Familial Epilepsy Research Articles

Neuronal cytoplasmic inclusion bodies in the brain of Lagotto Romagnolo dogs: A qualitative and quantitative histologic evaluation.

Four neurologic diseases affect dogs of the Lagotto Romagnolo (LR) breed, namely benign familial juvenile epilepsy (BFJE), vacuolar storage disease, and 2 forms of cerebellar cortical degeneration. Intraneuronal inclusion bodies in cerebellar Purkinje cells were first described in the BFJE phenotype. Upon further characterization of these diseases, similar inclusions were also noted in the brain of LRs used as controls. This study investigated the clinical, histologic, and electron microscopic findings in 23 LRs to determine the nature of their neuronal inclusions and whether the presence, distribution, or number of inclusions is associated with neurologic signs. Electron microscopy of the inclusions revealed a cytoplasmic aggregate without a limiting membrane. The inclusions appeared proteinaceous on histochemical staining and positive on phosphotungstic-acid-hematoxylin (PTAH) stain for proteins rich in basic amino acids. Markers of commonly known proteinopathies of humans (ubiquitin, p62, LC3, α-synuclein, and β-amyloid) were not detected in the inclusions when assessed by immunohistochemistry. The overall presence of inclusion bodies was not significantly associated with the dog's neurologic status. The results show an association between inclusions in the cerebral cortex and an absence of clinical neurologic disease in LRs. There was no significant difference in the quantitative inclusion body burden when compared in LRs with or without neurologic signs. Although PTAH-positive proteinaceous neuronal inclusions are a common finding in LRs regardless of neurologic signs, these inclusions may be a protective response when present in the cerebral cortex.

Clinical efficacy of low-dose Perampanel correlates with neurophysiological changes in familial adult myoclonus epilepsy 2.

Familial adult myoclonus epilepsy (FAME) management relies on antiseizure medications (ASMs), which inadequately address myoclonus and cortical tremor. This study evaluates Perampanel (PER), an AMPA-receptor antagonist, for treating FAME symptoms. Fifteen FAME2 patients participated in an observational prospective study. They received up to 6 mg daily of PER and underwent Unified-Myoclonus-Rating-Scale (UMRS) before and after treatment. Neurophysiological evaluations, including somatosensory evoked potentials (SEPs) and transcranial magnetic stimulation (TMS), assessed PER's impact on cortical glutamatergic excitatory and GABAergic inhibitory circuits. PER treatment significantly reduced UMRS total scores (p = 0.001) and action-myoclonus subscores (p = 0.002), irrespective of disease duration, age at onset, or testing time (p >0.05). Patients with more severe baseline myoclonus demonstrated significant improvements. Neurophysiological assessments revealed a PER-induced decrease in sensorimotor hyperexcitability, characterized by diminished N33 amplitudes, attenuated glutamatergic facilitation, and enhanced GABAergic inhibition in the motor cortex. In conclusion, low-dose PER is well tolerated and effective in alleviating myoclonus in FAME2 patients, supported by its modulatory effects on glutamatergic and GABAergic neuronal circuits. Plain Language Summary: This study investigated the effects of low-dose perampanel in individuals with Familial Adult Myoclonus Epilepsy2 (FAME2), a hereditary condition characterized by epilepsy and tremors. Perampanel, an antiepileptic drug, blocks AMPA receptors in the brain, reducing excessive neural activity that causes seizures and abnormal movements. The results showed significant symptom improvement, which correlated with changes in brain activity as measured by neurophysiological tests. This study suggests that perampanel helps regulate abnormal brain signals and may help managing FAME2 symptoms.

Investigating the effect of polygenic background on epilepsy phenotype in ‘monogenic’ families

Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies. We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models. 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR=1.39, 95% CI 1.08, 1.80, padj=0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of+0.19 higher than relatives with a milder phenotype (padj=0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype-phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (padj=0.0010), the effect was not significant for SCN1B p.Cys121Trp. We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with 'monogenic' epilepsies. In GEFS+families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients. National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

Exome Sequencing of Consanguineous Pashtun Families With Familial Epilepsy Reveals Causative and Candidate Variants in TSEN54, MOCS2, and OPHN1.

Next-generation sequencing is advancing in low- and middle-income countries, but accessibility remains limited. In Pakistan, many members of the Pashtun population practice familial marriage and maintain distinct socio-cultural traditions, isolating them from other ethnic groups. As a result, they may harbor genetic variants that could unveil new gene-disease associations. To investigate the genetic basis of epilepsy in the Pashtun community we recently established a collaboration between Bannu University and the University of Tuebingen. Here we report our first results of exome sequencing of four families with presumed monogenetic epilepsy and Mendelian inheritance pattern. In Family #201, we identified distinct disease-causing variants. One had a homozygous pathogenic missense variant in TSEN54 (c.919G > T, p.(Ala307Ser)), linked to Pontocerebellar Hypoplasia Type 2A. The second individual had a homozygous class IV missense variant in MOCS2 (c.226G > A, p.(Gly76Arg)) which is associated with Molybdenum cofactor deficiency. In family EP02, one affected individual carried a heterozygous class III variant in OPHN1 (c.1490G > A, p.(Arg497Gln)), related to syndromic X-linked intellectual disability with epilepsy. Our small study demonstrates the promise of next-generation sequencing in genetic epilepsies among the Pashtun population. Diagnostic next-generation sequencing should be established in Pakistan as soon as possible, and if not feasible, genetic research projects may pioneer this path.

Clinical and genetic analysis of a Chinese pedigree affected with Familial focal epilepsy with variable foci due to variant of NPRL3 gene

To explore the clinical manifestations and genetic etiology of a Chinese pedigree affected with Familial focal epilepsy with variable foci (FFEVF). A FFEVF pedigree presented at the Department of Medical Genetics of Linyi Maternal and Child Health Care Hospital on March 14, 2023 was selected as the study subject. The proband was subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing of the proband and other affected members and bioinformatic analysis. This study was approved by the Linyi Maternal and Child Health Care Hospital (Ethics No. QTL-YXLL-2023048). WES revealed that the proband has harbored a heterozygous c.1642C>T (p.Arg548Cys) missense variant in exon 15 of the NPRL3 gene. Sanger sequencing confirmed that the variant was inherited from the proband's father, and multiple members of the pedigree had also harbored the same variant. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as variant of unknown significance (PM2_supporting + PP3). The clinical phenotype of FFEVF patients caused by variants of NPRL3 gene is extensive, and the patients may present with neurological abnormality of autism spectrum disorder in addition to seizures.

Causal associations between gut microbiota, circulating inflammatory proteins, and epilepsy: a multivariable Mendelian randomization study.

Previous studies have suggested that gut microbiota (GM) may be involved in the pathogenesis of epilepsy through the microbiota-gut-brain axis (MGBA). However, the causal relationship between GM and different epilepsy subtypes and whether circulating inflammatory proteins act as mediators to participate in epileptogenesis through the MGBA remain unclear. Therefore, it is necessary to identify specific GM associated with epilepsy and its subtypes and explore their underlying inflammatory mechanisms for risk prediction, personalized treatment, and prognostic monitoring of epilepsy. We hypothesized the existence of a pathway GM-inflammatory proteins-epilepsy. We found genetic variants strongly associated with GM, circulating inflammatory proteins, epilepsy and its subtypes, including generalized and partial seizures, from large-scale genome-wide association studies (GWAS) summary data and used Multivariate Mendelian Randomization to explore the causal relationship between the three and whether circulating inflammatory proteins play a mediating role in the pathway from GM to epilepsy, with inverse variance weighted (IVW) method as the primary statistical method, supplemented by four methods: MR-Egger, weighted median estimator (WME), Weighted mode and Simple mode. 16 positive and three negative causal associations were found between the genetic liability of GM and epilepsy and its subtypes. There were nine positive and nine negative causal associations between inflammatory proteins and epilepsy and its subtypes. Furthermore, we found that C-X-C motif chemokine 11 (CXCL11) levels mediated the causal association between Genus Family XIII AD3011 group and epilepsy. Our study highlights the possible causal role of specific GM and specific inflammatory proteins in the development of epilepsy and suggests that circulating inflammatory proteins may mediate epileptogenesis through the MGBA.

The Spectrum of Self-Limited Infantile Epilepsy Syndromes

AbstractInfantile epilepsy syndromes' nomenclature has changed over time. The International League Against Epilepsy (ILAE) revised its 2021 classification and definition of epilepsy syndromes in neonates and infants, replacing the term “benign” with “self-limited,” and now identifies them as “self-limited infantile epilepsy” (SeLIE). SeLIE is characterized by seizures that begin during infancy and resolve spontaneously with normal developmental progress. The recognition of infantile seizures with favorable outcomes dates back more than 60 years, as noted by Fukuyama in Japan. Thirty years later, Watanabe et al reported benign focal seizures in infancy, with the majority of cases being nonfamilial. These seizures' self-limited nature during infancy has since been acknowledged in various countries, spanning diverse ethnic populations beyond Japan. Infants who undergo such seizures are now recognized as having self-limited nonfamilial infantile epilepsy (SeLNFIE). Initially, Vigevano et al detailed the familial variant in five infants, coining the term “benign familial infantile seizures” to characterize this condition, now known as self-limited familial infantile epilepsy (SeLFIE). SeLNFIE and SeLFIE may present similarly with the exception of a positive family history. After the initial description and classification of these syndromes (familial and nonfamilial) in the ILAE's 1989 Classification of Epilepsies and Epileptic Syndromes, several less frequently encountered related syndromes have been recognized. These conditions comprise a spectrum including SeLFIE with choreoathetosis and paroxysmal dyskinesia, now termed infantile convulsions with paroxysmal choreoathetosis syndrome (ICCA); self-limited focal epilepsy in infancy with midline spikes and waves during sleep (SeLIMSE); self-limited infantile seizures with mild gastroenteritis (SeLISwG); SeLFIE associated with familial hemiplegic migraine (FHM); and self-limited familial neonatal-infantile epilepsy (SeLFNIE). This review aims to document the prevalence of these SeLIEs, elucidate their unique characteristics, and underscore their self-limited nature.

Danish population based study of familial epilepsy and childhood cancer.

Results from studies investigating the association between maternal or child epilepsy, use of anticonvulsants in pregnancy, and childhood cancer are inconsistent and at times contradictory. Linking Danish national databases, we obtained epilepsy and childhood cancer diagnoses, and anticonvulsant use data. We estimated adjusted odds ratios of all or specific childhood cancers in relation to maternal or child epilepsy and anticonvulsant therapies using conditional logistic regression. Maternal epilepsy was positively associated with all childhood cancers in offspring, specifically, with acute lymphoblastic leukemia (Odds Ratio (OR) = 1.68, 95% Confidence Interval (CI) = 1.16, 2.43) and Wilms tumor (OR = 2.13, 95% CI = 0.97, 4.68). When considering maternal ever (lifetime) ingestion of anticonvulsants, a positive association was found with all cancers (OR = 1.14, 95% CI = 1.00, 1.30), and central nervous system tumors (CNS) (OR = 1.36, 95% CI = 1.04, 1.76) as well as neuroblastoma (OR = 1.76, 95% CI = 1.06, 2.90) among offspring. Maternal anticonvulsant use before or during the index pregnancy was related to CNS tumors in offspring (OR = 1.99, 95% CI = 0.99, 4.00).

Clinical and genetic analysis of 23 Chinese children with epilepsy associated with KCNQ2 gene mutations.

To summarize the clinical features and genetic mutation characteristics of Chinese children with KCNQ2-related epilepsy. A cohort of children with genetically caused epilepsy was evaluated at Linyi People's Hospital from January 2017 to December 2023. After next-generation sequencing and pathogenicity analysis, we summarized the medical records and genetic testing data of the children who had KCNQ2 gene mutations. We identified 23 KCNQ2 gene mutations. 73.9% (n = 17) of the mutation sites were located in S5-S6 segments and the C-terminal region. In addition to the common phenotypes, 2 new phenotypes were identified: infantile convulsion with paroxysmal choreoathetosis (ICCA) and febrile seizure plus (FS+). Of all the cases with abnormal video-electro-encephalography, three cases with self-limited familial infantile epilepsy (SeLNE) exhibited a small number of multifocal discharges. Of the patients who have taken a particular antiepileptic drug, the statistics on the number of patients who have responded to the drug are as follows: oxcarbazepine (8/9, 88.9%), levetiracetam (5/7, 71.4%), phenobarbital (9/16, 56.3%), and topiramate (2/5, 40.0%). However, the efficacy of phenobarbital varied widely in treating SeLNE and KCNQ2-DEE. At the final follow-up, 1 case with SeLNE had a transient developmental regression and 7 cases with KCNQ2-DEE had mild to severe developmental backwardness. Although clinically rare, we report 10 new KCNQ2 mutations and two new phenotypes: ICCA and FS+. This further expands genetic and phenotypic spectrum of KCNQ2-related epilepsy. The gene mutation sites are mostly located in S5-S6 segments and the C-terminal region, and the former is usually associated with KCNQ2-DEE. Sodium channel blockers (including oxcarbazepine and topiramate) and levetiracetam should be prioritized over phenobarbital for KCNQ2-DEE. Some cases with KCNQ2-related epilepsy may have transient developmental regression during periods of frequent seizures. Early treatment and early seizure control may be beneficial for willing outcomes in children with KCNQ2-DEE. This article reports 23 cases of children with KCNQ2-related epilepsy, including 10 new mutation sites and 2 new phenotypes. It further expands the genetic and phenotypic spectrum of KCNQ2-related epilepsy. In addition, the article summarizes the gene mutation characteristics and clinical manifestations of children with KCNQ2-related epilepsy, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of such patients.

Familial mesial temporal lobe epilepsy phenotype is associated with novel LGI1 variants: A report of two families

ObjectiveTo expand the clinical phenotype and mutation spectrum of familial mesial temporal lobe epilepsy (FMTLE) and provide a new perspective for exploring the pathological mechanisms of epilepsy caused by leucine-rich glioma inactivated 1 (LGI1) variants. MethodsWe reported clinical data from two families with FMTLE and screened patients for variants in the LGI1 gene using Whole-exome sequencing and Sanger sequencing. The clinical features of FMTLE were analysed. The pathogenicity of the causative loci was assessed according to the American College of Medical Genetics and Genomics guidelines, and potential pathogenic mechanisms were predicted through multiple bioinformatics and molecular dynamics software. ResultsWe identified two novel LGI1 truncating variants within two large families with FMTLE: LGI1 (c.1174C>T, p.Q392X) and LGI1 (c.703C>T, p.Q235X). Compared to previous reports, we found that focal to bilateral tonic-clonic seizures are a common type of seizure in FMTLE. The clinical phenotypes of patients with FMTLE caused by LGI1 variants were relatively mild, and all patients responded well to valproic acid. Bioinformatics analyses and molecular dynamics simulations showed that protein structure and interactions were considerably weakened or damaged as a result of both variants. ConclusionThis study presents the first report identifying LGI1 as a potential novel pathogenic gene within FMTLE families, thereby broadening the mutation spectrum associated with FMTLE. The findings of this study offer novel insights and avenues for understanding the intricate molecular mechanisms underlying LGI1 variants and their correlations with patient phenotypes. This study proposes the possibility of familial focal epilepsy syndromes overlapping.

ADGRL1 variants: From developmental and epileptic encephalopathy to genetic epilepsy with febrile seizures plus.

To expand the phenotypic spectrum of ADGRL1 and explore the correlation between epilepsy and the ADGRL1 genotype. We performed whole-exome sequencing in a cohort of 115 families (including 195 males and 150 females) with familial febrile seizure or epilepsy with unexplained aetiology. The damaging effects of variants was predicted using protein modelling and multiple in silico tools. All reported patients with ADGRL1 pathogenic variants were analysed. One new ADGRL1 variant (p.Pro753Leu) was identified in one family with genetic epilepsy with febrile seizures. Further analysis of 12 ADGRL1 variants in 16 patients revealed that six patients had epilepsy. Epilepsy types ranged from early-onset epileptic encephalopathy to genetic epilepsy with febrile seizures plus (GEFS+). All four variants associated with epilepsy were located in the non-helix or sheet region of ADGRL1. Three of the four epilepsy-associated variants were missense variants. Thus, all three variants located in the G-protein-coupled receptor autoproteolytic-inducing domain exhibited epilepsy. We found one new missense variant of ADGRL1 in one family with GEFS+. ADGRL1 may be a potential candidate or susceptibility gene for epilepsy. ADGRL1-associated epilepsy ranged from benign GEFS+ to severe epileptic encephalopathy; the genotypes and variant locations may help explain the phenotypic heterogeneity of patients with the ADGRL1 variant.

Novel KCNQ2 missense variant expands the genotype spectrum of DEE7.

KCNQ is a voltage-gated K + channel that controls neuronal excitability and is mutated in epilepsy and autism spectrum disorder (ASD). We focus on the KV7.2 voltage-gated potassium channel gene (KCNQ2), which is known for its association with developmental delay and various seizures (including self-limited benign familial neonatal epilepsy and epileptic encephalopathy). But the pathogenicity of many variants remains unproven, potentially leading to misinterpretation of their functional consequences. In this study, we studied a patient who visited Nanhua Hospital. Targeted next-generation sequencing and Sanger sequencing were used to identify the pathogenic variants. Meanwhile, computational models, including hydrogen bonding and docking analyses, suggest that variants cause functional impairment. In addition, functional validation was performed in the drosophila to further evaluate the missense variant in the KCNQ2 gene as the cause of this patient. A new missense variant in the KCNQ2 gene was identified: NM_172107.4:c.1007C > A(p.ALa336Glu), which resulted in the change from alanine to glutamate at amino acid position 336 in the KCNQ2 gene. After computational modeling, including hydrogen bond analysis and docking analysis, it is indicated that the variants cause functional impairment. Furthermore, RNAi-mediated KCNQ knockout in flies led to the onset of epileptic behavior, lifespan and climbing capacity were affected, expression of the normal human KCNQ2 rescues the in flies RNAi-mediated KCNQ knockout behavioral abnormalities. Our findings expands the genetic profile of KCNQ2 and enhances the genotype - phenotype link.

Redefined giant somatosensory evoked potentials: Evoked epileptic complexes of excitatory and inhibitory components

ObjectiveGiant somatosensory evoked potentials (SEPs) are observed in patients with cortical myoclonus. Short-latency components (SLC), are regarded as evoked epileptic activities or paroxysmal depolarization shifts (PDSs). This study aimed to reveal the electrophysiological significance of the middle-latency component (MLC) P50 of the SEPs. MethodsTwenty-two patients with cortical myoclonus having giant SEPs (patient group) and 15 healthy controls were included in this study. Waveform changes in SEPs before and after perampanel (PER) treatment were evaluated in the patient group. The wide range, time–frequency properties underlying the waveforms were compared between the groups. ResultsAfter PER treatment, SLC was prolonged and positively correlated with PER concentration, whereas MLC showed no correlation with PER concentration. Time–frequency analysis showed a power increase (156 Hz in all patients, 624 Hz in benign adult familial myoclonus epilepsy patients) underlying SLC and a power decrease (156 Hz, 624 Hz) underlying MLC in the patient group. ConclusionsThe high-frequency power increase in SLCs and decrease in MLCs clearly reflected PDS and subsequent hyperpolarization, respectively. This relationship was similar to that of interictal epileptiform discharges, suggesting that giant SEPs evoke epileptic complexes of excitatory and inhibitory components. SignificanceMLCs of giant SEPs reflected inhibitory components.

Missense variants in ANO4 cause sporadic encephalopathic or familial epilepsy with evidence for a dominant-negative effect

Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca2+-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca2+-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease.

Familial aggregation of seizure outcomes in four familial epilepsy cohorts.

To assess the possible effects of genetics on seizure outcome by estimating the familial aggregation of three outcome measures: seizure remission, history of ≥4 tonic-clonic seizures, and seizure control for individuals taking antiseizure medication. We analyzed families containing multiple persons with epilepsy in four previously collected retrospective cohorts. Seizure remission was defined as being 5 and 10 years seizure-free at last observation. Total number of tonic-clonic seizures was dichotomized at <4 and ≥4 seizures. Seizure control in patients taking antiseizure medication was defined as no seizures for 1, 2, and 3 years. We used Bayesian generalized linear mixed-effects model (GLMM) to estimate the intraclass correlation coefficient (ICC) of the family-specific random effect, controlling for epilepsy type, age at epilepsy onset, and age at last data collection as fixed effects. We analyzed each cohort separately and performed meta-analysis using GLMMs. The combined cohorts included 3644 individuals with epilepsy from 1463 families. A history of ≥4 tonic-clonic seizures showed strong familial aggregation in three separate cohorts and meta-analysis (ICC .28, 95% confidence interval [CI] .21-.35, Bayes factor 8 × 1016). Meta-analyses did not reveal significant familial aggregation of seizure remission (ICC .08, 95% CI .01-.17, Bayes factor 1.46) or seizure control for individuals taking antiseizure medication (ICC .13, 95% CI 0-.35, Bayes factor 0.94), with heterogeneity among cohorts. A history of ≥4 tonic-clonic seizures aggregated strongly in families, suggesting a genetic influence, whereas seizure remission and seizure control for individuals taking antiseizure medications did not aggregate consistently in families. Different seizure outcomes may have different underlying biology and risk factors. These findings should inform the future molecular genetic studies of seizure outcomes.

A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.

Familial epilepsy with auditory features (FEAF), previously known as autosomal-dominant lateral temporal lobe epilepsy (ADLTE) is a genetically heterogeneous syndrome, clinically characterized by focal seizures with prominent auditory symptoms. It is inherited with autosomal-dominant pattern with reduced penetrance (about 70%). Sporadic epilepsy with auditory features cases are more frequent and clinically indistinguishable from familial cases. One causal gene, MICAL-1, encodes MICAL-1, an intracellular multi-domain enzyme that is an important regulator of filamentous actin (F-actin) structures. Pathogenic variants in MICAL-1 account for approximately 7% of FEAF families. Here, we describe a de novo MICAL-1 pathogenic variant, p.Arg915Cys, in a sporadic case, an affected 21-year-old Italian man with no family history of epilepsy. Genetic testing was performed in the patient and his parents, using a next-generation sequencing panel. In cell-based assay, this variant significantly increased MICAL-1 oxidoreductase activity, which likely resulted in dysregulation of F-actin organization. This finding provides further support for a gain-of-function effect underlying MICAL-1-mediated epilepsy pathogenesis, as previously seen with other pathogenic variants. Furthermore, the case study provides evidence that de novo MICAL-1 pathogenic variants can occur in sporadic cases with epilepsy with auditory feature (EAF). PLAIN LANGUAGE SUMMARY: In this study, we report a new MICAL-1 pathogenic variant in a patient without family history for epilepsy, not inherited from his parents. MICAL-1 is a protein with enzymatic activity that reorganizes the structure of the cell. We proved the pathological effect of this variant by testing its enzymatic activity and found an increase of this activity. This result suggests that non-familial cases should be tested to find novel pathogenic variants in this gene.

Identification of a de novo CACNA1B variant and a start-loss ADRA2B variant in paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) represents the most prevalent form of paroxysmal dyskinesia, characterized by recurrent and transient attacks of involuntary movements triggered by a sudden voluntary action. In this study, whole-exome sequencing was conducted on a cohort of Chinese patients to identify causal mutations. In one young female case, a de novo CACNA1B variant (NM_000718.3:exon3:c.479C > T:p.S160F) was identified as the causative lesion. This finding may broaden the phenotypic spectrum of CACNA1B mutations and provide a prospective cause of primary PKD. Additionally, a novel start-loss variant (NM_000682.7:c.3G > A) within ADRA2B further denied its association with benign adult familial myoclonic epilepsy, and a KCNQ2 E515D variant that was reported as a genetic susceptibility factor for seizures had no damaging effect in this family. In sum, this study established a correlation between CACNA1B and primary PKD, and found valid evidence that further negates the pathogenic role of ADRA2B in benign adult familial myoclonic epilepsy.

Gene-gene interaction network analysis indicates CNTN2 is a candidate gene for idiopathic generalized epilepsy.

Twin and family studies have established the genetic contribution to idiopathic generalized epilepsy (IGE). The genetic architecture of IGE is generally complex and heterogeneous, and the majority of the genetic burden in IGE remains unsolved. We hypothesize that gene-gene interactions contribute to the complex inheritance of IGE. CNTN2 (OMIM* 615,400) variants have been identified in cases with familial adult myoclonic epilepsy and other epilepsies. To explore the gene-gene interaction network in IGE, we took the CNTN2 gene as an example and investigated its co-occurrent genetic variants in IGE cases. We performed whole-exome sequencing in 114 unrelated IGE cases and 296 healthy controls. Variants were qualified with sequencing quality, minor allele frequency, in silico prediction, genetic phenotype, and recurrent case numbers. The STRING_TOP25 gene interaction network analysis was introduced with the bait gene CNTN2 (denoted as A). The gene-gene interaction pair mode was presumed to be A + c, A + d, A + e, with a leading gene A, or A + B + f, A + B + g, A + B + h, with a double-gene A + B, or other combinations. We compared the number of gene interaction pairs between the case and control groups. We identified three pairs in the case group, CNTN2 + PTPN18, CNTN2 + CNTN1 + ANK2 + ANK3 + SNTG2, and CNTN2 + PTPRZ1, while we did not discover any pairs in the control group. The number of gene interaction pairs in the case group was much more than in the control group (p = 0.021). Taking together the genetic bioinformatics, reported epilepsy cases, and statistical evidence in the study, we supposed CNTN2 as a candidate pathogenic gene for IGE. The gene interaction network analysis might help screen candidate genes for IGE or other complex genetic disorders.

MLe-KCNQ2: An Artificial Intelligence Model for the Prognosis of Missense KCNQ2 Gene Variants.

Despite the increasing availability of genomic data and enhanced data analysis procedures, predicting the severity of associated diseases remains elusive in the absence of clinical descriptors. To address this challenge, we have focused on the KV7.2 voltage-gated potassium channel gene (KCNQ2), known for its link to developmental delays and various epilepsies, including self-limited benign familial neonatal epilepsy and epileptic encephalopathy. Genome-wide tools often exhibit a tendency to overestimate deleterious mutations, frequently overlooking tolerated variants, and lack the capacity to discriminate variant severity. This study introduces a novel approach by evaluating multiple machine learning (ML) protocols and descriptors. The combination of genomic information with a novel Variant Frequency Index (VFI) builds a robust foundation for constructing reliable gene-specific ML models. The ensemble model, MLe-KCNQ2, formed through logistic regression, support vector machine, random forest and gradient boosting algorithms, achieves specificity and sensitivity values surpassing 0.95 (AUC-ROC > 0.98). The ensemble MLe-KCNQ2 model also categorizes pathogenic mutations as benign or severe, with an area under the receiver operating characteristic curve (AUC-ROC) above 0.67. This study not only presents a transferable methodology for accurately classifying KCNQ2 missense variants, but also provides valuable insights for clinical counseling and aids in the determination of variant severity. The research context emphasizes the necessity of precise variant classification, especially for genes like KCNQ2, contributing to the broader understanding of gene-specific challenges in the field of genomic research. The MLe-KCNQ2 model stands as a promising tool for enhancing clinical decision making and prognosis in the realm of KCNQ2-related pathologies.

Clinical features and genetic analysis of five children with epilepsies due to variants of SCN8A gene

To explore the clinical and genetic characteristics of five children with epilepsies due to variants of SCN8A gene. Clinical data of five children (four males and one female) admitted to Linyi People's Hospital due to hereditary epilepsies between August 2015 and August 2022 were collected. Whole exome sequencing was carried out for these children, and candidate variants were verified by Sanger sequencing. All of the five children were found to harbor variants of the SCN8A gene. Case 1, who had benign familial infantile epilepsy, inherited a known pathogenic c.4840A>G variant from his father with similar symptoms. Cases 2 to 4 had presented with intermediate epilepsy. Among these, case 2 has harbored a de novo c.3967G>A variant which was rated as pathogenic (PS1+PS2+PM1+PM2_Supporting+PP3) based on the guidelines from the American College of Medical Genetics and Genomics. Cases 3 and 4 were found to respectively harbor a de novo c.415A>T and a c.4697C>T variant, which were both rated as likely pathogenic (PS2+PM1+PM2_Supporting+PP3). Case 5, who had early-onset infantile epileptic encephalopathy transformed into Lennox Gastaut-like syndrome, has harbored a de novo c.5615G>A variant, which was known to be pathogenic. The children had their age of onset ranging from 2 to 14 months, and all had focal seizures and generalized tonic clonic seizures. Four children (cases 1, 2, 3 and 5) had cluster seizures, four (cases 1 to 4) had become seizure-free after single or dual treatment and showed normal growth and development, whilst case 5 was drug-resistant and showed severe developmental retardation. The five children had new features such as cluster seizures, occasional benign seizures in adulthood, and intermediate epilepsy which are prone to relapse after discontinuation of medication, which may be attributed to the pathogenic variants of the SCN8A gene.