RARE DISEASE
Myoclonic epilepsy of infancy
Myoclonic epilepsy of infancy
Myoclonic epilepsy of infancy
Synonyms: Benign myoclonic epilepsy of infancy, Benign myoclonus epilepsy of infancy
Synonyms: Benign myoclonic epilepsy of infancy, Benign myoclonus epilepsy of infancy
Synonyms: Benign myoclonic epilepsy of infancy, Benign myoclonus epilepsy of infancy
Drug discovery
0
drugs
With orphan designations
Overview
Myoclonic epilepsy of infancy (MEI) is a rare, self-limited genetic generalized epilepsy characterized by brief myoclonic seizures starting between 6 months and 3 years of age. Seizures may occur spontaneously or be reflex-triggered (e.g., noise, touch) [1][2][6]. Most cases show excellent response to anti-seizure medications, with remission typically within 5 years, though 30% develop mild cognitive impairment [1][7][15]. Neuroimaging is normal, and EEG shows generalized spike-and-wave discharges [1][11].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
190 drug discovery papers about Myoclonic epilepsy of infancy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
190 drug discovery papers about Myoclonic epilepsy of infancy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-03-15 | The Genetic Facets of Dravet Syndrome: Recent Insights
Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is a severe epileptic syndrome affecting children, with an incidence of 1/22,000 to 1/49,900 live births annually. Characterized by resistant and prolonged seizures, it often leads to intellectual impairment, with males being twice as susceptible as females. Its clinical features include recurrent seizures triggered by fever initially, but later occurring spontaneously, developmental delays, behavioral issues, and movement disorders. Sodium voltage-gated channel alpha subunit 1 (SCN1A) mutations, observed in about 90% of cases, are usually de novo, while mutations in other genes, such as protocadherin 19 (PCDH19), gamma-aminobutyric acid type A receptor subunit gamma 2 (GABRG2), and sodium voltage-gated channel alpha subunit 2 (SCN2A), can also contribute to the condition. Next-generation sequencing aids in identifying these genetic abnormalities. First-line treatments include anticonvulsant drugs such as valproate, clobazam, stiripentol, topiramate, and bromide. Second-line treatments for drug-resistant DS include stiripentol, fenfluramine, and cannabidiol. This literature review provides a comprehensive update on the genetic underpinnings of DS, highlighting SCN1A's predominant role and the emerging significance of other genes. Moreover, it emphasizes novel therapeutic approaches for drug-resistant forms, showcasing the efficacy of newer drugs such as stiripentol, fenfluramine, and cannabidiol. This synthesis contributes to our understanding of the genetic landscape of DS and informs clinicians about evolving treatment strategies for enhanced patient care.
2023-12-04 | Epileptic seizures worsen the gait and motor abnormalities in adult patients with Dravet syndrome (with a case report and literature review).
Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is considered the most serious "epileptic encephalopathy." Here, we present a man with a de novo SCN1A mutation who was diagnosed with DS at the age of 29. In addition to pharmaco-resistant seizures and cognitive delay, he also developed moderate to severe motor and gait problems, such as crouching gait and Pisa syndrome. Moreover, it deteriorated significantly following an epileptic seizure. The patient presented with severe flexion of the head and trunk in the sagittal plane and fulfilled the diagnostic criteria for camptocormia and antecollis. After a week, it spontaneously alleviated partially. We applied levodopa to the patient and had a good response. Functional Gait Assessment (FGA) was assessed at three different times: 4 days after the seizure, 1 week after the seizure, and after taking levodopa for 2 years. The results were 4, 12, and 19 points, respectively. We postulated that: (1) gait and motor deficits are somehow influenced by recurrent epileptic episodes;(2) the nigrostriatal dopamine system is involved. To our knowledge, we were the ones who first reported this phenomenon.
2023-08-04 | Case analysis of epilepsy, neurodevelopmental disorder, and motor disorders associated with mutations in the dehydrodolichyl diphosphate synthase gene.
The objective of this study is to analyze the role of dehydrodolichyl diphosphate synthase (DHDDS), a crucial enzyme in the mevalonate pathway, and its encoded mutations in the onset of developmental delay and seizures, with or without movement abnormalities. Its genotype-phenotype characteristics are still inconclusive. We analyzed the clinical characteristics of epilepsy, and neurodevelopmental and motor disorders related to DHDDS gene mutations and report the genotype-phenotype characteristics of a child with epilepsy caused by DHDDS gene mutation, providing a summary and a statistical analysis of epilepsy cases associated with DHDDS gene mutation up until February 2022. Using "DHDDS; epilepsy; neurodevelopmental disorder" as the keywords, the literature relevant to DHDDS gene mutations up until February 2022 was reviewed. A total of 25 cases were retrieved, among which 21 cases with complete data were included in the chi-squared test. The clinical characteristics of DHDDS gene-related cases were summarized and analyzed. The onset of epilepsy caused by mutations of the DHDDS gene typically occurs during infancy. Predominantly, the mutation occurs in the locus of c.632G>A p.R211Q. Myoclonus is frequently the initial manifestation of epilepsy; it frequently coexists with neurodevelopmental disorder and intellectual disability, and patients have no specific type of motor disorder. Cranial magnetic resonance imaging (MRI) reveals no abnormalities, whereas electroencephalogram (EEG) frequently exhibits abnormalities. Valproic acid (VPA) yields good curative effects. Mutations in the DHDDS gene are associated with congenital glycosylation disorder, autosomal recessive retinitis pigmentosa, and epilepsy. According to statistical analysis using the chi-squared test, for pediatric patients with mutations in this gene locus, most of the epilepsy types are myoclonic epilepsies with intellectual disability and neurodevelopmental disorders. They have normal brain MRIs and abnormal EEGs. VPA produces beneficial therapeutic results and the differences are all statistically significant. The current diagnosis still relies on next-generation sequencing or whole-exome sequencing.
2023-02-03 | An infant sleep electroencephalographic marker of thalamocortical connectivity predicts behavioral outcome in late infancy
Infancy represents a critical period during which thalamocortical brain connections develop and mature. Deviations in the maturation of thalamocortical connectivity are linked to neurodevelopmental disorders. There is a lack of early biomarkers to detect and localize neuromaturational deviations, which can be overcome with mapping through high-density electroencephalography (hdEEG) assessed in sleep. Specifically, slow waves and spindles in non-rapid eye movement (NREM) sleep are generated by the thalamocortical system, and their characteristics, slow wave slope and spindle density, are closely related to neuroplasticity and learning. Spindles are often subdivided into slow (11.0-13.0 Hz) and fast (13.5-16.0 Hz) frequencies, for which not only different functions have been proposed, but for which also distinctive developmental trajectories have been reported across the first years of life. Recent studies further suggest that information processing during sleep underlying sleep-dependent learning is promoted by the temporal coupling of slow waves and spindles, yet slow wave-spindle coupling remains unexplored in infancy. Thus, we evaluated three potential biomarkers: 1) slow wave slope, 2) spindle density, and 3) the temporal coupling of slow waves with spindles. We use hdEEG to first examine the occurrence and spatial distribution of these three EEG features in healthy infants and second to evaluate a predictive relationship with later behavioral outcomes. We report four key findings: First, infants' EEG features appear locally: slow wave slope is maximal in occipital and frontal areas, whereas slow and fast spindle density is most pronounced frontocentrally. Second, slow waves and spindles are temporally coupled in infancy, with maximal coupling strength in the occipital areas of the brain. Third, slow wave slope, fast spindle density, and slow wave-spindle coupling are not associated with concurrent behavioral status (6 months). Fourth, fast spindle density in central and frontocentral regions at age 6 months predicts overall developmental status at age 12 months, and motor skills at age 12 and 24 months. Neither slow wave slope nor slow wave-spindle coupling predict later behavioral development. We further identified spindle frequency as a determinant of slow and fast spindle density, which accordingly, also predicts motor skills at 24 months. Our results propose fast spindle density, or alternatively spindle frequency, as early EEG biomarker for identifying thalamocortical maturation, which can potentially be used for early diagnosis of neurodevelopmental disorders in infants. These findings are in support of a role of sleep spindles in sensorimotor microcircuitry development. A crucial next step will be to evaluate whether early therapeutic interventions may be effective to reverse deviations in identified individuals at risk.
2021-09-03 | Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies
Developmental and epileptic encephalopathies (DEEs) are the most severe group of drug-resistant epilepsies. Alternatives to oral therapies are urgently needed to reduce seizures and improve developmental outcomes and comorbidities in this medically complex population.To assess the safety and tolerability of cannabidiol (CBD) transdermal gel in children with DEEs and to evaluate seizure frequency, sleep, and quality of life.This nonrandomized controlled trial was conducted in 2 centers in Australia and New Zealand from April 2018 to July 2019. Children and adolescents aged 3 to 18 years with DEEs who were receiving a stable regimen of 1 to 4 antiseizure medications were eligible for this study. After 1-month baseline and titration periods, patients entered a 5.5-month flexible-dosing maintenance period for a total of 6.5 months of treatment. Data were analyzed throughout the 6.5-month treatment period.Twice-daily applications of CBD transdermal gel at doses of 125 to 500 mg for 6.5 months.Safety and tolerability assessments included adverse events (AEs) and examination of skin. The outcome for seizures was the median percentage change from baseline in monthly (28-day) seizure frequency of focal impaired awareness seizures (FIAS) and tonic-clonic seizures (TCS) over 6.5 months.Of 48 patients (mean [SD] age, 10.5 [3.8] years; 26 [54%] boys), 29 (60%) had at least 1 treatment-related AE over 6.5 months; 44 of 46 treatment-related AEs (96%) were mild or moderate. Treatment-related AEs that occurred in at least 5% of patients were application-site dryness, application-site pain, and somnolence (each reported by 4 patients [8%]). The only treatment-related gastrointestinal AE was diarrhea, reported in a single patient. CBD treatment was associated with reductions in FIAS and TCS frequency. Analysis of the 33 patients with FIAS and TCS showed a median (interquartile range) monthly reduction in seizures of 58% (-5.3% to 81.8%) at 5 months and 43.5% (-23.8% to 57.5%) over the entire 6.5-month study period. Parents and caregivers noted improvements in social or interpersonal engagement and irritability (33 of 43 [77%] participants); alertness, energy, and sleep (23 of 43 [53%]); and cognition or concentration (20 of 43 [47%]).In this study, CBD transdermal gel was safe, well tolerated, and was associated with reductions in FIAS and TCS frequency and disease burden.ClinicalTrials.gov Identifier: ACTRN12618000516280.
gene therapies
2024-01-12 | Clinical and Genetic Features of Dravet Syndrome: A Prime Example of the Role of Precision Medicine in Genetic Epilepsy.
Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.
2015-06-18 | Book Review
Epileptic Encephalopathies & Related Syndromes in Children [ [1] Mukhin K. Yu Mirinov M.B. Petrukhin A.S. Holtahausen H. Epileptic encephalopathies: & related syndromes in children. John Libbey Eurotext, London2015 Google Scholar ] is a timely and comprehensive book illustrating this group of severe brain disorders in which cognitive, sensory, and motor development is impaired by recurrent clinical seizures or prominent interictal epileptiform discharges. They include Ohtahara syndrome, early myoclonic epileptic encephalopathy, West syndrome, malignant migrating partial seizures in infancy, Dravet syndrome, Lennox–Gastaut syndrome, myoclonic atonic epilepsy, continuous spike–wave in slow sleep, and other conditions. This large group of nosologies are generally related to early age and manifest with multiform and intractable seizures and EEG paroxysmal activity that is often aggressive. The etiopathology of epileptic encephalopathies has not been fully elucidated. It may be multiple and not necessarily the same for all [ [2] Panayiotopoulos C.P. A clinical guide to epileptic syndromes and their treatment. 2nd ed. Springer, London2007 Google Scholar ]. The major determinant is the brain functional and structural immaturity, with a ‘cause–effect’ interaction between abnormal electrical discharges generated by and modifying/acting upon neuronal circuits in development. In addition, rare but treatable metabolic disorders such as pyridoxine dependency, folinic acid-responsive seizures, and disorders of glucose transport should also be considered before antiepileptic treatment. However, now that increasing numbers of genetic causes of EE are being discovered, we should start targeting the underlying cause rather than the symptoms. Indeed, several gene mutations have been recently identified in patients with epileptic encephalopathies, including CDKL5, SCN1A, and PCDH19 mutations [ [3] Striano P. de Jonghe P. Zara F. Genetic epileptic encephalopathies: is all written into the DNA?. Epilepsia. 2013; 54: 22-26 Crossref PubMed Scopus (18) Google Scholar ].
2007-07-31 | The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy
The mammalian genome contains four voltage-gated sodium channel genes that are primarily expressed in the central nervous system: SCN1A, SCN2A, SCN3A and SCN8A. Mutations in SCN1A and SCN2A are responsible for several dominant idiopathic epilepsy disorders, including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). Mutations in SCN8A are associated with cognitive deficits and neuropsychiatric illness in humans and movement disorders in mice; however, a role for SCN8A (Nav1.6) in epilepsy has not been investigated. To determine the relationship between Nav1.6 dysfunction and seizure susceptibility, we examined the thresholds of two Scn8a mouse mutants, Scn8amed and Scn8amed-jo, to flurothyl- and kainic acid (KA)-induced seizures. Both mutants were more seizure resistant than wild-type littermates, suggesting that altered Nav1.6 function reduces neuronal excitability. To determine whether impaired Nav1.6 function could ameliorate seizure severity in a mouse model of SMEI, we generated Scn1a+/−; Scn8amed-jo/+ double heterozygous mice. Unlike Scn1a+/− mice that are more susceptible to flurothyl-induced seizures, Scn1a+/−; Scn8amed-jo/+ mice displayed thresholds that were comparable to wild-type littermates. The Scn8amed-jo allele was also able to rescue the premature lethality of Scn1a+/− mice and extend the lifespan of Scn1a−/− mutants. These results demonstrate that genetic interactions can alter seizure severity and support the hypothesis that genetic modifiers contribute to the clinical variability observed in SMEI and GEFS+.
small molecules
2024-03-15 | The Genetic Facets of Dravet Syndrome: Recent Insights
Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is a severe epileptic syndrome affecting children, with an incidence of 1/22,000 to 1/49,900 live births annually. Characterized by resistant and prolonged seizures, it often leads to intellectual impairment, with males being twice as susceptible as females. Its clinical features include recurrent seizures triggered by fever initially, but later occurring spontaneously, developmental delays, behavioral issues, and movement disorders. Sodium voltage-gated channel alpha subunit 1 (SCN1A) mutations, observed in about 90% of cases, are usually de novo, while mutations in other genes, such as protocadherin 19 (PCDH19), gamma-aminobutyric acid type A receptor subunit gamma 2 (GABRG2), and sodium voltage-gated channel alpha subunit 2 (SCN2A), can also contribute to the condition. Next-generation sequencing aids in identifying these genetic abnormalities. First-line treatments include anticonvulsant drugs such as valproate, clobazam, stiripentol, topiramate, and bromide. Second-line treatments for drug-resistant DS include stiripentol, fenfluramine, and cannabidiol. This literature review provides a comprehensive update on the genetic underpinnings of DS, highlighting SCN1A's predominant role and the emerging significance of other genes. Moreover, it emphasizes novel therapeutic approaches for drug-resistant forms, showcasing the efficacy of newer drugs such as stiripentol, fenfluramine, and cannabidiol. This synthesis contributes to our understanding of the genetic landscape of DS and informs clinicians about evolving treatment strategies for enhanced patient care.
2023-12-04 | Epileptic seizures worsen the gait and motor abnormalities in adult patients with Dravet syndrome (with a case report and literature review).
Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is considered the most serious "epileptic encephalopathy." Here, we present a man with a de novo SCN1A mutation who was diagnosed with DS at the age of 29. In addition to pharmaco-resistant seizures and cognitive delay, he also developed moderate to severe motor and gait problems, such as crouching gait and Pisa syndrome. Moreover, it deteriorated significantly following an epileptic seizure. The patient presented with severe flexion of the head and trunk in the sagittal plane and fulfilled the diagnostic criteria for camptocormia and antecollis. After a week, it spontaneously alleviated partially. We applied levodopa to the patient and had a good response. Functional Gait Assessment (FGA) was assessed at three different times: 4 days after the seizure, 1 week after the seizure, and after taking levodopa for 2 years. The results were 4, 12, and 19 points, respectively. We postulated that: (1) gait and motor deficits are somehow influenced by recurrent epileptic episodes;(2) the nigrostriatal dopamine system is involved. To our knowledge, we were the ones who first reported this phenomenon.
2023-08-04 | Case analysis of epilepsy, neurodevelopmental disorder, and motor disorders associated with mutations in the dehydrodolichyl diphosphate synthase gene.
The objective of this study is to analyze the role of dehydrodolichyl diphosphate synthase (DHDDS), a crucial enzyme in the mevalonate pathway, and its encoded mutations in the onset of developmental delay and seizures, with or without movement abnormalities. Its genotype-phenotype characteristics are still inconclusive. We analyzed the clinical characteristics of epilepsy, and neurodevelopmental and motor disorders related to DHDDS gene mutations and report the genotype-phenotype characteristics of a child with epilepsy caused by DHDDS gene mutation, providing a summary and a statistical analysis of epilepsy cases associated with DHDDS gene mutation up until February 2022. Using "DHDDS; epilepsy; neurodevelopmental disorder" as the keywords, the literature relevant to DHDDS gene mutations up until February 2022 was reviewed. A total of 25 cases were retrieved, among which 21 cases with complete data were included in the chi-squared test. The clinical characteristics of DHDDS gene-related cases were summarized and analyzed. The onset of epilepsy caused by mutations of the DHDDS gene typically occurs during infancy. Predominantly, the mutation occurs in the locus of c.632G>A p.R211Q. Myoclonus is frequently the initial manifestation of epilepsy; it frequently coexists with neurodevelopmental disorder and intellectual disability, and patients have no specific type of motor disorder. Cranial magnetic resonance imaging (MRI) reveals no abnormalities, whereas electroencephalogram (EEG) frequently exhibits abnormalities. Valproic acid (VPA) yields good curative effects. Mutations in the DHDDS gene are associated with congenital glycosylation disorder, autosomal recessive retinitis pigmentosa, and epilepsy. According to statistical analysis using the chi-squared test, for pediatric patients with mutations in this gene locus, most of the epilepsy types are myoclonic epilepsies with intellectual disability and neurodevelopmental disorders. They have normal brain MRIs and abnormal EEGs. VPA produces beneficial therapeutic results and the differences are all statistically significant. The current diagnosis still relies on next-generation sequencing or whole-exome sequencing.
2023-02-03 | An infant sleep electroencephalographic marker of thalamocortical connectivity predicts behavioral outcome in late infancy
Infancy represents a critical period during which thalamocortical brain connections develop and mature. Deviations in the maturation of thalamocortical connectivity are linked to neurodevelopmental disorders. There is a lack of early biomarkers to detect and localize neuromaturational deviations, which can be overcome with mapping through high-density electroencephalography (hdEEG) assessed in sleep. Specifically, slow waves and spindles in non-rapid eye movement (NREM) sleep are generated by the thalamocortical system, and their characteristics, slow wave slope and spindle density, are closely related to neuroplasticity and learning. Spindles are often subdivided into slow (11.0-13.0 Hz) and fast (13.5-16.0 Hz) frequencies, for which not only different functions have been proposed, but for which also distinctive developmental trajectories have been reported across the first years of life. Recent studies further suggest that information processing during sleep underlying sleep-dependent learning is promoted by the temporal coupling of slow waves and spindles, yet slow wave-spindle coupling remains unexplored in infancy. Thus, we evaluated three potential biomarkers: 1) slow wave slope, 2) spindle density, and 3) the temporal coupling of slow waves with spindles. We use hdEEG to first examine the occurrence and spatial distribution of these three EEG features in healthy infants and second to evaluate a predictive relationship with later behavioral outcomes. We report four key findings: First, infants' EEG features appear locally: slow wave slope is maximal in occipital and frontal areas, whereas slow and fast spindle density is most pronounced frontocentrally. Second, slow waves and spindles are temporally coupled in infancy, with maximal coupling strength in the occipital areas of the brain. Third, slow wave slope, fast spindle density, and slow wave-spindle coupling are not associated with concurrent behavioral status (6 months). Fourth, fast spindle density in central and frontocentral regions at age 6 months predicts overall developmental status at age 12 months, and motor skills at age 12 and 24 months. Neither slow wave slope nor slow wave-spindle coupling predict later behavioral development. We further identified spindle frequency as a determinant of slow and fast spindle density, which accordingly, also predicts motor skills at 24 months. Our results propose fast spindle density, or alternatively spindle frequency, as early EEG biomarker for identifying thalamocortical maturation, which can potentially be used for early diagnosis of neurodevelopmental disorders in infants. These findings are in support of a role of sleep spindles in sensorimotor microcircuitry development. A crucial next step will be to evaluate whether early therapeutic interventions may be effective to reverse deviations in identified individuals at risk.
2021-09-03 | Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies
Developmental and epileptic encephalopathies (DEEs) are the most severe group of drug-resistant epilepsies. Alternatives to oral therapies are urgently needed to reduce seizures and improve developmental outcomes and comorbidities in this medically complex population.To assess the safety and tolerability of cannabidiol (CBD) transdermal gel in children with DEEs and to evaluate seizure frequency, sleep, and quality of life.This nonrandomized controlled trial was conducted in 2 centers in Australia and New Zealand from April 2018 to July 2019. Children and adolescents aged 3 to 18 years with DEEs who were receiving a stable regimen of 1 to 4 antiseizure medications were eligible for this study. After 1-month baseline and titration periods, patients entered a 5.5-month flexible-dosing maintenance period for a total of 6.5 months of treatment. Data were analyzed throughout the 6.5-month treatment period.Twice-daily applications of CBD transdermal gel at doses of 125 to 500 mg for 6.5 months.Safety and tolerability assessments included adverse events (AEs) and examination of skin. The outcome for seizures was the median percentage change from baseline in monthly (28-day) seizure frequency of focal impaired awareness seizures (FIAS) and tonic-clonic seizures (TCS) over 6.5 months.Of 48 patients (mean [SD] age, 10.5 [3.8] years; 26 [54%] boys), 29 (60%) had at least 1 treatment-related AE over 6.5 months; 44 of 46 treatment-related AEs (96%) were mild or moderate. Treatment-related AEs that occurred in at least 5% of patients were application-site dryness, application-site pain, and somnolence (each reported by 4 patients [8%]). The only treatment-related gastrointestinal AE was diarrhea, reported in a single patient. CBD treatment was associated with reductions in FIAS and TCS frequency. Analysis of the 33 patients with FIAS and TCS showed a median (interquartile range) monthly reduction in seizures of 58% (-5.3% to 81.8%) at 5 months and 43.5% (-23.8% to 57.5%) over the entire 6.5-month study period. Parents and caregivers noted improvements in social or interpersonal engagement and irritability (33 of 43 [77%] participants); alertness, energy, and sleep (23 of 43 [53%]); and cognition or concentration (20 of 43 [47%]).In this study, CBD transdermal gel was safe, well tolerated, and was associated with reductions in FIAS and TCS frequency and disease burden.ClinicalTrials.gov Identifier: ACTRN12618000516280.
gene therapies
2024-01-12 | Clinical and Genetic Features of Dravet Syndrome: A Prime Example of the Role of Precision Medicine in Genetic Epilepsy.
Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.
2015-06-18 | Book Review
Epileptic Encephalopathies & Related Syndromes in Children [ [1] Mukhin K. Yu Mirinov M.B. Petrukhin A.S. Holtahausen H. Epileptic encephalopathies: & related syndromes in children. John Libbey Eurotext, London2015 Google Scholar ] is a timely and comprehensive book illustrating this group of severe brain disorders in which cognitive, sensory, and motor development is impaired by recurrent clinical seizures or prominent interictal epileptiform discharges. They include Ohtahara syndrome, early myoclonic epileptic encephalopathy, West syndrome, malignant migrating partial seizures in infancy, Dravet syndrome, Lennox–Gastaut syndrome, myoclonic atonic epilepsy, continuous spike–wave in slow sleep, and other conditions. This large group of nosologies are generally related to early age and manifest with multiform and intractable seizures and EEG paroxysmal activity that is often aggressive. The etiopathology of epileptic encephalopathies has not been fully elucidated. It may be multiple and not necessarily the same for all [ [2] Panayiotopoulos C.P. A clinical guide to epileptic syndromes and their treatment. 2nd ed. Springer, London2007 Google Scholar ]. The major determinant is the brain functional and structural immaturity, with a ‘cause–effect’ interaction between abnormal electrical discharges generated by and modifying/acting upon neuronal circuits in development. In addition, rare but treatable metabolic disorders such as pyridoxine dependency, folinic acid-responsive seizures, and disorders of glucose transport should also be considered before antiepileptic treatment. However, now that increasing numbers of genetic causes of EE are being discovered, we should start targeting the underlying cause rather than the symptoms. Indeed, several gene mutations have been recently identified in patients with epileptic encephalopathies, including CDKL5, SCN1A, and PCDH19 mutations [ [3] Striano P. de Jonghe P. Zara F. Genetic epileptic encephalopathies: is all written into the DNA?. Epilepsia. 2013; 54: 22-26 Crossref PubMed Scopus (18) Google Scholar ].
2007-07-31 | The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy
The mammalian genome contains four voltage-gated sodium channel genes that are primarily expressed in the central nervous system: SCN1A, SCN2A, SCN3A and SCN8A. Mutations in SCN1A and SCN2A are responsible for several dominant idiopathic epilepsy disorders, including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). Mutations in SCN8A are associated with cognitive deficits and neuropsychiatric illness in humans and movement disorders in mice; however, a role for SCN8A (Nav1.6) in epilepsy has not been investigated. To determine the relationship between Nav1.6 dysfunction and seizure susceptibility, we examined the thresholds of two Scn8a mouse mutants, Scn8amed and Scn8amed-jo, to flurothyl- and kainic acid (KA)-induced seizures. Both mutants were more seizure resistant than wild-type littermates, suggesting that altered Nav1.6 function reduces neuronal excitability. To determine whether impaired Nav1.6 function could ameliorate seizure severity in a mouse model of SMEI, we generated Scn1a+/−; Scn8amed-jo/+ double heterozygous mice. Unlike Scn1a+/− mice that are more susceptible to flurothyl-induced seizures, Scn1a+/−; Scn8amed-jo/+ mice displayed thresholds that were comparable to wild-type littermates. The Scn8amed-jo allele was also able to rescue the premature lethality of Scn1a+/− mice and extend the lifespan of Scn1a−/− mutants. These results demonstrate that genetic interactions can alter seizure severity and support the hypothesis that genetic modifiers contribute to the clinical variability observed in SMEI and GEFS+.
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