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Epilepsy is a chronic disorder of the nervous system caused by abnormal discharges from brain cells. Structural, infectious, metabolic, immunologic, and unknown causes can contribute to the development of seizures. In recent years, there has been increasing attention on epilepsy caused by genetic metabolic disorders. More than two hundred inherited metabolic disorders have been identified as potential cause of seizures, and they are mainly associated with energy deficiency in the brain, accumulation of toxic substances, abnormal neurotransmitter transmission, and deficiency of cofactors. Vitamins play a crucial role as components of several enzymes or coenzymes. Impaired metabolism of thiamine, biotin, vitamin B6, vitamin B12 and folic acid can contribute to early-onset seizures and developmental abnormalities in infants. However, timely supplementation therapy can significantly improve patient prognosis of affected patients. Therefore, a thorough understanding and investigation of the metabolic basis of epilepsy is essential for the development of precise therapeutic approaches, which could provide significant therapeutic benefits for patients. [ABSTRACT FROM AUTHOR]

Background: The Coiled-Coil Domain-Containing Protein 88 A (CCDC88A) gene encodes the actin-binding protein Girdin, which plays important roles in maintaining the actin cytoskeleton and in cell migration and was recently associated with a specific form of epileptic encephalopathy. Biallelic protein-truncating variants of CCDC88A have been considered responsible for progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome. To date, only three consanguineous families with loss-of-function homozygous variants in the CCDC88A gene have been reported. The described patients share many clinical features, such as microcephaly, neonatal hypotonia, seizures, profound developmental delay, face and limb edema, and dysmorphic features, with a similar appearance of the eyes, nose, mouth, and fingers. Case presentation: We report on a child from a nonconsanguineous family who presented with profound global developmental delay, severe epilepsy, and brain malformations, including subcortical band heterotopia. The patient harbored two heterozygous pathogenic variants in the trans configuration in the CCDC88A gene, which affected the coiled-coil and C-terminal domains. Conclusions: We detail the clinical and cerebral imaging data of our patient in the context of previously reported patients with disease-causing variants in the CCDC88A gene, emphasizing the common phenotypes, including cortical malformations, that warrant screening for sequence variants in this gene. [ABSTRACT FROM AUTHOR]

Microcephaly, epilepsy and diabetes syndrome 1 (MEDS1) is a rare autosomal recessive disorder caused by defects in the immediate early response 3 interacting protein 1 (IER3IP1) gene. Only nine cases have been described in the literature. MEDS1 manifests as microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes. A simplified gyral pattern has been described in all cases reported to date. Diagnosis is made by demonstration of specific mutations in the IER3IP1 gene. In this study, we present an additional case of a patient with MEDS1 who was homozygous for the c.53C>T p.(Ala18Val) variant. This case, the first to be reported from Turkey, differs from other cases due to the absence of a typical simplified gyral pattern on early brain magnetic resonance imaging, the late onset of diabetes, and the presence of a new genetic variant. The triad of microcephaly, generalized seizures and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. [ABSTRACT FROM AUTHOR]

Migraine and epilepsy belong to the category of chronic paroxysmal neurological disorders and share numerous clinical features, as well as potential treatment options. This narrative review emphasizes the similarities between pediatric migraine and epilepsy, exploring epidemiology, pathophysiology, genetics, clinical presentation, and pharmacology. Although various syndromes exhibit symptoms common to both conditions, further research is needed to clarify the underlying pathophysiological and genetic connections contributing to their coexistence. Prophylactic medications used in the management of both migraines and epilepsy exhibit similar pharmacological characteristics. The review assesses treatment strategies for epilepsy and migraines, emphasizing antiseizure medications alongside nonpharmacological interventions like ketogenic diet, supplements, and vagal nerve stimulation. It aims to highlight how these interventions, originally targeted for epilepsy, may also show promise in preventing migraines. The urgent need for further randomized, controlled clinical trials investigating both pharmacological and nonpharmacological interventions for treating both disorders is emphasized, aiming to pave the way for innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]

This article, published in the Indian Journal of Experimental Biology, examines the levels of serum miR-146a and COX-2 in children with drug-resistant epilepsy and their relationship to prognosis. The study reveals that the drug-resistant group had higher levels of miR-146a and COX-2 compared to the non-drug resistant group. The article proposes that measuring the expression of these biomarkers could be useful for predicting and assessing the risk of recurrence in drug-resistant epilepsy. However, the study did not include continuous monitoring of miR-146a and COX-2 levels. [Extracted from the article]

Background: Genetic generalized epilepsy (GGE) accounts for nearly one-third of all epilepsies. The feature of status epilepticus (SE) in patients with GGE has been rarely studied. We aimed to determine the electroclinical characteristics of SE in patients with GGE. Methods: In this retrospective study, nine patients with GGE were enrolled at Xijing Hospital, Xi'an, China from May 2014 to May 2020. SE was confirmed by 24-h video-EEG recording. The demography, clinical manifestation, brain MRI and SE pattern were analyzed. Results: Of the nine patients in the study, seven were female. The mean age of the patients at the time of inclusion was 16.8 years (range 7–31 years), and the mean age at the onset of epilepsy was 10.9 years (range 6–17 years). The follow-up time ranged from 3 months to 6 years. Myoclonic absence status was identified in four patients showing eyelid myoclonia with absence and one patient showing perioral myoclonia with absences. Myoclonic SE was identified in three patients showing juvenile myoclonic epilepsy. Autonomic SE was found in one patient with eyelid myoclonia with absence. SE was terminated by oral midazolam in four patients. In the other five patients, SE terminated spontaneously. Conclusions: The seizure type of SE in patients with GGE is often consistent with their major symptoms. Oral midazolam may be an option to terminate SE in patients with GGE. [ABSTRACT FROM AUTHOR]

Variations in the PRRT2 gene have been shown to cause a variety of diseases, including benign familial infantile epilepsy (BFIE) and paroxysmal kinesigenic dyskinesia (PKD). Next-generation sequencing techniques have allowed the broadening of this disease spectrum. In this study, we aimed to present patients with epilepsy who were shown to have PRRT2 variants in our clinic. The characteristics of 13 patients with epilepsy, including two families with PRRT2 variants and one patient with a sporadic homozygous variant, were reviewed by screening the epilepsy archive. P.R217Pfs∗8 variation was detected in patients of our first family with both BFIE and PKD diseases. This family was included in the article in which this gene was first described in 2012. In the first generation there were 3 patients with BFIE, in the second generation there were 2 patients with BFIE-PKD and one patient with BFIE. The second family had only BFIE. In this family, the c.604_607del (p.Ser202HisfsTer26) variation was detected in the PRRT2 gene in the index case. In this phenotypically homogeneous family, BFIE was present in all 3 generations. Although the seizures remitted, electroencephalography abnormalities continued for 2 years in our index case. Migration of the epileptogenic focus to the posterior of the hemispheres over time is an interesting observation. Our sporadic case was a patient with a diagnosis of juvenile absence epilepsy, and a homozygous c.67G>A;p.(Glu23Lys) variant was detected in this patient. Findings in PRRT2-associated epilepsy patients show the importance of next-generation sequencing techniques. It indicates that different epilepsy phenotypes can be seen in variations associated with a single gene. With better recognition of epilepsy associated with PRRT2 gene variants, which are considered as synaptopathy, it will be possible to switch from current symptomatic treatments to therapeutic options targeting specific pathophysiological changes. [ABSTRACT FROM AUTHOR]

Epilepsy is a recurring neurological disease caused by the abnormal electrical activity in the brain. This disease has caused about 50 new cases in 100,000 populations every year with the clinical manifestations of awareness loss, bruising, and mobility abnormalities. Due to the lack understanding of the pathophysiology behind the illness, a wide variety of medications are available to treat epilepsy. Epileptogenesis is the process by which a normally functioning brain undergoes alterations leading to the development of epilepsy, involving various factors. This is related to the inflammation which is driven by cytokines like IL-1 and tumor necrosis factor-α (TNF-α) leads to neuronal hyperexcitability. Pro-inflammatory cytokines from activated microglia and astrocytes in epileptic tissue initiate an inflammatory cascade, heightening neuronal excitability and triggering epileptiform activity. The blood-brain barrier (BBB) maintains central nervous system integrity through its tight endothelial connections, but inflammation impact BBB structure and function which leads to immune cell infiltration. The mammalian target of rapamycin (mTOR) pathway's excessive activation influences epileptogenesis, impacting neuronal excitability, and synapse formation, with genetic mutations contributing to epilepsy syndromes and the modulation of autophagy playing a role in seizure onset. The apoptotic pathway contribute to cell death through glutamate receptor-mediated excitotoxicity, involving pro-apoptotic proteins like p53 and mitochondrial dysfunction, leading to the activation of caspases and the disruption of calcium homeostasis. Ionic imbalances within neural networks contribute to the complexity of epileptic seizures, involving alterations in voltage-gated sodium and potassium channels, and the formation of diverse ion channel subtypes. Epileptogenesis triggers molecular changes in hippocampus, including altered neurogenesis and enhanced expression of neurotrophic factors and proteins. Oxidative stress leads to cellular damage, disrupted antioxidant systems, and mitochondrial dysfunction, making it a key player in epileptogenesis and potential neuroprotective interventions. Thalamocortical circuitry disruption is central to absence epilepsy, the normal circuit becomes faulty and results in characteristic brain wave patterns. [ABSTRACT FROM AUTHOR]

Background: Developmental and epileptic encephalopathy (DEE) is a group of rare inherited disorders characterized by intellectual disability, delayed development, epileptic seizures, and other related symptoms. DEE44 is caused by mutations in the UBA5 gene, which encodes a ubiquitin-like protein involved in protein degradation and cell signaling. However, there is limited information on the genotype–phenotype correlation of DEE44, and its clinical features remain to be fully characterized. Case presentation: We report a 12-month-old infant who presented with epileptic spastic seizures beginning at 4 months of age, accompanied by overall developmental delay, short stature, microcephaly, inability to hold his head upright, chasing vision, and high muscle tone in the extremities. Genetic findings showed compound heterozygous mutations of the UBA5 gene: NM_024818 c.562C > T(p.R188X) from the mother and NM_024818 c.214C > T(p.R72C) from the father. Conclusions: This case report expands the clinical spectrum of DEE44 and highlights the importance of considering DEE44 in the differential diagnosis of developmental delay and epilepsy, even in the absence of classical symptoms suggestive of the condition. We hope that this case report will advance the understanding of DEE44 and improve the expertise of clinicians and early diagnose of this disease. [ABSTRACT FROM AUTHOR]

Background: Despite the high consanguinity rates, data on genetic epilepsy in Saudi Arabia is limited. The objective of the current study was to characterize genetic mutations associated with epilepsy in pediatric patients and describe their phenotypic presentations. Methods: A retrospective chart review was conducted among children presented with epilepsy in one center in Saudi Arabia between 2015 and 2018. Only those who had undergone genetic testing were included. Results: A total of 45 patients had positive whole-exome sequencing (WES) genetic testing with 37 mutations. Six mutations (SCN1A, DENND5A, KCNQ2, ACY1, SCN2A, and PCDH19) were repeated in 15 patients, with largely heterogeneous phenotypic presentations in patients with the same mutation. Several mutations are reported for the first time in Saudi Arabia. The median age at epilepsy onset was four months. Consanguineous parents and family history of epilepsy were frequent (31.8% and 33.3%, respectively). Developmental delay (44.4%), cognitive delay (42.2%), language delay (40.0%), behavioral features (28.9%), and microcephaly (20.0%) were frequent presentations. At initial diagnosis, 68.9% of EEG and 48.9% of brain MRI were abnormal. The most currently used antiseizure medications (ASMs) were levetiracetam (48.9%), topiramate (28.9%), and valproic acid (20.0%). Approximately 60% of the patients were controlled with (47.6%) or without (11.9%) ASMs, and three (7.1%) patients died. Conclusions: Multiple mutations among children with epilepsy are reported in one hospital in Saudi Arabia, with the majority reported for the first time. The current findings highlight the importance of doing genetic testing for the evaluation of childhood epilepsy. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disease characterized by excessive and abnormal hyper-synchrony of electrical discharges of the brain and a predisposition to generate epileptic seizures resulting in a broad spectrum of neurobiological insults, imposing psychological, cognitive, social and also economic burdens to the sufferer. Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials throughout the central nervous system. Dysfunction of these channels has been implicated in the pathogenesis of epilepsy. VGSC inhibitors have been demonstrated to act as anticonvulsants to suppress the abnormal neuronal firing underlying epileptic seizures, and are used for the management and treatment of both genetic-idiopathic and acquired epilepsies. We discuss the forms of idiopathic and acquired epilepsies caused by VGSC mutations and the therapeutic efficacy of VGSC blockers in idiopathic, acquired and pharmacoresistant forms of epilepsy in this review. We conclude that there is a need for better alternative therapies that can be used alone or in combination with VGSC inhibitors in the management of epilepsies. The current anti-seizure medications (ASMs) especially for pharmacoresistant epilepsies and some other types of epilepsy have not yielded expected therapeutic efficacy partly because they do not show subtype-selectivity in blocking sodium channels while also bringing side effects. Therefore, there is a need to develop novel drug cocktails with enhanced selectivity for specific VGSC isoforms, to achieve better treatment of pharmacoresistant epilepsies and other types of epileptic seizures. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy (SMA) could be classified as 5q and non-5q, based on the chromosomal location of causative genes. A rare form of non-5q SMA is an autosomal-recessive condition called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by myoclonic and generalized seizures with progressive neurological deterioration. SMA-PME is a clinically heterogeneous disorder that arises from biallelic pathogenic variants in ASAH1 gene. Methods: Following clinical and primary laboratory assessments, whole-exome sequencing was performed to detect the disease-causing variants in three cases of SMA-PME from different families. Also, Multiplex ligation-dependent probe amplification (MLPA) was employed for determining the copy numbers of SMN1 and SMN2 genes to rule out 5q SMA. Results: Exome sequencing revealed two different homozygous missense mutations (c.109 C > A [p.Pro37Thr] or c.125 C > T [p.Thr42Met]) in exon 2 of the ASAH1 gene in the affected members of the families. Sanger sequencing of the other family members showed the expected heterozygous carriers. In addition, no clinically relevant variant was identified in patients by MLPA. Conclusion: This study describes two different ASAH1 mutations and the clinical picture of 3 SMA-PME patients. In addition, previously reported mutations have been reviewed. This study could help to fortify the database of this rare disease with more clinical and genomic data. [ABSTRACT FROM AUTHOR]

Introduction: Familial Adult Myoclonic Epilepsy (FAME) is an autosomal dominant disease characterized by cortical tremor, myoclonus and epileptic seizures. In this article, we aimed to review the main clinical characteristics, pathophysiology and diagnostic work-up of this disease to increase awareness. Method: PubMed and Web of Science databases were used and all types of articles available in full text and Englishwere selected Results: The first symptom of this rare condition is involuntary tremor-like finger movements that appear often in the second decade. Generalized tonic-clonic and myoclonic seizures are the most common types of seizures which develop later in the course of the disease. Additional clinical symptoms enlarging the clinical spectrum have been described, such as cognitive decline, migraine, night blindness. Electroencephalography shows usually normal background activity with/without generalized spike and wave activities. Giant somatosensory evoked potentials (SEP) and long loop latency reflexes which indicate the cortical origin can be detected. Genetic side of the disorder is rather complicated, linkage analyses defined four independent loci on chromosome 2, 3, 5 and 8. Recent studies disclose abnormal pentanucleotide repeat expansions of intronic TTTCA and TTTTA that are involved in the pathogenesis of FAME. Conclusion: However, as it is not classified as an individual epileptic syndrome by the ILAE, there are still some question marks about this under-recognized disease. The insidious progression of the clinical findings and similarity in phenotypes may lead to misdiagnosis. Clinical and electroclinical international collaborations may help distinguish FAME from other myoclonic epilepsies including juvenile myoclonic epilepsy and slow-progressive forms of progressive myoclonic epilepsy and movement disorders like essential tremor. [ABSTRACT FROM AUTHOR]

Background: Various cardiac and autonomic manifestations are frequently reported during seizures. Among the seizure-related arrhythmia, ictal tachycardia is the most common, followed by ictal bradycardia, with ictal asystole being the rarest. The occurrence of ictal asystole may obscure the clinical presentation and delay the diagnosis, representing a life-threatening presentation of epilepsy, with an elevated risk of sudden unexpected death in epilepsy patients (SUDEP). These cardiac abnormalities are being increasingly recognized as the key to elucidating the mechanisms of SUDEP. Case presentation: We present a 35-year-old man with a history of focal-onset seizures with impaired consciousness since his mid-20 s. He developed different types of seizures for 2 years, described as tonic seizure and atonic seizure (drop attack). During such clinical events, he suffered from falls and cardiac arrest. However, thorough cardiac electrophysiology and imaging workup failed to reveal a cardiac etiology. Subsequent video electroencephalograph (EEG) monitoring was performed, and ictal bradycardia and ictal asystole were discovered. A cardiac pacemaker was implanted, and at 3-year follow-up, the patient did not suffer more atonic seizures, or falls. Genetic tests discovered a de novo variant of Adhesion G Protein-Coupled Receptor V1 (ADGRV1), which may provide a clue for the patient's ictal asystole and the increased risk of SUDEP. Conclusions: Considering the important impact of ictal bradycardia and asystole on the morbidity and potential mortality of epileptic patients, it is important to simultaneously utilize EEG and electrocardiogram to confirm the diagnosis. This case report highlights the link between the de novo variant of ADGRV1 and the ictal bradycardia/asystole phenotype and implicates the importance of genetic testing in adult epilepsy patients. [ABSTRACT FROM AUTHOR]

An understanding of epilepsy genetics is important for adult neurologists, as making a genetic diagnosis gives clinical benefit. In this review, we describe the key features of different groups of genetic epilepsies. We describe the common available genetic tests for epilepsy, and how to interpret them. [ABSTRACT FROM AUTHOR]

The genetic generalized epilepsies (GGEs) have been proved to generate from genetic impact by twin studies and family studies. The genetic mechanisms of generalized epilepsies are always updating over time. Although the genetics of GGE is complex, there are always new susceptibility genes coming up as well as copy number variations which can lead to important breakthroughs in exploring the problem. At the same time, the development of ClinGen fades out some of the candidate genes. This means we have to figure out what accounts for a reliable gene for GGE, in another word, which gene has sufficient evidence for GGE. This will improve our understanding of the genetic mechanisms of GGE. In this review, important up-to-date genetic mechanisms of GGE were discussed. [ABSTRACT FROM AUTHOR]

Epilepsy syndromes are defined either by a specific set of symptoms or by the area of the brain where the seizures originate. Some of the symptoms include types of seizures and age of seizure onset. Other symptoms include the frequency and severity of the seizures and the time of day in which they occur. Epilepsy syndromes are likely to be present at birth or appear during childhood. The treatment for childhood epilepsy syndromes may include medication, diet therapy, nerve stimulation, or surgery. [ABSTRACT FROM AUTHOR]

Background: Vitamin B6-dependent epilepsies include treatable diseases responding to pyridoxine or pyridoxal-5Iphosphate (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects). Patients and methods: We conducted a systematic review of published pediatric cases with a confirmed molecular genetic diagnosis of vitamin B6-dependent epilepsy according to PRISMA guidelines. Data on demographic features, seizure semiology, EEG patterns, neuroimaging, treatment, and developmental outcomes were collected. Results: 497 published patients fulfilled the inclusion criteria. Seizure onset manifested at 59.8 ± 291.6 days (67.8% of cases in the first month of life). Clonic, tonic-clonic, and myoclonic seizures accounted for two-thirds of the cases, while epileptic spasms were observed in 7.6%. Burst-suppression/suppression-burst represented the most frequently reported specific EEG pattern (14.4%), mainly in PLPB, ALDH7A1, and PNPO deficiency. Pyridoxine was administered to 312 patients (18.5% intravenously, 76.9% orally, 4.6% not specified), and 180 also received antiseizure medications. Pyridoxine dosage ranged between 1 and 55 mg/kg/die. Complete seizure freedom was achieved in 160 patients, while a significant seizure reduction occurred in 38. PLP, lysine-restricted diet, and arginine supplementation were used in a small proportion of patients with variable efficacy. Global developmental delay was established in 30.5% of a few patients in whom neurocognitive tests were performed. Conclusions: Despite the wide variability, the most frequent hallmarks of the epilepsy phenotype in patients with vitamin B6-dependent seizures include generalized or focal motor seizure semiology and a burst suppression/suppression burst pattern in EEG. [ABSTRACT FROM AUTHOR]

Background: SYNGAP1 is a significant genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. De novo loss-of-function variants in this gene cause a neurodevelopmental disorder, for example, early-onset and drug-refractory seizures. We report two children with global developmental delay and epileptic encephalopathy, which are caused by SYNGAP1 gene novel mutations, and drug treatment is effective. Case presentation: We report a boy and a girl presented with global developmental delay when they were young babies; as they grew up, cognitive impairment and social-communication disorder became more and more prominent; unfortunately, the patients developed into various seizure types, including eyelid myoclonia, myoclonic and absences when the boy was 1 year 8 mouths old and the girl was 3 years old. The two patients were found two previously unknown mutations by high throughput sequencing [c.3271_ c.3272insT; (p.L1091L fs*62), c.2515A > T (p.K839*)] in exon 15 of the SYNGAP in the proband. Sanger sequencing confirmed the heterozygous nature, and neither of their parents carried the same mutation. The girl treated with valproic acid and prednisone became seizure-free, and valproic acid and levetiracetam combined with clonazepam were influential in the other. Conclusions: The global developmental delay and epileptic encephalopathy of the children were probably due to the pathogenic mutation of the SYNGAP1 gene, and prednisone and clonazepam may be effective in achieving seizure-free. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that the ACTL6B monoallelic variant is responsible for an autosomal dominant inherited intellectual developmental disorder with severe speech and ambulation deficits. The clinical phenotype of developmental and epileptic encephalopathy type 76 (DEE76) due to ACTL6B biallelic variants was first reported in 2019, with an autosomal recessive mode of inheritance. In this paper, we report on a child in China with DEE76 caused by a compound heterozygous variant of the ACTL6B gene, and we review the literature on ACTL6B gene variants causing DEE76 with complete clinical information. Including our case 1, the genotype and phenotypic characteristics of 18 children from 14 families are summarized. All 18 cases are autosomal recessive, including 12 with homozygous variants and six with compound heterozygous variants. A total of 17 variants have been reported so far, including 14 variants of the loss function. We summarize the clinical features using Human Phenotype Ontology (HPO) terms. We find that DEE76, caused by the ACTL6B biallelic variant, is an early-onset drug-refractory epilepsy with global developmental delayHP:0001263, hypertoniaHP:0001276, and microcephalyHP:0000252, and imaging is characterized by brain delayed myelinationHP:0012448. Our case of DEE76 had not been reported when the patient underwent genetic testing in 2018, and the diagnosis was clarified by the reanalysis of the data 2 years later, being the first reported Chinese patient and the only one in which the application of a ketogenic diet for antiepileptic treatment may have been effective. [ABSTRACT FROM AUTHOR]

Genetics is rapidly evolving and is actively playing a role in how we diagnose and manage epilepsy. The definition of an epilepsy syndrome has changed throughout the years. The International League Against Epilepsy (ILAE) has developed a classification of the epilepsies and has recently described specific epilepsy syndromes taking into account emerging genetic information which is rapidly evolving as well as etiology-specific syndromes. Understanding genetics can help clarify the syndrome and its treatment. This review provides a history of the definition of a syndrome, and the evolving contribution of genetic information that is part of the syndromic classification. We provide few examples of several phenotypes/genotypes of epilepsy syndromes in infancy and childhood and treatment issues that may arise from the available genetic information. Epilepsy syndromes and their genetics have been rapidly changing as new gene technologies are being developed. Understanding genetics can help clarify the syndrome, its treatment, and will help change the field of epilepsy to improve patients qualify of life by creating new means of preventing, controlling, and curing epilepsy. [ABSTRACT FROM AUTHOR]

Background: Pathogenic variants in SCN1B, the gene encoding voltage-gated sodium channel b1/b1B subunits are associated with a spectrum of epileptic disorders. This study describes a child with early myoclonic encephalopathy and a compound heterozygous variant in the SCN1B gene (p.Arg85Cys and c.3G>C/p.Met1), along with the child's clinical response to anti-seizure medications (ASMs) and the ketogenic diet. We reviewed the current clinical literature pertinent to SCN1B-related epilepsy. Methods: We described the evaluation and management of a patient with SCN1B-related developmental and epileptic encephalopathy (DEE). We used the Medline and Pubmed databases to review the various neurological manifestations associated with SCN1B genetic variants, and summarize the functional studies performed on SCN1B variants. Results: We identified 20 families and six individuals (including the index case described herein) reported to have SCN1B-related epilepsy. Individuals with monoallelic pathogenic variants in SCN1B often present with genetic epilepsy with febrile seizures plus (GEFS+), while those with biallelic pathogenic variants may present with developmental and epileptic encephalopathy (DEE). Individuals with DEE present with seizures of various semiologies (commonly myoclonic seizures) and status epilepticus at early infancy and are treated with various antiseizure medications. In our index case, adjunctive fenfluramine was started at 8 months of age at 0.2 mg/kg/day with gradual incremental increases to the final dose of 0.7 mg/kg/day over 5 weeks. Fenfluramine was effective in the treatment of seizures, resulting in a 50% reduction in myoclonic seizures, status epilepticus, and generalized tonic-clonic seizures, as well as a 70–90% reduction in focal seizures, with no significant adverse effects. Following the initiation of fenfluramine at eight months of age, there was also a 50% reduction in the rate of hospitalizations. Conclusions: SCN1B pathogenic variants cause epilepsy and neurodevelopmental impairment with variable expressivity and incomplete penetrance. The severity of disease is associated with the zygosity of the pathogenic variants. Biallelic variants in SCN1B can result in early myoclonic encephalopathy, and adjunctive treatment with fenfluramine may be an effective treatment for SCN1B-related DEE. Further research on the efficacy and safety of using newer ASMs, such as fenfluramine in patients under the age of 2 years is needed. [ABSTRACT FROM AUTHOR]

Background: Mutations in the neuronal sodium voltage-gated channel, alpha subunit 1 (SCN1A) gene have been associated with epilepsy. We investigated the SCN1A-A3184G polymorphism among Egyptian children and adolescents with non-lesional epilepsy. Methods: A prospective case – control observational study was done in Mansoura University Children's Hospital, Egypt including 326 children with non-lesional epilepsy (163 antiepileptic drugs (AEDs) resistant cases & 163 AEDs responders) and 163 healthy controls. One step real time polymerase chain reaction (PCR) was used for the molecular analysis. Student's t-test, and Monto Carlo, chi-square and Mann–Whitney tests were used for the statistical analysis. Results: All study participants were matched as regards the age, sex and body weight (p = 0.07, 0.347 and 0.462, respectively). They had the (AA) and (AG) genotypes but not the (GG) variant. No significant differences were found between cases and controls regarding (AG) and (AA) genotypes and A- and G-alleles (p = 0.09 and 0.3, respectively). We did not find significant differences between AEDs responders and resistant cases regarding the studied genotypes and alleles (p = 0.61 and 0.746, respectively). In the resistant group, we observed significant associations between the (AG) genotype and seizure frequency (p = 0.05), the tonic-clonic seizure (p < 0.001), the younger age of first seizure attack (p = 0.03), abnormal electroencephalogram (EEG) (p < 0.001), the positive family history of epilepsy (p = 0.006), topiramate (p = 0.03) and valproic acid (p < 0.001), while the (AA) genotype was associated with carbamazepine (p = 0.03). While in AEDs responders, there were significant associations between the AG genotype and the abnormal EEG activity, levetiracetam and carbamazepine (p = 0.016, 0.028 and 0.02). Conclusions: The SCN1A-A3184G genotypes and alleles were not associated with the epilepsy risk among Egyptian children. Significant associations were reported between the AG genotype and some predictors of refractory epilepsy. [ABSTRACT FROM AUTHOR]

Autosomal dominant epilepsy with auditory features (OMIM 600512) is characterised by focal seizures with distinctive auditory auras and/or ictal aphasia. We describe a 17-year-old girl with recurrent attacks of ictal aphasia and rare nocturnal convulsions. She had a four-generation paternal family history of epilepsy. Her father and aunt perceived bells ringing at the onset of seizures. Sequence analysis of the leucine-rich glioma-inactivated 1 (LGI1) gene identified a novel heterozygous variant in the proband and her father. LGI1-related genetic epilepsy has a benign clinical course with a favourable response to antiseizure medications. Auditory or vertiginous seizures may be mistaken for peripheral audiovestibular symptoms, while complex auditory ictal symptoms may be misattributed to primary psychiatric disorders. Recognising this distinctive inherited syndrome should prompt targeted analysis of the LGI1 gene. [ABSTRACT FROM AUTHOR]

Background: Advancement in genetic technology has led to the identification of an increasing number of genes in epilepsy. This will provide a lot of information in clinical practice and improve the diagnosis and treatment of epilepsy. Aim: To show the importance of genes in the next‐generation sequencing (NGS) panel during the evaluation of epilepsy and to emphasise the importance of genetic studies in different populations for the evaluation of genes that cause disease. Methods: This was a single‐centre retrospective cohort study of 80 patients who underwent NGS testing with a customised epilepsy panel. Results: In a total of 54 (67.5%) out of 80 patients, pathogenic or likely pathogenic variants and variants of uncertain significance (VOUS) were identified according to the American College of Medical Genetics and Genomics criteria. Pathogenic or likely pathogenic variants (n = 35) were identified in 29 (36.25%) out of 80 individuals. VOUS (n = 34) were identified in 28 (35%) out of 80 patients. Pathogenic, likely pathogenic and VOUS were most frequently identified in TSC2 (n = 11), SCN1A (n = 6) and TSC1 (n = 5) genes. Other common genes were KCNQ2 (n = 3), AMT (n = 3), CACNA1H (n = 3), CLCN2 (n = 3), MECP2 (n = 2), ASAH1 (n = 2) and SLC2A1 (n = 2). Conclusions: NGS‐based testing panels contribute to the diagnosis of epilepsy and might change the clinical management by preventing unnecessary and potentially harmful diagnostic procedures and management in patients. Thus, our results highlight the benefit of genetic testing in children suffering with epilepsy. [ABSTRACT FROM AUTHOR]

Epilepsy is a dynamic and heterogeneous neurological disease, and in long-term studies on prognosis, classically 5 basic patterns (early remission, late remission, relapsing-remitting, worsening, and non- remitting) have been identified. The most frequent pattern was relapsing- remitting course, and factors such as the presence of genetic etiology, rare seizures at the beginning of epilepsy and the absence of psychiatric comorbid diseases were found to be related with this pattern as well as reaching 5 years of remission in the follow-ups. Anti-seizure drug resistance (ASD-R) and factors affecting the presence of this resistance (such as symptomatic etiology, abnormal electroencephalographic findings, having multiple seizure types together, status epilepticus and febrile seizure history) decrease the chance of remission, while idiopathic/genetic etiology, generalized epilepsy, and absence of comorbid diseases seem to be associated with achieving long-term remission. Apart from these basic course patterns, there are some patients with an "atypical prognosis" such as drug-resistant juvenile myoclonic epilepsy (JME), benign hippocampal sclerosis-related mesial temporal lobe epilepsy (HS-MTLE), and severe childhood epilepsy with centro-temporal spikes (CESTS), in which the pathophysiological mechanisms underlying these patterns have not been clarified despite the suggestions of various hypotheses. The presence of comorbid diseases such as hormonal factors (as in catamenial epilepsy), autoimmune processes, thyroid disorders and metabolic and psychiatric diseases may also cause an atypical prognostic pattern by affecting the course of the disease. In this review, our aim is to provide the clinician with an up-to-date and questioning perspective on the prognostic markers of epilepsy, by examining in detail some specific epilepsy syndromes that may show atypical prognosis as well as the general prognostic features of epilepsy. [ABSTRACT FROM AUTHOR]

Study Objectives: To describe early diagnostic clues in Cyclin-Dependent Kinase-Like 5 (CDKL5) refractory encephalopathy, to improve treatment strategies. Methods: We retrospectively studied 35 patients (25 females, 10 males) with CDKL5 gene mutations or deletion, focusing on their early seizure semiology, the electroencephalogram (EEG) pattern, the effect of treatment, and developmental outcome. Results: The first seizures were recognizable and consisted of tonic, then clonic, and spasms phases, occurring in sleep at a median age of 6 weeks. Clusters of spasms were observed in quiet sleep or slow-wave sleep (SWS), with screaming, staring, and arms' extension that mimicked sleep terror in 28 of 35 patients (80%). Programmed awakening prevented these spasms in 9 of 16 patients and small doses of clonazepam given at night improved epilepsy in 14 of 23 patients. Conclusions: Peculiar seizures with spasms starting in SWS are an early diagnostic clue in infants with CDKL5 encephalopathy. Sleep video-EEG polygraphy is an easy tool to disclose these early seizures and epileptic spasms in infants during the first months of life while polysomnography is unlikely to give a contribution at that early age. While conventional antiepileptic treatment and corticosteroids are poorly, transiently, or not efficient, therapeutic strategy used for sleep terror could help, although the mechanism of spasms generation in SWS needs to be elucidated. [ABSTRACT FROM AUTHOR]

Epilepsy develops related to a complex genetic heredity as many diseases in society. Lafora disease (LD) is an autosomal recessive inheritance. It is localized at EPM2A gen 6q23-25 and encodes tyrosine phosphatase (Laforin protein). About 80% of the patients have mutations in this gene. In a case of LD, rapid and progressive dementia and frequent occipital seizures are clinical symptoms. For definitive diagnosis, through genetical study, EPM2A and EPM2B genes should be analyzed. A male at the age of 18, with a medical history of meningitis and seizures with high temperature. Starting from the age of 10, there have been symptoms such as generalized tonic-clonic (GTC) seizures, startles in the whole body, and forgetfulness. In genetical tests, homozygote deletion of adenine nucleotide in the position of 468 at codon 156 and guanine nucleotide in the position of 469 at codon 157 is found. In other words, there has been dinucleotide deletion which is compatible with LD. A 20-year-old male was examined because of such symptoms as forgetfulness, myoclonia, hallucinations, and GTC clonic seizures. He was diagnosed with LD because of the heterozygote transformation of CCC to CTC at codon 111. Even though genetic disorders have many different reasons, it is advised that every society should have their own advanced studies on gene mutation. In Turkish cases, both of these genes were found mutated, each in different patients through various studies. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the epileptic predispositions of recurrent febrile seizures (onset of age 1 and below) could be predicted earlier using analysis of SCN1A gene sequencing. Material and Methods: The study included 55 patients aged between 0-18 who were admitted to pediatric emergency service with a febrile seizure. Patients were selected based on the criteria of presenting recurrent (two or more) febrile seizures with the onset of age one and below, having normal cranial imaging and central nervous system infections being ruled out. SCN1A gene sequence analysis was performed using the next-generation sequencing method. Results: The c.1738C>T and c.4181C>T were the previously reported whereas the c.2914-1G>A and c.473A>G were novel SCN1A heterozygous disease-causing variants which were identified in five of 55 patients from 55 unrelated families (9.09%). The patients with c.1738C>T, c.2914-1G>A, and c.4181C>T variants presented probable Dravet syndrome or Dravet syndrome phenotype, but then the other two with c.473A> G demonstrated genetic epilepsy with febrile seizure plus. Conclusion: Beforehand administration of SCN1A genetic testing in early-onset febrile seizures could be a more significant indicator rather than the clinical risk factors for determining the prognosis and designing the long-term follow-up. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and epilepsy are neurological disorders that affect a large cohort of people worldwide. Although both of the two diseases could be influenced by genetic factors, the shared genetic mechanism underlying the pathogenesis of them is still unclear. In this study, we aimed to identify the shared genetic networks and corresponding hub genes for AD and epilepsy. Firstly, the gene coexpression modules (GCMs) were constructed by weighted gene coexpression network analysis (WGCNA), and 16 GCMs were identified. Through further integration of GCMs, genome-wide association studies (GWASs), and expression quantitative trait loci (eQTLs), 4 shared GCMs of AD and epilepsy were identified. Functional enrichment analysis was performed to analyze the shared biological processes of these GCMs and explore the functional overlaps between these two diseases. The results showed that the genes in shared GCMs were significantly enriched in nervous system-related pathways, such as Alzheimer's disease and neuroactive ligand-receptor interaction pathways. Furthermore, the hub genes of AD- and epilepsy-associated GCMs were captured by weighted key driver analysis (wKDA), including TRPC1, C2ORF40, NR3C1, KIAA0368, MMT00043109, STEAP1, MSX1, KL, and CLIC6. The shared GCMs and hub genes might provide novel therapeutic targets for AD and epilepsy. [ABSTRACT FROM AUTHOR]

Mutations in seizure threshold 2 (SZT2) gene on chromosome 1p34.2 are an of late identified cause of epilepsy and epileptic encephalopathy. We report a 3-year-old girl who presented with developmental delay, dysmorphic facies, refractory seizures, and subsequent developmental regression. Despite significant multifocal epileptiform abnormalities on her electroencephalogram, she had a paucity of generalized discharges indicating a functional deficiency of corpus callosum inspite of its increased thickness seen on magnetic resonance imaging. Her clinical exome sequencing revealed a homozygous single base pair duplication in the SZT2 gene that resulted in a frameshift mutation and premature truncation of the protein. Our case emphasizes the role of SZT2 gene in the diagnostic algorithm of early childhood refractory epilepsy especially in the context of a thick yet dysfunctional corpus callosum. [ABSTRACT FROM AUTHOR]

Background: Control charting is routine in the quality assurance of traditional clinical laboratory testing. Genomic tests are not typically managed by control charting. We examined control charting to monitor the performance of a clinical next-generation sequencing (NGS) assay. Methods: We retrospectively examined 3 years of control material (NA12878) data from clinical genomic epilepsy testing. Levey-Jennings plots were used to visualize changes in control material depth of sequencing coverage in genomic regions of an epilepsy genomic panel. Changes in depth of coverage were correlated with changes in the manufactured lot of capture probe reagent. Depth of coverage was also correlated between quality control material and clinical samples. Results: Fifty-seven sequencing runs of NA12878 were analyzed for 1811 genomic regions targeting 108 genes. Manufactured probe lot changes were associated with significant changes in the average coverage of 537 genomic regions and the lowest coverage of 173 regions (using a critical cut-off of P<5.52 x 10-6). Genomic regions with the highest sensitivity to lot-to-lot variation by average sequencing depth of coverage were not the same regions with the highest sensitivity by lowest sequencing depth of coverage. Levey-Jennings plots displayed differences in genomic depth of coverage across capture probe reagent lot changes. There was moderate correlation between the changes in depth of sequencing across lot changes for control material and clinical cases (r² ¼ 0.45). Conclusions: Genomic control charting can be used routinely by clinical laboratories to monitor assay performance and ensure the quality of testing. [ABSTRACT FROM AUTHOR]

A case study of a five‑year‑old girl, first born to a third‑degree consanguineous couple was brought for evaluation of developmental delay and seizures noticed from 18 months of age. Topics include Inborn errors of metabolism (IEM) are a heterogeneous group of inherited disorders that may result from enzyme deficiencies or cofactor defects; and urine organic acid analysis by gas chromatography‑mass spectrometry revealed an approximately ten‑fold increase in the excretion of fumaric acid.

Objective. Study the clinical and neurophysiological evolution of early infantile epileptic encephalopathy type 4 (EIEE4) caused by a STXBP1 gene mutation.Material and methods. During 2016-2019, we conducted dynamic observation and treatment of a girl with EIEE4 combined with a mutation in the STXBP1 gene. DNA sequencing was performed using the "Hereditary epilepsies" panel (Next Generation Sequencing on the platform of Illumina HiSeq 2500, USA). Dynamic video-EEG monitoring was performed with an “Encephalan-Video" RM-19/26 ("Medicom MTD“, Russia).Results. In this 3.5 y.o. patient with infantile epileptic encephalopathy, a heterozygous autosomal dominant de novo mutation in the STXBP1 gene was found. This mutation (not described previously) is located in chromosome 9, specifically, in the 20th exon with genome coordinates Chr9:130453 (C.*96T>A). This child suffered from severe neonatal hypoxic-ischemic encephalopathy, which led to spastic cerebral palsy. In addition, she developed seizures as early as at the age of 6 month; the seizures (flexor tonic spasms) were paralleled with EEG changes similar to the Mar-kand-Blume-Ohtahara syndrome, namely, multiple independent spike-wave foci in combination with the partial attenuation pattern (kind of the "burst-suppression" pattern). Valproate monotherapy had little effect, and hormonal treatment caused a temporary improvement. Permanent clinical remission with no seizures was achieved by including leveti-racetam in the therapeutic combination. A number of studies demonstrated a high efficacy of levetiracetam in cases of STXBP1 gene mutations. At the age of 2,5years, the girl demonstrated changes in her EEG records toward the continuous spike-wave during sleep (CSWS) pattern with the morphology of "benign epileptiform discharges of childhood" ("BEDC").Conclusions. In spite of the aggravated perinatal anamnesis, children with epileptic encephalopathy need genetic examination using the Next Generation Sequencing (NGS) methods (such as "Hereditary epilepsies" panel), combined with full exome sequencing. Such genetic examinations are helpful for establishing the exact etiology of epilepsy and developing a personalized approach to antiepileptic therapy.

Objectives: Epileptogenesis is still not clearly understood. Therefore, there is an inevitable need for research that investigates triggers for reflex seizures and neuropsychological activation (NPA) methods using electroencephalography (EEG) in different epileptic syndromes. In this regard, we aimed to examine the characteristics and frequency of triggers for reflex seizures as well as changes in the frequency of epileptiform discharges (EDs), according to the stimulus in patients with generalized genetic epilepsy (GGE) and drug-resistant focal epilepsy (FE) by performing a comparative study with a survey and a neuropsychological EEG activation method, besides routine EEG. Methods: A detailed and structured survey questioning seizure triggers was applied to patients with FE and GGE. Afterward, the changes in EDs in juvenile myoclonic epilepsy (JME), absence epilepsy (AE), and resistant FE groups were examined using NPA methods with EEG. Results: The most frequently reported triggers in all patient groups (n=66) were sleep deprivation (68.2%), stress (65.3%), fatigue/physical stress (53%), awakening (42.4%), and light stimuli (25.8%). There was no significant difference between the JME (n=34), AE (n=16), and resistant FE (n=16) groups in terms of either the triggering or inhibition of EDs in EEG by conventional activation and NPA methods. While the triggering of EDs occurred in 24% of patients by hyperventilation and in 18.1% of patients by intermittent photic stimulation, a similar triggering rate was detected in 21.2% of patients by NPA methods. In addition, while the results of the conventional EEG activation methods were negative, a triggered ED was observed in six patients during NPA (11%). Only two patients showed an inhibition by the NPA methods. Four patients had EDs on their EEGs during the NPA methods associated with triggers reported in the questionnaire. Conclusion: In 11% of patients, while an ED was not seen in conventional methods, we observed that ED triggering occurred with the NPA methods. Planning the NPA methods for specific triggers during EEG recordings by prior questioning on the seizure triggers of the patients and applying NPA as an additional triggering method, especially for patients who do not have EDs in EEG with standard activation methods, may be beneficial in terms of the correct diagnosis. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the correlation between GRIN2A rs387906637 polymorphism and susceptibility to epilepsy. Blood samples were collected from 85 volunteers, dividing into 60 epilepsy patients (34 males and 26 females) and 25 healthy subjects (19 males and 6 females).The DNA was extracted and GRIN2A rs387906637 polymorphism was analyzed by Real-time PCR using two probes and primers. The results showed no significant differences between patients and control samples; therefore, there are no allelic and genotypic correlations of this SNP with epilepsy. This study indicated that GRIN2A rs387906637 polymorphism is not a risk factor for epilepsy in the studied set of patients. [ABSTRACT FROM AUTHOR]

Background: Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies. Methods: This is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age. Results: The average age at enrolment was 39.9 months, with a mean age at seizure onset of 30.9 months and a mean time interval between seizure onset and targeted resequencing of 9 months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G > C in TPP1 was identified, leading to a CLN2 diagnosis. Three pathogenic variants in MECP2 were also detected in three patients, including the frameshift variant c.1157_1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects. Conclusions: Our findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions. [ABSTRACT FROM AUTHOR]

Mutations in the voltage-gated sodium channel Nav1.1 (SCN1A) are linked to various epileptic phenotypes with different severities, however, the consequences of newly identified SCN1A variants on patient phenotype is uncertain so far. The functional impact of nine SCN1A variants, including five novel variants identified in this study, was studied using whole-cell patch-clamp recordings measurement of mutant Nav1.1 channels expressed in HEK293T mammalian cells. E78X, W384X, E1587K, and R1596C channels failed to produce measurable sodium currents, indicating complete loss of channel function. E788K and M909K variants resulted in partial loss of function by exhibiting reduced current density, depolarizing shifts of the activation and hyperpolarizing shifts of the inactivation curves, and slower recovery from inactivation. Hyperpolarizing shifts of the activation and inactivation curves were observed in D249E channels along with slower recovery from inactivation. Slower recovery from inactivation was observed in E78D and T1934I with reduced current density in T1934I channels. Various functional effects were observed with the lack of sodium current being mainly associated with severe phenotypes and milder symptoms with less damaging channel alteration. In vitro functional analysis is thus fundamental for elucidation of the molecular mechanisms of epilepsy, to guide patients' treatment, and finally indicate misdiagnosis of SCN1A related epilepsies. [ABSTRACT FROM AUTHOR]

KIF1A‐related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological, and radiological features which may occur in childhood‐onset KRD. We report on all the children and young people seen at a single large tertiary centre. Data were collected through a retrospective case‐notes review. Twelve individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent—but sometimes progressive—changes in white matter on MRI. Epilepsy was common among the more severely affected children. This case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits. [ABSTRACT FROM AUTHOR]

The MnSOD Ala16Val single nucleotide polymorphism (SNP) has been associated with different diseases. However, there are scarcely studies relating this SNP in epilepsy, a neurologic disease that involves some interacting pathways, such as apoptotic and inflammatory factors. In this sense, we decided to investigate the relationship of MnSOD Ala16Val SNP with apoptotic markers in epilepsy and its relation with inflammatory pathway and seizure type. Ninety subjects were evaluated (47 epilepsies; 43 controls) by questionnaires and laboratorial exams. We observed a higher percentage of VV genotype in the epilepsy group when compared to the control group. IL-1β, IL-6, caspase-1, and caspase-3 levels were increased in the epilepsy group (VV genotype). Furthermore, an important correlation between IL-1β vs. caspase-1 and IL-6 vs. caspase-3 was observed in the epilepsy group (VV genotype). The epilepsy group which presented generalized seizures also demonstrated a positive correlation between IL-1β vs. CASP1 and IL-6 vs. CASP3. Thus, it is a plausible propose that epilepsy patients with VV genotype and generalized seizures present a worse inflammatory and apoptotic status. Our findings suggest that the knowledge of MnSOD Ala16Val polymorphism existence is important to evaluate molecular mechanisms associated to seizure and improve the treatment of these patients. [ABSTRACT FROM AUTHOR]

Objective: CDKL5-related disorders (CDD) is an epileptic encephalopathy resulted of gene mutations of CDKL5. This study aimed to explore the development process of CDD and to expand its mutation spectrum. Methods: Clinic datawas collected about three infantile epileptic encephalopathy cases diagnosed at Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine. Next generation sequencing technology was used to find three de novo mutations of CDKL5. We searched published literatures about CDKL5 in pubmed and made an analysis about our clinic data and the related literatures. Results: The three patients were all girls. Their average onset age of seizures was around 2 months, and all of them have intractable epileptic seizures, severe intellectual disability, and hypotension. Among them, two presented infantile spasm and high arrhythmia in EEG, and the other manifested clonic seizure and broad epileptiform discharge in EEG. Extracerebral space widening in cranial MRIs was demonstrated in two cases. Visual evoked potential was abnormal in two cases. Seizures were resistant to all kinds of antiepileptic drugs (AEDs). Gene tests showed three de novo mutations of CDKL5: one was a truncated mutation (c.2254A > T,P.R752X, stop279), which was pathogenic according to the ACMG guide, the other two were missense mutations (c.377G > T,p.Cys126Phe) and a frameshift mutation (c.362-362insG(p.Ala122GlyfsTer7), which were likely pathogenic according to the ACMG. Conclusions: All three de novo mutations are first reported. Based on the combined related literature and the manifestations observed, we diagnosed the three children as CDKL5-related disorders, and concluded that the de novo CDKL5 mutations are the reason for their epilepsy. [ABSTRACT FROM AUTHOR]

Background: Migraine is a neurovascular disease with recurrent headache attacks. A polymorphism (rs2651899) of the PRDM16 gene, which is associated with migraine, was identified in recent genome‐wide association studies. The potential role of the PRDM16 rs2651899 polymorphism in migraine is still unknown. Therefore, we conducted this systematic review and meta‐analysis to examine this issue. Methods: We performed a comprehensive literature search of the PubMed, Embase, and Google Scholar databases to identify eligible studies published before October 2018. Individual odds ratio and 95% confidence interval was used to estimate the pooled strength of the association between the PRDM16 rs2651899 polymorphism and common migraine subtypes, including migraine with aura (MA) and migraine without aura (MO). Results: Six studies with 2853 cases and 9319 controls that fulfilled the inclusion and exclusion criteria were selected for this meta‐analysis. Of the 6 included studies, 4 studies had available data for MWA and another 4 studies had data for MWoA. Overall, significant migraine risks of 1.257, 1.305, and 1.419 were found under allele model (C vs T), dominant model (C/C+T/C vs T/T), and recessive model (C/C vs T/C+T/T), respectively. In the recessive model, significantly increased risks of 1.454 and 1.546 were found for MA and MO, respectively. Conclusion: Our major findings suggest that PRDM16 rs2651899 polymorphism is associated with the risk of migraine. Furthermore, we found that PRDM16 rs2651899 polymorphism is significantly related to common migraine subtypes (MA and MO). [ABSTRACT FROM AUTHOR]

The article describes the case of a four-months female infant firstborn to a non-consanguineous couple with an uneventful perinatal period, presented with flexor epileptic spasms occurring in the clusters. Topics discussed include finding on her electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain, association between hypomagnesemia and hypocalcemia, and importance of considering the possibility of underlying CNNM2 gene mutation.

The article describes the case of a 21-year-old girl evaluated for drug-resistant epilepsy (DRE) associated with ring chromosome 20. Topics discussed include findings on her video electroencephalogram (EEG), reason for considering a possibility of R20 syndrome, and clinical characteristics of R20 syndrome, including DRE, mental disability, and multiple episodes of non-convulsive status epilepticus (NCSE).

Girls with pathogenic variants in FMR1, the gene responsible for Fragile X syndrome, have received relatively little attention in the literature. The reports of girls with trinucleotide expansions or deletions affecting FMR1 describe variable phenotypes; having normal intelligence and no severe neurologic sequelae is not uncommon. We reviewed epilepsy genetics research databases for girls with FMR1 pathogenic variants and seizures to characterize the spectrum of epilepsy phenotypes. We identified 4 patients, 3 of whom had drug-resistant focal epilepsy. Two had severe developmental and epileptic encephalopathy with late-onset epileptic spasms. Our findings demonstrate that FMR1 loss-of-function variants can result in severe neurologic phenotypes in girls. Similar cases may be missed because clinicians may not always perform Fragile X testing in girls, particularly those with severe neurodevelopmental impairment or late-onset spasms. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to determine the significance of six clinical predictors associated with medically intractable childhood epilepsy. Materials and Methods: A retrospective cohort study was conducted. A total of 241 children with diagnosed epilepsy were recruited and divided into two groups: 61 patients with intractable epilepsy, and the other 180 patients who responded well to antiepileptic drugs. We investigated seizure semiology, etiology of epileptic encephalopathy, EEG abnormalities and defined the odds ratios (ORs) of predictor factors for intractable childhood epilepsy; age of seizure onset, asphyxia, neonatal intensive care unit (NICU) history, consanguineous marriage, abnormal neuro-imaging, neuropathologic exam, prematurity, parents' seizure history. Results: According to logistic regression analysis, the major risk factors for intractable childhood epilepsy are (1) neuropathologic examination p=0.000, OR= 58.28 CI= 23.95-141.63; (2) abnormal neuro-imaging p=0.000, OR= 37.55 CI= 16.41-85.94 (3) age of seizure onset p=0.001, OR= 9.43 confidence interval (CI): 3.66-24.3 (4) asphyxia p=0.001 OR= 4.16 CI= 1.75-9.87 (5) consanguineous marriage p=0.001 OR= 3.02 CI= 1.53- 5.97 (6) NICU history p=0.003 OR= 2.59 CI= 1.38-4.87 (95% CI). Conclusion: The presented six predictors can be used to determine the medical intractability in children with epilepsy in order to provide early alternative treatment protocols for better seizure control. [ABSTRACT FROM AUTHOR]

Progressive myoclonic epilepsies (PME) are a clinically and genetically heterogeneous group of rare diseases characterized by myoclonic seizures, tonic-clonic seizures, and neurological deterioration. Here, we genetically analyzed a Chinese patient affected by infantile-onset progressive myoclonic epilepsy. We applied next-generation whole exome capture sequencing with Sanger direct sequencing to the proband and her unaffected parents. Two compound heterozygous mutations were identified in the KCTD7 gene. The first mutation [c. 434A > G(p.Q145R)] was inherited from her father, while the second [c.631C > T(p.R211X)] was inherited from her mother. The two were co-segregated with disease phenotype in the family. To our knowledge, this is the first report of KCTD7 mutations causing PME in the Chinese population, with c. 434A > G in particular being a novel mutation. Our findings supported the important role of KCTD7 in PME and broadened the gene's mutation spectrum. Thus, this study contributes to genetic diagnoses and counselling of families with PME. • The first report of KCTD7 mutations causing PME in Chinese population. • Two KCTD7 compound heterozygous mutations c. 434A>G and c.631C>T were identified • WES is a valuable approach for the diagnosis of clinically and genetically heterogeneous disorders. [ABSTRACT FROM AUTHOR]

The molecular-level cause of sleep is unknown. In 2012, we suggested that the cause of sleep stems from cumulative effects of numerous intracellular and extracellular protein fragments. According to the fragment generation (FG) hypothesis, protein fragments (which are continually produced through nonprocessive cleavages by intracellular, intramembrane, and extracellular proteases) can be beneficial but toxic as well, and some fragments are eliminated slowly during wakefulness. We consider the FG hypothesis and propose that, during wakefulness, the degradation of accumulating fragments is delayed within natural protein aggregates such as postsynaptic densities (PSDs) in excitatory synapses and in other dense protein meshworks, owing to an impeded diffusion of the ~3,000-kDa 26S proteasome. We also propose that a major function of sleep involves a partial and reversible expansion of PSDs, allowing an accelerated destruction of PSD-localized fragments by the ubiquitin/proteasome system. Expansion of PSDs would alter electrochemistry of synapses, thereby contributing to a decreased neuronal firing during sleep. If so, the loss of consciousness, a feature of sleep, would be the consequence of molecular processes (expansions of protein meshworks) that are required for degradation of protein fragments. We consider the concept of FG sentinels, which signal to sleep-regulating circuits that the levels of fragments are going up. Also discussed is the possibility that protein fragments, which are known to be overproduced during an epileptic seizure, may contribute to postictal sleep and termination of seizures. These and related suggestions, described in the paper, are compatible with current evidence about sleep and lead to testable predictions. [ABSTRACT FROM AUTHOR]