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Brain Communications 2023Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion...
Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in , encoding β1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, c.265C>T, predicting -p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic c.265C>T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in p.R89C to the mouse locus (). We then rederived the line on the C57BL/6J background to allow comparisons between and littermates with and mice, which are congenic on C57BL/6J, to determine whether the c.265C>T variant results in loss-of-function. mice have normal body weights and ∼20% premature mortality, compared with severely reduced body weight and 100% mortality in mice. β1-p.R89C polypeptides are expressed in brain at comparable levels to wild type. In heterologous cells, β1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wild type. Heterologous expression of β1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of , , and was increased in somatosensory cortex, with no changes in . In contrast, mouse somatosensory cortex is haploinsufficient for , suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. mice are more susceptible to hyperthermia-induced seizures at post-natal Day 15 compared with littermates. EEG recordings detected epileptic discharges in young adult mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult mice that had been exposed to hyperthermia at post-natal Day 15 versus a subset that were not hyperthermia exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the c.265C>T variant does not result in complete loss-of-function. mice more accurately model -linked variants with incomplete loss-of-function compared with mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.
PubMed: 38425576
DOI: 10.1093/braincomms/fcad283 -
Tropical Doctor Oct 2023Post-hypoxic myoclonus (PHM) is a rare neurological complication having two different variants depending on acute or chronic onset after cardiopulmonary resuscitation... (Review)
Review
Post-hypoxic myoclonus (PHM) is a rare neurological complication having two different variants depending on acute or chronic onset after cardiopulmonary resuscitation following cardiac arrest: myoclonic status epilepticus (MSE) and Lance-Adams syndrome (LAS) respectively. Clinical and simultaneous electro-encephalographic (EEG) and electromyographic (EMG) tracing can distinguish between the two. Anecdotal treatment with benzodiazepines and anaesthetics (in the case of MSE) have been tried. Although limited evidence is available, valproic acid, clonazepam and levetiracetam, either in combination with other drugs or alone, have shown to control epilepsy associated with LAS effectively. Deep brain stimulation is a novel and promising advance in LAS treatment.
Topics: Humans; Myoclonus; Hypoxia; Clonazepam; Cardiopulmonary Resuscitation; Valproic Acid; Syndrome
PubMed: 37287278
DOI: 10.1177/00494755231181153 -
Epilepsy & Behavior : E&B Sep 2023Idiopathic generalized epilepsy (IGE) is a common epilepsy syndrome with early age onset and generally good seizure outcomes. This study aims to determine the incidence... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Idiopathic generalized epilepsy (IGE) is a common epilepsy syndrome with early age onset and generally good seizure outcomes. This study aims to determine the incidence and predictive risk factors for drug-resistant IGE.
METHODS
We systematically searched three databases (PubMed, Embase, and Cochrane Library) in November 2022 and included 12 eligible studies which reported long-term outcomes (mean = 14.05) after antiseizure medications (ASMs) from 2001 to 2020. We defined drug resistance as the persistence of any seizure despite ASMs treatment (whether as monotherapies or in combination) given the criteria of drug resistance varied in original studies. A random-effects model was used to evaluate the prevalence of refractory IGE. Studies reporting potential poor prognostic factors were included for subsequent subgroup meta-analysis.
RESULTS
The pooled prevalence of drug resistance in IGE cohorts was 27% (95% CI: 0.19-0.36). Subgroup analysis of the risk factors revealed that the psychiatric comorbidities (odds ratio (OR): 4.87, 95% confidence interval (CI): 2.97-7.98), combined three seizure types (absences, myoclonic jerks, and generalized tonic-clonic seizures) (OR: 5.37, 95% CI: 3.16-9.13), the presence of absence seizure (OR: 4.38, 95% CI: 2.64-7.28), generalized polyspike trains (GPT) (OR: 4.83, 95% CI: 2.42-9.64), sex/catamenial epilepsy (OR: 3.25, 95% CI: 1.97-5.37), and status epilepticus (OR: 5.94, 95% CI: 2.23-15.85) increased the risk of poor prognosis. Other factors, including age onset, family history, and side effects of ASMs, were insignificantly associated with a higher incidence of refractory IGE.
CONCLUSION
Drug resistance is a severe complication of IGE. Further standardized research about clinical and electroencephalography factors is warranted.
Topics: Humans; Anticonvulsants; Prevalence; Epilepsy, Generalized; Seizures; Drug Resistant Epilepsy; Risk Factors; Immunoglobulin E
PubMed: 37523796
DOI: 10.1016/j.yebeh.2023.109364 -
Clinical Neurophysiology : Official... Apr 2024To test the hypothesis that myoclonic seizures can evolve to tonic seizures, we documented the electroclinical features of this under-recognized seizure type.
BACKGROUND AND PURPOSE
To test the hypothesis that myoclonic seizures can evolve to tonic seizures, we documented the electroclinical features of this under-recognized seizure type.
METHODS
We observed a distinct seizure pattern starting with myoclonus without returning to an interictal state, which subsequently evolved into generalized tonic seizures. The detailed symptomatic and electroencephalographic characteristics of this seizure were extracted, and the clinical manifestations, drug curative responses in patients with this seizure were reviewed and analyzed.
RESULTS
The onset of all seizures was characterized by a preceding period of myoclonus and bursts of generalized spike or poly-spike slow wave discharges with high amplitude. This was closely followed by the occurrence of tonic seizures, which were distinguished by bursts of generalized fast activity at 10 Hz or higher frequency. This under-recognized seizure type has been designated as myoclonic-to-tonic (MT) seizure. The number of patients identified with MT seizures in this study was 34. The prevalence rate of MT seizures was found to be higher in males. While MT seizures typically included a tonic component, it should be noted that some patients experiencing this seizure type never presented with isolated tonic seizures. Generalized Epilepsy not further defined (GE) accounted for approximately one-third of the diagnosed cases, followed by Lennox-Gastaut syndrome and Epilepsy with Myoclonic-Atonic seizures. In comparison to other types of epilepsy, GE with MT seizures demonstrated a more favorable prognosis.
CONCLUSIONS
The classification of myoclonic-to-tonic seizure represents a novel approach in comprehending the ictogenesis of generalized seizures and can provide valuable assistance to clinicians in epilepsy diagnosis.
PubMed: 38823261
DOI: 10.1016/j.clinph.2024.04.011 -
Brain : a Journal of Neurology Sep 2023Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core...
Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. The polygenic risk score for intelligence was lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors.
Topics: Humans; NAV1.1 Voltage-Gated Sodium Channel; Epilepsies, Myoclonic; Epilepsy; Phenotype; Genomics
PubMed: 37006128
DOI: 10.1093/brain/awad111 -
Epilepsia Aug 2023The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is...
The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome-wide molecular studies on remaining, well-selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole-exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype-phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.
Topics: Humans; Child; Myoclonic Epilepsies, Progressive; Seizures; Epilepsies, Myoclonic; Genotype; Movement Disorders; Carrier Proteins; Nuclear Proteins
PubMed: 36810721
DOI: 10.1111/epi.17557 -
Frontiers in Neuroscience 2023is one of the most common monogenic causes of epilepsy and is a well-established cause of neurodevelopmental disorders. -neurodevelopmental disorders have a consistent...
INTRODUCTION
is one of the most common monogenic causes of epilepsy and is a well-established cause of neurodevelopmental disorders. -neurodevelopmental disorders have a consistent phenotype of mild to severe intellectual disability (ID), epilepsy, language delay and behavioral disorders. This phenotypic description is mainly based on knowledge from the pediatric population.
METHOD
Here, we sought to describe patients with variants and age above 18 years through the ascertainment of published and unpublished patients. Unpublished patients were ascertained through international collaborations, while previously published patients were collected through a literature search.
RESULTS
A total of 15 adult patients with variants were included. 9/13 patients had moderate to severe ID (data not available in two). Epilepsy was prevalent (11/15) with seizure types such as absence, myoclonic, atonic, and tonic-clonic seizures. Epilepsy was refractory in 7/11, while four patients were seizure free with lamotrigine, valproate, or lamotrigine in combination with valproate. Language development was severely impaired in five patients. Behavioral disorders were reported in and mainly consisted of autism spectrum disorders and aggressive behavior. Schizophrenia was not reported in any of the patients.
DISCUSSION
The phenotype displayed in the adult patients presented here resembled that of the pediatric cohort with ID, epilepsy, and behavioral disturbances, indicating that the phenotype of -NDD is consistent over time. Seizures were refractory in >60% of the patients with epilepsy, indicating the lack of targeted treatment in -NDDs. With increased focus on repurposing drugs and on the development of new treatments, hope is that the outlook reflected here will change over time. ID appeared to be more severe in the adult patients, albeit this might reflect a recruitment bias, where only patients seen in specialized centers were included or it might be a feature of the natural history of -NDDs. This issue warrants to be explored in further studies in larger cohorts.
PubMed: 37662110
DOI: 10.3389/fnins.2023.1216653 -
Revue Neurologique Apr 2024The ILAE's Task Force on Nosology and Definitions revised in 2022 its definition of juvenile myoclonic epilepsy (JME), the most common idiopathic generalized epilepsy... (Review)
Review
The ILAE's Task Force on Nosology and Definitions revised in 2022 its definition of juvenile myoclonic epilepsy (JME), the most common idiopathic generalized epilepsy disorder, but this definition may well change again in the future. Although good drug response could almost be a diagnostic criterion for JME, drug resistance (DR) is observed in up to a third of patients. It is important to distinguish this from pseudoresistance, which is often linked to psychosocial problems or psychiatric comorbidities. After summarizing these aspects and the various definitions applied to JME, the present review lists the risk factors for DR-JME that have been identified in numerous studies and meta-analyses. The factors most often cited are absence seizures, young age at onset, and catamenial seizures. By contrast, photosensitivity seems to favor good treatment response, at least in female patients. Current hypotheses on DR mechanisms in JME are based on studies of either simple (e.g., cortical excitability) or more complex (e.g., anatomical and functional connectivity) neurophysiological markers, bearing in mind that JME is regarded as a neural network disease. This research has revealed correlations between the intensity of some markers and DR, and above all shed light on the role of these markers in associated neurocognitive and neuropsychiatric disorders in both patients and their siblings. Studies of neurotransmission have mainly pointed to impaired GABAergic inhibition. Genetic studies have generally been inconclusive. Increasing restrictions have been placed on the use of valproate, the standard antiseizure medication for this syndrome, owing to its teratogenic and developmental risks. Levetiracetam and lamotrigine are prescribed as alternatives, as is vagal nerve stimulation, and there are several other promising antiseizure drugs and neuromodulation methods. The development of better alternative treatments is continuing to take place alongside advances in our knowledge of JME, as we still have much to learn and understand.
Topics: Humans; Myoclonic Epilepsy, Juvenile; Anticonvulsants; Drug Resistant Epilepsy; Female; Risk Factors
PubMed: 38461125
DOI: 10.1016/j.neurol.2024.02.385 -
Acta Neurologica Belgica Apr 2024Familial Adult Myoclonus Epilepsy (FAME), with a prevalence of < 1/35 000, is known under different acronyms. The disease is transmitted in an autosomal dominant... (Review)
Review
Familial Adult Myoclonus Epilepsy (FAME), with a prevalence of < 1/35 000, is known under different acronyms. The disease is transmitted in an autosomal dominant manner and is characterized by the occurrence of cortical myoclonic tremor, overt myoclonus, and rare bilateral tonic-clonic seizures. FAME is considered neurodegenerative, although it is relatively slow in progression. Diagnosis is based on specific neurophysiological testing, namely jerk-locked back-averaging, somatosensory evoked potentials, long latency reflex, and motor evoked potentials, among others. Imaging data, including functional magnetic resonance imaging, indicate a cortical origin of the cortical myoclonic tremor and decreased cerebellar activation. Cerebellar changes in Purkinje cells have been noted, from few neuropathology reports, in patients from isolated pedigrees. The differential diagnosis includes essential tremor, some forms of genetic generalized epilepsy, and progressive myoclonus epilepsies. Treatment is mainly symptomatic.
Topics: Adult; Humans; Myoclonus; Tremor; Epilepsies, Myoclonic; Evoked Potentials, Somatosensory; Reflex; Electroencephalography
PubMed: 38114875
DOI: 10.1007/s13760-023-02432-6