examined functional and structural patterns of SI degeneration in drug-naïve PD patients according to the duration of parkinsonism before mild cognitive impairment (MCI) diagnosis. Twenty PD patients with a shorter duration (PD-MCI-SD, <1 year), 18 patients with a longer duration (PD-MCI-LD, ≥1 year), and 29 patients with intact cognition (PD-IC) were included. Seed-based resting-state functional connectivity (rsFC) analysis using bilateral SI seed and region-of-interest-based volumetric analysis were performed. Compared to PD-IC, the collapsed PD-MCI group showed altered rsFC in the right frontal and bilateral parietal areas. PD-MCI-SD showed rsFC alteration in broader frontal and parietal areas compared to the other groups. Decreased rsFC in the right frontal area was also significantly correlated with shorter disease duration. No significant SI volume change was found between the groups. Altered rsFC between the SI and the frontal and parietal areas might be relevant to cognitive dysfunction in PD. Decreased rsFC between the SI and frontal area might be associated with early-onset MCI, suggesting that cholinergic deficits in the frontal brain areas might play an important role in the acceleration of cognitive decline in PD.
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Project description:Cockayne syndrome (CS) is a rare genetic disorder in which 80% of cases are caused by mutations in the Excision Repair Cross-Complementation group 6 gene (ERCC6). The encoded ERCC6 protein is more commonly referred to as Cockayne Syndrome B protein (CSB). Classical symptoms of CS patients include failure to thrive and a severe neuropathology characterized by microcephaly, hypomyelination, calcification and neuronal loss. Modeling the neurological aspect of this disease has proven difficult since murine models fail to mirror classical neurological symptoms. Therefore, a robust human in vitro cellular model would advance our fundamental understanding of the disease and reveal potential therapeutic targets. Herein, we successfully derived functional CS neural networks from human CS induced pluripotent stem cells (iPSCs) providing a new tool to facilitate studying this devastating disease. We identified dysregulation of the Growth Hormone/Insulin-like Growth Factor-1 (GH/IGF-1) pathway as well as pathways related to synapse formation, maintenance and neuronal differentiation in CSB neurons using unbiased RNA-seq gene expression analyses. Moreover, when compared to unaffected controls, CSB-deficient neural networks displayed altered electrophysiological activity, including decreased synchrony, and reduced synapse density. Collectively, our work reveals that CSB is required for normal neuronal function and we have established an alternative to previously available models to further study neural-specific aspects of CS.
| S-EPMC4787902 | biostudies-literature
Project description:Non-familial Alzheimer’s disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer’s disease (EOAD) and constitutes ~5-6% of all Alzheimer’s disease (AD) cases. While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and motor dysfunction. Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2, but have been seldom used for sporadic forms of AD that display more heterogeneous disease manifestation. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA-sequencing. A modest difference in expression profiles between EOAD patients and non-demented control subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures during the iPSC reprogramming, are not an ideal model system to study sporadic AD.
2023-11-21 | GSE231341 | GEO
Project description:Background: Neonatal sepsis is a systemic condition widely affecting preterm infants and characterized by pro-inflammatory and anti-inflammatory responses. However, its pathophysiology is not yet fully understood. Epigenetics regulates the immune system, and its alteration leads to the impaired immune response underlying sepsis. DNA methylation may contribute to sepsis-induced immunosuppression which, if persistent, will cause long-term adverse effects in neonates. Objective: To analyze the methylome of preterm infants in order to determine whether there are DNA methylation marks that may shed light on the pathophysiology of neonatal sepsis. Design: Prospective observational cohort study performed in the neonatal intensive care unit (NICU) of a tertiary care center. Patients: Eligible infants were premature ?32 weeks admitted to the NICU with clinical suspicion of sepsis. The methylome analysis was performed in DNA from blood using Infinium Human Methylation EPIC microarrays to uncover methylation marks. Results: Methylation differential analysis revealed an alteration of methylation levels in genomic regions involved in inflammatory pathways which participate in both the innate and the adaptive immune response. Moreover, differences between early and late onset sepsis as compared to normal controls were assessed. Conclusions: DNA methylation marks can serve as a biomarker for neonatal sepsis and even contribute to differentiating between early and late onset sepsis.
| S-EPMC7917190 | biostudies-literature
Project description:ImportanceAlthough rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity.ObjectivesTo assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations.Design, setting, and participantsIn this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged ≤66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes. Recruitment took place from July 1, 2015, to June 30, 2019. Data were analyzed from February 1 to February 28, 2020.ExposuresRare and novel variants categorized as pathogenic or likely pathogenic.Main outcomes and measuresThe prevalence of rare and novel pathogenic variants in African American and Hispanic/Latinx probands with early-onset AF and genotype-phenotype associations.ResultsAmong 227 probands with early-onset AF, mean (SD) age at onset of AF was 51.0 (9.9) years, 132 probands (58.1%) were men, 148 (65.2%) were African American, and 79 (34.8%) were Hispanic/Latinx. A family history of AF was verified in 24 probands with early-onset AF (10.6%). Sequencing 60 candidate genes identified 53 (23 rare and 30 novel) variants with 16 of the 227 (7.0%) probands harboring likely pathogenic (43.8%) or pathogenic (56.2%) variants, with most loss-of-function variants in TTN, the gene encoding the sarcomeric protein titin (46.7%). In 6 families with more than 2 affected members, variants of unknown significance in sodium channel (SCN10A), potassium channel (KCNE5), sarcomeric proteins (MYH6 and TTN), and atrial natriuretic peptide (NPPA) cosegregated with AF.Conclusions and relevanceIn this study, likely pathogenic and pathogenic variants were identified, with most loss-of-function variants in TTN, that increase susceptibility to early-onset AF in African American and Hispanic/Latinx individuals. These findings provide further understanding toward molecular phenotyping of AF and suggest novel mechanism-based therapeutic approaches for this common arrhythmia in ethnic minority groups.
| S-EPMC8100900 | biostudies-literature
Project description:Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10-15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism.
| S-EPMC9965035 | biostudies-literature
Project description:The NICE audit of epilepsy related deaths revealed that 1200 epilepsy deaths occur every year in the UK, with 42% potentially avoidable.[1] Convulsive status epilepticus (SE) is a life-threatening condition with over 20% mortality rate, especially if early treatment is not initiated.[2] Ten percent of all UK emergency department (ED) admissions are due to epilepsy, usually over represented by cases of SE.[3] Six out of seven epilepsy cases seen in the ED are admitted into medical care.[4] Patients with chronic and/or treatment resistant epilepsy carry a higher risk of premature death. When a seizure lasts for five minutes or more then the patient is at high risk of continuing to SE and this may result in causing brain damage or death.[2] Buccal midazolam is an emergency rescue medication prescribed on a special named patient license to reduce the duration of an epileptic seizure and prevent SE.[2,5] It should be administered by a trained person and is widely used due to its effectiveness and social acceptability. In the UK, epilepsy education and training courses are expected to be conducted by epilepsy professionals in line with the agreed training guidelines of Joint Epilepsy Council (JEC) backed up by evidence from NICE.[6,7] Training should provide an overview of epilepsy to facilitate safe care and appropriate administration of rescue medication for people with epilepsy (PWE) when experiencing a prolonged seizure. The medication is prescribed on specialist advice by the GP or specialists directly. Unfortunately the JEC guidelines are not robust enough to provide assurances of safe care. This problem had a myriad of complexities and an appropriate solution using web based resource was piloted, tested, and applied successfully using quality improvement methodology.
| S-EPMC4645852 | biostudies-other
Project description:Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 functions at the epigenetic level, we tested whether these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders.
| S-EPMC4720528 | biostudies-literature