Dataset Information

Implication of sestrin3 in epilepsy and its comorbidities.

ABSTRACT: Epilepsy is a serious neurological disorder affecting about 1% of the population worldwide. Epilepsy may arise as a result of acquired brain injury, or as a consequence of genetic predisposition. To date, genome-wide association studies and exome sequencing approaches have provided limited insights into the mechanisms of acquired brain injury. We have previously reported a pro-epileptic gene network, which is conserved across species, encoding inflammatory processes and positively regulated by sestrin3 (SESN3). In this study, we investigated the phenotype of SESN3 knock-out rats in terms of susceptibility to seizures and observed a significant delay in status epilepticus onset in SESN3 knock-out compared to control rats. This finding confirms previous in vitro and in vivo evidence indicating that SESN3 may favour occurrence and/or severity of seizures. We also analysed the phenotype of SESN3 knock-out rats for common comorbidities of epilepsy, i.e., anxiety, depression and cognitive impairment. SESN3 knock-out rats proved less anxious compared to control rats in a selection of behavioural tests. Taken together, the present results suggest that SESN3 may regulate mechanisms involved in the pathogenesis of epilepsy and its comorbidities.

SUBMITTER: Lovisari F

PROVIDER: S-EPMC7966953 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Implication of sestrin3 in epilepsy and its comorbidities.

Lovisari Francesca F Roncon Paolo P Soukoupova Marie M Paolone Giovanna G Labasque Marilyne M Ingusci Selene S Falcicchia Chiara C Marino Pietro P Johnson Michael M Rossetti Tiziana T Petretto Enrico E Leclercq Karine K Kaminski Rafal M RM Moyon Ben B Webster Zoe Z Simonato Michele M Zucchini Silvia S

Brain communications 20201009 1

Epilepsy is a serious neurological disorder affecting about 1% of the population worldwide. Epilepsy may arise as a result of acquired brain injury, or as a consequence of genetic predisposition. To date, genome-wide association studies and exome sequencing approaches have provided limited insights into the mechanisms of acquired brain injury. We have previously reported a pro-epileptic gene network, which is conserved across species, encoding inflammatory processes and positively regulated by s ...[more]

PMID: 33758823

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Project description:Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. The objectives of the subgroup on biomarkers of comorbidities at the XIII Workshop on the Neurobiology of Epilepsy (WONOEP) were to present the state-of-the-art recent research findings in the field that highlighting potential biomarkers for comorbidities in epilepsy. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting on August 31-September 4, 2015, in Heybeliada Island (Istanbul, Turkey). We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as the "Janus Kinase/Signal Transducer and Activator of Transcription," "mammalian Target of Rapamycin," and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Furthermore, dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, the role of the inflammatory cytokines, and the contributions of genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate with epilepsy-associated comorbidities. A reliable biomarker will allow a more accurate diagnosis and improved treatment of epilepsy-associated comorbidities.

Project description:ObjectiveTo investigate the prevalence, risk factors, clinical features, and neurobehavioral comorbidities of epilepsy and acute symptomatic seizures in school-aged children in Kilifi, Kenya.MethodsRandomly selected children (N = 11,223) were screened for epilepsy and other neurodevelopmental disorders. Those who screened positive were invited for further clinical, electroencephalographic (EEG), and neuropsychological evaluations. Prevalence was measured by dividing cases by screened population, providing Agresti-Coull confidence intervals (CIs). Prevalence ratios were computed using log binomial regression, and odds ratios (ORs) were computed using logistic regression; both were implemented with generalized linear models. Attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other neurodevelopmental impairments were assessed in cases and controls.ResultsPrevalence of lifetime epilepsy was 20.9 per 1,000 (95% CI = 18.4-23.7), and that of active epilepsy was 11.5 per 1,000 (95% CI = 9.7-13.6). Prevalence of acute symptomatic seizures was 68.8 per 1,000 (95% CI = 64.2-73.6). Acute symptomatic seizures preceded a diagnosis of epilepsy in 8% of children. Of 98 children diagnosed with epilepsy, focal seizures were seen in 79%, abnormal EEG was seen in 39%, and 83% were not receiving antiepileptic drugs. Childhood absence epilepsy and Lennox-Gastaut epilepsy were the most easily identifiable epilepsy syndromes. Perinatal complications, previous hospitalization, geophagia, and snoring were risk factors for epilepsy. Family history of seizures, abnormal pregnancy, previous hospitalization, and snoring were risk factors for acute symptomatic seizures. Neurobehavioral comorbidities were present in 54% of subjects with lifetime epilepsy and in 3% of controls, with associations for individual comorbidities being statistically significant: ADHD (OR = 14.55, 95% CI = 7.54-28.06), ASD (OR = 36.83, 95% CI = 7.97-170.14), and cognitive impairments (OR = 14.55, 95% CI = 3.52-60.14).SignificanceThe burden of seizure disorders in this area is higher than in locations in high-income countries, and can be reduced by preventing risk factors. A comprehensive management plan for neurobehavioral comorbidities of epilepsy should be incorporated into standard epilepsy care.

Dataset Information

Implication of sestrin3 in epilepsy and its comorbidities.

Publications

Implication of sestrin3 in epilepsy and its comorbidities.

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