N-methyl-D-aspartate receptors (NMDAR) are ligand-gated ion channels mediating excitatory neurotransmission and are important for normal brain development, cognitive abilities, and motor functions. Pathogenic variants in the Glutamate receptor Ionotropic N-methyl-D-aspartate (GRIN) genes (GRIN1, GRIN2A-D) encoding NMDAR subunits have been associated with a wide spectrum of neurodevelopmental disorders and epilepsies ranging from treatable focal epilepsies to devastating early-onset developmental and epileptic encephalopathies. Genetic variants in NMDA receptor genes can cause a range of complex alterations to receptor properties resulting in various degrees of loss-of-function, gain-of-function, or mixtures thereof. Understanding how genetic variants affect the function of the receptors, therefore, represents an important first step in the ongoing development towards targeted therapies. Currently, targeted treatment options for GRIN-related diseases are limited. However, treatment with memantine has been reported to significantly reduce seizure frequency in a few individuals with developmental and epileptic encephalopathies harboring de novo gain-of-function GRIN2A missense variants, and supplementary treatment with L-serine has been associated with improved motor and cognitive performance as well as reduced seizure frequency in patients with GRIN2B loss-of-function missense variants as well as GRIN2A and GRIN2B null variants.

UNASSIGNED: Nearly 40% of pediatric epilepsies have a genetic basis. There is significant phenotypic and genotypic heterogeneity, especially in epilepsy syndromes caused by sodium channelopathies. Sodium channel subunit 1A (SCN1A)-related epilepsy represents the archetypical channel-associated gene that has been linked to a wide spectrum of epilepsies of varying severity. Subsequently, other sodium channels have also been implicated in epilepsy and other neurodevelopmental disorders. This study aims to describe the phenotypes in children with sodium channelopathies from a center in Southern India.
UNASSIGNED: This is a retrospective, descriptive, and single-center study. Out of 112 children presenting with epilepsy who underwent genetic testing between 2017 and 2021, 23 probands (M: F = 12:11) were identified to have clinically significant sodium channel mutations. Clinical presentation, electroencephalography, and imaging features of these patients were recorded. The utility of genetic test results (e.g., in planning another child, withdrawal of medications, or change in treatment) was also recorded.
UNASSIGNED: Age at onset of seizures ranged from day 4 of life to 3.5 years. Clinical epilepsy syndromes included generalized epilepsy with febrile seizures plus (n = 3), Dravet syndrome (n = 5), early infantile epileptic encephalopathy (n = 7), drug-resistant epilepsy (n = 5), and epilepsy with associated movement disorders (n = 3). The most common type of seizure was focal with impaired awareness (n = 18, 78.2%), followed by myoclonic jerks (n = 8, 34.78%), epileptic spasms (n = 7, 30.4%), bilateral tonic-clonic seizures/generalized tonic-clonic seizures (n = 3, 13%), and atonic seizures (n = 5, 23.8%). In addition to epilepsy, other phenotypic features that were discerned were microcephaly (n = 1), cerebellar ataxia (n = 2), and chorea and dystonia (n = 1).
UNASSIGNED: Sodium channelopathies may present with seizure phenotypes that vary in severity. In addition to epilepsy, patients may also have other clinical features such as movement disorders. Early clinical diagnosis may aid in tailoring treatment for the given patient.

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Many patients with epilepsy undergo exome or genome sequencing as part of a diagnostic workup; however, many remain genetically unsolved. There are various factors that account for negative results in exome/genome sequencing for patients with epilepsy: (1) the underlying cause is not genetic; (2) there is a complex polygenic explanation; (3) the illness is monogenic but the causative gene remains to be linked to a human disorder; (4) family segregation with reduced penetrance; (5) somatic mosaicism or the complexity of, for example, a structural rearrangement; or (6) limited knowledge or diagnostic tools that hinder the proper classification of a variant, resulting in its designation as a variant of unknown significance. The objective of this review is to outline some of the diagnostic options that lie beyond the exome/genome, and that might become clinically relevant within the foreseeable future. These options include: (1) re-analysis of older exome/genome data as knowledge increases or symptoms change; (2) looking for somatic mosaicism or long-read sequencing to detect low-complexity repeat variants or specific structural variants missed by traditional exome/genome sequencing; (3) exploration of the non-coding genome including disruption of topologically associated domains, long range non-coding RNA, or other regulatory elements; and finally (4) transcriptomics, DNA methylation signatures, and metabolomics as complementary diagnostic methods that may be used in the assessment of variants of unknown significance. Some of these tools are currently not integrated into standard diagnostic workup. However, it is reasonable to expect that they will become increasingly available and improve current diagnostic capabilities, thereby enabling precision diagnosis in patients who are currently undiagnosed.

The phenomenon of déjà vu (DV) is of interest, occurring in 97% of healthy individuals, while DV can be a manifestation of a number of pathologies, such as Charles Bonnet syndrome, depression, schizophrenia, or temporal lobe epilepsy. Most cases of DV type epiphenomena are associated with hippocampal sclerosis, while up to 90% of patients with mesial temporal sclerosis are drug resistant. Despite the success of pharmacotherapy, the frequency of «uncontrolled» epilepsy in industrialized countries that adhere to modern standards of treatment is from 30 to 40%, and this percentage is higher among patients with symptomatic and cryptogenic forms than among patients with idiopathic epilepsy (respectively: 40% and 26%). In turn, when studying the DV phenomenon and choosing a therapy strategy, it is necessary to establish its origin, determine its clinical significance (whether it is initially pathological or not), and the need for treatment. During the analysis of exome data, a search was made for substitutions in genes associated with arteriovenous malformations, both with autosomal dominant and autosomal recessive types of inheritance. The genes KRIT1, RASA1, IL6, FAM58A, GLML, EPHB4, CCM2, and ELMO2 were analyzed especially carefully. The analysis of genetic data is of great importance in the aspect of preventing cerebrovascular accidents, at the same time, in order to obtain reliable and significant results, in addition to time and financial costs, examination of relatives is also required. Meanwhile, this fact does not mean that every patient needs to conduct a genetic study. The paper presents detailed instructions for supplementing anamnestic information, as well as the results of personalized instrumental and laboratory diagnostics, which made it possible to carry out timely correction of therapy and achieve a prolonged positive effect.

UNASSIGNED: SLC6A1 is one of the most common monogenic causes of epilepsy and is a well-established cause of neurodevelopmental disorders. SLC6A1-neurodevelopmental disorders have a consistent phenotype of mild to severe intellectual disability (ID), epilepsy, language delay and behavioral disorders. This phenotypic description is mainly based on knowledge from the pediatric population.
UNASSIGNED: Here, we sought to describe patients with SLC6A1 variants and age above 18 years through the ascertainment of published and unpublished patients. Unpublished patients were ascertained through international collaborations, while previously published patients were collected through a literature search.
UNASSIGNED: A total of 15 adult patients with SLC6A1 variants were included. 9/13 patients had moderate to severe ID (data not available in two). Epilepsy was prevalent (11/15) with seizure types such as absence, myoclonic, atonic, and tonic-clonic seizures. Epilepsy was refractory in 7/11, while four patients were seizure free with lamotrigine, valproate, or lamotrigine in combination with valproate. Language development was severely impaired in five patients. Behavioral disorders were reported in and mainly consisted of autism spectrum disorders and aggressive behavior. Schizophrenia was not reported in any of the patients.
UNASSIGNED: The phenotype displayed in the adult patients presented here resembled that of the pediatric cohort with ID, epilepsy, and behavioral disturbances, indicating that the phenotype of SLC6A1-NDD is consistent over time. Seizures were refractory in >60% of the patients with epilepsy, indicating the lack of targeted treatment in SLC6A1-NDDs. With increased focus on repurposing drugs and on the development of new treatments, hope is that the outlook reflected here will change over time. ID appeared to be more severe in the adult patients, albeit this might reflect a recruitment bias, where only patients seen in specialized centers were included or it might be a feature of the natural history of SLC6A1-NDDs. This issue warrants to be explored in further studies in larger cohorts.

BACKGROUND: Next generation sequencing (NGS) has greatly expanded our understanding of genetic contributors in multiple epilepsy syndromes, including focal epilepsy. Describing the genetic architecture of common syndromes promises to facilitate the diagnostic process as well as aid in the identification of patients who stand to benefit from genetic testing, but most studies to date have been limited to examining children or adults with intellectual disability. Our aim was to determine the yield of targeted sequencing of 5 established epilepsy genes (DEPDC5, LGI1, SCN1A, GRIN2A, and PCHD19) in an extensively phenotyped cohort of focal epilepsy patients with normal intellectual function or mild intellectual disability, as well as describe novel variants and determine the characteristics of variant carriers.
METHODS: Targeted panel sequencing was performed on 96 patients with a strong clinical suspicion of genetic focal epilepsy. Patients had previously gone through a comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia. Variants of interest (VOI) were classified using the American College of Medical Genetics and the Association for Molecular Pathology criteria.
RESULTS: Six VOI in eight (8/96, 8.3%) patients were found in our cohort. Four likely pathogenic VOI were determined in six (6/96, 6.2%) patients, two DEPDC5 variants in two patients, one SCN1A variant in two patients and one PCDH19 variant in two patients. One variant of unknown significance (VUS) was found in GRIN2A in one (1/96, 1.0%) patient. Only one VOI in GRIN2A was classified as likely benign. No VOI were detected in LGI1.
CONCLUSIONS: Sequencing of only five known epilepsy genes yielded a diagnostic result in 6.2% of our cohort and revealed multiple novel variants. Further research is necessary for a better understanding of the genetic basis in common epilepsy syndromes in patients with normal intellectual function or mild intellectual disability.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

PCDH19-related epilepsy is a rare X-linked type of epilepsy caused by genomic variants of the Protocadherin 19 (PCDH19) gene. The clinical characteristics of PCDH19-related epilepsy are epileptic and non-epileptic symptoms with highly variable severity among patients.
We present a case of a 4-year old female with PCDH19-related epilepsycaused by new variants in the PCDH19 gene. Our patient was admitted for the first time at the age of 12 months for seizure clusters arising under condition of apyrexia. The electroencephalography (EEG) showed frontal paroxysmal activity. The genetic analysis identified the two variants c.1006G > A (p.Val336Met) and c.1014C > A (p.Asp338Glu) in the gene PCDH19. The patient was treated with Carbamazepine and Clonazepam achieving the disappearance of seizures. During the follow-up, the neurological examination was persistently normal with neither cognitive impairment nor behavior disturbances. From 2 years of age EEG controls were persistently normal.
This patient presents two novel variants of the PCDH19 gene associated with a mild form of epilepsy with normal cognitive development with an apparently better prognosis. According to our experience, the dual therapy with Carbamazepine and Clonazepam has led to a good control of seizures.

We report the genetic analysis of two consanguineous pedigrees of Pakistani ancestry in which two siblings in each family exhibited developmental delay, epilepsy, intellectual disability and aggressive behavior. Whole-genome sequencing was performed in Family 1, and we identified ~80,000 variants located in regions of homozygosity. Of these, 615 variants had a minor allele frequency ≤ 0.001, and 21 variants had CADD scores ≥ 15. Four homozygous exonic variants were identified in both affected siblings: PDZD7 (c.1348_1350delGAG, p.Glu450del), ALG6 (c.1033G>C, p.Glu345Gln), RBM20 (c.1587C>G, p.Ser529Arg), and CNTNAP2 (c.785G>A, p.Gly228Arg). Sanger sequencing revealed co-segregation of the PDZD7, RBM20, and CNTNAP2 variants with disease in Family 1. Pathogenic variants in PDZD7 and RBM20 are associated with autosomal recessive non-syndromic hearing loss and autosomal dominant dilated cardiomyopathy, respectively, suggesting that these variants are unlikely likely to contribute to the clinical presentation. Gene panel analysis was performed on the two affected siblings in Family 2, and they were found to also be homozygous for the p.Gly228Arg CNTNAP2 variant. Together these families provide a LOD score 2.9 toward p.Gly228Arg CNTNAP2 being a completely penetrant recessive cause of this disease. The clinical presentation of the affected siblings in both families is also consistent with previous reports from individuals with homozygous CNTNAP2 variants where at least one allele was a nonsense variant, frameshift or small deletion. Our data suggests that homozygous CNTNAP2 missense variants can also contribute to disease, thereby expanding the genetic landscape of CNTNAP2 dysfunction.