Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific protease 25, a key member of the deubiquitinating enzyme family that is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown aetiology. Five heterozygous USP25 variants, including two de novo and three co-segregated variants, were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared with the East Asian population and all populations in the gnomAD database. The mean age at onset of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom, except that one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was expressed ubiquitously in mouse brain with two peaks, on embryonic Days 14-16 and postnatal Day 21, respectively. In human brain, likewise, USP25 is expressed in the fetus/early childhood stage and with a second peak at ∼12-20 years old, consistent with the seizure onset age in patients during infancy and in juveniles. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knockout mice, which showed increased seizure susceptibility compared with wild-type mice in a pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we used multiple functional detections. In HEK293 T cells, the variant associated with a severe phenotype (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed stable truncated dimers with an increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del variants increased neuronal excitability in mouse brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating that USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play an epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have a profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

Structural and functional abnormalities in first-episode drug-naïve pediatric idiopathic generalized epilepsy.

The aim of this study was to investigate brain structure and corresponding static and dynamic functional connectivity (sFC & dFC) abnormalities in untreated, first-episode pediatric idiopathic generalized epilepsy (IGE), with the goal of better understanding the underlying pathological mechanisms of IGE. Thirty-one children with IGE and 31 age-matched healthy controls (HC) were recruited. Structural magnetic resonance imaging (sMRI) data were acquired, and voxel-based morphometry (VBM) analysis were performed to reveal abnormal gray matter volume (GMV). Moreover, sFC and dFC analyses were conducted using the brain areas exhibiting abnormal GMV as seed regions to explore abnormal functional couplings. Compared to HC, the IGE group exhibited increased GMV in left middle cingulate cortex (MCC) and right parahippocampus (ParaHipp). In addition, the analyses of dFC and sFC with MCC and ParaHipp as seeds revealed more extensive functional connectivity (FC) changes in dFC. Notably, the structurally and functionally abnormal brain areas were primarily localized in the default mode network (DMN). However, our study did not find any significant associations between these altered neuroimaging measurements and clinical outcomes. This study uncovered microstructural changes as well as corresponding sFC and dFC changes in patients with new-onset, untreated pediatric IGE. The affected brain regions were primarily located within the DMN, highlighting the DMN's crucial role in the development of pediatric IGE.

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals.

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

The role of the primary sensorimotor system in generalized epilepsy: Evidence from the cerebello-cerebral functional integration.

The interaction between cerebellum and cerebrum participates widely in function from motor processing to high-level cognitive and affective processing. Because of the motor symptom, idiopathic generalized epilepsy (IGE) patients with generalized tonic-clonic seizure have been recognized to associate with motor abnormalities, but the functional interaction in the cerebello-cerebral circuit is still poorly understood. Resting-state functional magnetic resonance imaging data were collected for 101 IGE patients and 106 healthy controls. The voxel-based functional connectivity (FC) between cerebral cortex and the cerebellum was contacted. The functional gradient and independent components analysis were applied to evaluate cerebello-cerebral functional integration on the voxel-based FC. Cerebellar motor components were further linked to cerebellar gradient. Results revealed cerebellar motor functional modules were closely related to cerebral motor components. The altered mapping of cerebral motor components to cerebellum was observed in motor module in patients with IGE. In addition, patients also showed compression in cerebello-cerebral functional gradient between motor and cognition modules. Interestingly, the contribution of the motor components to the gradient was unbalanced between bilateral primary sensorimotor components in patients: the increase was observed in cerebellar cognitive module for the dominant hemisphere primary sensorimotor, but the decrease was found in the cerebellar cognitive module for the nondominant hemisphere primary sensorimotor. The present findings suggest that the cerebral primary motor system affects the hierarchical architecture of cerebellum, and substantially contributes to the functional integration evidence to understand the motor functional abnormality in IGE patients.

Centromedian region thalamic responsive neurostimulation mitigates idiopathic generalized and multifocal epilepsy with focal to bilateral tonic-clonic seizures.

OBJECTIVE: Although >30% of epilepsy patients have drug-resistant epilepsy (DRE), typically those with generalized or multifocal disease have not traditionally been considered surgical candidates. Responsive neurostimulation (RNS) of the centromedian (CM) region of the thalamus now appears to be a promising therapeutic option for this patient population. We present outcomes following CM RNS for 13 patients with idiopathic generalized epilepsy (IGE) and eight with multifocal onsets that rapidly generalize to bilateral tonic-clonic (focal to bilateral tonic-clonic [FBTC]) seizures. METHODS: A retrospective review of all patients undergoing bilateral CM RNS by the senior author through July 2022 were reviewed. Electrodes were localized and volumes of tissue activation were modeled in Lead-DBS. Changes in patient seizure frequency were extracted from electronic medical records. RESULTS: Twenty-one patients with DRE underwent bilateral CM RNS implantation. For 17 patients with at least 1 year of postimplantation follow-up, average seizure reduction from preoperative baseline was 82.6% (SD = 19.0%, median = 91.7%), with 18% of patients Engel class 1, 29% Engel class 2, 53% Engel class 3, and 0% Engel class 4. There was a trend for average seizure reduction to be greater for patients with nonlesional FBTC seizures than for other patients. For patients achieving at least Engel class 3 outcome, median time to worthwhile seizure reduction was 203.5 days (interquartile range = 110.5-343.75 days). Patients with IGE with myoclonic seizures had a significantly shorter time to worthwhile seizure reduction than other patients. The surgical targeting strategy evolved after the first four subjects to achieve greater anatomic accuracy. SIGNIFICANCE: Patients with both primary and rapidly generalized epilepsy who underwent CM RNS experienced substantial seizure relief. Subsets of these patient populations may particularly benefit from CM RNS. The refinement of lead targeting, tuning of RNS system parameters, and patient selection are ongoing areas of investigation.

Focal electroclinical features in generalized tonic-clonic seizures: Decision flowchart for a diagnostic challenge.

OBJECTIVE: Bilateral tonic-clonic seizures with focal semiology or focal interictal electroencephalography (EEG) can occur in both focal and generalized epilepsy types, leading to diagnostic errors and inappropriate therapy. We investigated the prevalence and prognostic values of focal features in patients with idiopathic generalized epilepsy (IGE), and we propose a decision flowchart to distinguish between focal and generalized epilepsy in patients with bilateral tonic-clonic seizures and focal EEG or semiology. METHODS: We retrospectively analyzed video-EEG recordings of 101 bilateral tonic-clonic seizures from 60 patients (18 with IGE, 42 with focal epilepsy). Diagnosis and therapeutic response were extracted after ≥1-year follow-up. The decision flowchart was based on previous observations and assessed concordance between interictal and ictal EEG. RESULTS: Focal semiology in IGE was observed in 75% of seizures and 77.8% of patients, most often corresponding to forced head version (66.7%). In patients with multiple seizures, direction of head version was consistent across seizures. Focal interictal epileptiform discharges (IEDs) were observed in 61.1% of patients with IGE, whereas focal ictal EEG onset only occurred in 13% of seizures and 16.7% of patients. However, later during the seizures, a reproducible pattern of 7-Hz lateralized ictal rhythm was observed in 56% of seizures, associated with contralateral head version. We did not find correlation between presence of focal features and therapeutic response in IGE patients. Our decision flowchart distinguished between focal and generalized epilepsy in patients with bilateral tonic-clonic seizures and focal features with an accuracy of 96.6%. SIGNIFICANCE: Focal semiology associated with bilateral tonic-clonic seizures and focal IEDs are common features in patients with IGE, but focal ictal EEG onset is rare. None of these focal findings appears to influence therapeutic response. By assessing the concordance between interictal and ictal EEG findings, one can accurately distinguish between focal and generalized epilepsies.

The role of copy number variants in the genetic architecture of common familial epilepsies.

OBJECTIVE: Copy number variants (CNVs) contribute to genetic risk and genetic etiology of both rare and common epilepsies. Whereas many studies have explored the role of CNVs in sporadic or severe cases, fewer have been done in familial generalized and focal epilepsies. METHODS: We analyzed exome sequence data from 267 multiplex families and 859 first-degree relative pairs with a diagnosis of genetic generalized epilepsies or nonacquired focal epilepsies to predict CNVs. Validation and segregation studies were performed using an orthogonal method when possible. RESULTS: We identified CNVs likely to contribute to epilepsy risk or etiology in the probands of 43 of 1116 (3.9%) families, including known recurrent CNVs (16p13.11 deletion, 15q13.3 deletion, 15q11.2 deletion, 16p11.2 duplication, 1q21.1 duplication, and 5-Mb duplication of 15q11q13). We also identified CNVs affecting monogenic epilepsy genes, including four families with CNVs disrupting the DEPDC5 gene, and a de novo deletion of HNRNPU in one affected individual from a multiplex family. Several large CNVs (>500 kb) of uncertain clinical significance were identified, including a deletion in 18q, a large duplication encompassing the SCN1A gene, and a 15q13.3 duplication (BP4-BP5). SIGNIFICANCE: The overall CNV landscape in common familial epilepsies is similar to that of sporadic epilepsies, with large recurrent deletions at 15q11, 15q13, and 16p13 contributing in 2.5%-3% of families. CNVs that interrupt known epilepsy genes and rare, large CNVs were also identified. Multiple etiologies were found in a subset of families, emphasizing the importance of genetic testing for multiple affected family members. Rare CNVs found in a single proband remain difficult to interpret and require larger cohorts to confirm their potential role in disease. Overall, our work indicates that CNVs contribute to the complex genetic architecture of familial generalized and focal epilepsies, supporting the role for clinical testing in affected individuals.

Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor regulatory protein expression during the development of absence seizures in genetic absence epilepsy rats from Strasbourg.

The transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) regulatory proteins (TARPs), γ2 (stargazin), γ3, γ4, γ5, γ7, and γ8, are a family of proteins that regulate AMPAR trafficking, expression, and biophysical properties that could have a role in the development of absence seizures. Here, we evaluated the expression of TARPs and AMPARs across the development of epilepsy in the genetic absence epilepsy rats from Strasbourg (GAERS) model of idiopathic generalized epilepsy (IGE) with absence seizures. Pre-epileptic (7-day-old), early epileptic (6-week-old), and chronically epileptic (16-week-old) GAERS, and age-matched male nonepileptic control rats (NEC) were used. Electroencephalographic (EEG) recordings were acquired from the 6- and 16-week-old animals to quantify seizure expression. Somatosensory cortex (SCx) and whole thalamus were collected from all the animals to evaluate TARP and AMPAR mRNA expression. Analysis of the EEG demonstrated a gradual increase in the number and duration of seizures across GAERS development. mRNA expression of the TARPs γ2, γ3, γ4, γ5, and γ8 in the SCx, and γ4 and γ5 in the thalamus, increased as the seizures started and progressed in the GAERS compared to NEC. There was a temporal association between increased TARP expression and seizures in GAERS, highlighting TARPs as potential targets for developing novel treatments for IGE with absence seizures.

Epilepsy with generalized tonic-clonic seizures alone: Electroclinical features and prognostic patterns.

OBJECTIVE: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients. METHODS: In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors. RESULTS: We included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13-22) and a median follow-up duration of 10 years (IQR = 5-20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2-year remission was 24 months (IQR = 24-46.5) with a median number of 1 (IQR = 1-2) ASM. During the long-term follow-up (i.e., 202 patients followed ≥5-years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no-remission and relapsing-remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic-clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12-month follow-up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression. SIGNIFICANCE: GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations.

Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing.

OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM. METHODS: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder). RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM- remains to be elucidated.

Valproate use associated with frontal and cerebellar gray matter volume reductions: A voxel-based morphometry study.

Recent morphometric magnetic resonance imaging (MRI) studies suggested the possibility that valproate (VPA) use is associated with parieto-occipital cortical thinning in patients with heterogeneous epilepsy syndromes. In this study, we examined the effect of VPA on the brain volume using a large number of homogenous patients with idiopathic generalized epilepsy. Voxel-based morphometry was used to compare regional gray matter (GM) volume between 112 patients currently taking VPA (VPA+ group), 81 patients not currently taking VPA (VPA- group), and 120 healthy subjects (control group). The VPA+ group showed a significant GM volume reduction in the bilateral cerebellum, hippocampus, insula, caudate nucleus, medial frontal cortex/anterior cingulate cortex, primary motor/premotor cortex, medial occipital cortex, and anteromedial thalamus, as compared to the control group. The VPA- group showed a significant GM volume reduction in the anteromedial thalamus and right hippocampus/temporal cortex, as compared to the control group. Compared to the VPA- group, the VPA+ group had a significant GM volume reduction in the bilateral cerebellum, primary motor/premotor cortex, and medial frontal cortex/anterior cingulate cortex. We have provided evidence that VPA use could result in GM volume reductions in the frontal cortex and cerebellum. Our findings should be acknowledged as a potential confounding factor in morphometric MRI studies that include subjects taking VPA.

Lamotrigine vs levetiracetam in female patients of childbearing age with juvenile absence epilepsy: A Bayesian reanalysis.

OBJECTIVE: Women of childbearing age with juvenile absence epilepsy (JAE) face treatment challenges due to limited access to safe and effective anti-seizure medications (ASMs). In a previous study we compared the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) in women with idiopathic generalized epilepsy (IGE), highlighting a superiority of LEV in juvenile myoclonic epilepsy. In this study, we specifically reanalyzed, through a Bayesian approach and by expanding the previously published cohort, the comparative effectiveness of these ASMs as initial monotherapy in JAE. METHODS: We conducted a multicenter, retrospective, comparative effectiveness study on women of childbearing age diagnosed with JAE and prescribed LEV or LTG as the initial ASM. Inverse probability treatment weighting (IPTW) Bayesian Cox proportional hazard models were employed to evaluate treatment failure (TF) due to ineffectiveness and ASM retention. The patients' center of provenance and year of prescription were considered as random effect factors. Posterior probabilities and relative log-risk distribution were computed, and the distribution of posterior draws was analyzed to assess the evidence supporting LTG superiority over LEV. RESULTS: Of 123 patients, those treated with LTG (n = 67) demonstrated lower TF and higher ASM retention than those treated with LEV (n = 56), with the IPTW-weighted Bayesian Cox proportional hazards model showing a 99.2% posterior probability of LTG being superior on TF and a 99.5% probability on ASM retention. Additional analyses on ≥50% and ≥75% seizure reduction through IPTW-weighted Bayesian logistic regression largely confirmed these findings, whereas the two ASMs did not show evident differences in terms of seizure freedom. The two ASMs showed comparable safety profiles, with only a minority of patients discontinuing treatment due to side effects. SIGNIFICANCE: Bayesian reanalysis supports LTG as first-line monotherapy for JAE in women of childbearing age, emphasizing the importance of individualized treatment strategies in women with IGE. This study underscores the value of Bayesian methods in refining clinical research and treatment decisions.

Predictors of drug-resistant epilepsy in childhood epilepsy syndromes: A subgroup analysis from a prospective cohort study.

OBJECTIVE: Previous studies assessing factors associated with drug-resistant epilepsy (DRE) were constrained by their amalgamation of all epilepsy syndromes in their analyses and the absence of uniform criteria for defining DRE. Our objective was to identify predictors of DRE among the four primary childhood epilepsy syndrome groups within a cohort of children with new onset seizures, using the International League Against Epilepsy (ILAE) definition of DRE and the recent classification of epilepsies. METHODS: This is a prospective study of 676 children with new onset seizures initiated on antiseizure medication. Patients were monitored for the occurrence of DRE according to the ILAE criteria and were categorized into one of four epilepsy groups: self-limited focal epilepsies (SeLFEs), genetic generalized epilepsies (GGEs), developmental epileptic encephalopathies (DEEs), and focal epilepsies. Cox regression analysis was performed to identify predictors of DRE within each epilepsy group. RESULTS: Overall, 29.3% of children were classified as having DRE, with the highest incidence observed among children diagnosed with DEEs (77.7%), followed by focal epilepsies (31.5%). Across the entire cohort, predictors of DRE included the presence of an epileptogenic lesion, a higher pretreatment number of seizures, experiencing multiple seizure types, presence and severity of intellectual and developmental delay, myoclonus, and younger age at epilepsy onset. Within the GGEs, only a younger age at seizure onset and experiencing multiple seizure types predicted DRE. Among focal epilepsies, predictors of DRE included the presence of an epileptogenic lesion, experiencing multiple seizure types, and having a greater number of pretreatment seizures. Within the DEEs, predictors of DRE were the occurrence of tonic seizures. Predictors of DRE within SeLFEs could not be identified. SIGNIFICANCE: This study indicates that different epilepsy syndromes are associated with distinct predictors of drug resistance. Anticipation of drug resistance within various groups is feasible using accessible clinical variables throughout the disease course.

Comprehensive phenotypes of patients with SYNGAP1-related disorder reveals high rates of epilepsy and autism.

OBJECTIVE: To delineate the comprehensive phenotypic spectrum of SYNGAP1-related disorder in a large patient cohort aggregated through a digital registry. METHODS: We obtained de-identified patient data from an online registry. Data were extracted from uploaded medical records. We reclassified all SYNGAP1 variants using American College of Medical Genetics criteria and included patients with pathogenic/likely pathogenic (P/LP) single nucleotide variants or microdeletions incorporating SYNGAP1. We analyzed neurodevelopmental phenotypes, including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), behavioral disorders, and gait dysfunction for all patients with respect to variant type and location within the SynGAP1 protein. RESULTS: We identified 147 patients (50% male, median age 8 years) with P/LP SYNGAP1 variants from 151 individuals with data available through the database. One hundred nine were truncating variants and 22 were missense. All patients were diagnosed with global developmental delay (GDD) and/or ID, and 123 patients (84%) were diagnosed with epilepsy. Of those with epilepsy, 73% of patients had GDD diagnosed before epilepsy was diagnosed. Other prominent features included autistic traits (n = 100, 68%), behavioral problems (n = 100, 68%), sleep problems (n = 90, 61%), anxiety (n = 35, 24%), ataxia or abnormal gait (n = 69, 47%), sensory problems (n = 32, 22%), and feeding difficulties (n = 69, 47%). Behavioral problems were more likely in those patients diagnosed with anxiety (odds ratio [OR] 3.6, p = .014) and sleep problems (OR 2.41, p = .015) but not necessarily those with autistic traits. Patients with variants in exons 1-4 were more likely to have the ability to speak in phrases vs those with variants in exons 5-19, and epilepsy occurred less frequently in patients with variants in the SH3 binding motif. SIGNIFICANCE: We demonstrate that the data obtained from a digital registry recapitulate earlier but smaller studies of SYNGAP1-related disorder and add additional genotype-phenotype relationships, validating the use of the digital registry. Access to data through digital registries broadens the possibilities for efficient data collection in rare diseases.

Interictal head-turning sign in patients with idiopathic generalized epilepsy during initial medical interview: A matched multicenter study.

BACKGROUND: Utilizing interictal manifestations for the diagnosis of epilepsy is challenging. We investigated whether an interictal "head-turning sign," typically indicative of dependence on others observed in Alzheimer's disease, can act as a behavioral marker of idiopathic generalized epilepsy. METHODS: This multicenter study examined 579 consecutive patients, with a mean age of 36.8 ± 20.4 years, who did not have an intellectual disability and had their first outpatient visit for epilepsy evaluation between 2019 and 2023. Patients were categorized into IGE, non-IGE epilepsy, non-epileptic, and psychiatric conditions based on their ultimate diagnostic outcomes to identify difference of the occurrence of the head-turning sign among them. Additionally, we extracted data from patients under the age of 40, specifically adolescents and young adults (AYA). Then we used propensity score matching to confirm the reproducibility of observed differences and to identify associated factors within the AYA age group. RESULTS: The occurrence of the head-turning sign was significantly more prevalent in the IGE group compared to the non-IGE group (20.4 % vs. 2.2 %; P<0.0001) and non-epileptic group (20.4 % vs. 8.3 %; P=0.033). Following the matching, the head-turning sign was still evident in IGE relative to non-IGE patients (14.6 % vs. 4.5; P=0.004), yielding a 94 % specificity for IGE. IGE diagnosis (P<0.0001), myoclonic seizure (P<0.0001), being visited by a parent (P=0.017), and comorbidity with headache (P=0.021) were significantly associated with the head-turning sign. Multivariate analysis revealed that IGE (odds ratio: OR=2.80, P=0.028), attending with a parent (OR=2.92, P=0.029), and comorbidity with headache (OR=4.06, P=0.016) were independently associated with the head-turning sign. CONCLUSIONS: We confirmed a substantial association between the interictal "head-turning sign" and IGE. This unique sign may reflect a tendency towards dependence on others in IGE, and may serve as a promising diagnostic auxiliary marker for identifying IGE in the AYA age group.

Antiseizure medication withdrawal in adult patients with idiopathic generalized epilepsy: Performance of two seizure recurrence prediction models.

PURPOSE: Currently, there is a limited availability of tools to predict seizure recurrence after discontinuation of antiseizure medications (ASMs). This study aimed to establish the seizure recurrence rate following ASM cessation in adult patients with idiopathic generalized epilepsy (IGE) and to assess the predictive performance of the Lamberink and the Stevelink prediction models using real-world data. METHODS: Retrospective longitudinal study in IGE patients who underwent ASM withdrawal in a tertiary epilepsy clinic since June 2011, with the latest follow up in January 2024. The minimum follow-up period was 12 months. Clinical and demographic variables were collected, and the seizure recurrence prediction models proposed by Lamberink and Stevelink were applied and evaluated. RESULTS: Forty-seven patients (mean age 33.15 ± 8 [20-55] years; 72.35 % women) were included. During the follow-up period, seizures recurred in 25 patients (53.2 %). Median time to recurrence was 8 months [IQR 3-13.5 months], and 17 patients (68 %) relapsed within the first year. None of the relapsing patients developed drug-resistant epilepsy. The only significant risk factor associated with recurrence was a seizure-free period of less than 2 years before discontinuing medication (91.7 % vs 40 %, p =.005). The Stevelink prediction model at both 2 (p =.015) and 5 years (p =.020) achieved statistical significance, with an AUC of 0.72 (95 % CI 0.56-0.88), while the Lamberink model showed inadequate prognostic capability. CONCLUSION: In our real-world cohort, a seizure-free period of at least 2 years was the only factor significantly associated with epilepsy remission after ASM withdrawal. Larger studies are needed to accurately predict seizure recurrence in IGE patients.

Theory of mind in epilepsy.

Epilepsy is characterized by recurrent, chronic, and unprovoked seizures. Epilepsy has a significant negative impact on a patient's quality of life even if seizures are well controlled. In addition to the distress caused by seizures, patients with epilepsy (PwE) may suffer from cognitive impairment with serious social consequences such as poor interpersonal relationships, loss of employment, and reduced social networks. Pathological changes and functional connectivity abnormalities observed in PwE can disrupt the neural network responsible for the theory of mind. Theory of mind is the ability to attribute mental states to other people (intentions, beliefs, and emotions). It is a complex aspect of social cognition and includes cognitive and affective constructs. In recent years, numerous studies have assessed the relationship between social cognition, including the theory of mind, in PwE, and suggested impairment in this domain. Interventions targeting the theory of mind can be potentially helpful in improving the quality of life of PwE.

Effects of valproic acid and levetiracetam monotherapy on balance functions in patients with generalized epilepsy.

BACKGROUND: It is reported that antiepileptic drugs have an effect on balance functions. The aim of the study was to evaluate and compare the effects of valproic acid and levetiracetam monotherapy on balance functions in patients with generalized epilepsy using objective test methods. METHODS: The study included 43 generalized epilepsy patients aged 18-60 years, including 20 patients receiving valproic acid monotherapy, 23 patients receiving levetiracetam monotherapy, and 25 healthy individuals as controls, in the Neurology Clinic of a university hospital in eastern Turkey. The demographic data form was filled out and the Video Head Impulse Test and Vestibular Evoked Myogenic Potentials test were performed. RESULTS: Statistically significant differences were obtained between the groups in lateral, posterior, and anterior semicircular canal gains and RALP and LARP asymmetry values in the V-HIT test (p < 0.05). Statistically significant differences were obtained between the groups in P1, N1 latency and asymmetry values in the C-VEMP test and in N1, P1 latency, amplitude, and asymmetry values in the o-VEMP test (p < 0.05). CONCLUSION: Valproic acid and levetiracetam may affect the vestibulocular and vestibulocolic reflex pathways negatively. In this cohort, valproic acid had more pronounced adverse effects on balance functions as compared to levetiracetam.

Sub-region analysis of DMD gene in cases with idiopathic generalized epilepsy.

Gene sub-region encoded protein domain is the basic unit for protein structure and function. The DMD gene is the largest coding gene in humans, with its phenotype relevant to idiopathic generalized epilepsy. We hypothesized variants clustered in sub-regions of idiopathic generalized epilepsy genes and investigated the relationship between the DMD gene and idiopathic generalized epilepsy. Whole exome sequencing was performed in 106 idiopathic generalized epilepsy individuals. DMD variants were filtered with variant type, allele frequency, in silico prediction, hemizygous or homozygous status in the population, inheritance mode, and domain location. Variants located at the sub-regions were selected by the subRVIS software. The pathogenicity of variants was evaluated by the American College of Medical Genetics and Genomics criteria. Articles on functional studies related to epilepsy for variants clustered protein domains were reviewed. In sub-regions of the DMD gene, two variants were identified in two unrelated cases with juvenile absence epilepsy or juvenile myoclonic epilepsy. The pathogenicity of both variants was uncertain significance. Allele frequency of both variants in probands with idiopathic generalized epilepsy reached statistical significance compared with the population (Fisher's test, p = 2.02 × 10-6, adjusted α = 4.52 × 10-6). The variants clustered in the spectrin domain of dystrophin, which binds to glycoprotein complexes and indirectly affects ion channels contributing to epileptogenesis. Gene sub-region analysis suggests a weak association between the DMD gene and idiopathic generalized epilepsy. Functional analysis of gene sub-region helps infer the pathogenesis of idiopathic generalized epilepsy.

Thalamocortical circuits in generalized epilepsy: Pathophysiologic mechanisms and therapeutic targets.

Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can cause seizures that rapidly generalize and cause altered awareness and unconsciousness. Here, we review the most recent advances in our understanding of how thalamic activity is regulated and discuss the gaps in our understanding of the mechanisms of generalized epilepsy syndromes. Elucidating the role of the thalamus in generalized epilepsy syndromes may lead to new opportunities to better treat pharmaco-resistant generalized epilepsy by thalamic modulation and dietary therapy.