Search Results (175)

Background: Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by treatment-resistant seizures and significant morbidity. Despite multiple approved anti-seizure medications (ASMs), optimal seizure control remains elusive. This has led to ongoing interest in newer ASMs, including those not specifically approved for LGS. This review evaluates the emerging evidence on the use of these agents in LGS management. Methods: We conducted a comprehensive literature search of PubMed, Web of Science, and Embase to identify studies examining perampanel, brivaracetam, cenobamate, ganaxolone, and stiripentol in LGS populations. Both randomized controlled trials and observational studies were included. Results: Perampanel was studied in approximately 300 patients across one Phase 3 trial and seven observational studies, showing responder rates of 26–69% with particular efficacy for generalized tonic–clonic and myoclonic seizures, though behavioral side effects (irritability, aggression) were dose-related concerns. Brivaracetam demonstrated inconsistent efficacy in 59 patients across six studies (0–61.5% responder rates) but offered better behavioral tolerability than levetiracetam. Cenobamate showed exceptional promise in 223 patients across seven studies with 50–85% responder rates and significant polypharmacy reduction, though requiring careful titration. Ganaxolone demonstrated efficacy in LGS-like CDKL5 deficiency phenotypes with 28.2% drop seizure reduction versus placebo. Stiripentol showed potential benefit for generalized seizures in limited LGS data. Conclusions: Several newer ASMs show therapeutic promise in LGS. Perampanel offers the most extensive evidence base, cenobamate demonstrates exceptional efficacy potential, while brivaracetam provides an alternative for levetiracetam-intolerant patients. Further controlled studies are needed to define optimal treatment algorithms. Full article

Hyperammonaemia in dogs is most frequently associated with hepatic encephalopathy caused by portosystemic shunting. This retrospective multicentre study aimed to investigate the prevalence of hyperammonaemia and hepatic encephalopathy in dogs with recent or ongoing epileptic seizures. Furthermore, we sought to evaluate if transient post-ictal hyperammonaemia as a sequela to seizure activity occurs, as reported in humans and recently in cats. The medical records of all dogs presented between 2014 and 2024 to ten AniCura Veterinary Hospitals in Sweden were retrospectively reviewed to obtain those with recent or ongoing epileptic seizures with concurrent analysis of ammonia. The records of 267 dogs were extracted for further review. Inclusion criteria included information regarding the description and characterisation of the seizures and the analysis of ammonia within 24 h after last reported seizure activity. Additionally, hepatic function tests were required in dogs with elevated ammonia. In total, 58 dogs fulfilled the inclusion criteria, and 10 of those dogs (17%) had hyperammonaemia. Three dogs had documented hepatopathy, and two of them had surgically corrected portosystemic shunts. In seven dogs, no definitive cause of hyperammonaemia could be established. Three of the seven dogs had no evidence of portosystemic shunts, and six had no laboratory evidence supporting acute liver failure. According to the findings in this retrospective study, hyperammonaemia in the absence of evident acute hepatic failure or portosystemic shunting can occur in dogs with epileptic seizures, indicating that other differentials than hepatic encephalopathy should be considered. This study could not confirm the hypothesis of hyperammonaemia being a transient consequence of seizures. Full article

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate channels that play a pivotal role in brain development and the regulation of learning and memory processes. De novo pathogenic variants in four genes encoding NMDA receptor subunits (GRIN1, GRIN2A, GRIN2B, and GRIN2D) have been implicated in a broad spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorders, epilepsy, and movement disorders. Mutations in the GRIN1 and GRIN2B genes, which encode the GluN1 and GluN2B subunits, respectively, are strongly associated with malformations of cortical development, including diffuse dysgyria, bilateral polymicrogyria, hippocampal dysplasia, corpus callosum hypoplasia, and other findings such as ventricular enlargement and basal ganglia abnormalities. Conversely, GRIN2A mutations are associated with heterogeneous and less specific neuroimaging patterns. We reviewed the existing literature on the neuroradiological features associated with GRIN gene mutations, also providing pictorial representations from our patient cohort. The analysis revealed a more consistent association of malformations of cortical development with GRIN1 and GRIN2B variants, likely reflecting the critical role of these genes in neuronal migration and proper development of cortical structures. In comparison, GRIN2A mutations are associated with milder brain abnormalities. An integrated assessment of neuroimaging patterns and GRIN gene variants provides valuable insights for differential diagnosis and supports targeted genetic screening in patients presenting with epileptic encephalopathy, global developmental delay, and autism spectrum disorders. Full article

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, which is a developmental and epileptic encephalopathy occurring in 1 in every 40,000 to 60,000 live births, was the subject of this computational investigation. This study provided a comprehensive list of missense variants (156) seen in the human population within the CDKL5 protein. Furthermore, the list of CDKL5 binding partners was updated to include four new entries. Computational modeling resulted in 3D structure models of twenty-four CDKL5-target protein complexes. The CDKL5 stability changes upon the above-mentioned missense mutations that were modeled, and it was shown that the corresponding folding free energy changes (ΔΔG_folding) caused by pathogenic variants are much larger than the ΔΔG_folding caused by benign variants. The same observation was made for the binding free energy change (ΔΔG_binding). This resulted in a protocol that allowed for the reclassification of missense variants with unknown or conflicting significance into pathogenic or benign. It was demonstrated that such reclassification is more reliable than using leading tools for pathogenicity predictions, since the latter failed to correctly predict known pathogenic/benign variants. Furthermore, the study demonstrated that pathogenicity is linked with the disturbance of thermodynamics quantities such as ΔΔG_folding and ΔΔG_binding, paving the way for development of therapeutic solutions. Full article

The relationship between sleep and epilepsy involves complex interactions between thalamocortical circuits, circadian mechanisms, and sleep architecture that fundamentally influence seizure susceptibility and cognitive outcomes. Epileptic activity disrupts essential sleep oscillations, particularly sleep spindles generated by thalamic circuits. Thalamic epileptic spikes actively compete with physiological sleep spindles, impairing memory consolidation and contributing to cognitive dysfunction in epileptic encephalopathy. This disruption explains why patients with epilepsy often experience learning difficulties despite adequate seizure control. Sleep stages show differential seizure susceptibility. REM sleep provides robust protection through enhanced GABAergic inhibition and motor neuron suppression, while non-REM sleep, particularly slow-wave sleep, increases seizure risk. These observations reveal fundamental mechanisms of seizure control within normal brain physiology. Circadian clock genes (BMAL1, CLOCK, PER, CRY) play crucial roles in seizure modulation. Dysregulation of these molecular timekeepers creates permissive conditions for seizure generation while being simultaneously disrupted by epileptic activity, establishing a bidirectional relationship. These mechanistic insights are driving chronobiological therapeutic approaches, including precisely timed antiseizure medications, sleep optimization strategies, and orexin/hypocretin system interventions. This understanding enables a paradigm shift from simple seizure suppression toward targeted restoration of physiological brain rhythms, promising transformative epilepsy management through sleep-informed precision medicine. Full article

Background: CRELD1 encodes a cell adhesion molecule initially implicated in atrioventricular septal defects (AVSDs). More recently, biallelic CRELD1 variants have been associated with syndromic and non-syndromic neurodevelopmental disorders (NDDs). Methods: We describe three individuals from unrelated families with compound heterozygous CRELD1 variants, identified through exome sequencing. Clinical and genetic data were reviewed to delineate shared and divergent features. Results: All three patients presented with developmental delay, intellectual disability, seizures, hypotonia, and dysmorphic facial features. Patient 1 and patient 2 carried a recurrent variant combination previously reported in five individuals, while Patient 3 harboured the recurrent frameshift p.(Gln320Argfs*25) variant in trans with a novel missense variant. The milder clinical course of patient 3 highlights phenotypic heterogeneity. Notably, none of the patients had cardiac anomalies or immunological abnormalities, further expanding the clinical spectrum associated with CRELD1. Conclusion: Our findings reinforce genotype–phenotype correlations and provide additional evidence that biallelic CRELD1 variants underlie a distinct autosomal recessive neurodevelopmental disorder, broadening both the phenotypic and genetic spectrum of this emerging syndrome. Full article

Giant somatosensory evoked potentials (gSEPs) are abnormally high-amplitude cortical responses to peripheral nerve stimulation, traditionally regarded as electrophysiological hallmarks of progressive myoclonic epilepsies (PMEs). However, accumulating evidence shows their presence in a broader range of non-epileptic conditions, including focal lesions, metabolic encephalopathies, neurodegenerative diseases, and even functional disorders. This review offers a comprehensive analysis of the physiological mechanisms, diagnostic criteria, and clinical significance of gSEPs, integrating data from both classical and emerging neurophysiological techniques. gSEPs are mainly produced in the primary somatosensory cortex through mechanisms involving cortical disinhibition, impaired GABAergic transmission, and altered thalamocortical connectivity. In epileptic syndromes such as Unverricht–Lundborg disease and other PMEs, gSEPs reflect cortical hyperexcitability and are closely linked to cortical myoclonus. Conversely, in non-epileptic contexts, they may indicate transient or chronic cortical dysfunction. The diagnostic utility of gSEPs ranges from differential diagnosis of myoclonus to monitoring disease. However, heterogeneity in amplitude definitions and recording protocols hinders the standardization of these measurements. This may result in the identification of the right threshold to differentiate conditions associated with simple increased versus giant SEP, the latter of which may help identify truly epileptic conditions from other disorders simply associated with increased SEP amplitude. Full article

Pyridoxine-dependent epilepsy (PDE) represents a group of rare developmental and epileptic encephalopathies. The most common PDE is caused by biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1; OMIM #266100), which encodes α-aminoadipate semialdehyde (α-AASA) dehydrogenase, a key enzyme in lysine catabolism. Affected individuals present with seizures unresponsive to conventional anticonvulsant medications but responsive to high-dose of pyridoxine (vitamin B6). Adjunctive lysine restriction and arginine supplementation have also shown potential in improving neurodevelopmental outcomes. Given the significant benefit of early intervention, PDE-ALDH7A1 is a strong candidate for newborn screening (NBS). However, traditional biomarkers are biochemically unstable at room temperature (α-AASA and piperideine-6-carboxylate) or lack sufficient specificity (pipecolate), limiting their utility for biomarker-based NBS. The recent identification of two novel and stable biomarkers, 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylate (2-OPP) and 6-oxo-pipecolate (oxo-PIP), offers renewed potential for biochemical NBS. We evaluated the feasibility of incorporating 2-OPP, oxo-PIP, and pipecolate into routine butylated FIA-MS/MS workflows used for biochemical NBS. A total of 9402 dried blood spots (DBS), including nine confirmed PDE-ALDH7A1 patients and 9393 anonymized controls were analyzed using a single multiplex assay. 2-OPP emerged as the most sensitive biomarker, identifying all PDE-ALDH7A1 patients with 100% sensitivity and a positive predictive value (PPV) of 18.4% using a threshold above the 99.5th percentile. Combining elevated 2-OPP (above the 99.5th percentile) with either pipecolate or oxo-PIP (above the 85.0th percentile) as secondary marker detected within the same multiplex FIA-MS/MS assay further improved the PPVs to 60% and 45%, respectively, while maintaining compatibility with butanol-derivatized method. Notably, increasing the 2-OPP threshold above the 99.89th percentile, in combination with either pipecolate or oxo-PIP above the 85.0th percentile resulted in both 100% sensitivity and 100% PPV. This study supports the strong potential of 2-OPP-based neonatal screening for PDE-ALDH7A1 within existing NBS infrastructures. The ability to multiplex 2-OPP, pipecolate and oxo-PIP within a single assay offers a robust, practical, high-throughput and cost-effective approach. These results support the inclusion of PDE-ALDH7A1 in existing biochemical NBS panels. Further prospective studies in larger cohorts are needed to refine cutoffs and confirm clinical performance. Full article

The sodium–citrate cotransporter (NaCT) plays a crucial role in citrate transport during amelogenesis. Mutations in the SLC13A5 gene, which encodes the NaCT, cause early infantile epileptic encephalopathy 25 and amelogenesis imperfecta. We analyzed developing pig molars and determined that the citrate concentrations in secretory- and maturation-stage enamel are both 5.3 µmol/g, with about 95% of the citrate being bound to mineral. To better understand how citrate might enter developing enamel, we developed Slc13a5^Flag reporter mice that express NaCT with a C-terminal Flag-tag (DYKDDDDK) that can be specifically and accurately recognized by commercially available anti-Flag antibodies. The 24-base Flag coding sequence was located immediately upstream of the natural translation termination codon (TAG) and was validated by Sanger sequencing. The general development, physical activities, and reproductive outcomes of this mouse strain were comparable to those of the C57BL/6 mice. No differences were detected between the Slc13a5^Flag and wild-type mice. Tooth development was extensively characterized using dissection microscopy, bSEM, light microscopy, in situ hybridization, and immunohistochemistry. Tooth formation was not altered in any detectable way by the introduction of the Flag. The Slc13a5^Flag citrate transporter was observed on all outer membranes of secretory ameloblasts (distal, lateral, and proximal), with the strongest signal on the Tomes process, and was detectable in all but the distal membrane of maturation-stage ameloblasts. The papillary layer also showed positive immunostaining for Flag. The outer membrane of odontoblasts stained stronger than ameloblasts, except for the odontoblastic processes, which did not immunostain. As NaCT is thought to only facilitate citrate entry into the cell, we performed in situ hybridization that showed Ank is not expressed by secretory- or maturation-stage ameloblasts, ruling out that ANK can transport citrate into enamel. In conclusion, we developed Slc13a5^Flag reporter mice that provide specific and sensitive localization of a fully functional NaCT-Flag protein. The localization of the Slc13a5^Flag citrate transporter throughout the ameloblast membrane suggests that either citrate enters enamel by a paracellular route or NaCT can transport citrate bidirectionally (into or out of ameloblasts) depending upon local conditions. Full article

Zebrafish is a well-recognized model for studying human genetic disorders. Recently, we proposed the homozygous cdkl5^sa21938 mutant zebrafish as a model of CDKL5 deficiency disorder (CDD), a developmental epileptic encephalopathy with diverse symptoms. This study aimed to explore Cdkl5-associated molecular mechanisms in zebrafish and assess their similarity to those in mammals. We conducted RNA sequencing on whole cdkl5^−/− zebrafish and wild-type siblings at 5 and 35 days post-fertilization (dpf) to compare their gene expression profiles. Most significant differentially expressed genes (DEGs) were related to muscle, neuronal, and visual systems which are affected in CDD. Gene Ontology analysis revealed downregulated DEGs enriched in muscle development, extracellular matrix, and actin cytoskeleton functions at both stages, while upregulated DEGs were enriched in eye development functions at 35 dpf. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed enrichment of downregulated DEGs in focal adhesion and extracellular matrix (ECM)-receptor interaction pathways at both stages. Neuronal development DEGs were mainly downregulated at both stages, while synaptic signaling DEGs were upregulated at 35 dpf. Crossing cdkl5^−/− mutants with the Hb9:GFP transgenic line showed fewer motor neuron cells with shorter axons compared to the wild type, which may explain the impaired motor phenotype observed in zebrafish and CDD patients. Moreover, we identified key downregulated DEGs related to cartilage development at both stages and bone development at 35 dpf, potentially explaining the skeletal defects seen in zebrafish and CDD individuals. In conclusion, Cdkl5 loss in zebrafish leads to dysregulation of genes involved in CDKL5-associated functions in mammals, providing new insights into its less studied functions and phenotypes. Full article

Background: Uniparental disomy (UPD) refers to the condition in which both chromosomes (or part of chromosome) of a pair are inherited from the same parent. There are two types of UPD: uniparental isodisomy (both chromosomes inherited from one parent are identical copies) and uniparental heterodisomy (two different chromosomes are inherited from one parent). UPD presents two primary developmental risks: recessive trait inheritance or an imprinting disorder. These risks may coexist, leading to an ultra-rare comorbidity. Managing the comorbidities associated with rare diseases presents unique clinical challenges. Results: The existence of such phenomena is evidenced by our case report of a boy who was ultimately diagnosed with two rare diseases: Prader–Willi syndrome (PWS), due to the maternal uniparental disomy of chromosome 15 (UPD), and autosomal recessive Lodder–Merla type 1 syndrome, linked to a novel pathogenic variant in the G protein subunit β 5 (GNB5) gene, as detailed in this paper. Conclusions: An unusual or severe phenotype in a patient diagnosed with PWS should invariably prompt the consideration of a comorbid genetic disease attributable to genes located in the PWS critical region of chromosome 15q, or elsewhere on chromosome 15. In cases of epileptic encephalopathy with cardiac arrhythmia, prompt consultation with a cardiologist and comprehensive genetic testing are essential to reduce the risks associated with untreated arrhythmia and ensure the provision of appropriate and safe anti-epileptic therapy. The presented case provides further support for the hypothesis that uniparental disomy may serve as an underlying cause of Lodder–Merla syndrome. This underscores the significance of comprehensive genetic testing, encompassing parental testing and familial cascade testing (in selected cases where there is consanguinity, or the likelihood of close common ancestral background between partners) to establish the recurrence risk. Full article

Background: Developmental epileptic encephalopathies (DEEs) are often associated with variably severe cognitive and motor impairment and frequent refractory epilepsy, with many children not achieving adequate seizure control via standard antiepileptic medications. The classic ketogenic diet (KD) has proven effective in reducing seizure frequency and/or severity in a category of DEEs and in certain refractory epilepsies of infancy. However, its multifaceted mechanisms, e.g., epigenetic modulation, anti-inflammatory and antioxidative effects, and direct neuronal excitability changes, are balanced by a high burden and low long-term adherence. Medium-chain triglycerides (MCTs), particularly decanoic acid (C10:0), have gained attention in recent years for their potential direct inhibitory action on AMPA receptors, contributing to seizure reduction. Methods: A systematic review was conducted, including articles from January 2000 to January 2025, to explore the potential role of medium-chain triglyceride (MCT) add-on to classic KD and as MCT supplementation in free diets in the management of pediatric drug-resistant epilepsy (DRE). Results: Selected studies show how the action of MCTs, and decanoic acid in particular, is via negative modulation of AMPA receptors, with a positive impact on epileptic seizures. Conclusions: This review discusses the complexities of implementing and sustaining KD in children and presents recent pre-clinical and clinical evidence, including trials where MCTs (often enriched in decanoic acid) serve as an add-on therapy in both ketogenic and free/unrestricted diets. The summarized findings reinforce the therapeutic potential of MCTs, highlighting both the beneficial seizure outcomes and the hurdles that remain to be addressed through future research. Full article

CSMD1 is a gene involved in various biological processes and is highly expressed in the central nervous system, where it plays a key role in complement activity, brain circuit development, and cognitive function. It has been implicated as a susceptibility gene for schizophrenia and a causative factor in developmental epileptic encephalopathy, neurodevelopmental disorders, and intellectual disability. However, no MIM phenotype number has been assigned to CSMD1 for a specific disorder. Here, we report an individual presenting with moderate intellectual disability, anxiety disorder, obsessive–compulsive personality traits, and facial dysmorphisms. Trio-based whole-exome sequencing (WES) identified two heterozygous CSMD1 variants, c.8095A>G and c.5315T>C, both classified as variants of uncertain significance (VUS) according to ACMG criteria. Computational analysis using the DOMINO tool supported an autosomal recessive inheritance model for CSMD1. This study contributes to the growing evidence linking CSMD1 to neurodevelopmental phenotypes, highlighting the need for further investigations to clarify its pathogenic role. Full article

Mirror movements (MMs) are related to structural alterations of the pyramidal tract or transcallosal pathways, as well as functional impairment of the interhemispheric inhibitory effects on motor planning skills, leading to the inability to perform limb movements independently. On the other hand, white matter bundles that connect distant cortical regions are thought to be the anatomical substrate of seizure propagation in epileptic subjects, and the spread of excitation through intracortical and transcallosal pathways is a well-recognized pathophysiological abnormality in epilepsies. To investigate this possible association, we searched the MEDLINE and Embase electronic databases, and only original articles were considered eligible for inclusion; we found thirteen patients from eleven articles, all of them case study reports. Therefore, epilepsy and MM co-morbidity has rarely been reported in the same subjects, even if changes in interhemispheric modulation are shared by both conditions. However, the study of this co-morbidity may help in elucidating the exact pathophysiological mechanisms of MMs and to better understand the pathological interhemispheric connections in epilepsy patients. Full article

Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification. Full article