Zinc Finger Protein 711 (ZNF711) is a Krüppel-type zinc finger transcription factor highly expressed in the brain and whose mutations have been associated with neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, and epilepsy. While most pathogenic variants previously described affect the C-terminal DNA-binding domain, we report two siblings carrying a rare hemizygous missense variant in the N-terminal transactivation domain, NM_001330574.2: c.65 T > C (p.Ile22Thr), inherited from their heterozygous unaffected mother. Patient #1 presents with autism spectrum disorder, epilepsy, moderate intellectual disability, and mild facial dysmorphisms, whereas Patient #2 shows milder autism spectrum disorder traits and no clinical seizures, although electroencephalogram abnormalities are present. In silico analyses predict that this variant, affecting a highly conserved residue, may disrupt protein structure and thus impair its proper function. The recurrence of this variant in the two siblings reported here and in those reported in Minerva et al. (2025) sharing overlapping phenotypes strengthens its potential pathogenicity, despite current classification as a variant of uncertain significance.

Objective:Poor documentation of seizures can be a major challenge in epilepsy. Objective seizure counting with mobile devices might improve this challenge and the patient management. We investigate whether ultra long-term subcutaneous EEG improves seizure documentation and disease monitoring in adults and adolescents with developmental and epileptic encephalopathies (DEEs). Methods:Ultra long-term subcutaneous EEG Monitoring In Rare Epilepsies and DEE (EMIRE) is a multi-centre prospective interventional study with an expected duration of 6 months. 33 Adolescents and adult participants will be implanted with 24/7 EEG SubQ and collect 2-channel EEG data up to 6 months. Data will be reviewed by experts on a weekly basis and a summary sent to the treating clinician. Results:(1) safety and tolerability of subcutaneous EEG in this special patient population; (2) seizure detection sensitivity and specificity with respect to patients' seizure-diaries and 'ground truth'; (3) whether and how home monitoring can affect the clinical management of the patients. Conclusions:This project will investigate home and remote patient monitoring systems, offering an accuracy that is unthinkable today. Significance:This trial of home monitoring is intended to be of clinical utility to the patient by allowing objective assessment of therapeutic interventions and their effectiveness.Plain language summary.We present a clinical trial protocol for a prospective cohort study in people with severe epilepsies across Italy. The study aims to assess whether an EEG implant placed under the skin (1) is more accurate than patient-reported seizure diary, (2) is feasible and acceptable to patients and clinicians, (3) affect the clinical management of the patients, (4) reduces the impact of epilepsy.

OBJECTIVE:DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature. METHODS:Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains. RESULTS:DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum. SIGNIFICANCE:We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.

X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date (PCDH19-related DEE, CDKL5-related DEE, MECP2-related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX, DCX, FLNA) and DEEs associated with recently recognized genes (e.g., SLC9A6, SLC35A2, SYN1, ARHGEF9, ATP6AP2, IQSEC2, NEXMIF, PIGA, ALG13, FGF13, GRIA3, SMC1A). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype-phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance.

X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date (PCDH19-related DEE, CDKL5-related DEE, MECP2-related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX, DCX, FLNA) and DEEs associated with recently recognized genes (e.g., SLC9A6, SLC35A2, SYN1, ARHGEF9, ATP6AP2, IQSEC2, NEXMIF, PIGA, ALG13, FGF13, GRIA3, SMC1A). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype–phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance.

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.

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.

NAA20 is the catalytic subunit of the NatB complex, which is responsible for N-terminal acetylation of approximately 20% of the human proteome. Recently, pathogenic biallelic variants in NAA20 were associated with a novel neurodevelopmental disorder in five individuals with limited clinical information. We report two sisters harboring compound heterozygous variant (c.100C>T (p.Gln34Ter) and c.11T>C p.(Leu4Pro)) in the NAA20 gene, identified by exome sequencing. In vitro studies showed that the missense variant p.Leu4Pro resulted in a reduction of NAA20 catalytic activity due to weak coupling with the NatB auxiliary subunit. In addition, unpublished data of the previous families were reported, outlining the core phenotype of the NAA20-related disorder mostly characterized by cognitive impairment, microcephaly, ataxia, brain malformations, dysmorphism and variable occurrence of cardiac defect and epilepsy. Remarkably, our two patients featured epilepsy onset in adolescence suggesting this may be a part of syndrome evolution. Functional studies are needed to better understand the complexity of NAA20 variants pathogenesis as well as of other genes linked to N-terminal acetylation.

On the 27th– 28th of May 2022, the International Workshop on Familial Adult Myoclonus Epilepsy (FAME) was held in Naples, Italy (Figure 1). The event was endorsed by the International League Against Epilepsy and supported by a European Joint Programme on Rare Disease grant. More than sixty international researchers gathered together to discuss this unusual and interesting epileptic disorder. This supplement reports the clinical and experimental characteristics of this condition described over the past 30 years under different acronyms (BAFME: benign adult familial myoclonic epilepsy; ADCME: autosomal dominant cortical myoclonus and epilepsy; FCMTE: familial cortical myoclonic tremor and epilepsy),1 which were presented and discussed during the workshop. For consistency, we will use the acronym “FAME” throughout the supplement. The prevalence is not established yet, as this condition is often underrecognized, but it is estimated to be <1/35 000.2 Its diffusion and disease history across the world have been reviewed by Berkovic et al.3 This condition is transmitted in an autosomal dominant manner and is characterized by the occurrence of cortical myoclonic tremor, overt myoclonus, and rare bilateral tonic– clonic seizures. FAME is considered a neurodegenerative condition, although it is relatively slow in progression, as discussed by Giraldez et al.4 The diagnosis is based on specific neurophysiological testing, namely jerklocked backaveraging, somatosensory evoked potentials, longlatency reflex, and motor evoked potentials, among others. A review of the neurophysiological findings has been discussed by Dubbioso et al.5 Imaging data, including functional magnetic resonance imaging, indicates a cortical origin of the cortical myoclonic tremor and decreased cerebellar activation.6 Interestingly, cerebellar changes indicating changes in Purkinje cells emerged from few neuropathology reports, in patients from isolated pedigrees. These data have been reviewed by Van Rootselaar et al.7 The differential diagnosis may be challenging and should consider some forms of genetic generalized epilepsy and progressive myoclonus epilepsies. This topic is discussed by Baykan et al.8 The genetic cause of FAME has long remained elusive, but recently it has been identified for the four main geographical aggregates and consists of an intronic repeat pentameric expansion occurring in different genes and still causing an overlapping phenotype across the world. Although their protein products have different functions, the underlying pathogenic mechanism is likely the same. These aspects are discussed by Corbett et al.9 and Silveira et al.10 FAME treatment is so far symptomatic and often elusive, as discussed by Coppola et al.11 Elucidating the

Familial adult myoclonus epilepsy (FAME) is a genetic condition characterized by the occurrence of cortical tremor, myoclonus, and epilepsy. To date, there is neither a curative nor a preventive treatment for FAME. Clinical management is essentially symptomatic and based on antiseizure medications (ASMs). The choice of the correct therapeutic option is limited to ASMs that have both an antiseizure and an antimyoclonic effect, such as valproate, levetiracetam, benzodiazepines, and perampanel. However, these medications control seizures well while having a limited effect on myoclonus and cortical tremor. In addition, many ASMs, including sodium channel blockers and gabapentin, are contraindicated in this condition. The ideal therapeutic option would be a precision treatment able to revert the genetic defect underlying it. Nevertheless, this does not seem to be an option that will be available soon.

Status epilepticus (SE) in pregnancy represents a life-threatening medical emergency for both mother and fetus. Pregnancy-related pharmacokinetic modifications and the risks for fetus associated with the use of antiseizure medications (ASMs) and anesthetic drugs complicate SE management. No standardized treatment protocol for SE in pregnancy is available to date.In this review, we provide an overview of the current literature on the management of SE in pregnancy and we propose a multidisciplinary-based protocol approach.Literature data are scarce (mainly anecdotal case reports or small case series). Prompt treatment of SE during pregnancy is paramount and a multidisciplinary team is needed. Benzodiazepines are the drugs of choice for SE in pregnancy. Levetiracetam and phenytoin represent the most suitable second-line agents. Valproic acid should be administered only if other ASMs failed and preferably avoided in the first trimester of pregnancy. For refractory SE, anesthetic drugs are needed, with propofol and midazolam as preferred drugs. Magnesium sulfate is the first-line treatment for SE in eclampsia. Termination of pregnancy, via delivery or abortion, is recommended in case of failure of general anesthetics. Further studies are needed to identify the safest and most effective treatment protocol.

Introduction Status epilepticus (SE) in pregnancy represents a life-threatening medical emergency for both mother and fetus. Pregnancy-related pharmacokinetic modifications and the risks for fetus associated with the use of antiseizure medications (ASMs) and anesthetic drugs complicate SE management. No standardized treatment protocol for SE in pregnancy is available to date. Areas covered In this review, we provide an overview of the current literature on the management of SE in pregnancy and we propose a multidisciplinary-based protocol approach. Expert opinion Literature data are scarce (mainly anecdotal case reports or small case series). Prompt treatment of SE during pregnancy is paramount and a multidisciplinary team is needed. Benzodiazepines are the drugs of choice for SE in pregnancy. Levetiracetam and phenytoin represent the most suitable second-line agents. Valproic acid should be administered only if other ASMs failed and preferably avoided in the first trimester of pregnancy. For refractory SE, anesthetic drugs are needed, with propofol and midazolam as preferred drugs. Magnesium sulfate is the first-line treatment for SE in eclampsia. Termination of pregnancy, via delivery or abortion, is recommended in case of failure of general anesthetics. Further studies are needed to identify the safest and most effective treatment protocol.

Pathogenic variants in KAT6A, encoding a histone acetyltransferase, have been identified as a cause of a developmental disorder with a definite clinical spectrum including intellectual disability, speech delay, dysmorphic facial features, microcephaly, cardiac and gastrointestinal defects. Seizures have been described in a minority of patients without a detailed characterization. In this work we focus on epilepsy in KAT6A syndrome, reporting two affected girls with history of seizures, bearing a KAT6A de novo heterozygous variant, of which one is novel. We describe the different epilepsy phenotypes of these two patients and compare them to the other individuals in literature presenting with epilepsy.

Pathogenic variants in CENPJ have been first identified in consanguineous Pakistani families with Hereditary Primary Microcephaly type 6 (MCPH6). In addition to primary microcephaly, the CENPJ-related phenotypic spectrum lately included also distinctive and peculiar 'bird-like' craniofacial dysmorphisms, intrauterine and/or postnatal growth retardation, and moderate to severe intellectual disability (ID). These features are also part of the clinical spectrum of Seckel syndrome (SCKL) a genetically heterogeneous neurodevelopmental condition caused by mutations in different genes involved in cell cycle progression. Among these, CENPJ is responsible for type 4 Seckel syndrome (SCKL4). The literature reports two individuals affected by SCKL4 suffering from seizures and other two individuals with other brain malformations in addition to microcephaly. However, neither epilepsy nor brain malformations are described in detail and genotype-phenotype information remains limited. We describe the first Caucasian affected with SCKL4 and harboring a novel, homozygous mutation in CENPJ. We detail the clinical and neuroradiological findings including structural focal epilepsy and a severe brain malformation (i.e., hydranencephaly) that was never associated with SCKL4 to date.

Background: Epilepsy has been associated with an increased risk of cardiovascular events. Anti-seizure medication (ASM) may contribute to vascular risk by several mechanisms, including increased homocysteine levels. This study aims to assess the global vascular burden in hyperhomocysteinemic people with epilepsy (PWE) on longterm ASM before and after folic acid supplementation and in subgroups of PWE treated with single enzymeinducing or single non-enzyme inducing ASM. Methods: One hundred and seventy-four hyperhomocysteinemic (HHcy) PWE who met the inclusion criteria were enrolled. Carotid Doppler ultrasonography, FMD and ultrasound assessment of the brachial artery properties at the baseline and after 90 days of folic acid supplementation were performed. The vascular biomarkers MMP-9 and TIMP-1 were also detected. Results: After folic acid supplementation, in HHcy patients homocysteine levels reduced from 26.8 +/- 10.5 to 20.2 +/- 5.3 mu mol/L, carotid Intima-Media-Thickness reduced from 0.83+0.06 mm to 0.79 +/- 0.05 mm, and FMD, distensibility coefficient and beta-stiffness improved (p < 0.05). Moreover, MMP-9 and TIMP-1 reduced after supplementation (p < 0.05). PWE treated with a single enzyme-inducing ASM showed an impairment of vascular parameters compared to patients treated with non-enzyme inducing ASM. Conclusions: The results highlight the importance of assessing homocysteine levels and estimating the cardiovascular risk of PWE, preferring non-enzyme inducing ASM in high cardiovascular-risk patients. An adequate correction of homocysteine levels with folate supplementation should be considered to improve the cardiovascular profile.

Introduction: Progressive myoclonic epilepsies (PMEs) are a heterogenous group of genetic diseases presenting with epilepsy, cognitive impairment, and severe action myoclonus, which can severely affect daily life activities and independent walking ability. Perampanel is a recent commercially available antiseizure medication with high efficacy against generalized seizures. Some reports supported the role of perampanel in ameliorating action myoclonus in PMEs. Here, we aimed to describe a case series and provide a systematic literature review on perampanel effects on PMEs.Methods: We report the perampanel effectiveness on myoclonus, daily life activities, and seizures on an original Italian multicenter case series of 11 individuals with PMEs. Then, using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, we performed a systematic review on perampanel effect on myoclonus and disability in PMEs. We searched PubMed, Scopus, and Google Scholar articles on perampanel and PMEs up to June 2020. No prospective trials were found. We reviewed 11 case series manuscripts reporting 104 cases of different PMEs.Results: Here, we are reporting the effectiveness of perampanel in five individuals affected by Unverricht–Lundborg disease, three by Lafora disease, two by sialidosis, and one by an undetermined PME. Nine out of 11 individuals improved their disability related to the action myoclonus (two with Lafora disease did not). Among the 104 persons with PMEs collected by the systematic review, we found that more than half of the patients receiving perampanel exhibited an amelioration of action myoclonus and, consequently, of their independence in daily life activities. The Unverricht–Lundborg disease seemed to show the best clinical response to perampanel, in comparison with the other more severe PMEs. A significant seizure reduction was achieved by almost all persons with active epilepsy. Only 11% of PME patients dropped out due to inefficacy.Conclusions: Perampanel demonstrated a beneficial effect with regard to action myoclonus, disability, and seizures and was well-tolerated in people with PMEs, independently from their genetic diagnosis. Given the limited scientific evidence, broader prospective trials should be encouraged.

Most families with genetic epilepsy with febrile seizures plus show a mutation in the sodium channel alpha 1 subunit gene, however, but there is much phenotypic heterogeneity and focal epilepsy remains relatively rare. Here, we report a family with electroclinical features indicative of temporal-parietaloccipital carrefour epilepsy with common occurrence of post-ictal migraine. We studied a four-generation family including nine affected subjects by means of EEG and MRI. Genetic testing was performed by targeted re-sequencing (gene panel). In most patients, seizure semiology included cognitive, autonomic, and emotional symptoms, eventually evolving towards sensory visual phenomena. Focal sensory vestibular seizures and changes in body perception were also reported in some cases. Post-ictal migraine was common, occurring in five out of the six (83%) epilepsy patients. A missense mutation (c.1130 G>A; p.R377Q) affecting the S5-S6 segment (pore region) of the sodium channel alpha 1 subunit was identified in all affected and four unaffected subjects. Temporal-parietal-occipital carrefour epilepsy is part of the genetic epilepsy with febrile seizures plus spectrum. The electroclinical features in this family support the involvement of a genetically impaired neural network. High prevalence of post-ictal migraine suggests the role of posterior brain areas in the clinical expression of this gene defect.