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Further evidence of affected females with a heterozygous variant in FGF13 causing X-linked developmental and epileptic encephalopathy 90.
Narayanan, DL, Majethia, P, Shrikiran, A, Siddiqui, S, Dalal, A, Shukla, A
European journal of medical genetics. 2022;(1):104403
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Abstract
Developmental and epileptic encephalopathies (DEE) are a genetically heterogeneous group of disorders characterised by early onset epilepsy, epileptiform activity on electroencephalogram and associated developmental delay or neuroregression. With the advent of high throughput sequencing, novel gene-disease associations have been described for DEEs. Voltage activated sodium channels (Nav) regulate neuronal excitability. Fibroblast growth factor homologous factors (FHFs) are proteins, which bind to the C terminal cytoplasmic tails of alpha subunits of Nav channels and influence their function and surface expression. Gain of function hemizygous or heterozygous variants in FGF13 (also known as FHF2) were recently identified as the cause for X-linked developmental and epileptic encephalopathy 90 (DEE90; MIM# 301058) in seven individuals from five families, which included one female. We report an additional female, providing further evidence for a novel de novo heterozygous missense variant in FGF13, NM_004114.5: c.14T > G p.(Ile5Ser) causing X-linked DEE90. In addition, we review the genotype and phenotype of affected individuals with DEE90.
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The initial impact of the SARS-CoV-2 pandemic on epilepsy research.
Volkers, N, Wiebe, S, Asadi-Pooya, AA, Balagura, G, Gómez-Iglesias, P, Guekht, A, Hall, J, Ikeda, A, Jetté, N, Kishk, NA, et al
Epilepsia open. 2021;(2):255-265
Abstract
The COVID-19 pandemic has changed the face of many practices throughout the world. Through necessity to minimize spread and provide clinical care to those with severe disease, focus has been on limiting face-to-face contact. Research in many areas has been put on hold. We sought to determine the impact of the COVID-19 pandemic on epilepsy research from international basic science and clinical researchers. Responses to five questions were solicited through a convenience sample by direct email and through postings on the ILAE social media accounts and an ILAE online platform (utilizing Slack). Information was collected from 15 respondents in 11 countries by email or via Zoom interviews between May 19, 2020, and June 4, 2020. Several themes emerged including a move to virtual working, project delays with laboratory work halted and clinical work reduced, funding concerns, a worry about false data with regard to COVID research and concern about research time lost. However, a number of positive outcomes were highlighted, not least the efficiency of online working and other adaptations that could be sustained in the future.
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Reviving mitochondrial bioenergetics: A relevant approach in epilepsy.
Singh, S, Singh, TG, Rehni, AK, Sharma, V, Singh, M, Kaur, R
Mitochondrion. 2021;:213-226
Abstract
Epileptogenesis is most commonly associated with neurodegeneration and a bioenergetic defect attributing to the fact that mitochondrial dysfunction plays a key precursor for neuronal death. Mitochondria are the essential organelle of neuronal cells necessary for certain neurophysiological processes like neuronal action potential activity and synaptic transmission. The mitochondrial dysfunction disrupts calcium homeostasis leading to inhibitory interneuron dysfunction and increasing the excitatory postsynaptic potential. In epilepsy, the prolonged repetitive neuronal activity increases the excessive demand for energy and acidosis in the brain further increasing the intracellular calcium causing neuronal death. Similarly, the mitochondrial damage also leads to the decline of energy by dysfunction of the electron transport chain and abnormal production of the ROS triggering the apoptotic neuronal death. Thus, the elevated level of cytosolic calcium causes the mitochondria DNA damage coinciding with mtROS and releasing the cytochrome c binding to Apaf protein further initiating the apoptosis resulting in epileptic encephalopathies. The various genetic and mRNA studies of epilepsy have explored the various pathogenic mutations of genes affecting the mitochondria functioning further initiating the neuronal excitotoxicity. Based on the results of previous studies, the recent therapeutic approaches are targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria and hold great promise to attenuate epileptogenesis. Therefore, the current review emphasizes the emerging insights to uncover the relation between mitochondrial dysfunction and ROS generation contributing to mechanisms underlying epileptic seizures.
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Treating epilepsy with options other than antiepileptic medications.
Muthaffar, OY
Neurosciences (Riyadh, Saudi Arabia). 2020;(4):253-261
Abstract
Epilepsy is a common health burden worldwide. Epilepsy is linked to variety of factors, including infectious, vascular, immune, structural, genetic, and metabolic etiologies. Despite the existence of multiple antiepileptic drugs (AEDs), many patients are diagnosed with intractable epilepsy. Many nonpharmacological options are available for epilepsy. Some types of epilepsy respond to cofactors. Other patients may be candidates for a ketogenic diet. Inflammatory mediators, such as intravenous immunoglobulins (IVIgs) and steroids, are other options for epilepsy. Recently, cannabinoids have been approved for epilepsy treatment. Refractory epilepsy can be treated with surgical interventions. Focal resections, hemispherectomies, and corpus callosotomies are some common epilepsy surgery approaches. Neuromodulation techniques are another option. Thermal ablation is a minimally invasive approach for epilepsy treatment. Epilepsy outcomes are improving, and treatment modalities are expanding. Trials of nonpharmacological options for epilepsy patients are recommended. This article summarizes available nonpharmacological options other than AEDs for the treatment of epilepsy.
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Ketogenic diet, neuroprotection, and antiepileptogenesis.
Murugan, M, Boison, D
Epilepsy research. 2020;:106444
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Abstract
High fat, low carbohydrate ketogenic diets (KD) have been in use for the treatment of epilepsy for almost a hundred years. Remarkably, seizures that are resistant to conventional anti-seizure drugs can in many cases be controlled by the KD therapy, and it has been shown that many patients with epilepsy become seizure free even after discontinuation of the diet. These findings suggest that KD combine anti-seizure effects with disease modifying effects. In addition to the treatment of epilepsy, KDs are now widely used for the treatment of a wide range of conditions including weight reduction, diabetes, and cancer. The reason for the success of metabolic therapies is based on the synergism of at least a dozen different mechanisms through which KDs provide beneficial activities. Among the newest findings are epigenetic mechanisms (DNA methylation and histone acetylation) through which KD exerts long-lasting disease modifying effects. Here we review mechanisms through which KD can affect neuroprotection in the brain, and how a combination of those mechanisms with epigenetic alterations can attenuate and possibly reverse the development of epilepsy.
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The ketogenic diet all grown up-Ketogenic diet therapies for adults.
Husari, KS, Cervenka, MC
Epilepsy research. 2020;:106319
Abstract
The use of ketogenic diet therapies (KDT) in adults has expanded in the last two decades and has been accompanied by a surge of new retrospective as well as prospective studies evaluating its efficacy in adults with epilepsy. In this review article, we will highlight the recent clinical trials and advances in the use of the ketogenic diet therapy (KDT) in adult patients with epilepsy. We will analyze the responder rate in regard to the epilepsy syndrome (focal vs generalized) to identify adults who are optimal to consider for KDT. In addition to its role in treating patients with chronic epilepsy, we will explore the emerging use of the KDT in the critical care setting in adults with refractory and super-refractory status epilepticus as well as other neurologic disorders. Finally, we will discuss special considerations for the use of KDT in adults with epilepsy including its potential long-term effects on bone and cardiovascular health, and its use in pregnancy.
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The evolving indications of KD therapy.
Armeno, M, Caraballo, R
Epilepsy research. 2020;:106340
Abstract
Despite the rapid increase of clinical and basic-science knowledge on ketogenic diet therapies over the past years, it has not always been easy to determine the adequate indications of this treatment. Over the nearly 100 years of use, from being a last resource in the therapeutic algorithm, the diet has become one of the four main treatments for patients with difficult-to-control epilepsy together with antiepileptic drugs, surgery, and vagus nerve stimulation. The use of the diet has also changed. The current paper will briefly discuss the history of the diet together with a review of the literature regarding its most important indications and how they have evolved. The concept of the importance of defining the type of seizure, type of syndrome, and etiology in the selection of patients and timing of diet initiation has been gaining importance. This paper explores how the indications of the diet changed together with the shifting focus of epilepsy teams towards its use in different types of epilepsy and epilepsy syndromes and according to etiologies and as an alternative option in refractory and superrefractory status epilepticus.
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Genetic potassium channel-associated epilepsies: Clinical review of the Kv family.
Allen, NM, Weckhuysen, S, Gorman, K, King, MD, Lerche, H
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2020;:105-116
Abstract
Next-generation sequencing has enhanced discovery of many disease-associated genes in previously unexplained epilepsies, mainly in developmental and epileptic encephalopathies and familial epilepsies. We now classify these disorders according to the underlying molecular pathways, which encompass a diverse array of cellular and sub-cellular compartments/signalling processes including voltage-gated ion-channel defects. With the aim to develop and increase the use of precision medicine therapies, understanding the pathogenic mechanisms and consequences of disease-causing variants has gained major relevance in clinical care. The super-family of voltage-gated potassium channels is the largest and most diverse family among the ion channels, encompassing approximately 80 genes. Key potassium channelopathies include those affecting the KV, KCa and Kir families, a significant proportion of which have been implicated in neurological disease. As for other ion channel disorders, different pathogenic variants within any individual voltage-gated potassium channel gene tend to affect channel protein function differently, causing heterogeneous clinical phenotypes. The focus of this review is to summarise recent clinical developments regarding the key voltage-gated potassium (KV) family-related epilepsies, which now encompasses approximately 12 established disease-associated genes, from the KCNA-, KCNB-, KCNC-, KCND-, KCNV-, KCNQ- and KCNH-subfamilies.
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Diet in the Treatment of Epilepsy: What We Know So Far.
Verrotti, A, Iapadre, G, Di Francesco, L, Zagaroli, L, Farello, G
Nutrients. 2020;(9)
Abstract
Epilepsy is a chronic and debilitating neurological disorder, with a worldwide prevalence of 0.5-1% and a lifetime incidence of 1-3%. An estimated 30% of epileptic patients continue to experience seizures throughout life, despite adequate drug therapy or surgery, with a major impact on society and global health. In recent decades, dietary regimens have been used effectively in the treatment of drug-resistant epilepsy, following the path of a non-pharmacological approach. The ketogenic diet and its variants (e.g., the modified Atkins diet) have an established role in contrasting epileptogenesis through the production of a series of cascading events induced by physiological ketosis. Other dietary regimens, such as caloric restriction and a gluten free diet, can also exert beneficial effects on neuroprotection and, therefore, on refractory epilepsy. The purpose of this review was to analyze the evidence from the literature about the possible efficacy of different dietary regimens on epilepsy, focusing on the underlying pathophysiological mechanisms, safety, and tolerability both in pediatric and adult population. We believe that a better knowledge of the cellular and molecular biochemical processes behind the anticonvulsant effects of alimentary therapies may lead to the development of personalized dietary intervention protocols.
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The 'epileptic diet'- ketogenic and/or slow release of glucose intervention: A review.
Qi, X, Tester, RF
Clinical nutrition (Edinburgh, Scotland). 2020;(5):1324-1330
Abstract
BACKGROUND & AIMS The ketogenic diet is high in fat content, adequate with respect to protein but low in carbohydrate and designed to provide brain energy as ketone bodies rather than glucose. The consequence is that epilepsy can be managed and endurance (sport) related energy be derived from fat rather than ingested or stored (glycogen) carbohydrate. This review aims to set the diet in context for seizure related intervention, sport and potential modern variants with respect to glucose management - which have many medical (including epilepsy potentially) and activity related applications. METHODS The literature was reviewed using relevant data bases (e.g. Pubmed, Science Direct, Web of Science, Wiley on Line Library) and relevant articles were selected to provide historic and contemporary data for the text and associated Tables. RESULTS It is clear great health related benefits have been achieved by feeding the ketogenic to individuals subject to seizures where it helps manage the malaise. Sports applications are evident to. Glucose control diets provide health benefits of the ketogenic diet potentially and there is some evidence they are/can be very effective. CONCLUSIONS Key to epilepsy and sport performance is the control of blood glucose. The ketogenic diet has proven to be very effective in this regard but now other approaches to control blood glucose ae being evaluated which have advantages over the ketogenic diet. This therapeutic approach of clinical nutrition will undoubtedly move forwards over the next few years in view of the negative aspects of the ketogenic diet.