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Neurology Jan 2024Heterozygous variants in RAR-related orphan receptor B () have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have...
BACKGROUND AND OBJECTIVES
Heterozygous variants in RAR-related orphan receptor B () have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with pathogenic variants and to provide arguments in favor of the pathogenicity of variants.
METHODS
Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in . To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology.
RESULTS
We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in , including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function.
DISCUSSION
In most patients, the phenotype of the -related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.
Topics: Humans; Male; Animals; Mice; Child, Preschool; Child; Adolescent; Young Adult; Adult; Infant; Seizures; Phenotype; Epilepsy, Absence; Epilepsy, Generalized; Genotype; Intellectual Disability; Nuclear Receptor Subfamily 1, Group F, Member 2
PubMed: 38165337
DOI: 10.1212/WNL.0000000000207945 -
Cerebral Cortex (New York, N.Y. : 1991) Aug 2023Mutations of the voltage-gated sodium channel SCN1A gene (MIM#182389) are among the most clinically relevant epilepsy-related genetic mutations and present variable...
Mutations of the voltage-gated sodium channel SCN1A gene (MIM#182389) are among the most clinically relevant epilepsy-related genetic mutations and present variable phenotypes, from the milder genetic epilepsy with febrile seizures plus to Dravet syndrome, a severe developmental and epileptic encephalopathy. Qualitative neuroimaging studies have identified malformations of cortical development in some patients and mild atrophic changes, partially confirmed by quantitative studies. Precise correlations between MRI findings and clinical variables have not been addressed. We used morphometric methods and network-based models to detect abnormal brain structural patterns in 34 patients with SCN1A-related epilepsy, including 22 with Dravet syndrome. By measuring the morphometric characteristics of the cortical mantle and volume of subcortical structures, we found bilateral atrophic changes in the hippocampus, amygdala, and the temporo-limbic cortex (P-value < 0.05). By correlating atrophic patterns with brain connectivity profiles, we found the region of the hippocampal formation as the epicenter of the structural changes. We also observed that Dravet syndrome was associated with more severe atrophy patterns with respect to the genetic epilepsy with febrile seizures plus phenotype (r = -0.0613, P-value = 0.03), thus suggesting that both the underlying mutation and seizure severity contribute to determine atrophic changes.
Topics: Humans; NAV1.1 Voltage-Gated Sodium Channel; Seizures, Febrile; Epilepsies, Myoclonic; Epilepsy; Mutation; Phenotype
PubMed: 37344172
DOI: 10.1093/cercor/bhad224 -
The Neuroscientist : a Review Journal... Dec 2023Dravet syndrome is a severe developmental and epileptic encephalopathy mostly caused by heterozygous mutation of the gene encoding the voltage-gated sodium channel α... (Review)
Review
Dravet syndrome is a severe developmental and epileptic encephalopathy mostly caused by heterozygous mutation of the gene encoding the voltage-gated sodium channel α subunit Na1.1. Multiple seizure types, cognitive deterioration, behavioral disturbances, ataxia, and sudden unexpected death associated with epilepsy are a hallmark of the disease. Recently approved antiseizure medications such as fenfluramine and cannabidiol have been shown to reduce seizure burden. However, patients with Dravet syndrome are still medically refractory in the majority of cases, and there is a high demand for new therapies aiming to improve behavioral and cognitive outcome. Drug-repurposing approaches for -related Dravet syndrome are currently under investigation (i.e., lorcaserin, clemizole, and ataluren). New therapeutic concepts also arise from the field of precision medicine by upregulating functional or by activating Na1.1. These include antisense nucleotides directed against the nonproductive transcript of with the poison exon 20N and against an inhibitory noncoding antisense RNA of . Gene therapy approaches such as adeno-associated virus-based upregulation of using a transcriptional activator (ETX101) or CRISPR/dCas technologies show promising results in preclinical studies. Although these new treatment concepts still need further clinical research, they offer great potential for precise and disease modifying treatment of Dravet syndrome.
Topics: Humans; NAV1.1 Voltage-Gated Sodium Channel; Epilepsies, Myoclonic; Epilepsy; Seizures; Neurodevelopmental Disorders
PubMed: 35414300
DOI: 10.1177/10738584221088244 -
Indian Journal of Pediatrics Dec 2023Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare autosomal recessive disorder due to mutations in the ASAH1 gene. SMA-PME is characterized...
Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare autosomal recessive disorder due to mutations in the ASAH1 gene. SMA-PME is characterized by progressive muscle weakness from three to seven years of age, drug refractory epilepsy, and variable degree of cognitive decline. Nearly 50 cases have been reported worldwide so far. Here the authors present a case of 9-y-old boy affected by SMA-PME characterized by progressive proximal weakness, and lower motor neuron disease, as proven by muscle biopsy, electro diagnostic studies and whole exome sequencing (WES). WES revealed compound heterozygous missense variant in exon 12 of ASAH1 gene (chr8: g.18059385G>C) and exon 2 of ASAH1 gene (chr8: g.18075542T>C). Patient did not have cognitive decline and epilepsy and EEG record obtained was normal. In addition to reporting a novel variant in the ASAH1 gene causing SMA-PME disease, this paper discusses previous reports and literature of the disease.
PubMed: 38079070
DOI: 10.1007/s12098-023-04957-3 -
Epilepsia Open Sep 2023This study evaluated sleep and respiratory abnormalities, and their relationship with seizures, in adults with developmental and epileptic encephalopathies (DEEs). We...
This study evaluated sleep and respiratory abnormalities, and their relationship with seizures, in adults with developmental and epileptic encephalopathies (DEEs). We studied consecutive adults with DEEs undergoing inpatient video-EEG monitoring and concurrent polysomnography between December 2011 and July 2022. Thirteen patients with DEEs were included (median age: 31 years, range: 20-50; 69.2% female): Lennox-Gastaut syndrome (n = 6), Lennox-Gastaut syndrome-like phenotype (n = 2), Landau-Kleffner syndrome (n = 1), epilepsy with myoclonic-atonic seizures (n = 1), and unclassified DEEs (n = 3). Sleep architecture was often fragmented by epileptiform discharges and seizures resulting in arousals (median arousal index: 29.0 per h, range: 5.1-65.3). Moderate-to-severe obstructive sleep apnea (OSA) was observed in seven patients (53.8%). Three patients (23.1%) had tonic seizures that frequently occurred with central apnea; one met criteria for mild central sleep apnea. Of the patients with tonic seizures, two had other identifiable seizure manifestations, but in one patient, central apnea was commonly the only discernable seizure manifestation. Polysomnography during video-EEG is an effective diagnostic tool in detecting sleep and seizure-related respiratory abnormalities. Clinically significant OSA may increase the risk of comorbid cardiovascular disease and premature mortality. Treatment of epilepsy may improve sleep quality, and conversely, improved sleep, may decrease seizure burden.
Topics: Female; Male; Humans; Polysomnography; Lennox Gastaut Syndrome; Sleep Apnea, Central; Sleep; Seizures; Electroencephalography; Sleep Apnea, Obstructive
PubMed: 37277988
DOI: 10.1002/epi4.12772 -
Seminars in Pediatric Neurology Oct 2023Phillip L. Pearl Seminars in Pediatric Neurology Volume 23, Issue 2, May 2016, Pages 158-166 Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable...
Phillip L. Pearl Seminars in Pediatric Neurology Volume 23, Issue 2, May 2016, Pages 158-166 Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, including early onset epileptic encephalopathy (refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalop athy), infantile spasms, or mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood. The disorders are presented as vitamin responsive epilepsies such as pyridoxine, pyridoxal-5-phosphate, folinic acid, and biotin; transportopathies like GLUT-1, cerebral folate deficiency, and biotin thiamine responsive disorder; amino and organic acidopathies including serine synthesis defects, creatine synthesis disorders, molybdenum cofactor deficiency, and cobalamin deficiencies; mitochondrial disorders; urea cycle disorders; neurotransmitter defects; and disorders of glucose homeostasis. In each case, targeted intervention directed toward the underlying metabolic pathophysiology affords for the opportunity to significantly effect the outcome and prognosis of an otherwise severe pediatric epilepsy.
Topics: Infant, Newborn; Adolescent; Child; Humans; Biotin; Epilepsy; Seizures; Spasms, Infantile; Vitamins; Electroencephalography
PubMed: 37919041
DOI: 10.1016/j.spen.2023.101073 -
Epilepsia Apr 2024SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants...
OBJECTIVE
SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood.
METHODS
We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype.
RESULTS
DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS.
SIGNIFICANCE
Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.
Topics: Humans; Retrospective Studies; NAV1.1 Voltage-Gated Sodium Channel; Epilepsy; Epilepsies, Myoclonic; Seizures, Febrile; Phenotype; Genetic Association Studies; Status Epilepticus; Mutation
PubMed: 38410936
DOI: 10.1111/epi.17882 -
Neurobiology of Disease Sep 2023The progressive myoclonic epilepsies (PMEs) are a group of rare neurodegenerative diseases characterized by myoclonus, epileptic seizures, and progressive neurological... (Review)
Review
The progressive myoclonic epilepsies (PMEs) are a group of rare neurodegenerative diseases characterized by myoclonus, epileptic seizures, and progressive neurological deterioration with cerebellar involvement. They include storage diseases like Gaucher disease, Lafora disease, and forms of neuronal ceroid lipofuscinosis (NCL). To date, 13 NCLs have been reported (CLN1-CLN8, CLN10-CLN14), associated with mutations in different genes. These forms, which affect both children and adults, are characterized by seizures, cognitive and motor impairments, and in most cases visual loss. In NCLs, as in other PMEs, central nervous system (CNS) neurodegeneration is widespread and involves different subpopulations of neurons. One of the most affected regions is the cerebellar cortex, where motor and non-motor information is processed and transmitted to deep cerebellar nuclei through the axons of Purkinje cells (PCs). PCs, being GABAergic, have an inhibitory effect on their target neurons, and provide the only inhibitory output of the cerebellum. Degeneration of PCs has been linked to motor impairments and epileptic seizures. Seizures occur when some insult upsets the normal balance in the CNS between excitatory and inhibitory impulses, causing hyperexcitability. Here we review the role of PCs in epilepsy onset and progression following their PME-related loss. In particular, we focus on the involvement of PCs in seizure phenotype in NCLs, highlighting findings from case reports and studies of animal models in which epilepsy can be linked to PC loss.
Topics: Animals; Neuronal Ceroid-Lipofuscinoses; Purkinje Cells; Myoclonic Epilepsies, Progressive; Epilepsy; Seizures
PubMed: 37573956
DOI: 10.1016/j.nbd.2023.106258 -
Epilepsia Aug 2023This study was undertaken to evaluate perampanel (PER) when used under real-world conditions to treat people with idiopathic generalized epilepsy (IGE) included in the... (Clinical Trial)
Clinical Trial
OBJECTIVE
This study was undertaken to evaluate perampanel (PER) when used under real-world conditions to treat people with idiopathic generalized epilepsy (IGE) included in the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study.
METHODS
The multinational, retrospective, pooled analysis PERMIT explored the use of PER in people with focal and generalized epilepsy treated in clinical practice across 17 countries. This subgroup analysis included PERMIT participants with IGE. Time points for retention and effectiveness measurements were 3, 6, and 12 months (last observation carried forward, defined as "last visit," was also applied to effectiveness). Effectiveness was evaluated by seizure type (total seizures, generalized tonic-clonic seizures [GTCS], myoclonic seizures, absence seizures) and included ≥50% responder rate and seizure freedom rate (defined as no seizures since at least the previous visit). Safety/tolerability was monitored throughout PER treatment and evaluated by documenting the incidence of adverse events (AEs), including psychiatric AEs and those leading to treatment discontinuation.
RESULTS
The Full Analysis Set included 544 people with IGE (51.9% women, mean age = 33.3 years, mean epilepsy duration = 18.1 years). At 3, 6, and 12 months, 92.4%, 85.5%, and 77.3% of participants were retained on PER treatment, respectively (Retention Population, n = 497). At the last visit, responder and seizure freedom rates were, respectively, 74.2% and 54.6% (total seizures), 81.2% and 61.5% (GTCS), 85.7% and 66.0% (myoclonic seizures), and 90.5% and 81.0% (absence seizures) (Effectiveness Population, n = 467). AEs occurred in 42.9% of patients and included irritability (9.6%), dizziness/vertigo (9.2%), and somnolence (6.3%) (Tolerability Population, n = 520). Treatment discontinuation due to AEs was 12.4% over 12 months.
SIGNIFICANCE
This subgroup analysis of the PERMIT study demonstrated the effectiveness and good tolerability of PER in people with IGE when administered under everyday clinical practice conditions. These findings are in line with clinical trial evidence, supporting PER's use as broad-spectrum antiseizure medication for the treatment of IGE.
Topics: Adult; Female; Humans; Male; Anticonvulsants; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy, Absence; Epilepsy, Generalized; Immunoglobulin E; Pyridones; Retrospective Studies; Seizures; Treatment Outcome
PubMed: 37114853
DOI: 10.1111/epi.17631 -
Progressive Myoclonus Epilepsy: A Scoping Review of Diagnostic, Phenotypic and Therapeutic Advances.Genes Jan 2024The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe.... (Review)
Review
The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe. While each of the disorders is individually rare, they collectively make up a non-trivial portion of the complex epilepsy and myoclonus cases that are seen in tertiary care centers. The last decade has seen substantial progress in our understanding of the pathophysiology, diagnosis, prognosis, and, in select disorders, therapies of these diseases. In this scoping review, we examine English language publications from the past decade that address diagnostic, phenotypic, and therapeutic advances in all PMEs. We then highlight the major lessons that have been learned and point out avenues for future investigation that seem promising.
Topics: Humans; Myoclonus; Myoclonic Epilepsies, Progressive
PubMed: 38397161
DOI: 10.3390/genes15020171