The growing interest in Kv7.2/7.3 agonists originates from the involvement of these channels in several brain hyperexcitability disorders. In particular, Kv7.2/7.3 mutants have been clearly associated with epileptic encephalopathies (DEEs) as well as with a spectrum of focal epilepsy disorders, often associated with developmental plateauing or regression. Nevertheless, there is a lack of available therapeutic options, considering that retigabine, the only molecule used in clinic as a broad-spectrum Kv7 agonist, has been withdrawn from the market in late 2016. This is why several efforts have been made both by both academia and industry in the search for suitable chemotypes acting as Kv7.2/7.3 agonists. In this context, in silico methods have played a major role, since the precise structures of different Kv7 homotetramers have been only recently disclosed. In the present review, the computational methods used for the design of Kv.7.2/7.3 small molecule agonists and the underlying medicinal chemistry are discussed in the context of their biological and structure-function properties.

UNASSIGNED: Landau-Kleffner syndrome (LKS) is a rare epileptic encephalopathy characterized by language regression and abnormal electroencephalogram (EEG) patterns. This case report highlights the importance of early recognition and intervention in LKS, as well as the challenges in diagnosis and management due to its varied clinical manifestations.
UNASSIGNED: An 8-year-old girl presented with delayed speech, suspected hearing loss, and regression in language skills. Diagnostic tests revealed mild sensorineural hearing loss and EEG abnormalities consistent with LKS. The patient underwent speech therapy and received pharmacological treatment with valproic acid, resulting in significant improvements in language function.
UNASSIGNED: This case report provides insights into the typical features of LKS, including language regression and EEG abnormalities. It also highlights uncommon findings such as sensorineural hearing loss and mild intellectual delay. The multidisciplinary approach involving neurology, audiology, speech therapy, and education is crucial in the diagnosis and management of LKS.
UNASSIGNED: Early recognition and intervention, along with tailored pharmacological approaches and a multidisciplinary care approach, are essential in managing LKS. Further research is needed to better understand the pathophysiology, natural history, and optimal treatment of LKS, aiming to improve long-term outcomes for affected children and their families.

OBJECTIVE: To analyze cerebellar atrophy in genetic epileptic encephalopathies (EEs).
METHODS: This research included a retrospective cohort study conducted from January 2016 to December 2023 and a systematic review on cerebellar atrophy in genetic EEs. Pediatric individuals who were diagnosed with EEs based on electroclinical features, carried causative gene variants, and exhibited cerebellar atrophy were recruited. Electroclinical features, neuroimaging findings, and causative variants of eligible individuals were analyzed.
RESULTS: The cohort study showed 10 of 67 pediatric individuals (10/67; 15 %) who were diagnosed with genetic EEs had cerebellar atrophy; and 6 of the 10 individuals (6/10; 60 %) exhibited cerebellar signs. Diagnostic delay between the detection of cerebellar atrophy and the identification of genetic diagnosis existed in 6 individuals (6/10; 60 %) and the median duration was 4.4 years. A total of 32 genes, including 31 genes from the literature review and a newly identified SCN2A gene in this cohort, were reported associated with cerebellar atrophy in genetic EEs. Twenty-six genes (26/32; 81 %) accounted for cerebellar atrophy associated with other brain anomalies and 6 genes (6/32; 19 %) caused isolated cerebellar atrophy. Twenty-five genes (25/32; 78 %) showed late-onset cerebellar atrophy identified after the age of 1 year old.
CONCLUSIONS: Cerebellar atrophy is not uncommon in genetic EEs and may serve as an indicator for molecular diagnosis in clinical practice. To shorten the diagnostic delay, follow-up neuroimaging study is crucial because of high rate of clinico-radiological dissociation and late-onset cerebellar atrophy in this patient group.

OBJECTIVE: Epileptic Encephalopathy / Developmental Epileptic Encephalopathy with spike-and-wave activation during sleep (EE/DEE-SWAS) is a self-limiting childhood epilepsy syndrome but may cause permanent neurocognitive impairment. Surgical interventions have been controversial in the treatment of EE/DEE-SWAS. This systematic review aims to evaluate the efficacy of various surgical procedures on the outcomes of EE/DEE-SWAS.
METHODS: A systematic review was performed per the PRISMA guidelines. A total of 14 retrospective studies were identified, comprising 131 cases of EE/DEE-SWAS treated with epilepsy surgery. The review analyzed presurgical data, surgical interventions, as well as outcomes related to seizures, EEG, and neuropsychological assessments.
RESULTS: Epilepsy surgery was successfully performed in 131 cases with minor complications. The average age was 2.6 years at seizure onset and 5.0 years at diagnosis of SWAS. Excellent seizure control (Engel I and II) was achieved in 80.6 %, 78.6 %, 77.4 % and 27.2 % of patients receiving hemispherectomies, focal resections, multiple subpial transections (MSTs), and corpus callosotomies (CCTs), respectively. EEG SWAS resolution was seen in 79.7 % of hemispherectomy cases, 78.6 % in focal resections, 63.9 % in MSTs, and 8.3 % in CCTs. Neurocognitive and behavioral improvement was noted in 58.0 %, 71.4 %, 58.3 % and 16.7 % for patients receiving hemispherectomies, focal resections, MSTs, and CCTs, respectively. A correlation between improved seizure control and SWAS resolution was observed with improved neuropsychological outcomes.
CONCLUSIONS: Epilepsy surgery is a safe and effective treatment for carefully selected children with drug-resistant EE/DEE-SWAS. Patients who underwent epilepsy surgery had reduction of seizure burden, SWAS resolution and improvements in neurocognitive and behavioral function.

BACKGROUND: Developmental and epileptic encephalopathies (DEE) encompass a group of rare diseases with hereditary and genetic causes as well as acquired causes such as brain injuries or metabolic abnormalities. The phosphofurin acidic cluster sorting protein 2 (PACS2) is a multifunctional protein with nuclear gene expression. The first cases of the recurrent c.625G>A pathogenic variant of PACS2 gene were reported in 2018 by Olson et al. Since then, several case reports and case series have been published.
METHODS: We performed a systematic review of the PUBMED and SCOPUS databases using Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Our search parameters included DEE66 with a pathogenic PACS2 gene p.Glu209Lys mutation published cases to which we added our own clinical experience regarding this pathology.
RESULTS: A total of 11 articles and 29 patients were included in this review, to which we added our own experience for a total of 30 patients. There was not a significant difference between sexes regarding the incidence of this pathology (M/F: 16/14). The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait. Facial dysmorphism and other organs\' involvement were also frequently reported. Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement. Genetic testing is more frequent in children. Only 4 cases have been reported in adults to date.
CONCLUSIONS: It is important to maintain a high suspicion of new pathogenic gene variants in adult patients presenting with a characteristic clinical picture correlated with radiologic changes. The neurologist must gradually recognize the distinct evolving phenotype of DEE66 in adult patients, and genetic testing must become a scenario with which the neurologist attending adult patients should be familiar. Accurate diagnosis is required for adequate treatment, genetic counseling, and an improved long-term prognosis.

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and \"symptomatic\" etiology. Obesity and Cushing\'s syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort.
METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized.
RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years).
CONCLUSIONS: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

UNASSIGNED: Rho-related BTB domain-containing protein 2 (RHOBTB2) is a protein that interacts with cullin-3, a crucial E3 ubiquitin ligase for mitotic cell division. RHOBTB2 has been linked to early infantile epileptic encephalopathy, autosomal dominant type 64 (OMIM618004), in 34 reported patients.
UNASSIGNED: We present a case series of seven patients with RHOBTB2-related disorders (RHOBTB2-RD), including a description of a novel heterozygous variant. We also reviewed previously published cases of RHOBTB2-RD.
UNASSIGNED: The seven patients had ages ranging from 2 years and 8 months to 26 years, and all had experienced seizures before the age of one (onset, 4-12 months, median, 4 months), including various types of seizures. All patients in this cohort also had a movement disorder (onset, 0.3-14 years, median, 1.5 years). Six of seven had a baseline movement disorder, and one of seven only had paroxysmal dystonia. Stereotypies were noted in four of six, choreodystonia in three of six, and ataxia in one case with multiple movement phenotypes at baseline. Paroxysmal movement disorders were observed in six of seven patients for whom carbamazepine or oxcarbazepine treatment was effective in controlling acute or paroxysmal movement disorders. Four patients had acute encephalopathic episodes at ages 4 (one patient) and 6 (three patients), which improved following treatment with methylprednisolone. Magnetic resonance imaging scans revealed transient fluid-attenuated inversion recovery abnormalities during these episodes, as well as myelination delay, thin corpus callosum, and brain atrophy. One patient had a novel RHOBTB2 variant (c.359G>A/p.Gly120Glu).
UNASSIGNED: RHOBTB2-RD is characterized by developmental delay or intellectual disability, early-onset seizures, baseline movement disorders, acute or paroxysmal motor phenomena, acquired microcephaly, and episodes of acute encephalopathy. Early onsets of focal dystonia, acute encephalopathic episodes, episodes of tongue protrusion, or peripheral vasomotor disturbances are important diagnostic clues. Treatment with carbamazepine or oxcarbazepine was found to be effective in controlling acute or paroxysmal movement disorders. Our study highlights the clinical features and treatment response of RHOBTB2-RD.

Advances in disease-related gene discovery have led to tremendous innovations in the field of epilepsy genetics. Identification of genetic mutations that cause epileptic encephalopathies has opened new avenues for the development of targeted therapies. Clinical testing using extensive gene panels, exomes, and genomes is currently accessible and has resulted in higher rates of diagnosis and better comprehension of the disease mechanisms underlying the condition. Children with developmental disabilities have a higher risk of developing epilepsy. As our understanding of the mechanisms underlying encephalopathies and epilepsies improves, there may be greater potential to develop innovative therapies tailored to an individual\'s genotype. This article provides an overview of the significant progress in epilepsy genomics in recent years, with a focus on developmental and epileptic encephalopathies in children. The aim of this review is to enhance comprehension of the clinical utilization of genetic testing in this particular patient population. The development of effective and precise therapeutic strategies for epileptic encephalopathies may be facilitated by a comprehensive understanding of their molecular pathogenesis.

UNASSIGNED: SLC13A5 (solute carrier family 13, member 5) encodes sodium/citrate cotransporter, which mainly localizes in cellular plasma membranes in the frontal cortex, retina, and liver. Pathogenic variants of the gene cause an autosomal recessive syndrome known as \"developmental and epileptic encephalopathy 25 with amelogenesis imperfecta.\"
UNASSIGNED: Here, we have investigated six patients from three different consanguineous Saudi families. The affected individuals presented with neonatal seizures, developmental delay, and significant defects in tooth development. Some patients showed other clinical features such as muscle weakness, motor difficulties, intellectual disability, microcephaly, and speech problems in addition to additional abnormalities revealed by electroencephalography (EEGs) and magnetic resonance imaging (MRI). One of the MRI findings was related to cortical thickening in the frontal lobe. To diagnose and study the genetic defects of the patients, whole exome sequencing (WES) coupled with confirmatory Sanger sequencing was utilized. Iterative filtering identified two variants of SLC13A5, one of which is novel, in the families. Families 1 and 2 had the same insertion (a previously reported mutation), leading to a frameshift and premature stop codon. The third family had a novel splice site variant. Confirmatory Sanger sequencing corroborated WES results and indicated full segregation of the variants in the corresponding families. The patients\' conditions were poorly controlled by multiple antiepileptics as they needed constant care.
UNASSIGNED: Considering that recessive mutations are common in the Arab population, SLC13A5 screening should be prioritized in future patients harboring similar symptoms including defects in molar development.