ATP1A3-related syndromes: our case-series unveiling a dynamic, fever-triggered and overlapping array of neurological phenotypes G. Errichiello, P. Bernardo, F. Acquaviva, S. Troisi, M. Rosa, G. Bargiacchi, F. Esposito, A. Rubino, M. Carotenuto, A. Varone, L. D’Acunto Neurological Sciences, 2026 Introduction ATP1A3-related neurological disorders show a broad spectrum of manifestations, usually with autosomal dominant transmission. Classical phenotypes include alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), and syndrome characterized by cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS). Additional rarer forms include childhood-onset-schizophrenia (COS), encephalopathy with MRI abnormalities without hemiplegia (D-DEMØ), fever-induced paroxysmal weakness and encephalopathy (FIPWE), and relapsing encephalopathy with cerebellar ataxia (RECA). These conditions often overlap, sharing core symptoms due to dysfunction of the Na⁺/K⁺-ATPase α3 subunit. Some mutations result in a thermolabile enzyme, which impairs its function under stress, leading to weakness’ episodes, encephalopathy and ataxia. Case series We report a patients’ cohort with ATP1A3 mutations followed at Santobono-Pausilipon Children’s Hospital in Naples. The first family includes three siblings with RECA (p.Arg756Cys). The second cluster comprises a mother and son with FIPWE (p.Arg756His). We also describe one case of AHC (p.Asp801Asn) and one of CAPOS (p.Arg756Cys). All patients showed marked susceptibility to infection and fever. Discussion and conclusion Our case series confirms the complex clinical scenarios in ATP1A3-related disorders, with symptoms overlapping and possible interfamilial variability, contributing to the diagnostic challenge posed by a rare genetic disorder, already observed in individuals with ATP1A3 gene mutations. The ongoing effort to characterize the clinical phenotype and identify “core” symptoms is necessary to expand our knowledge of the genotype-phenotype correlation, which is currently unclear. More importantly, our series highlights the molecular fragility of mutant ATP1A3, particularly its sensitivity to fever. Proactive prevention of fever and time management may be crucial to reducing the risk of neurological deterioration in affected individuals.
EVALUATION OF FIRST SEIZURE IN CHILDHOOD: NEUROIMAGING OVERTURES Paolo F.M. Guarneri Euromediterranean Biomedical Journal, 2026 While mucosal-based melanomas of the head and neck region are uncommon lesions, when they do arise, they usually exhibit a highly aggressive clinical course. Experience with these tumors is, limited; as such, well worked out treatment protocols for the treat- ment of such lesions are in short supply. It appears as though mucosal melanomas (MuMs) develop more frequently in the nasal cavity and paranasal sinus region, and less often in the oral cavity. The incidence of nodal metastasis seems to be significantly lower in si- nonasal MuMs than it is in MuMs of the oral cavity; this observation may be useful in evalu- ating whether a neck dissection is necessary to determine the location of the primary MuM.
Clinical and genetic landscape of epilepsies with absence seizures and single-gene etiology Simona Balestrini, Ilaria Galli, Maria Luisa Ricci, Elena Parrini, Davide Mei, Mario Mastrangelo, Francesco Pisani, Corinna Filippi, Lucio Giordano, Elisabetta Cesaroni, Carla Marini, Emanuele Cerulli Irelli, Carlo di Bonaventura, Marica Rubino, Antonietta Coppola, Jacopo Proietti, Tommaso Lo Barco, Francesca Darra, Laura Licchetta, Francesca Bisulli, Marco Perulli, Domenica Battaglia, Angela De Dominicis, Marina Trivisano, Nicola Specchio, Roberta Solazzi, Davide Caputo, Laura Canafoglia,, Renzo Guerrini Epilepsia, 2026 Objective To characterize the clinical, electroencephalographic, and genetic features of epilepsies featuring absence seizures within monogenic etiology, highlighting the diagnostic, treatment and prognostic implications. Methods We conducted a retrospective, multicenter study including patients with monogenic epilepsies and electroencephalography (EEG)–documented absence seizures. We analyzed clinical data, electroclinical findings, neurodevelopmental outcomes, and treatment responses through standardized questionnaires and medical records. We classified genetic variants according to American College of Medical Genetics and Genomics (ACMG) guidelines and performed univariate and multivariate analyses to identify predictors of developmental outcomes. Results We included 160 patients (111 female; median age at last follow‐up: 13 years) with absence seizures and confirmed pathogenic or likely pathogenic monogenic variants. The most frequently implicated genes were SLC2A1, SLC6A1, SYNGAP1 , CHD2, and SCN1A . Four genes— HESX1, NCKAP1, SON, STARD9 —had not been previously associated with absence seizures. In 35% of patients, absence seizures were the only seizure type and in 67% were the initial manifestation. Atypical features included irregular EEG discharges (56%) eyelid myoclonia (42%), and automatisms (33%). Early‐onset (before age 3) seizures occurred in 58% and was significantly associated with atypical features ( p < .03). Using existing International League Against Epilepsy (ILAE) epilepsy syndrome classification, 60% of patients could not be classified. Developmental delay occurred in 54%, intellectual disability in 65%, and other neurodevelopmental comorbidities in 49%. Predictors of poor developmental outcomes included early developmental delay, drug‐resistant epilepsy, and early absence onset. We found no difference in the prevalence of drug resistance across the various genetic etiologies. The most effective medications for absence seizures included valproate, ethosuximide, benzodiazepines, and lamotrigine. Disease‐specific therapies (e.g., ketogenic diet in SLC2A1 , stiripentol/fenfluramine in SCN1A) were effective in select cases. Significance Absence seizures are a common manifestation of different monogenic epilepsies, often associated with early onset, atypical clinical and/or EEG features, developmental delay or drug resistance. Classification models should incorporate genetic data alongside electroclinical features, especially as next‐generation sequencing is increasingly used.
Non-Convulsive Status Epilepticus and Mild Neurodevelopmental Phenotype in a Female with a Novel p.Thr657Ala Variant in the GRIA3 Gene Alfonso Rubino, Giorgia Bruno, Gabriella Errichiello, Fabio Acquaviva, Daniele De Brasi, Alfonsina Tirozzi, Pia Santangelo, Carmela Russo, Antonio Varone, Geremia Zito Marinosci, Pia Bernardo Children, 2025 Background: The GRIA3 gene encodes the GluA3 subunit of AMPA-type glutamate receptors, which are crucial for excitatory neurotransmission in the central nervous system. Pathogenic GRIA3 variants cause X-linked neurodevelopmental disorders of varying severity, including developmental delay, behavioral abnormalities, and epilepsy. Case Summary: Here, we present the case of a seven-year-old female patient presenting with developmental delay, spastic gait, and non-convulsive status epilepticus (NCSE), who was found to carry a novel de novo GRIA3 missense variant (c.1969A > G; p.Thr657Ala). The EEG revealed high-amplitude diffuse rhythmic theta/delta activity consistent with NCSE. A brain MRI showed transient cortical and thalamic T2-FLAIR hyperintensities, likely postictal. Metabolic investigations were unremarkable. Following intensive treatment with levetiracetam and midazolam, the patient gradually recovered to her baseline neurological status. Genetic Finding: Whole-exome sequencing (WES) identified a novel de novo variant in GRIA3, c.1969A > G; p.Thr657Ala, involving the replacement of threonine with alanine at position 657 within the coding region. Significance: This case expands the clinical and molecular spectrum of GRIA3-related disorders, demonstrating that females with de novo variants may experience severe epilepsy. This is the first reported case of NCSE in a female patient with a GRIA3 variant.
Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children Anna Fetta, Francesco Toni, Ilaria Pettenuzzo, Emilia Ricci, Alessandro Rocca, Caterina Gambi, Luca Soliani, Veronica Di Pisa, Silvia Martini, Giacomo Sperti, Valeria Cagnazzo, Patrizia Accorsi, Emanuele Bartolini, Domenica Battaglia, Pia Bernardo, Maria Paola Canevini, Anna Rita Ferrari, Lucio Giordano, Chiara Locatelli, Margherita Mancardi, Alessandro Orsini, Tommaso Pippucci, Dario Pruna, Anna Rosati, Agnese Suppiej, Sara Tagliani, Alessandro Vaisfeld, Aglaia Vignoli, Kosuke Izumi, Ian Krantz, Duccio Maria Cordelli Orphanet Journal of Rare Diseases, 2024 Background Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population. Results Thirty-one individuals were enrolled (17 females/14 males; age range 0.1–17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14. Conclusions Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.
Low-grade epilepsy-associated tumors: Epilepsy outcome and antiseizure medication discontinuation after lesionectomies as first-line surgical approach in pediatric population Pia Bernardo, Maria Rosaria Scala, Alfonso Rubino, Pietro Spennato, Giuseppe Mirone, Carmela Russo, Pia Santangelo, Eugenio Covelli, Giampina Grimaldi, Vittoria D'Onofrio, Giuseppe Cinalli Epileptic Disorders, 2024 ObjectiveThis study aimed to evaluate epilepsy outcome and antiseizure medication (ASM) discontinuation after lesionectomies as first surgical approach in pediatric population diagnosed with low‐grade epilepsy‐associated neuroepithelial tumors (LEATs).MethodsWe conducted a retrospective study. Thirty‐six consecutive patients with histological diagnoses of LEATs who underwent surgery between 2018 and 2021 at our institution were included. The clinical and surgical data were retrospectively analyzed.ResultsThirty (83.3%) of 36 patients are free of disabling seizures (Engel class I) and 19 (63,4%) of them are classified as Engel Ia. In 17 (47.2%) patients, ASM could be discontinued. The mean age at surgery was 8.6 years (±4.04) and the mean age at onset of epilepsy was 7.2 years (±3.8), whereas the mean duration of epilepsy in months at the time of surgery was 21.3 months (±23.7). The epileptogenic tumor was in the temporal lobe in 20 (55.5%) patients. Because of seizure persistence, a second or a third surgery was necessary for six patients (16.7%) and four of them had residual lesions (three in temporal and one in extratemporal site). No perioperative complications were recorded, including acute seizures, with a median hospitalization time of 7 days. Shorter epilepsy duration at time of surgery as long as a single ASM was significantly correlated with an Engel class I outcome (p‐value = .01 and p‐value = .016, respectively). Focal seizure semeiology was associated with an increased probability of antiseizure medication discontinuation (p‐value = .042).SignificanceOur findings confirm that shorter epilepsy disease duration, monotherapy before surgery, and seizure semeiology are determinant factors for a positive seizure outcome and medication discontinuation, also with less invasive surgical approaches such as lesionectomies. However, considering the intrinsic multifactorial epileptogenic nature of LEATs, a tailored surgical approach should be considered to optimize clinical and seizure outcome, especially for lesions located in the temporal lobe.
Expanding the Mutational Landscape and Clinical Phenotype of CHD2-Related Encephalopathy Angela Clara-Hwang, Stefani Stefani, Tracy Lau, Marcello Scala, Busra Aynekin, Pia Bernardo, Francesca Madia, Sophia Bakhtadze, Rauan Kaiyrzhanov, Reza Maroofian, Federico Zara, Varunvenkat M. Srinivasan, Vykuntaraju Gowda, Ulviyya Guliyeva, Alexandra Montavont, Anne-Lise Poulat, Ayten Güleç, Colette Berger, Dorothee M. Ville, Julitta de Bellescize, Sara Cabet, Antje Wonneberger, Alexander Schulz, Agusti Rodriguez-Palmero, Nicolas Chatron, Gaetan Lesca, Hüseyin Per, Himanshu Goel, Janis Brown, Tanja Frey, Katharina Steindl, Anita Rauch, Mariasavina Severino, Henry Houlden, Paola Nicolaides, Pasquale Striano, Stephanie Efthymiou Neurology Genetics, 2024 Objectives To present a case series of novel CHD2 variants in patients presenting with genetic epileptic and developmental encephalopathy. Background CHD2 gene encodes an ATP-dependent enzyme, chromodomain helicase DNA-binding protein 2, involved in chromatin remodeling. Pathogenic variants in CHD2 are linked to early-onset conditions such as developmental and epileptic encephalopathy, drug-resistant epilepsies, and neurodevelopmental disorders. Approximately 225 diagnosed patients from 28 countries exhibit various allelic variants in CHD2, including small intragenic deletions/insertions and missense, nonsense, and splice site variants. Results We present the molecular and clinical characteristics of 17 unreported individuals from 17 families with novel pathogenic or likely pathogenic variants in CHD2. All individuals presented with severe global developmental delay, childhood-onset myoclonic epilepsy, and additional neuropsychiatric features, such as behavioral including autism, ADHD, and hyperactivity. Additional findings include abnormal reflexes, hypotonia and hypertonia, motor impairment, gastrointestinal problems, and kyphoscoliosis. Neuroimaging features included hippocampal signal alterations (4/10), with additional volume loss in 2 cases, inferior vermis hypoplasia (7/10), mild cerebellar atrophy (4/10), and cerebral atrophy (1/10). Discussion Our study broadens the geographic scope of CHD2-related phenotypes, providing valuable insights into the prevalence and clinical characteristics of this genetic disorder in previously underrepresented populations.
X-Linked Epilepsies: A Narrative Review Pia Bernardo, Claudia Cuccurullo, Marica Rubino, Gabriella De Vita, Gaetano Terrone, Leonilda Bilo, Antonietta Coppola International Journal of Molecular Sciences, 2024 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.
Profile of Trofinetide in the Treatment of Rett Syndrome: Design, Development and Potential Place in Therapy Laura Camillo, Marco Pozzi, Pia Bernardo, Simone Pisano, Maria Nobile Drug Design Development and Therapy, 2024 Trofinetide is a first-in-class pharmacological treatment proposed for patients with Rett Syndrome. It is a long half-life derivative of glycine-proline-glutamate, the tripeptide normally excided from Insulin-like Growth Factor 1 upon degradation. Due to containing glutamate and glycine in its structure, trofinetide is thought to act through NMDA receptor modulation, thus providing a normalization of neuronal activity and survival. Trofinetide was tested in a series of short and long-term trials, showing good efficacy at improving scores on the Clinical Global Impression-Improvement scale and Rett Syndrome Behavior Questionnaire, with specific effect only on some subscales, ie General Mood subscale and Repetitive Face Movement subscale. No effects were documented on other subscales or on epilepsy, heart and bone –related symptoms. The main adverse effects of trofinetide, severe enough to determine discontinuation, include diarrhea, vomiting, and consequent weight loss. These may be scarcely avoidable, given the need to assume a very large amount of trofinetide per day. Other inherent limitations of use possibly regard the limited duration of drug supplies, as one bottle may last three days only, depending on weight, and the relatively high cost per bottle. Trofinetide has no direct competitors: single symptoms of the Rett Syndrome, for instance, seizures or aggressive behaviors, are currently treated with drugs that have been developed for patients without the Rett Syndrome. This leads to suboptimal efficacy and increased risk of adverse effects. The place in therapy of trofinetide is yet to be determined, based on the results of clinical trials, on its practical usability, and on the windows of opportunity for intervention. Moreover, trofinetide may be curative if given early enough during brain development, or merely symptomatic if given to young adults, and no data exist on this aspect. The place in therapy of trofinetide will require reassessment after competing treatments enter the market.
