Search Results (90)

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodevelopmental condition characterized by early-onset, intractable epilepsy, motor and cognitive impairment, and autistic-like features. Although constitutive Cdkl5 knockout (KO) models have established the importance of CDKL5 during early brain development, CDKL5’s role in the mature brain remains poorly defined. Here, we employed an inducible, conditional KO model in which Cdkl5 is selectively deleted from forebrain glutamatergic neurons in adult mice to investigate the postdevelopmental functions of CDKL5. Using a total of 48 adult male mice, including Cdkl5^flox/Y(Cre⁺) (n = 30) and Cdkl5^flox/Y(Cre⁻) littermate controls (n = 18), we found that tamoxifen-induced Cdkl5 deletion led to prominent behavioral impairments, including deficits in motor coordination, reduced sociability, and impaired hippocampus-dependent spatial memory, while behavioral features such as hyperactivity and stereotypic jumping, typically present in germline KOs, were absent. Sensory functions, including olfaction and pain perception, were also preserved. At the cellular level, the loss of Cdkl5 resulted in a marked reduction in excitatory synapse density in the cortex and hippocampus, accompanied by increased numbers of immature dendritic spines and decreased mature spines. Neuronal loss in the hippocampal CA1 region and selective microglial activation in the cortex were also observed. These alterations closely resemble those seen in constitutive KO models, underscoring the ongoing requirement for CDKL5 expression in excitatory neurons for maintaining synaptic integrity and neuronal homeostasis in the adult brain. This study underscores the importance of temporally controlled models for investigating the mechanisms underlying CDD pathophysiology in the adult brain. Full article

Epilepsy is a prevalent neurological condition, having a wide range of phenotypic traits, which complicate the diagnosis process. Next-generation sequencing (NGS) techniques have improved the diagnostics for unexplained epilepsies. Our goal was to evaluate the utility and impact of genetic testing in the clinical management of pediatric epilepsies. In addition, we aimed to identify clinical factors that could predict a genetic diagnosis. This was a retrospective study of 140 pediatric patients with epilepsy with or without other neurological conditions that underwent NGS testing (multigene panel, WES = whole exome sequencing and/or WGS = whole genome sequencing). A comparison between genetically diagnosed versus non-diagnosed children was performed based on different clinical features. Univariate and multivariate logistic regression analysis was performed to identify clinical predictors of a positive genetic diagnosis. Most children underwent gene panel testing, while 30 had exome sequencing and 3 had genome sequencing. The overall diagnostic yield of genetic testing was 28.6% (40/140) for more than 28 genes. The most frequently identified genes with causative variants were SCN1A (n = 4), SCN2A (n = 3), STXBP1 (n = 3), MECP2 (n = 2), KCNQ2 (n = 2), PRRT2 (n = 2), and NEXMIF (n = 2). Significant predictors from the logistic regression model were a younger age at seizure onset (p = 0.015), the presence of intellectual disability (p = 0.021), and facial dysmorphism (p = 0.049). A genetic diagnosis led to an impact on the choice or duration of medication in 85% (34/40) of the children, as well as the recommendation for screening of comorbidities or multidisciplinary referrals in 45% (18/40) of children. Epilepsy is a highly heterogeneous disorder, both genetically and phenotypically. Less than one third of patients had a genetic diagnosis identified using panels, exomes, and/or genomes. An early onset and syndromic features (including global developmental delay) were more likely to receive a diagnosis and benefit from optimized disease management. Full article

This article examines the complex relationship between seizures, epilepsy, and multiple sclerosis (MS) in pediatric patients, based on detailed findings from a single-center study. Background: Although multiple sclerosis is primarily recognized as an adult-onset disease, its occurrence in children presents distinctive challenges, especially related to seizure disorders. Methods: We reviewed 120 pediatric MS patients evaluated over 7 years; six of these (5%) experienced seizures (including one case of acute status epilepticus), and five were diagnosed with epilepsy according to the latest International League Against Epilepsy (ILAE) classification. This study aimed to evaluate the occurrence rates and types of seizures while investigating their management strategies in this specific group. Results: Through a detailed case analysis and patient follow-up, we identified key factors contributing to seizure onset and explored implications for treatment and care. In our cohort, children with MS and seizures showed a higher risk for disease progression and greater cumulative disability, evidenced by a significantly higher last Expanded Disability Status Scale (EDSS) score (after a minimum 2-year follow-up) in the seizure group (p < 0.006). The analysis recognized early MS onset and highly active disease types as further risk factors that led to worse health outcomes. Conclusions: Genetic causes of epilepsy in children are common and may interact with MS-related inflammation in the same patient; our observations underscore the need to investigate how these two conditions interact. This work contributes to the broader understanding of epilepsy comorbid with MS among pediatric patients, seeking to facilitate the creation of improved interdisciplinary clinical practices in pediatric neurology. 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

Background/Objectives: Cerebral folate transporter deficiency is characterized by pauses and regression in general development stages, with ataxia, choreoathetoid movements, and myoclonic epilepsy generally resistant to treatment. The aim of this study was to comprehensively evaluate cases followed up in two centres in Türkiye for a diagnosis of folate receptor-α deficiency. Methods: The study included nine cases from six different families. Results: The patients comprised 22.2% males and there was parental consanguinity in 88.9% of cases. The mean age at which complaints were first noticed was 3.7 years, and the age of definitive diagnosis was 10.4 years. The most frequently seen first complaints were febrile convulsions and attention deficit-hyperactivity-learning difficulties. The diagnosis most commonly made before the definitive diagnosis was epilepsy, and the first seizure occurred at a mean of 5.2 years. On cranial imaging, white matter involvement, cerebellar atrophy and cerebral atrophy were determined most often. Definitive diagnosis was established solely through clinical findings and genetic analysis. Three different variants in the FOLR1 gene were determined. Treatment with folinic acid at a dose of 5.2 mg/kg/day of PO was started at the age of 9.8 years on average, and intravenous folinate was started at different doses. Conclusions: This study stands out as one of the largest case series in the literature and identifies a previously unreported novel variant. Our study suggests that FOLR1-related CFD should be considered in cases with febrile convulsions, developmental delay, ataxia, autism spectrum disorder, acquired microcephaly, and MRI findings of white matter involvement and cerebellar atrophy. Due to an asymptomatic early period, CFD diagnosis may be delayed, and treatment after symptom onset may be less effective. Incorporating FOLR1 gene analysis into newborn screening programmes could facilitate early diagnosis and treatment. It is thought that the application of vagus nerve stimulation, in addition to folinic acid and anticonvulsant drug treatment, could be effective in seizure control. Full article

Background: Epilepsy, particularly early-onset and drug-resistant forms, presents a significant challenge in pediatric neurology. Inborn errors of metabolism are increasingly recognized as important contributors to these types of epilepsy. Timely diagnosis and treatment are crucial in preventing irreversible metabolic damage and improving clinical outcomes in CAD deficiency. This condition is a progressive and severe metabolic disorder caused by biallelic deleterious variants in CAD gene, and is characterized by long seizures, psychomotor regression, and dyserythropoietic anemia. Methods: In this paper, we present four new cases of EIEE-50, emphasizing the importance of early, specific therapeutic interventions. Results: Oral uridine 100 mg/kg/day was administrated with improvement of motor and cognitive function as well as immediate seizures control. Conclusions: Our findings underscore the potential for improved outcomes of EIEE-50 trought timely diagnosis and targeted treatment strategies, reinforcing the role of uridine supplementation as a promising therapeutic approach. Full article

Cortical stimulation is the process of delivering brief pulses of electrical current and visualizing the distributed pattern of evoked responses across the brain. Compared to high-frequency stimulation, which has long been used for seizure provocation and functional mapping, low-frequency stimulation (<1–2 Hz) is rarely incorporated into the epilepsy surgery evaluation. Increasingly, researchers have demonstrated that various cortico-cortical evoked potential (CCEP) features, including early and delayed responses, evoked high-frequency oscillations, and derived network metrics, may be useful biomarkers of tissue excitability and abnormal connectivity. Emerging evidence also highlights a potential role of CCEPs in guiding neuromodulatory therapies like responsive neurostimulation. In this review, we examine the past two decades of innovation in low-frequency stimulation as it pertains to pre-surgical evaluation. We begin with a basic overview of single-pulse electrical stimulation and CCEPs, including definitions, methodology, physiology, and traditional interpretation. We then explore the literature examining CCEPs as markers of cortical excitability, seizure onset, and network-level dysfunction. Finally, the relationship between stimulation-induced and spontaneous seizures is considered. By examining these questions, we identify both opportunities and pitfalls along the path towards integrating low-frequency stimulation into clinical practice. Full article

CDKL5 deficiency disorder (CDD), a developmental encephalopathy caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene, is characterized by a complex and severe clinical picture, including early-onset epilepsy and cognitive, motor, visual, and gastrointestinal disturbances. This disease still lacks a medical treatment to mitigate, or reverse, its course and improve the patient’s quality of life. Although CDD is primarily a genetic brain disorder, some evidence indicates systemic abnormalities, such as the presence of a redox imbalance in the plasma and skin fibroblasts from CDD patients and in the cardiac myocytes of a mouse model of CDD. In order to shed light on the role of oxidative stress in the CDD pathophysiology, in this study, we aimed to investigate the therapeutic potential of Coenzyme Q10 (CoQ10), which is known to be a powerful antioxidant, using in vitro and in vivo models of CDD. We found that CoQ10 supplementation not only reduces levels of reactive oxygen species (ROS) and normalizes glutathione balance but also restores the levels of markers of DNA damage (γ-H2AX) and senescence (lamin B1), restoring cellular proliferation and improving cellular survival in a human neuronal model of CDD. Importantly, oral supplementation with CoQ10 exerts a protective role toward lipid peroxidation and DNA damage in the heart of a murine model of CDD, the Cdkl5 (+/−) female mouse. Our results highlight the therapeutic potential of the antioxidant supplement CoQ10 in counteracting the detrimental oxidative stress induced by CDKL5 deficiency. Full article

Epileptic and developmental encephalopathies (EDEs) are a group of severe, genetically various neurological conditions characterized by early-onset seizures and developmental impairments. Recent advances in molecular genetics and diagnostic tools have led to the development of precision therapies, aiming to address the deep causes of these disorders. Examples, such as pyridoxine for pyridoxine-dependent epilepsy and the ketogenic diet for GLUT1 deficiency syndrome illustrate the potential of presumed tailored treatments. However, challenges persist, as current therapies often fail to fully mitigate neurodevelopmental impairments. Moreover, traditional phenotype-based management strategies, while effective for seizure control, do not address the root causes of these disorders, underscoring the limitations of existing approaches. This article explores the evolving landscape of precision medicine in EDEs, emphasizing the importance of genetic insights in therapy design and the need for a multidisciplinary approach. It also highlights the barriers to widespread implementation, including diagnostic delays, accessibility, and a lack of robust clinical evidence. To fully realize the potential of precision therapies, comprehensive genetic integration, innovation in treatment, and global collaboration are essential. The future of EDE management lies in therapies that not only control symptoms but also correct genetic and molecular defects, offering a more effective, individualized approach to care. Full article

Background: Childhood-onset progressive ataxias are rare neurodegenerative disorders characterized by cerebellar signs, sometimes associated with other neurological or extra-neurological features. The autosomal dominant forms, known as spinocerebellar ataxias (SCAs), linked to trinucleotide (i.e., CAG) repeat disorders, are ultra-rare in children. We describe three patients from two unrelated families affected by spinocerebellar ataxia type 2 (SCA2) and present a literature review of pediatric cases. Methods: The patients’ clinical and genetic data were collected retrospectively. Results: The first case was a 9.5-year-old boy, affected by ataxia with oculomotor apraxia and cerebellar atrophy, subcortical myoclonus, and peripheral axonal sensitive polyneuropathy caused by a pathologic expansion in ATXN2, inherited from his asymptomatic father. Two brothers with familial SCA2 presented neurodegeneration leading to early death in one case and progressive ataxia, parkinsonism, and epilepsy with preserved ambulation at age 18 years in the second. To date, 19 pediatric patients affected by SCA2 have been reported, 3 of whom had a phenotype consistent with progressive ataxia with shorter CAG repeats, while 16 had more severe early-onset encephalopathy, with longer alleles. Conclusions: Although they are ultra-rare, trinucleotide repeat disorders must be considered in differential diagnosis of hereditary progressive ataxias in children, especially considering that they require targeted genetic testing and can manifest even before a parental carrier becomes symptomatic. Thus, they must also be taken into account with negative family history and when Next-Generation Sequencing (NGS) results are inconclusive. Notably, the association between cerebellar ataxia and other movement disorders should raise suspicion of SCA2 among differential diagnoses. Full article

Glycosylphosphatidylinositol (GPI) biosynthesis defect 11 (GPIBD11), part of the heterogeneous group of congenital disorders of glycosylation, is caused by biallelic pathogenic variants in PIGW. This rare disorder has previously been described in only 12 patients. We report four novel patients: two sib fetuses with congenital anomalies affecting several organs, including the heart; a living girl with tetralogy of Fallot, global developmental delay, behavioral abnormalities, and atypic electroencephalography (EEG) without epilepsy; a girl with early-onset, treatment-resistant seizures, developmental regression, and recurrent infections, that ultimately passed away prematurely due to pneumonia. We also illustrate evolving facial appearance and biochemical abnormalities. We identify two novel genotypes and the first frameshift variant, supporting a loss-of-function pathogenic mechanism. By merging our cohort with patients documented in the literature, we deeply analyzed the clinical and genetic features of 16 patients with PIGW-related disorder, revealing a severe multisystemic condition deserving complex management and with uncertain long-term prognosis. We consider the role of PIGW within the critical 17q12 region, which is already associated with genomic disorders caused by deletion or duplication and characterized by variable expressivity. Finally, we discuss PIGW dosage effects and a second hit hypothesis in human development and disease. Full article

Developing interfaces for seizure diagnosis, often challenging to detect visually, is rising. However, their effectiveness is constrained by the need for diverse and extensive databases. This study aimed to create a seizure detection methodology incorporating detailed information from each EEG channel and accounts for frequency band variations linked to the primary brain pathology leading to ICU admission, enhancing our ability to identify epilepsy onset. This study involved 460 video-electroencephalography recordings from 71 patients under monitoring. We applied signal preprocessing and conducted a numerical quantitative analysis in the frequency domain. Various machine learning algorithms were assessed for their efficacy. The k-nearest neighbours (KNN) model was the most effective in our overall sample, achieving an average F1 score of 0.76. For specific subgroups, different models showed superior performance: Decision Tree for ‘Epilepsy’ (average F1 score of 0.80) and ‘Craniencephalic Trauma’ (average F1 score of 0.84), Random Forest for ‘Cardiorespiratory Arrest’ (average F1 score of 0.89) and ‘Brain Haemorrhage’ (average F1 score of 0.84). In the categorisation of seizure types, Linear Discriminant Analysis was most effective for focal seizures (average F1 score of 0.87), KNN for generalised (average F1 score of 0.84) and convulsive seizures (average F1 score of 0.88), and logistic regression for non-convulsive seizures (average F1 score of 0.83). Our study demonstrates the potential of using classifier models based on quantified EEG data for diagnosing seizures in ICU patients. The performance of these models varies significantly depending on the underlying cause of the seizure, highlighting the importance of tailored approaches. The automation of these diagnostic tools could facilitate early seizure detection. Full article

Background/Objectives: Developmental and epileptic encephalopathy 9 (DEE9) (MIM #300088) affects heterozygous females and males with somatic pathogenic variants, while male carriers with hemizygous PCDH19 pathogenic variants are clinically unaffected. There are hundreds of pathogenic single nucleotide variants in the PCDH19 gene reported in the literature, which lead to the loss of function of the PCDH19 protein. To date, no phenotypes associated with overexpression or copy number gains have been described in this gene. Methods and results: We present a female patient with a de novo triplication in the Xq21.3–q22.1 chromosomal region, which includes the PCDH19 gene, which implies an unbalanced dose gain. This patient displayed a phenotype of epileptic encephalopathy compatible with DEE9. By comparison, another male patient with a similar duplication showed mild developmental delay and autism but never developed epilepsy. Conclusions: Here, we propose the dose gain of PCDH19 as a new pathogenic mechanism that results in a phenotype similar to that found in patients with loss-of-function variants in PCDH19, when present in a heterozygous state. Full article

Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers. The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBD’s antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids’ pharmacodynamics. This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid’s potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid’s therapeutic potential for CDD. Full article

Background: Developmental and epileptic encephalopathies (DEE) are a group of disorders often linked to de novo mutations, including those in the ATP6V1A gene. These mutations, particularly dominant gain-of-function (GOF) variants, have been associated with a spectrum of phenotypes, ranging from severe DEE and infantile spasms to milder conditions like autism spectrum disorder and language delays. Methods: We aim to expand ATP6V1A-related disease spectrum by describing a six-year-old boy who presented with a febrile seizure, mild intellectual disability (ID), language delay, acquired microcephaly, and dysmorphic features. Results: Genetic analysis revealed a novel de novo heterozygous pathogenic variant (c.82G>A, p.Val28Met) in the ATP6V1A gene. He did not develop epilepsy, and neuroimaging remained normal over five years of follow-up. Although ATP6V1A mutations have traditionally been linked to severe neurodevelopmental disorders, often with early-onset epilepsy, they may exhibit milder, non-progressive phenotypes, challenging previous assumptions about the severity of ATP6V1A-related conditions. Conclusions: This case expands the known clinical spectrum, illustrating that not all patients with ATP6V1A mutations exhibit severe neurological impairment or epilepsy and underscoring the importance of including this gene in differential diagnoses for developmental delays, especially when febrile seizures or dysmorphic features are present. Broader genotype–phenotype correlations are essential for improving predictive accuracy and guiding clinical management, especially as more cases with mild presentations are identified. Full article