Search Results (159)

Background: Spectrin proteins are critical cytoskeleton components that maintain cellular structure and mediate intracellular transport. Pathogenic variants in SPTBN1, encoding βII-spectrin, have been associated with various neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorder, and epilepsy. Here we report a Korean infant with infantile epileptic spasms syndrome (IESS) and an SPTBN1 mutation and provide a review of this mutation. Methods: The genomic data of the patient were analyzed by whole exome sequencing. A comprehensive literature review was conducted to identify and analyze all reported SPTBN1 variants, resulting in a dataset of 60 unique mutations associated with neurodevelopmental phenotypes. Case Presentation: A 10-month-old Korean female presented with IESS associated with a de novo heterozygous SPTBN1 mutation (c.785A>T; p.Asp262Val). The patient exhibited global developmental delay, microcephaly, hypotonia, spasticity, and MRI findings of diffuse cerebral atrophy and corpus callosum hypoplasia. Electroencephalography revealed hypsarrhythmia, confirming the diagnosis of IESS. Seizures persisted despite initial treatment with vigabatrin and steroids. Genetic analysis identified a likely pathogenic variant within the calponin homology 2 (CH2) domain of SPTBN1. Conclusions: This is the first report of an association between IESS and an SPTBN1 CH2 domain mutation in a Korean infant. This finding expands the clinical spectrum of SPTBN1-related disorders and suggests domain-specific effects may critically influence phenotypic severity. Further functional studies are warranted to elucidate the pathogenic mechanisms of domain-specific variants. Full article

Biallelic pathogenic variants in DHCR7 result in decreased activity of 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, and causes Smith–Lemli–Opitz syndrome (SLOS). Elevated serum 7-DHC levels are indicative of SLOS as are intellectual disability (ID), growth retardation, microcephaly, craniofacial anomalies, and 2–3 toe syndactyly. Additional congenital malformations may be present in SLOS, and broad clinical variability has been recognized in SLOS. Rarely, biallelic pathogenic DHCR7 variants were reported with low-normal and normal intelligence quotient (IQ) and development. We report here a pair of siblings with mild global developmental delay, infrequent epileptic seizures, and elevated serum 7-DHC levels, associated with the homozygous DHCR7 variant c.988G>A (p.Val330Met). Remarkably, neither sibling displayed congenital anomalies nor dysmorphisms. Quattro-exome sequencing performed for global delay and mild ID in both siblings did not identify other ID causes. c.988G>A affects a highly conserved amino acid and displays a relatively high global population allele frequency of 0.04%, with absence of homozygotes from the population database gnomADv4.1.0. Our observation leads us to suggest that DHCR7 variant c.988G>A and other DHCR7 variants might be generally considered as underlying non-syndromic ID. Full article

Background: Alcohol withdrawal syndrome is a common clinical challenge that may lead to significant complications if not properly managed. Symptom-triggered therapy (STT) represents a promising alternative to fixed-dose regimens (FDRs) providing benzodiazepine prescriptions based on objectively quantified withdrawal symptoms. This study aimed to evaluate the effectiveness and safety of STT using the Hamburg Alcohol Withdrawal Scale (HAES) compared to FDRs in the management of inpatient alcohol detoxification. Methods: In a retrospective case–control study, alcohol detoxification treatment in STT was compared with FDRs. During a twelve-month observation period, a total of 123 patients in the STT group were recruited and compared with 123 controls in the FDR group (matched according to sex, age, and current amount of alcohol consumption) treated in the same hospital before the implementation of STT. The study outcomes included the total benzodiazepine dosage, duration of acute detoxification phase, length of inpatient stay, and occurrence of complications such as epileptic seizures and delirium tremens. Results: STT showed a significantly lower total benzodiazepine dosage (22.50 mg vs. 115.00 mg, p < 0.001), a shorter duration of the detoxification phase (48.00 h vs. 201.75 h, p < 0.001), and a reduced length of inpatient stay (23.00 days vs. 28.00 days, p = 0.003) compared to FDRs. There were no significant differences in the rates of complications between the two settings. Linear mixed model analysis revealed that the differences remained highly significant even after adjusting for various explanatory variables (i.e., age, sex, standard units of alcohol, psychiatric comorbidities, treatment discontinuation, and occurrence of any complication). Conclusions: STT appears to be as effective and safe as traditional fixed-dose regimens of benzodiazepines for the management of inpatient alcohol detoxification. This approach may thereby minimize unnecessary pharmacological exposure, facilitate the earlier integration of patients into psychoeducational and psychosocial interventions, and reduce healthcare costs. Full article

Objectives: The aim of this study was to evaluate the effectiveness of sequential treatments with adrenocorticotropic hormone (ACTH) or ketogenic diet therapy (KDT) in infants with infantile epileptic spasms syndrome (IESS) who did not achieve seizure freedom after initial treatment with either KDT or ACTH. Methods: We conducted a cohort study following a parallel-cohort randomized controlled trial comparing KDT with ACTH as first-line treatment for IESS. Infants who failed to respond were switched per protocol to the alternative treatment (ACTH or KDT) or, if this was not feasible or unsuccessful, to anti-seizure medications (ASMs). The primary outcome was the frequency of sustained seizure freedom at last follow-up. Results: Of 101 infants allocated to the initial treatment phase, N = 67 required further treatment. Of these, 31% (21/67) achieved sustained seizure freedom after the second treatment phase, and 15% (7/46) after rescue treatment with ASMs. KDT as the second treatment achieved sustained seizure freedom in 50% (12/24), compared to 19% (3/16) with ACTH and 9% (2/22) with ASMs. The cumulative response rate after the first and second treatments was 64% for the KDT-ACTH sequence and 68% for the ACTH-KDT sequence. The cumulative response after all three treatment phases was 78% (KDT-ACTH-ASM) and 72% (ACTH-KDT-ASM), respectively. Conclusions: KDT is at least as effective as ACTH as a second treatment and significantly more effective than ASMs in achieving sustained seizure freedom in infants with IESS. 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

Tools for measuring the likelihood of relapse in infantile epileptic spasms syndrome (IESS) treatment could aid clinicians in making critical management decisions. High-frequency oscillations (HFOs), transient bursts of electroencephalography (EEG) activity with frequencies beyond 80 Hz, are a new and promising noninvasive biomarker. The present study aimed to investigate the association between the Burden of Amplitudes and Epileptiform Discharges (BASED) scores, an interictal EEG grading scale for IESS, and scalp HFOs in patients with IESS. The study enrolled 50 patients, 25 with a clinical diagnosis of IESS and 25 without epilepsy. The percentage of patients with at least one scalp HFO detected, stratified by BASED scores, differed significantly: for BASED scores ≤ 2, 7.7%; for 3, 16.7%; for 4, 87.5%; and for 5, 100% (p < 0.001). Compared with BASED scores ≤ 2, the median scalp HFO detection rate was significantly highest for BASED scores of 5 (median [IQR]: 6.24 [2.25–8.32], p < 0.001), followed by BASED scores of 4. The scalp HFO detection rates showed a better performance in estimating patients with BASED scores of 4 and 5. It is hoped that scalp HFOs can be used as an objective indicator to validate the results of BASED scores. Full article

Background: Sandifer’s syndrome is an uncharacteristic symptom of gastroesophageal reflux disease (GERD). It is often misdiagnosed as epilepsy. Paramedics can play a crucial role in recognising the differences between Sandifer’s syndrome and epilepsy. Therefore, education is important to reduce the likelihood of misdiagnosis and the mistreatment of patients. This purpose of this study is to provides information and guidelines for collecting patients’ medical history and identifying the most common symptoms, which support pre-hospital suspicion of Sandifer’s syndrome. Methods: The study consisted of a clinical case study, concerning the management of the emergency team, in a 7-week-old child with symptoms indicative of an epileptic seizure. Results: The clinical case analysis showed that a thorough examination of the patient helped to rule out epilepsy in the child and observed the characteristic symptoms of Sandifer syndrome. While assisting the child, a rare symptom of apnoea was also observed. Conclusions: The role of the paramedics in diagnosing Sandifer’s syndrome can be crucial. Their experience and knowledge of emergency situations, as well as correctly conducted tests during and immediately after ailment symptoms, can provide medical teams with key information that can help in making a correct diagnosis. The presented framework can be helpful. In the majority of cases, a correct diagnosis leads to the complete cessation of symptoms and lowers the risk of side effects from unnecessarily applied anti-epilepsy medication. 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

The co-occurrence of autism spectrum disorder (ASD) and epilepsy is a complex neurological condition that presents significant challenges for both patients and clinicians. ASD is a group of complex developmental disorders characterized by the following: (1) Social communication difficulties: challenges in understanding and responding to social cues, initiating and maintaining conversations, and developing and maintaining relationships. (2) Repetitive behaviors: engaging in repetitive actions, such as hand-flapping, rocking, or lining up objects. (3) Restricted interests: focusing intensely on specific topics or activities, often to the exclusion of other interests. (4) Sensory sensitivities: over- or under-sensitivity to sensory input, such as sounds, touch, tastes, smells, or sights. These challenges can significantly impact individuals’ daily lives and require specialized support and interventions. Early diagnosis and intervention can significantly improve the quality of life for individuals with ASD and their families. Epilepsy is a chronic brain disorder characterized by recurrent unprovoked (≥2) seizures that occur >24 h apart. Single seizures are not considered epileptic seizures. Epilepsy is often idiopathic, but various brain disorders, such as malformations, strokes, and tumors, can cause symptomatic epilepsy. While these two conditions were once considered distinct, growing evidence suggests a substantial overlap in their underlying neurobiology. The prevalence of epilepsy in individuals with ASD is significantly higher than in the general population. This review will explore the epidemiology of this comorbidity, delve into the potential mechanisms linking ASD and epilepsy, and discuss the implications for diagnosis, treatment, and management. Full article

Pathogenic variants in the NEXMIF gene are associated with a broad neurodevelopmental phenotype, including autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. However, the role of NEXMIF in specific epileptic syndromes remains insufficiently explored. We present the case of an 11.9-year-old Romanian girl diagnosed with ASD, attention-deficit/hyperactivity disorder (ADHD), mild ID, and Jeavons syndrome (generalized epilepsy characterized by eyelid myoclonia, absence seizures, and photosensitivity). Genetic testing identified a pathogenic NEXMIF variant: c.1882C>T (p.Arg628*), a pathogenic variant rarely reported in the literature, with only two documented cases to date. To better understand the genotype–phenotype correlation, we conducted a systematic review of NEXMIF-associated disorders and compared our findings with previously reported cases. Our analysis suggests that NEXMIF variants may contribute to a broader spectrum of epileptic syndromes, including photosensitive epilepsy such as Jeavons syndrome. This highlights the need for a greater awareness of atypical seizure presentations in individuals with NEXMIF-related disorders. This study underscores the importance of genetic testing in individuals with overlapping ASD and epilepsy phenotypes as early diagnosis may facilitate targeted therapeutic interventions and genetic counseling. Further research is needed to clarify the molecular mechanisms linking NEXMIF dysfunction to epileptic syndromes and neurodevelopmental disorders. Full article

MOGAD is a demyelinating syndrome with the presence of antibodies against myelin oligodendrocyte glycoprotein, which is, next to multiple sclerosis and the neuromyelitis optica spectrum, one of the manifestations of the demyelinating process, more common in the pediatric population. MOGAD can take a variety of clinical forms: acute disseminated encephalomyelitis (ADEM), retrobulbar optic neuritis, often binocular (ON), transverse myelitis (TM), or NMOSD-like course (neuromyelitis optica spectrum disorders), less often encephalopathy. The course may be monophasic (40–50%) or polyphasic (50–60%), especially with persistently positive anti-MOG antibodies. Very rarely, the first manifestation of the disease, preceding the typical symptoms of MOGAD by 8 to 48 months, is focal seizures with secondary generalization, without typical demyelinating changes on MRI of the head. The paper presents a case of a 17-year-old patient whose first symptoms of MOGAD were focal epileptic seizures in the form of turning the head to the right with the elevation of the left upper limb and salivation. Seizures occurred after surgical excision of a tumor of the right adrenal gland (ganglioneuroblastoma). Then, despite a normal MRI of the head and the exclusion of onconeural antibodies in the serum and cerebrospinal fluid after intravenous treatment, a paraneoplastic syndrome was suspected. After intravenous steroid treatment and immunoglobulins, eight plasmapheresis treatments, and the initiation of antiepileptic treatment, the seizures disappeared, and no other neurological symptoms occurred for nine months. Only subsequent relapses of the disease with typical radiological and clinical picture (ADEM, MDEM, recurrent ON) allowed for proper diagnosis and treatment of the patient both during relapses and by initiating supportive treatment. The patient’s case allows us to analyze the multi-phase, clinically diverse course of MOGAD and, above all, indicates the need to expand the diagnosis of epilepsy towards demyelinating diseases: determination of anti-MOG and anti-AQP4 antibodies. 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

STXBP1 syndrome is a severe early-onset epileptic encephalopathy characterized by developmental delay and intellectual disability. This review addresses key challenges in STXBP1 syndrome research, focusing on advanced therapeutic approaches and experimental models. We explore gene therapy strategies, including CRISPR-Cas9, adeno-associated viral (AAV) vectors, and RNA therapies such as antisense oligonucleotides (ASOs), aimed at correcting STXBP1 genetic dysfunctions. This review presents in vivo and in vitro models, highlighting their contributions to understanding disease mechanisms. Additionally, we provide a proposal for a detailed bioinformatic analysis of a Spanish cohort of 41 individuals with STXBP1-related disorders, offering insights into specific mutations and their biological implications. Clinical and translational perspectives are discussed, emphasizing the potential of personalized medicine approaches. Future research directions and key challenges are outlined, including the identification of STXBP1 interactors, unexplored molecular pathways, and the need for clinically useful biomarkers. This comprehensive review underscores the complexity of STXBP1-related infantile epileptic encephalopathy and opens new avenues for advancing the understanding and treatment of this heterogeneous disease. Full article

Background: Cause of death analysis is fundamental to forensic pathology. We present the case of a 9½-year-old girl with a genetically confirmed diagnosis of Dravet syndrome who died in her sleep with no evidence of motor seizure. She also had a lifelong history of recurrent pneumonias and, along with her family, had tested positive for COVID-19 10 days before death. Methods: Long-term clinical history of Dravet Syndrome and respiratory infections were obtained from patient’s medical charts and radiology reports. A Rapid-Antigen Test was used to confirm SARS-CoV2 infection days prior to death. At autopsy, brain, heart and lung tissues were obtained. Paraffin-embedded tissues were double-stained with H&E, and immunohistochemically stained using various antibodies. Results: Autopsy revealed evidence of previous seizure activity in the brain and cellular interstitial thickening in the lung. The brain showed edema and fibrillary gliosis without neuronal loss in neocortex and hippocampus. The lung showed inflammatory interstitial thickening with histiocytes, megakaryocytes, B-lymphocytes, and T-lymphocytes, including helper/suppressor cells and cytotoxic T-lymphocytes. Diffuse alveolar damage was observed as alveolar flooding with proteinaceous fluid. Conclusions: The cause of death may be attributed to Sudden Unexpected Death in Epilepsy (SUDEP) in Dravet syndrome, sudden death in viral pneumonia, or some combination of the two. When two independent risk factors for sudden unexpected death are identified due to co-pathology, it may not be possible to determine a single cause of death beyond a reasonable doubt. Full article

Background: Epilepsy is a group of disorders characterized by a cluster of clinical and EEG signs leading to the formation of abnormal synchronous excitation of neurons in the brain. It is one of the most common neurological disorders worldwide; and is characterized by aberrant expression patterns; both at the level of matrix transcripts and at the level of regulatory RNA sequences. Aberrant expression of a number of microRNAs can mark a particular epileptic syndrome; which will improve the quality of differential diagnosis. Materials and Methods: In this work; the expression profile of six microRNAs was analyzed: hsa-miR-106b-5p; hsa-miR-134-5p; hsa-miR-122-5p; hsa-miR-132-3p; hsa-miR-155-5p; and hsa-miR-206-5p in the blood plasma of patients suffering from temporal lobe epilepsy (n = 52) and juvenile myoclonic epilepsy (n = 42); n—amount of participants; in comparison with healthy volunteers. The expression analysis was carried out using RT-PCR. Mathematical processing of the data was carried out according to the Livak method. Results: A statistically significant change in the expression of hsa-miR-106b-5p; hsa-miR-134-5p; hsa-miR-122-5p; and hsa-miR-132-3p was found. An increase in the expression of hsa-miR-134-5p and hsa-miR-122-5p was registered in the group of patients with temporal lobe epilepsy compared to the control; as well as an increase in the expression of hsa-miR-132-3p and hsa-miR-106b-5p in the juvenile myoclonic epilepsy group compared to the control. hsa-miR-122-5p; 106b-5p; 132-3p are also able to discriminate groups with different syndromes. Additionally; a number of microRNAs are able to discriminate patients with drug-resistant and drug-sensitive forms of epilepsy from the control; as well as patients with hippocampal sclerosis and patients without hippocampal sclerosis from the control. Conclusion. Our data allow us to propose these microRNAs as plasma biomarkers of various epileptic syndromes Full article