RESUMO
We identified six novel de novo human KCNQ5 variants in children with motor/language delay, intellectual disability (ID), and/or epilepsy by whole exome sequencing. These variants, comprising two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported KCNQ5 missense variants (Lehman A, Thouta S, Mancini GM, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R; CAUSES Study; EPGEN Study; Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T. Am J Hum Genet 101: 65-74, 2017). Surprisingly, all eight missense variants resulted in gain of function (GOF) due to hyperpolarized voltage dependence of activation or slowed deactivation kinetics, whereas the two nonsense variants were confirmed to be loss of function (LOF). One severe GOF allele (P369T) was tested and found to extend a dominant GOF effect to heteromeric KCNQ5/3 channels. Clinical presentations were associated with altered KCNQ5 channel gating: milder presentations with LOF or smaller GOF shifts in voltage dependence [change in voltage at half-maximal conduction (ΔV50) = â¼-15 mV] and severe presentations with larger GOF shifts in voltage dependence (ΔV50 = â¼-30 mV). To examine LOF pathogenicity, two Kcnq5 LOF mouse lines were created with CRISPR/Cas9. Both lines exhibited handling- and thermal-induced seizures and abnormal cortical EEGs consistent with epileptiform activity. Our study thus provides evidence for in vivo KCNQ5 LOF pathogenicity and strengthens the contribution of both LOF and GOF mutations to global pediatric neurological impairment, including ID/epilepsy.NEW & NOTEWORTHY Six novel de novo human KCNQ5 variants were identified from children with neurodevelopmental delay, intellectual disability, and/or epilepsy. Expression of these variants along with four previously reported KCNQ5 variants from a similar cohort revealed GOF potassium channels, negatively shifted in V50 of activation and/or delayed deactivation kinetics. GOF is extended to KCNQ5/3 heteromeric channels, making these the predominant channels affected in heterozygous de novo patients. Kcnq5 LOF mice exhibited seizures, consistent with in vivo pathogenicity.
Assuntos
Epilepsia , Deficiência Intelectual , Animais , Criança , Cricetinae , Cricetulus , Epilepsia/genética , Células HEK293 , Humanos , Deficiência Intelectual/genética , Canais de Potássio KCNQ , Camundongos , Mutação de Sentido Incorreto , ConvulsõesRESUMO
The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Assuntos
Canais de Cálcio Tipo N/genética , Cálcio/metabolismo , Discinesias/genética , Epilepsia/genética , Mutação , Transmissão Sináptica , Adolescente , Criança , Pré-Escolar , Discinesias/patologia , Epilepsia/patologia , Feminino , Humanos , Lactente , Perda de Heterozigosidade , Masculino , LinhagemRESUMO
OBJECTIVE: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. METHODS: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. RESULTS: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. INTERPRETATION: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284.
Assuntos
Epilepsia/diagnóstico por imagem , Epilepsia/genética , Variação Genética/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Serina-Treonina Quinases/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Criança , Estudos de Coortes , Epilepsia/metabolismo , Feminino , Seguimentos , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas Serina-Treonina Quinases/biossíntese , Adulto JovemRESUMO
This study assessed the effectiveness of genetic testing in shortening the time to diagnosis of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Individuals who received epilepsy gene panel testing through Behind the Seizure® , a sponsored genetic testing program (Cohort A), were compared to children outside of the sponsored testing program during the same period (Cohort B). Two cohorts were analyzed: children aged ≥24 to ≤60 months with unprovoked seizure onset at ≥24 months between December 2016 and January 2020 (Cohort 1) and children aged 0 to ≤60 months at time of testing with unprovoked seizure onset at any age between February 2019 and January 2020 (Cohort 2). The diagnostic yield in Cohort 1A (n = 1814) was 8.4% (n = 153). The TPP1 diagnostic yield within Cohort 1A was 2.9-fold higher compared to Cohort 1B (1.0%, n = 18/1814 vs. .35%, n = 8/2303; p = .0157). The average time from first symptom to CLN2 disease diagnosis was significantly shorter than previously reported (9.8 vs. 22.7 months, p < .001). These findings indicate that facilitated access to early epilepsy gene panel testing helps to increase diagnostic yield for CLN2 disease and shortens the time to diagnosis, enabling earlier intervention.
Assuntos
Epilepsia , Lipofuscinoses Ceroides Neuronais , Aminopeptidases/genética , Criança , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Epilepsia/diagnóstico , Epilepsia/genética , Testes Genéticos , Humanos , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/genética , Convulsões/genética , Serina Proteases/genética , Tripeptidil-Peptidase 1RESUMO
OBJECTIVE: Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel KV 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. METHODS: We evaluated a series of 17 KCNB1 variants associated with DEE or other neurodevelopmental disorders (NDDs) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant KV 2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. RESULTS: Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage dependence of activation and/or inactivation, as homotetramers or when coexpressed with wild-type KV 2.1. Quantification of protein expression also identified variants with reduced total KV 2.1 expression or deficient cell-surface expression. INTERPRETATION: Our study establishes a platform for rapid screening of KV 2.1 functional defects caused by KCNB1 variants associated with DEE and other NDDs. This will aid in establishing KCNB1 variant pathogenicity and the mechanism of dysfunction, which will enable targeted strategies for therapeutic intervention based on molecular phenotype. ANN NEUROL 2019;86:899-912.
Assuntos
Variação Genética/genética , Ensaios de Triagem em Larga Escala/métodos , Transtornos do Neurodesenvolvimento/genética , Canais de Potássio Shab/genética , Sequência de Aminoácidos , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Transtornos do Neurodesenvolvimento/diagnóstico , Estrutura Secundária de Proteína , Canais de Potássio Shab/químicaRESUMO
Congenital disorders of glycosylation (CDG) are metabolic disorders that affect the glycosylation of proteins and lipids. Since glycosylation affects all organs, CDG show a wide spectrum of phenotypes. We present a patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type 1 serum transferrin isoelectrofocusing due to a novel CDG caused by a homozygous variant in the oligosaccharyltransferase complex noncatalytic subunit (OSTC) gene involved in glycosylation and confirmed by serum transferrin electrophoresis.
Assuntos
Defeitos Congênitos da Glicosilação/genética , Epilepsia/genética , Hexosiltransferases/genética , Proteínas de Membrana/genética , Defeitos Congênitos da Glicosilação/complicações , Defeitos Congênitos da Glicosilação/patologia , Epilepsia/complicações , Epilepsia/patologia , Feminino , Humanos , Lactente , Masculino , Mutação/genética , Fenótipo , Transferrina/genética , Sequenciamento do ExomaRESUMO
Epilepsy and intellectual disability are associated with rare variants in the GluN2A and GluN2B (encoded by GRIN2A and GRIN2B) subunits of the N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel with essential roles in brain development and function. By assessing genetic variation across GluN2 domains, we determined that the agonist binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation. Notably, the agonist binding domain of GluN2B exhibited significantly more variation intolerance than that of GluN2A. To understand the ramifications of missense variation in the agonist binding domain, we investigated the mechanisms by which 25 rare variants in the GluN2A and GluN2B agonist binding domains dysregulated NMDAR activity. When introduced into recombinant human NMDARs, these rare variants identified in individuals with neurologic disease had complex, and sometimes opposing, consequences on agonist binding, channel gating, receptor biogenesis, and forward trafficking. Our approach combined quantitative assessments of these effects to estimate the overall impact on synaptic and non-synaptic NMDAR function. Interestingly, similar neurologic diseases were associated with both gain- and loss-of-function variants in the same gene. Most rare variants in GluN2A were associated with epilepsy, whereas GluN2B variants were associated with intellectual disability with or without seizures. Finally, discerning the mechanisms underlying NMDAR dysregulation by these rare variants allowed investigations of pharmacologic strategies to correct NMDAR function.
Assuntos
Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Epilepsia/genética , Exoma/genética , Ácido Glutâmico/metabolismo , Humanos , Deficiência Intelectual/genética , Modelos Moleculares , Mutação de Sentido Incorreto , Neurônios/metabolismo , Ligação Proteica/genética , Domínios Proteicos/genética , Transporte Proteico , Receptores de N-Metil-D-Aspartato/química , Convulsões/genéticaRESUMO
RATIONALE: Early-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts. METHODS: Children with newly diagnosed epilepsy and onset <3â¯years were prospectively recruited through 17 US hospitals, from 2012 to 2015 and followed for 1â¯year after diagnosis. Short-term outcome included mortality, drug resistance, evolution of nonsyndromic epilepsy to infantile spasms (IS) and from IS to other epilepsies, and developmental decline. Multivariable analyses assessed the risk of each outcome. RESULTS: Seven hundred seventy-five children were recruited, including 408 (53%) boys. Median age at onset was 7.5â¯months (interquartile range (IQR): 4.2-16.5), and 509 (66%) had onset in the first year of life. Of 22 deaths that occurred within one year of epilepsy diagnosis, 21 were children with epilepsy onset in infancy (<12â¯months). Of 680 children followed ≥6â¯months, 239 (35%) developed drug-resistant seizures; 34/227 (15%) infants with nonsyndromic epilepsy developed IS, and 48/210 (23%) initially presenting with IS developed additional seizure types. One hundred of 435 (23%) with initially typical development or only mild/equivocal delays at seizure onset, had clear developmental impairment within one year after initial diagnosis. Each outcome had a different set of predictors; however, younger age and impaired development at seizure onset were broadly indicative of poorer outcomes. Type of epilepsy and early identification of underlying cause were not reliable predictors of these outcomes. CONCLUSION: Early-life epilepsies carry a high risk of poor outcome which is evident shortly after epilepsy diagnosis. Onset in infancy and developmental delay is associated with an especially high risk, regardless of epilepsy type. The likelihood of poor outcomes is worrisome regardless of specific clinical profiles.
Assuntos
Deficiências do Desenvolvimento/etiologia , Espasmos Infantis , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Resistência a Medicamentos , Feminino , Humanos , Lactente , Masculino , Análise Multivariada , Prognóstico , Estudos Prospectivos , Convulsões/complicações , Convulsões/tratamento farmacológico , Espasmos Infantis/complicações , Espasmos Infantis/tratamento farmacológicoRESUMO
OBJECTIVE: The aim of this study was to investigate periictal central apnea as a seizure semiological feature, its localizing value, and possible relationship with sudden unexpected death in epilepsy (SUDEP) pathomechanisms. METHODS: We prospectively studied polygraphic physiological responses, including inductance plethysmography, peripheral capillary oxygen saturation (SpO2 ), electrocardiography, and video electroencephalography (VEEG) in 473 patients in a multicenter study of SUDEP. Seizures were classified according to the International League Against Epilepsy (ILAE) 2017 seizure classification based on the most prominent clinical signs during VEEG. The putative epileptogenic zone was defined based on clinical history, seizure semiology, neuroimaging, and EEG. RESULTS: Complete datasets were available in 126 patients in 312 seizures. Ictal central apnea (ICA) occurred exclusively in focal epilepsy (51/109 patients [47%] and 103/312 seizures [36.5%]) (P < .001). ICA was the only clinical manifestation in 16/103 (16.5%) seizures, and preceded EEG seizure onset by 8 ± 4.9 s, in 56/103 (54.3%) seizures. ICA ≥60 s was associated with severe hypoxemia (SpO2 <75%). Focal onset impaired awareness (FOIA) motor onset with automatisms and FOA nonmotor onset semiologies were associated with ICA presence (P < .001), ICA duration (P = .002), and moderate/severe hypoxemia (P = .04). Temporal lobe epilepsy was highly associated with ICA in comparison to extratemporal epilepsy (P = .001) and frontal lobe epilepsy (P = .001). Isolated postictal central apnea was not seen; in 3/103 seizures (3%), ICA persisted into the postictal period. SIGNIFICANCE: ICA is a frequent, self-limiting semiological feature of focal epilepsy, often starting before surface EEG onset, and may be the only clinical manifestation of focal seizures. However, prolonged ICA (≥60 s) is associated with severe hypoxemia and may be a potential SUDEP biomarker. ICA is more frequently seen in temporal than extratemporal seizures, and in typical temporal seizure semiologies. ICA rarely persists after seizure end. ICA agnosia is typical, and thus it may remain unrecognized without polygraphic measurements that include breathing parameters.
Assuntos
Apneia/diagnóstico , Apneia/epidemiologia , Convulsões/diagnóstico , Convulsões/epidemiologia , Apneia/fisiopatologia , Morte Súbita/prevenção & controle , Eletroencefalografia/tendências , Feminino , Humanos , Incidência , Masculino , Estudos Prospectivos , Convulsões/fisiopatologiaRESUMO
OBJECTIVE: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients. METHODS: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects. RESULTS: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg). SIGNIFICANCE: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.
Assuntos
Epilepsias Mioclônicas/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia/complicações , Ataxia/genética , Ataxia/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Epilepsias Parciais/complicações , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/complicações , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Resultado do Tratamento , Ácido Valproico/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
Assuntos
Encefalopatias/genética , Mutação/genética , Receptores de N-Metil-D-Aspartato/genética , Encefalopatias/tratamento farmacológico , Heterozigoto , Humanos , Imageamento por Ressonância Magnética , Memantina/uso terapêutico , Terapia de Alvo Molecular , Neuroimagem , Fenótipo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Variants in KCNQ2 encoding for Kv 7.2 neuronal K+ channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2-related epilepsy: infantile spasms without prior neonatal seizures associated with a gain-of-function gene variant. With use of an international registry, we identified four unrelated patients with the same de novo heterozygous KCNQ2 c.593G>A, p.Arg198Gln (R198Q) variant. All were born at term and discharged home without seizures or concern of encephalopathy, but developed infantile spasms with hypsarrhythmia (or modified hypsarrhythmia) between the ages of 4 and 6 months. At last follow-up (ages 3-11 years), all patients were seizure-free and had severe developmental delay. In vitro experiments showed that Kv7.2 R198Q subunits shifted current activation gating to hyperpolarized potentials, indicative of gain-of-function; in neurons, Kv 7.2 and Kv 7.2 R198Q subunits similarly populated the axon initial segment, suggesting that gating changes rather than altered subcellular distribution contribute to disease molecular pathogenesis. We conclude that KCNQ2 R198Q is a model for a new subclass of KCNQ2 variants causing infantile spasms and encephalopathy, without preceding neonatal seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Assuntos
Encefalopatias/genética , Canal de Potássio KCNQ2/genética , Mutação/genética , Espasmos Infantis/genética , Animais , Arginina/genética , Células CHO , Células Cultivadas , Criança , Pré-Escolar , Cricetulus , Glutamina/genética , Hipocampo/citologia , Humanos , Lactente , Estudos Longitudinais , Potenciais da Membrana/genética , Modelos Moleculares , Neurônios/fisiologia , Ratos , TransfecçãoRESUMO
OBJECTIVE: Hypsarrhythmia is the classic interictal electroencephalographic pattern associated with infantile spasms, and characterized by high voltage, disorganization, and multifocal independent epileptiform discharges. Given this seemingly simple definition, one might expect excellent interrater reliability (IRR) in the identification of this pattern. Alternatively, it may be argued that assessments of voltage and disorganization are fairly subjective, and thus quite challenging in borderline cases. We sought to test the IRR of hypsarrhythmia assessment in a systematic fashion. METHODS: Six blinded pediatric electroencephalographers from four centers reviewed 22 electroencephalography (EEG) samples from patients with infantile spasms. Each sample was 5 min in duration and included only wakefulness. Raters determined if each EEG was abnormal and if hypsarrhythmia was present/absent, and characterized relevant features: voltage, organization, epileptiform discharges, slowing, interictal attenuations, symmetry, and synchrony. In addition, raters indicated their level of confidence for each assessment. Multirater kappa statistics (κ) were calculated for the assessment of hypsarrhythmia and each feature. RESULTS: Although IRR was favorable in determining whether a study was normal or abnormal (κ=0.89), reliability was unfavorable for assessment of hypsarrhythmia (κ=0.40), modified hypsarrhythmia (κ=0.47), high voltage (κ=0.37), disorganization (κ=0.22), multifocal epileptiform discharges (κ=0.68), interictal voltage attenuations (κ=0.21), slowing (κ=0.20), asymmetry (κ=0.26), and asynchrony (κ=0.08). Despite generally unsatisfactory interrater agreement, raters consistently reported high confidence in assessments. SIGNIFICANCE: This study contradicts the view that hypsarrhythmia assessment is straightforward. Even small variability in the identification of hypsarrhythmia has potentially deleterious consequences for clinical care, as its presence or absence impacts decisions to pursue high-risk and high-cost therapies. These inconsistencies may similarly confound studies in which abolition of hypsarrhythmia is an outcome measure. There is a great need for practical, reliable, and unbiased measures of hypsarrhythmia.
Assuntos
Eletroencefalografia/estatística & dados numéricos , Neurologia/normas , Espasmos Infantis/diagnóstico , Pré-Escolar , Ensaios Clínicos como Assunto/normas , Humanos , Lactente , Variações Dependentes do Observador , Reprodutibilidade dos TestesRESUMO
Many generalized tonic-clonic seizures are accompanied by profound autonomic changes. However, autonomic seizures and autonomic status epilepticus can also be seen with specific electroclinical syndromes (Panayiotopoulos syndrome), etiologies, and localizations. Such autonomic symptoms may impact cardiorespiratory function. While it is likely that several factors contribute to SUDEP, further study of both ictal respiratory and cardiac changes and underlying neuroanatomical mechanisms involved in autonomic seizure semiology are likely to provide important data to improve our understanding of the pathophysiology of this devastating condition. This paper will review the association between autonomic symptoms and epileptic seizures and will highlight the work of three young investigators. Drs. Lisa Bateman and Brian Moseley will review their work on cardiorespiratory effects of recorded seizures and how this assists in our understanding of SUDEP. Dr. John Millichap will review autonomic seizures and autonomic dysfunctions related to childhood epilepsy and will discuss the importance of expanded research efforts in this field.
Assuntos
Doenças do Sistema Nervoso Autônomo/etiologia , Morte Súbita/etiologia , Epilepsia/complicações , Convulsões/complicações , Animais , HumanosRESUMO
Pathogenic variants in voltage-gated sodium (NaV) channel genes including SCN2A, encoding NaV1.2, are discovered frequently in neurodevelopmental disorders with or without epilepsy. SCN2A is also a high-confidence risk gene for autism spectrum disorder (ASD) and nonsyndromic intellectual disability (ID). Previous work to determine the functional consequences of SCN2A variants yielded a paradigm in which predominantly gain-of-function variants cause neonatal-onset epilepsy, whereas loss-of-function variants are associated with ASD and ID. However, this framework was derived from a limited number of studies conducted under heterogeneous experimental conditions, whereas most disease-associated SCN2A variants have not been functionally annotated. We determined the functional properties of SCN2A variants using automated patch-clamp recording to demonstrate the validity of this method and to examine whether a binary classification of variant dysfunction is evident in a larger cohort studied under uniform conditions. We studied 28 disease-associated variants and 4 common variants using two alternatively spliced isoforms of NaV1.2 expressed in HEK293T cells. Automated patch-clamp recording provided a valid high throughput method to ascertain detailed functional properties of NaV1.2 variants with concordant findings for variants that were previously studied using manual patch clamp. Many epilepsy-associated variants in our study exhibited complex patterns of gain- and loss-of-functions that are difficult to classify by a simple binary scheme. The higher throughput achievable with automated patch clamp enables study of variants with greater standardization of recording conditions, freedom from operator bias, and enhanced experimental rigor. This approach offers an enhanced ability to discern relationships between channel dysfunction and neurodevelopmental disorders.
Assuntos
Transtorno do Espectro Autista , Epilepsia , Transtornos do Neurodesenvolvimento , Humanos , Transtorno do Espectro Autista/genética , Epilepsia/genética , Células HEK293 , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Transtornos do Neurodesenvolvimento/genética , FenótipoRESUMO
Lennox-Gastaut syndrome (LGS) is a severe, chronic, complex form of early childhood-onset epilepsy characterized by multiple seizure types, generalized slow (≤2.5 Hz) spike-and-wave activity and other electroencephalography abnormalities, and cognitive impairment. A key treatment goal is early seizure control, and several anti-seizure medications (ASMs) are available. Due to the low success rate in achieving seizure control with monotherapy and an absence of efficacy data supporting any particular combination of ASMs for treating LGS, a rational approach to selection of appropriate polytherapy should be applied to maximize benefit to patients. Such "rational polytherapy" involves consideration of factors including safety (including boxed warnings), potential drug-drug interactions, and complementary mechanisms of action. Based on the authors' clinical experience, rufinamide offers a well-considered first adjunctive therapy for LGS, particularly in combination with clobazam and other newer agents for LGS, and may be particularly useful for reducing the frequency of tonic-atonic seizures associated with LGS.
Assuntos
Síndrome de Lennox-Gastaut , Humanos , Pré-Escolar , Síndrome de Lennox-Gastaut/tratamento farmacológico , Prova Pericial , Triazóis/uso terapêutico , Clobazam/uso terapêutico , Anticonvulsivantes/uso terapêuticoRESUMO
Objective: In a randomized trial, we aimed to evaluate the efficacy of cosyntropin injectable suspension, 1â mg/mL, compared to vigabatrin for infantile spasms syndrome. An additional arm was included to assess the efficacy of combination therapy (cosyntropin and vigabatrin) compared with cosyntropin monotherapy. Methods: Children (2 months to 2 years) with new-onset infantile spasms syndrome and hypsarhythmia were randomized into 3 arms: cosyntropin, vigabatrin, and cosyntropin and vigabatrin combined. Daily seizures and adverse events were recorded, and EEG was repeated at day 14 to assess for resolution of hypsarhythmia. The primary outcome measure was the composite of resolution of hypsarhythmia and absence of clinical spasms at day 14. Fisher exact test was used to compare outcomes. Results: 37 children were enrolled and 34 were included in the final efficacy analysis (1 withdrew prior to treatment and 2 did not return seizure diaries). Resolution of both hypsarhythmia and clinical spasms was achieved in in 9 of 12 participants (75%) treated with cosyntropin, 1/9 (11%) vigabatrin, and 5/13 (38%) cosyntropin and vigabatrin combined. The primary comparison of cosyntropin versus vigabatrin was significant (64% [95% confidence interval 21, 82], P < .01). Adverse events were reported in all 3 treatment arms: 31 (86%) had an adverse event, 7 (19%) had a serious adverse event, and 15 (42%) had an adverse event of special interest with no difference between treatment arms. Significance: This randomized trial was underpowered because of incomplete enrollment, yet it demonstrated that cosyntropin was more effective for short-term outcomes than vigabatrin as initial treatment for infantile spasms.
Assuntos
Espasmos Infantis , Vigabatrina , Anticonvulsivantes/efeitos adversos , Criança , Cosintropina/uso terapêutico , Humanos , Estudos Prospectivos , Espasmo/induzido quimicamente , Espasmo/complicações , Espasmo/tratamento farmacológico , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/etiologia , Resultado do Tratamento , Vigabatrina/efeitos adversosRESUMO
In 2020, the mission of Pediatric Neurology Briefs (PNB) remains the same: "PNB is a continuing education service designed to expedite and facilitate the review of current scientific research and advances in child neurology and related subjects."
RESUMO
Literature review of patients with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) reveals, based on 16 reports including 139 patients, a clinical phenotype that includes age- and disease-specific stereotyped seizures. The typical seizure type of KCNQ2-DEE, focal tonic, starts within 0-5 days of life and is readily captured by video-electroencephalography VEEG for clinical and genetic diagnosis. After initial identification, KCNQ2-DEE seizures are clinically apparent and can be clearly identified without the use of EEG or VEEG. Therefore, we propose that the 2019 recommendations from the International League against Epilepsy (ILAE), the Pediatric Epilepsy Research Consortium (PERC), for capturing and recording seizures for clinical trials (Epilepsia Open, 4, 2019, 537) are suitable for use in KCNQ2-DEEâassociated antiseizure medicine (ASM) treatment trials. The ILAE/PERC consensus guidance states that a caregiver-maintained seizure diary, completed by caregivers who are trained to recognize seizures using within-patient historical recordings, accurately captures seizures prospectively in a clinical trial. An alternative approach historically endorsed by the Food and Drug Administration (FDA) compares seizure counts captured on VEEG before and after treatment. A major advantage of the ILAE/PERC strategy is that it expands the numbers of eligible patients who meet inclusion criteria of clinical trials while maintaining accurate seizure counts (Epilepsia Open, 4, 2019, 537). Three recent phase 3 pivotal pediatric trials investigating ASMs to treat syndromic seizures in patients as young as 2 years of age (N Engl J Med, 17, 2017, 699; Lancet, 21, 2020, 2243; Lancet, 17, 2018, 1085); and ongoing phase 2 open-label pediatric clinical trial that includes pediatric epileptic syndromes as young as 1 month of age (Am J Med Genet A, 176, 2018, 773), have already used caregiver-maintained seizure diaries successfully. For determining the outcome of a KCNQ2-DEE ASM treatment trial, the use of a seizure diary to count seizures by trained observers is feasible because the seizures of KCNQ2-DEE are clinically apparent. This strategy is supported by successful precedent in clinical trials in similar age groups and has the endorsement of the international pediatric epilepsy community.
Assuntos
Encefalopatias/genética , Síndromes Epilépticas/genética , Canal de Potássio KCNQ2/genética , Convulsões , Gravação em Vídeo , Ensaios Clínicos como Assunto , Diários como Assunto , Eletroencefalografia , Humanos , Lactente , Recém-Nascido , Pediatria , Estudos Prospectivos , Convulsões/classificação , Convulsões/diagnóstico , Convulsões/genética , Estados UnidosRESUMO
Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells (iPSCs) and gene editing to establish a disease model and measured the functional properties of differentiated excitatory neurons. We find that patient iPSC-derived neurons exhibit faster action potential repolarization, larger post-burst afterhyperpolarization and a functional enhancement of Ca2+-activated K+ channels. These properties, which can be recapitulated by chronic inhibition of M-current in control neurons, facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. Our findings suggest that dyshomeostatic mechanisms compound KCNQ2 loss-of-function leading to alterations in the neurodevelopmental trajectory of patient iPSC-derived neurons.