SCN5A Research Articles

Genetic Variants in the SCN9A Gene are Detected in a Minority of Erythromelalgia Patients.

Gain-of-function variants in the voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, have previously been identified in patients with erythromelalgia, a clinical diagnosis defined by intermittent attacks of painful, hot, swollen, and red skin, predominantly involving the hands and feet. Symptoms are induced or aggravated by warming and relieved by cooling. In primary erythromelalgia there is no known underlying disease. This study investigated the frequency of SCN9A variants in a cohort of primary erythromelalgia patients collected at a single centre, and examined the clinical signs and symptoms associated with identified variants. One hundred patients with possible erythromelalgia were collected prospectively and evaluated by clinical examination. Thirty-five patients fulfilling the clinical criteria of primary erythromelalgia were screened for variants in SCN9A. Five were found to carry likely causal variants, including a variant found in 2 related individuals and a variant not previously described in patients with erythromelalgia. The clinical findings differed significantly between the patients. Overall, in this cohort only 4/34 (11.7%) of unrelated patients had erythromelalgia likely caused by gain-of-function variants in SCN9A. Variants in SCN9A are therefore likely to cause or contribute to primary erythromelalgia in only a small proportion of patients.

SCN10A gene polymorphism is associated with pain sensitivity and postoperative analgesic effects in patients undergoing gynecological laparoscopy

BackgroundPostoperative pain intensity is influenced by various factors, including genetic variations. The SCN10A gene encodes the Nav1.8 sodium channel protein, which is crucial for pain signal transmission in peripheral sensory neurons.ObjectivesThis study aims to investigate the relationship between genetic mutations in the SCN10A gene (rs6795970) and postoperative analgesic effects following gynecological laparoscopic surgery.MethodsTwo hundred female patients undergoing gynecological laparoscopic surgery under general anesthesia were included. pain sensitivity was evaluated using the catastrophizing scale and pain sensitivity questionnaire (PSQ). Patients received patient-controlled intravenous analgesia with sufentanil and dexmedetomidine for 48 h post-surgery. Postoperative pain indicators, such as visual analog scale (VAS) scores, Ramsay scores, and side effects were recorded. SCN10A rs6795970 mutations were identified using MassARRAY SNP typing technology, and patients were categoried into homozygous mutant (AA), wild type (GG), and heterozygous mutation (GA) groups for analysis.ResultsPatients in the AA group had higher scores on the pain Catastrophizing Scale, PSQ-total, PSQ-minor, and PSQ-moderate compared to GA and GG groups (P < 0.05). VAS scores at 4, 6, and 12 h post-operation were higher in the AA group than the GG group (P < 0.05). Ramsay scores were lower in AA patients at 2 and 4 h post-operation compared to GA and GG groups (P < 0.05). The AA group exhibited more self-control analgesic pump compressions within the first 24 h post-surgery, quicker depletion of analgesics in the pump, and lower patient satisfaction with pain relief compared to GA and GG groups (P < 0.05).ConclusionsFemale patients with homozygous SCN10A mutations may experience higher preoperative pain scores and increased sensitivity to postoperative pain following gynecological laparoscopic surgery with intravenous patient-controlled analgesia.Trial registration: www.chictr.org.cn, registration number: ChiCTR2200062425.

Genetic and Environmental Influences on Autism Spectrum Disorder: A Multi-Center Study Exploring Gene-Environment Interactions and Biomarkers in Indonesia

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental condition with a complex etiology involving genetic and environmental factors. This multi-center study investigated gene-environment interactions and potential biomarkers associated with ASD in the Indonesian population. Methods: Children diagnosed with ASD (n=500) and age-matched typically developing controls (n=500) were recruited across five major Indonesian cities. Whole-exome sequencing targeted genotyping, and environmental risk factor assessments were conducted. Biomarker analyses included cytokine levels, oxidative stress markers, and neurotransmitters. Results: Genetic analysis revealed both rare and common variants associated with ASD risk, including variants in CHD8, SCN2A, NRXN1, and novel genes. Prenatal exposures (maternal medication use, infections), perinatal complications (preterm birth, low birth weight), and postnatal factors (pesticide exposure, air pollution) were associated with increased ASD risk. Children with ASD exhibited elevated inflammatory markers (TNF-α, IL-6, IL-1β), increased oxidative stress (higher MDA, lower GSH), and altered neurotransmitter levels (lower serotonin and dopamine) compared to controls. Conclusion: This study provides insights into the interplay of genetic and environmental factors contributing to ASD risk in Indonesia. The identified genetic variants, environmental risk factors, and potential biomarkers may contribute to our understanding of ASD etiology and inform the development of targeted interventions and early detection strategies.

Cardiac Implications in Dravet Syndrome: Can Electrocardiogram and Echocardiography Detect Hidden Risks?

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy associated with loss-of-function variants in the SCN1A gene. Although predominantly expressed in the central nervous system, SCN1A is also expressed in the heart, suggesting a potential link between neuronal and cardiac channelopathies. Additionally, DS carries a high risk of sudden unexpected death in epilepsy (SUDEP). This study investigates electrocardiographic (EKG) and echocardiographic findings in patients with DS to assess potential cardiac risks. This prospective study recruited 34 patients with DS with confirmed SCN1A pathogenic variants during the 2024 family meeting of the Dravet Syndrome Foundation Spain. Participants underwent standard 12-lead EKG, high-lead EKG for Brugada pattern detection, and a standing test to evaluate QT interval response. When available, echocardiogram data were collected. QTc and P wave dispersion were calculated. To establish a basis for comparison, cases were matched with age- and sex-matched epileptic patients without DS. No significant EKG abnormalities suggesting long QT syndrome or Brugada syndrome were detected. However, QT and P wave dispersion, previously reported as markers of autonomic dysfunction associated with arrhythmias and SUDEP risk, were elevated. Echocardiograms in 21 patients showed normal cardiac structure, even in those on fenfluramine. Although no significant EKG or echocardiographic abnormalities were identified, elevated QTc and P wave dispersion, along with the elevated risk of SUDEP and past reports of arrhythmias, suggest the need for continued cardiac surveillance. Further studies are essential to explore the predictive value of QTc and P wave dispersion in assessing SUDEP and arrhythmia risk, and to identify other potential cardiac markers.

Identification of Lauric Acid as a Potent Sodium Channel NaV1.5 Blocker from Compound Chinese Medicine Wenxin Keli.

The major cardiac voltage-gated sodium channel NaV1.5 (INa) is essential for cardiac action potential initiation and subsequent propagation. Compound Chinese medicine Wenxin Keli (WXKL) has been shown to suppress arrhythmias and heart failure. However, its active components have not been fully elucidated. This study focused on identifying the active inhibitor of INa in WXKL and exploring their mode of action in electrophysiological conduction. A chemical fraction library was constructed from an aqueous extract of WXKL and screened using an automated patch-clamping system in cells stably expressing the NaV1.5 gene SCN5A. Candidate fractions with INa-inhibition activity were analyzed by HPLC-ESI-IT-TOF-MS and GC-MS to identify the ingredients. NaV1.5 blocker molecules identified by single-cell electrocardiogram were tested in hiPSC-derived cardiomyocytes. We evaluated the SCN5A inhibitory potential of Wenxin Keli effective monomer employing molecular docking and molecular dynamics simulation approaches. A primary screen of the WXKL chemical library identified five fractions that significantly inhibited the NaV1.5 channel, with one of them rich in poly-saturated fatty acids. Molecular structural characterization revealed the presence of lauric acid, myristic acid, palmitic acid, and stearic acid in the active subfraction. Electrophysiological characterization demonstrated lauric acid (LA) as the most effective monomer for INa-inhibition with an IC50 at 27.40 ± 12.78 μM. LA shifted the steady-state inactivation of INa to more negative potentials and decreased the amplitude of extracellular field potential in hiPSC-derived cardiomyocytes. We demonstrate for the first time that naturally poly-saturated fatty acid, lauric acid, as a potential novel INa blocker. Molecular docking and molecular dynamics simulation suggested that LA binds to the NaV1.5 protein, with a significant binding affinity forming interactions with functionally essential residues and blocks the inward flow of Na+. Mechanistically, lauric acid acts on the fast inactivation of NaV1.5 alter electrophysiology conduction of hiPSC-derived cardiomyocytes and contribute to the antiarrhythmic effect of WXKL. Lauric acid is a potent blocker for sodium channel NaV1.5 and alleviates arrhythmia via inhibiting INa.

A high seizure burden increases brain concentrations of specialized pro-resolving mediators in the Scn1a+/- mouse model of Dravet syndrome.

Dravet syndrome is a severe, intractable epilepsy in which 80 % of patients have a de novo mutation in the gene SCN1A. We recently reported that a high seizure burden increased hippocampal concentrations of an array of pro-inflammatory prostaglandins in the Scn1a+/- mouse model of Dravet syndrome. This raised the possibility that a high seizure burden might also trigger the accumulation of specialized pro-resolving mediators that facilitate the resolution of neuroinflammation and brain repair. The present study therefore aimed to examine whether a high seizure burden increased hippocampal concentrations of various specialized pro-resolving mediators in the Scn1a+/- mouse model of Dravet syndrome. Scn1a+/- mice at postnatal day 21 (P21) were primed with a single hyperthermia-induced seizure event to induce a high seizure burden. On P24 primed Scn1a+/- mice with a high seizure burden, unprimed naïve Scn1a+/- mice and wild-type (WT) mice were euthanized and hippocampal tissue was collected for analysis of various specialized pro-resolving mediators using liquid chromatography mass spectrometry. Scn1a+/- mice with a high seizure burden showed increased hippocampal concentrations of the pro-inflammatory leukotrienes B4 and E4. Further, a high seizure burden increased hippocampal concentrations of various special pro-resolving mediators, including the maresins (maresin1), D-series resolvins (RVD1 and RVD4), and protectin (PCTR1). To further characterize these changes, we determined the mRNA expression of lipoxygenase genes, as these synthetic enzymes are common across classes of specialized pro-resolving mediators. However, hippocampal expression of Alox5, Alox12 and Alox15 were not influenced by a high seizure burden. We report for the first time that a high seizure burden increases the hippocampal concentrations of various specialized pro-resolving mediators in Scn1a+/- mice. This provides a platform for future studies to examine whether modulation of these mediators might be exploited to reduce seizures and facilitate brain repair in intractable epilepsy syndromes.

Multiple time points of transcriptome analysis revealed altered genes involved in maintaining hibernation in the hypothalamus of Tamias sibiricus

Hibernation, an adaptive mechanism to extreme environmental conditions, is prevalent among mammals. Its main characteristics include reduced body temperature and metabolic rate. However, the mechanisms by which hibernating animals re-enter deep sleep during the euthermic phase to sustain hibernation remain poorly understood. We selected the Tamias sibiricus as a model organism and conducted transcriptomic sequencing of its hypothalamus at multiple time points throughout hibernation. Through the strategies of gene set filtering and intersection analysis, we effectively filtered out redundant data, identifying a subset of genes whose expression was downregulated during the euthermic phase potentially inducing re-enter deep sleep, thereby maintaining the periodic cycles of torpor and arousal. These cycles are crucial for sustaining the overall hibernation process. Notably, genes associated with sodium and potassium ion channels were significantly enriched. Specifically, potassium ion-related genes such as Kcnc1, Kcna2, Kcng4, and Kcna6, along with sodium ion-related genes such as Scn1a and Hcn2, were markedly downregulated. qRT-PCR validation of four of these genes (Kcnc1, Kcna6, Scn1a, and Hcn2) confirmed significant downregulation during the euthermic phase compared to the deep sleep phase, further supporting our transcriptomic findings. This study provides novel insights into the hypothalamic transcriptome dynamics at various hibernation stages. Although the functional roles of these genes require further investigation, our findings lay the groundwork for future studies to elucidate the molecular mechanisms underlying hibernation.

High Glucose Sensitizes Male and Female Rat Cardiomyocytes to Wnt/β-Catenin Signaling.

Wnt/β-catenin signaling has been shown to regulate gene expressions in cardiomyocytes. However, it is not known if this effect is dependent on the sex of cells or the glucose level in the culture medium. In the present study, ventricular myocytes were prepared from male and female neonatal rats and maintained in either a glucose-rich (25 mM) medium or a low-glucose (3 mM), lipid-rich medium. Real-time quantitative PCR was used to measure changes in target genes (Axin2, Scn5a, and Tbx3) after treatment with 1, 3, or 10 µM of CHIR-99021, an activator of Wnt/β-catenin signaling. CHIR induced similar changes in Axin2, Tbx3, and Scn5a transcripts in male and female NRVMs in both media, suggesting the absence of sex difference. However, cells in a high-glucose medium showed greater increases in Axin2 and Tbx3 transcripts than cells in a low-glucose medium. In addition, a low concentration of CHIR (1 µM) reduced the Scn5a transcript in cells in a high-glucose medium but not in a low-glucose medium, suggesting an increased sensitivity to Wnt signaling by high glucose. A non-linear relationship was identified between Axin2 transcript upregulation and Scn5a transcript downregulation in CIHR-treated NRVMs. These data suggest that high glucose sensitizes both male and female cardiomyocytes to Wnt/β-catenin signaling.

Paroxysmal extreme pain disorder associated with a mutation in SCN9A gene - Case report and own experiences.

Pain is an unpleasant sensory and emotional experience, influenced by various factors. Paroxysmal extreme pain disorder (PEPD) is a rare genetic condition characterized by sudden bouts of pain accompanied by autonomic symptoms. This manuscript presents the case of a 9-year-old boy with paroxysmal extreme pain syndrome and provides a review of the literature. Additionally, a genealogical analysis of the boy's family was conducted to determine the total number of affected family members. The clinical data included an analysis of genetic tests to identify the mutation confirming PEPD. A mutation in the SCN9A gene causes the disease, and due to the small number of patients worldwide (around 500, according to literature reports), an effective method of preventing extreme pain attacks had not been established at the time of writing this manuscript. Based on information from scientific sources and the authors' experiences, it can be firmly stated that various, often difficult-to-identify factors cause paroxysmal extreme pain. This syndrome necessitates further research and the exploration of effective treatment methods.

The QRS and T wave alternans — a new ECG pattern in Long QT syndrome

We present a case of a new ECG phenomenon that has not been described previously in patients with long QT syndrome (LQTS). Prolongation of the QT interval (QTc) to 568 ms were revealed in girl 6 years old on the resting ECG. There were no symptoms, syncope or family history of sudden death. A molecular genetic study revealed mutation «de novo» in the SCN5A gene (p.Val1411Met), a pathogenic class V that typical for the third molecular genetic variant of LQTS (LQT3). During Holter monitoring a «hyperadaptation» of the QT interval was noted (slope QT/RR 0.37 with normal limit till 0,24). New ECG pattern of the combination T wave alternans and QRS alternans (AT/AQRS) at the night sleep (possibly in REM sleep) were recorded. This pattern has not been described previously in patients with LQTS. Atenolol 1 mg/kg was prescribed. During therapy, AT/AQRS did not record after 2 months. Possible mechanisms and prognostic significance of the identified ECG pattern, issues of treatment of patients with LQT3 are discussed. Conclusions: Combined of T wave alternans and QRS alternans (AT/AQRS) is a new ECG pattern in patients with LQTS that is likely to increase the risk of cardiac events. “Hyperadaptation” of the QT interval may be one of the electrocardiological features of LQT3. The emergence of the AT/AQRS pattern during REM sleep makes this period perhaps the most dangerous for the development of cardiac events in patients with LQT3.

The sodium/glucose cotransporter 2 inhibitor Empagliflozin inhibits long QT 3 late sodium currents in a mutation specific manner

BackgroundSodium/glucose cotransporter 2 inhibitors (SGLT2is) like empagliflozin have demonstrated cardioprotective effects in patients with or without diabetes. SGLT2is have been shown to selectively inhibit the late component of cardiac sodium current (late INa). Induction of late INa is the primary mechanism in the pathophysiology of congenital long QT syndrome type 3 (LQT3) gain-of-function mutations in the SCN5A gene encoding Nav1.5. We investigated empagliflozin's effect on late INa in thirteen known LQT3 mutations located in distinct regions of the channel. MethodsThe whole-cell patch-clamp technique was used to investigate the effect of empagliflozin on late INa in recombinantly expressed Nav1.5 channels containing different LQT3 mutations. Molecular modeling of human Nav1.5 and simulations in a mathematical model of human ventricular myocytes were used to extrapolate our experimental results to excitation-contraction coupling. ResultsEmpagliflozin selectively inhibited late INa in LQT3 mutations in the inactivation gate region of Nav1.5, without affecting peak current or channel kinetics. In contrast, empagliflozin inhibited both peak and late INa in mutations in the S4 voltage-sensing regions, altered channel gating, and slowed recovery from inactivation. Empagliflozin had no effect on late/peak INa or channel kinetics in channels with mutations in the putative empagliflozin binding region. Simulation results predict that empagliflozin may have a desirable therapeutic effect in LQT3 mutations in the inactivation gate region. ConclusionsEmpagliflozin selectively inhibits late INa, without affecting channel kinetics, in LQT3 mutations in the inactivation gate region. Empagliflozin may thus be a promising precision medicine approach for patients with specific LQT3 mutations.

Generation of induced pluripotent stem cell line, NIMHi013-A, from PBMCs of a female child with epilepsy carrying a novel SCN1A variant

The iPSC line NIMHi013-A was generated from peripheral blood mononuclear cells of a paediatric patient with drug resistant epilepsy. The proband was found to have a likely pathogenic missense variant in the SCN1A gene in heterozygous state, which segregated in the affected in dominant fashion. The variant is in the Nav1.1 subunit of the voltage gated sodium ion channel. The iPSCs were generated using Sendai virus-based reprogramming. These iPSCs express pluripotent markers, present a normal karyotype and could differentiate into three germ layers. The iPSC line NIMHi013-A can be used to investigate epileptogenesis in vitro

Causal Relationships Between Epilepsy, Anti-Epileptic Drugs, and Serum Vitamin D and Vitamin D Binding Protein: A Bidirectional and Drug Target Mendelian Randomization Study.

Previous studies suggest potential associations between epilepsy, anti-epileptic drugs (AEDs), and levels of vitamin D and vitamin D-binding protein (VDBP). This study aims to investigate the causal relationships among these variables using Mendelian Randomization (MR) methods. Using summary data from genome-wide association studies on serum 25-hydroxyvitamin D [25(OH)D] levels (N = 417,580), VDBP concentrations (N = 65,589), and various types of epilepsy (Ncases = 27,559), MR analyses were conducted to determine bidirectional causal relationships among these variables. Additionally, eQTL data from eQTLGen (N = 31,684) were employed to model the effects of AEDs and evaluate their causal impact on both biomarkers. No causal relationships were found between serum 25(OH)D or VDBP levels and epilepsy. Although genetically predicted focal epilepsy risk was potentially associated with increased serum 25(OH)D levels (OR 1.031, 95% CI: 1.006-1.058, p = 0.017), and a higher genetic risk of juvenile myoclonic epilepsy was linked to lower VDBP levels (OR 0.977, 95% CI: 0.961-0.993, p = 0.004), both associations lost significance after multiple correction. Furthermore, significant associations were observed between serum 25(OH)D levels and AED target genes SCN4A, GABBR1, CA13, ALDH5A1, and CA8. No significant associations were found between AED target genes and VDBP levels after correction. No causal relationships were found between genetically determined serum 25(OH)D levels, VDBP, and epilepsy or its subtypes. Furthermore, the use of AEDs, such as Carbamazepine, Oxcarbazepine, Progabide, and Valproic Acid, reduces serum 25(OH)D levels, while not affect VDBP levels.

Cortical Vision Impairment (CVI)-informed assessment and treatment of challenging behavior in a child with SCN2A-related disorder

This report presents results of parent-implemented behavioral treatments for a child with cortical visual impairment (CVI), intellectual disability (ID), epilepsy, and autism spectrum disorder (ASD) associated with a pathogenic variant in the SCN2A gene (i.e., SCN2A-Related Disorder). Treatment evaluations were informed by combined results of functional behavior assessment (FBA) and functional vision assessment (FVA) which yielded CVI-related accommodations. The treatment of escape-maintained challenging behavior involved the evaluation of behavioral prompting strategies in accordance with CVI-related accommodations, extinction (EXT), and differential reinforcement modifications. The treatment for behavior problems maintained by access to food (tangible-edible) included functional communication training (FCT), EXT, and schedule thinning with schedule-correlated visual signals. Overall, integrating child-specific CVI-related accommodations was essential for developing effective behavioral interventions for this child. FVAs are accessible and practical for uptake by behavior analysts in vision-informed assessment and treatment of challenging behavior.

Dravet Syndrome – Clinical and Developmental Characteristics: A Case Report

Introduction: Dravet syndrome is a rare, genetically determined epilepsy and epileptic encephalopathy primarily caused by a loss-of-function mutation in the SCN1A gene, also associated with autism spectrum disorder. Follow-ing birth, patients have typical neurodevelopment, but the regression of cognitive, motor and speech abilities become noticeable after the onset of seizures.Aims and case report: We report on the case of a five-year-old girl with characteristic clinical features of Dravet syndrome, detailing her basic clinical and developmental characteristics, disease course and treatment. The first seizure occured at four months of age, coinciding with increased body temperature, and by the end of first year she developed recurrent seizures. While the baseline electroencephagram was nomal, follow-up examinations revealed continuous high-amplitude and sharp, multifocal spike waves. During her second year of life, significant delay in psychomotor development became apparent. The Bayley-III scale was used to assess psychomotor de-velopment in cognition area, comprehension and quality of speech, as well as fine and gross motor skills. The results indicated that her cognitive abilities corresponded to those of an eight-month-old child, while her motor skills were at the level of an 18-month-old. Notable gait impairment was observed, with a wide-based crouch gait. The patient was also diagnosed with an autism spectrum disorder.Conclusion: Although rare, Dravet syndrome is an important differential diagnosis in children presenting with early-onset epilepsy and progressive developmental delays. It is essential to evaluate patients for common comor-bidities, such as autism, gait disorders, and intellectual disability, important determinants of patients’ quality of life.

Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation.

Neuronal hyperexcitability is a hallmark of epilepsy. It has been recently shown in rodent models of seizures that microglia, the brain's resident immune cells, can respond to and modulate neuronal excitability. However, how human microglia interact with human neurons to regulate hyperexcitability mediated by an epilepsy-causing genetic mutation found in patients is unknown. The SCN2A gene is responsible for encoding the voltage-gated sodium channel Nav1.2, one of the leading contributors to monogenic epilepsies. Previously, we demonstrated that the recurring Nav1.2-L1342P mutation leads to hyperexcitability in a male donor (KOLF2.1) hiPSC-derived cortical neuron model. Microglia originate from a different lineage (yolk sac) and are not naturally present in hiPSCs-derived neuronal cultures. To study how microglia respond to neurons carrying a disease-causing mutation and influence neuronal excitability, we established a co-culture model comprising hiPSC-derived neurons and microglia. We found that microglia display increased branch length and enhanced process-specific calcium signal when co-cultured with Nav1.2-L1342P neurons. Moreover, the presence of microglia significantly lowered the repetitive action potential firing and current density of sodium channels in neurons carrying the mutation. Additionally, we showed that co-culturing with microglia led to a reduction in sodium channel expression within the axon initial segment of Nav1.2-L1342P neurons. Furthermore, we demonstrated that Nav1.2-L1342P neurons release a higher amount of glutamate compared to control neurons. Our work thus reveals a critical role of human iPSCs-derived microglia in sensing and dampening hyperexcitability mediated by an epilepsy-causing mutation.Significance Statement Seizure studies in mouse models have highlighted the role of microglia in modulating neuronal activity, particularly in the promotion or suppression of seizures. However, a gap persists in comprehending the influence of human microglia on intrinsically hyperexcitable neurons carrying epilepsy-associated pathogenic mutations. This research addresses this gap by investigating human microglia and their impact on neuronal functions. Our findings demonstrate that microglia exhibit dynamic morphological alterations and calcium fluctuations in the presence of neurons carrying an epilepsy-associated SCN2A mutation. Furthermore, microglia suppressed the excitability of hyperexcitable neurons, suggesting a potential beneficial role. This study underscores the role of microglia in the regulation of abnormal neuronal activity, providing insights into therapeutic strategies for neurological conditions associated with hyperexcitability.

ESTUDO COMPARATIVO DOS EFEITOS COLATERAIS DO CANABIDIOL E OUTRAS DROGAS NO TRATAMENTO DE EPILEPSIA DO TIPO SÍNDROME DE DRAVET

Introduction: Dravet Syndrome is a complex neurological disorder that begins in the first months of life due to a mutation in the SCN1A gene. This syndrome is pharmacoresistant and requires specific medications to prevent worsening in the development of these children. Cannabidiol is a phytocannabinoid extracted from the Cannabis sativa plant that acts as a modulator in the endocannabinoid system. Objective: To compare conventional drugs with cannabidiol, their side effects, and the quality of life of patients after using cannabidiol. Method: This is an integrative literature review. The sources used were PubMed, ScienceDirect, and SCIELO. The searches were conducted using the descriptors: Cannabidiol, Dravet Syndrome, epilepsy, SCN1A gene mutation, CBD efficacy, mechanism of action, conventional drugs. Results: Of the 64 selected articles, 26 reported a significant reduction in seizure frequency; 6 did not yield favorable results regarding the use of cannabidiol in epilepsy treatment; 12 showed long-term efficacy of cannabidiol use; 12 reported benefits of cannabidiol use in children with Dravet Syndrome; and 8 indicated an improvement in quality of life. Conclusion: There is significant progress that cannabidiol has brought to patients with Dravet Syndrome, improving the quality of life for both patients and their caregivers. However, more studies, especially long-term, need to be conducted.

Abstract 4138514: From Treatment to Trigger: A Case of Atomoxetine-Induced Brugada Pattern

Introduction: Brugada syndrome is an inherited cardiac disorder characterized by specific ECG patterns, notably the coved-type ST-segment elevation in the right precordial leads (V1-V3), leading to an increased risk of sudden cardiac death. This condition often stems from mutations in the SCN5A gene, which impair cardiac sodium channel function. The manifestation of Brugada Pattern, showing typical ECG findings without clinical criteria like sudden cardiac arrest or syncope, is significant. We highlight a case where atomoxetine, a selective norepinephrine reuptake inhibitor used for ADHD, unveiled a type 1 Brugada pattern. Case Presentation: A 26-year-old male with a history of ADHD on atomoxetine only presented to the emergency department with sudden substernal chest pain radiating to his left arm. His initial ECG showed right bundle branch block and type 1 Brugada pattern (Figure.1). Despite normal troponin levels and a negative coronary CT angiography, the patient's ECG abnormalities raised concerns. With no personal or familial history of arrhythmia or SCD and no other medications, atomoxetine was suspected as the trigger. Upon discontinuation, the patient's ECG type 1 Brugada pattern resolved (Figure. 2), and he remained asymptomatic with a normal Holter monitor at a 1-month follow-up. Discussion: Brugada syndrome is marked by dynamic ECG abnormalities, which can surface due to triggers like fever, certain medications, and electrolyte imbalances. Atomoxetine, an ADHD treatment and selective norepinephrine reuptake inhibitor, affects the human cardiac sodium channel (hNav1.5), encoded by the SCN5A gene. This interaction can disrupt heart action potentials, leading to conditions like long QT syndrome and Brugada pattern, by slowing cardiomyocyte depolarization and conduction. Its effect on hNav1.5 resembles that of antidepressants like Fluoxetine, increasing the risk of Brugada pattern. In our case, a patient's type 1 Brugada pattern, with no underlying heart disease or family history, pointed to atomoxetine as the cause. Discontinuing the drug resolved the ECG abnormalities. Conclusion: This case emphasizes the importance of assessing cardiovascular risk before prescribing atomoxetine, especially in individuals at risk for cardiac sodium channel dysfunctions. Immediate intervention and monitoring are critical to prevent severe arrhythmias.

Genetic analysis of a child with Congenital insensitivity to pain due to compound heterozygous variants of SCN9A gene

To explore the genetic etiology of a child featuring multiple fractures and congenital insensitivity to pain (CIP). A child who had presented at the West China Hospital of Sichuan University on March 16, 2023 for recurrent fractures and CIP was selected as the study subject. Peripheral blood samples of the child and his parents was collected. Trio-whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. This study has been approved by the Medical Ethics Committee of West China Hospital of Sichuan University (No. 2019-772). Trio-whole exome sequencing revealed that the child has harbored compound heterozygous variants of the SCN9A gene, namely c.560delC (p.P187Rfs*15) and c.829C>T (p.R277*), which were respectively inherited from his father and mother. Homozygous c.829C>T variant had been demonstrated as pathogenic among CIP patients, whilst the c.560delC (p.P187Rfs*15) variant was unreported previously and predicted to be pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (ACMG). The child was diagnosed with CIP due to the compound heterozygous variants of the SCN9A gene. Above finding has enabled genetic counselling and reproductive guidance for this family.

The Yield of Genetic Testing and Putative Genetic Factors of Disease Heterogeneity in Long QT Syndrome Patients.

Genetic overdiagnosis of long QT syndrome (LQTS) becomes a critical concern due to the high clinical significance of DNA diagnosis. Current guidelines for LQTS genetic testing recommend a limited scope and strict referral based on the Schwartz score. Nevertheless, LQTS may be underdiagnosed in patients with borderline phenotypes. We aimed to evaluate the total yield of rare variants in cardiac genes in LQTS patients. The cohort of 82 patients with LQTS referral diagnosis underwent phenotyping, Schwartz score counting, and exome sequencing. We assessed known LQTS genes for diagnostics, as per guidelines, and a broader set of genes for research. Diagnostic testing yield reached 75% in index patients; all causal variants were found in KCNQ1, KCNH2, and SCN5A genes. Research testing of 248 heart-related genes achieved a 50% yield of molecular diagnosis in patients with a low Schwartz score (<3.5). In patients with LQTS-causing variants, each additional rare variant in heart-related genes added 0.94 points to the Schwartz score (p value = 0.04), reflecting the more severe disease in such patients than in those with causal variants but without additional findings. We conclude that the current LQTS genetic diagnosis framework is highly specific but may lack sensitivity for patients with a Schwartz score <3.5. Improving referral criteria for these patients could enhance DNA diagnosis. Also, our results suggest that additional variants in cardiac genes may affect the severity of the disease in the carriers of LQTS-causing variants, which may aid in identifying new modifier genes.