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OBJECTIVE: To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS). METHODS: All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE-SWAS and EE-SWAS. Brain-specific gene co-expression analysis was performed for D/EE-SWAS genes. RESULTS: We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE-SWAS and 13/47 (28%) with EE-SWAS. A genetic etiology was identified in 31/91 (34%). D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE-SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS. INTERPRETATION: DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE-SWAS and EE-SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024.
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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, χ2 = 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.
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Epilepsias Mioclônicas , Epilepsia , Convulsões Febris , Estado Epiléptico , Humanos , Estudos Retrospectivos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Epilepsia/genética , Epilepsia/diagnóstico , Epilepsias Mioclônicas/genética , Convulsões Febris/genética , Fenótipo , Estudos de Associação Genética , Mutação/genéticaRESUMO
PRKACA and PRKACB code for two catalytic subunits (Cα and Cß) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cß subunits of PKA during human development.
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Anormalidades Múltiplas/genética , Disfunção Cognitiva/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Dedos/anormalidades , Mutação em Linhagem Germinativa , Defeitos dos Septos Cardíacos/genética , Polidactilia/genética , Dedos do Pé/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Animais , Sequência de Bases , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , AMP Cíclico/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/química , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/deficiência , Feminino , Dedos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Defeitos dos Septos Cardíacos/diagnóstico , Defeitos dos Septos Cardíacos/patologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Holoenzimas/química , Holoenzimas/deficiência , Holoenzimas/genética , Humanos , Recém-Nascido , Masculino , Camundongos , Modelos Moleculares , Mosaicismo , Células NIH 3T3 , Linhagem , Polidactilia/diagnóstico , Polidactilia/patologia , Estrutura Secundária de Proteína , Dedos do Pé/patologiaRESUMO
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.
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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
Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs.1-3 This suggests that unknown genetic etiologies exist, potentially in the â¼98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a "poison" exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons,4,5 including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly.6 Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics.
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Epilepsias Mioclônicas/genética , Epilepsia/genética , Éxons/genética , Variação Genética/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/genética , Canais de Sódio/genética , Transcriptoma/genéticaRESUMO
OBJECTIVE: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. METHODS: We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. RESULTS: We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81). INTERPRETATION: Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020;87:281-288.
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Predisposição Genética para Doença/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões Febris/genética , Vacinas/efeitos adversos , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Estudos ProspectivosRESUMO
OBJECTIVE: The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6-month-old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year. SCN1A pathogenic variants are found in >80% of patients. Many patients have atypical features resulting in diagnostic delay and inappropriate therapy. We aimed to provide an evidence-based definition of SCN1A-Dravet syndrome in readiness for precision medicine trials. METHODS: Epilepsy patients were recruited to the University of Melbourne Epilepsy Genetics Research Program between 1995 and 2020 by neurologists from around the world. Patients with SCN1A pathogenic variants were reviewed and only those with Dravet syndrome were included. Clinical data, including seizure and developmental course, were analyzed in all patients with SCN1A-Dravet syndrome. RESULTS: Two hundred and five patients were studied at a median age of 8.5 years (range 10 months to 60 years); 25 were deceased. The median seizure-onset age was 5.7 months (range 1.5-20.6 months). Initial seizures were tonic-clonic (52%) and hemiclonic (35%), with only 55% being associated with fever. Only 34% of patients presented with status epilepticus (seizure lasting ≥30 minutes). Median time between first and second seizure was 30 days (range 4 hours to 8 months), and seven patients (5%) had at least 6 months between initial seizures. Median ages at onset of second and third seizure types were 9.1 months (range 3 months-25.4 years) and 15.5 months (range 4 months-8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%. SIGNIFICANCE: An evidence-based definition of SCN1A-Dravet syndrome is essential for early diagnosis. We refine the spectrum of Dravet syndrome, based on patterns of seizure onset, type, and progression. Understanding of the full spectrum of SCN1A-Dravet syndrome presentation is essential for early diagnosis and optimization of treatment, especially as precision medicine trials become available.
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Epilepsias Mioclônicas , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Tardio , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Epilepsia , Síndromes Epilépticas , Humanos , Lactente , Pessoa de Meia-Idade , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Medicina de Precisão , Convulsões , Espasmos Infantis , Adulto JovemRESUMO
Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.
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Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Epilepsias Mioclônicas Progressivas/genética , Proteínas Ligases SKP Culina F-Box/genética , Espasmos Infantis/genética , Adolescente , Adulto , Encefalopatias/complicações , Encefalopatias/genética , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Códon sem Sentido , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/fisiopatologia , Epilepsia Resistente a Medicamentos/complicações , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletroencefalografia , Síndromes Epilépticas/complicações , Síndromes Epilépticas/genética , Síndromes Epilépticas/fisiopatologia , Feminino , Mutação da Fase de Leitura , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto , Epilepsias Mioclônicas Progressivas/complicações , Epilepsias Mioclônicas Progressivas/fisiopatologia , Fenótipo , Espasmos Infantis/complicações , Espasmos Infantis/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
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Deficiências do Desenvolvimento/epidemiologia , Epilepsias Mioclônicas/epidemiologia , Espasmos Infantis/epidemiologia , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/fisiopatologia , Progressão da Doença , Eletroencefalografia , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/fisiopatologia , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/epidemiologia , Síndromes Epilépticas/etiologia , Síndromes Epilépticas/fisiopatologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Síndrome de Lennox-Gastaut/tratamento farmacológico , Síndrome de Lennox-Gastaut/epidemiologia , Síndrome de Lennox-Gastaut/etiologia , Síndrome de Lennox-Gastaut/fisiopatologia , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/epidemiologia , Malformações do Desenvolvimento Cortical/cirurgia , Mortalidade , Índice de Gravidade de Doença , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/etiologia , Espasmos Infantis/fisiopatologia , Vitória/epidemiologiaRESUMO
AIM: The objective of the study was to delineate the cognitive, behavioral, psychological, and social functioning of individuals with Dravet syndrome. METHOD: Cognitive, behavioral, and social functioning were assessed in patients with Dravet syndrome by comprehensive, age-appropriate standardized neuropsychological testing. Primary caregivers completed standardized measures regarding participants' behavior, psychological status, adaptive functioning, and social skills, including their involvement with intervention services. RESULTS: The cohort comprised 45 patients, aged 2-30â¯years. Intellectual functioning ranged from average intellect to profound intellectual disability, with a decrease in cognitive and adaptive functioning with age. Only 6 children were able to complete the entire neuropsychological battery and showed a range of cognitive profiles. Five of 6 participants scored within the average range on Affect Recognition and 5/6 on Motor Free Visual Perception tests. Twenty-one (58%) participants had deficits in social skills and 18/27 (67%) in social communication, with 10 participants, who did not yet have a diagnosis of autism spectrum disorder (ASD), screening positive for social communication deficits. Behavioral problems were frequently reported, with attention problems in 24 (65%) and atypicality in 25 (70%). Despite this, parents reported that psychological services were the least utilized health interventions. CONCLUSIONS: Cognitive functioning varies markedly in individuals with Dravet syndrome, with some patients demonstrating global impairment while others have a discordant neuropsychological profile. Behavioral, psychological, social problems, and ASD are common. Social deficits should be reviewed to identify those who warrant ASD assessment. Early identification of behavioral and psychological disorders and targeted use of psychological intervention are essential components of holistic care in Dravet syndrome.
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Transtorno do Espectro Autista , Epilepsias Mioclônicas , Adolescente , Adulto , Criança , Pré-Escolar , Cognição , Humanos , Interação Social , Habilidades Sociais , Adulto JovemRESUMO
Epilepsy of infancy with migrating focal seizures (EIMFS), one of the most severe developmental and epileptic encephalopathy syndromes, is characterized by seizures that migrate from one hemisphere to the other. EIMFS is genetically heterogeneous with 33 genes. We report five patients with EIMFS caused by recessive BRAT1 variants, identified via next generation sequencing. Recessive pathogenic variants in BRAT1 cause the rigidity and multifocal seizure syndrome, lethal neonatal with hypertonia, microcephaly, and intractable multifocal seizures. The epileptology of BRAT1 encephalopathy has not been well described. All five patients were profoundly impaired with seizure onset in the first week of life and focal seizure migration between hemispheres. We show that BRAT1 is an important recessive cause of EIMFS with onset in the first week of life, profound impairment, and early death. Early recognition of this genetic aetiology will inform management and reproductive counselling.
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Encefalopatias/genética , Epilepsia/genética , Epilepsia/patologia , Proteínas Nucleares/genética , Convulsões/genética , Convulsões/patologia , Encéfalo/patologia , Genes Recessivos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Imageamento por Ressonância MagnéticaRESUMO
Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gß. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gß binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gßγ interaction (resulting in a constitutively active Gßγ) or through the disruption of residues relevant for interaction between Gßγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.
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Deficiências do Desenvolvimento/etiologia , Subunidades beta da Proteína de Ligação ao GTP/genética , Mutação em Linhagem Germinativa/genética , Deficiência Intelectual/etiologia , Hipotonia Muscular/etiologia , Convulsões/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Exoma/genética , Feminino , Subunidades beta da Proteína de Ligação ao GTP/química , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Fenótipo , Conformação Proteica , Convulsões/patologia , Transdução de Sinais , Adulto JovemRESUMO
OBJECTIVE: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). METHODS: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. RESULTS: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. INTERPRETATION: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934.
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Epilepsias Mioclônicas/genética , Proteínas de Homeodomínio/genética , Fenótipo , Convulsões/genética , Adolescente , Criança , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/genética , Feminino , Humanos , Lactente , Masculino , Adulto JovemRESUMO
AIM: To assess the relevance and generalizability across countries of concepts of the impact of Dravet syndrome beyond seizures, as recognized by families. METHOD: Caregivers of children with Dravet syndrome in four countries (Australia [n=8]; USA, UK, and Italy [all n=4]) participated in 1-hour qualitative telephone interviews, identifying key Dravet syndrome concepts. Interviews were recorded, transcribed, and, where necessary, translated into English for thematic analysis. Conceptual saturation was assessed and findings compared to the previously developed French conceptual disease model. RESULTS: The most common seizure types reported by caregivers were tonic-clonic, absence, or focal-impaired awareness (localized/partial). Fever and physical activity were the most commonly reported triggers. Patient-relevant impacts included impairment in cognition, motor skills, communication, social skills, and behavioural functioning. Caregivers consistently reported negative social, physical, and family impacts. Concepts identified in the interviews showed similarity with the French conceptual model. Minor differences between countries are likely to reflect variations in health care systems. INTERPRETATION: Findings in Italy, Australia, UK, and USA confirm that the key impacts of Dravet syndrome on children and caregivers identified in France are generalizable across countries. Key symptom and impact concepts relevant to children and parents should be targeted as critical outcomes in new therapy evaluations. WHAT THIS PAPER ADDS: Relevance of the impact of Dravet syndrome on children and caregivers was confirmed across countries. Patient and caregiver-relevant Dravet syndrome impacts contribute to poorer health-related quality of life. Indirect seizure impacts were reported to be as important as direct impacts. Country-specific differences in concepts probably reflect differences in health care systems.
PERCEPCIÓN DEL IMPACTO DEL SÍNDROME DE DRAVET EN NIÑOS Y CUIDADORES EN MÚLTIPLES PAÍSES: UNA OBSERVACIÓN MÁS ALLÁ DE LAS CONVULSIONES: OBJETIVO: Evaluar la relevancia y la generalización de los conceptos del impacto del síndrome de Dravet, más allá de las convulsiones, en distintos países y como lo reconocen las familias. METODO: Cuidadores de niños con síndrome de Dravet en cuatro países (Australia [n=8], EEUU, Reino Unido e Italia [todos n=4]) participaron de una entrevista cualitativa de una hora de duración, identificando conceptos claves en el síndrome de Dravet. Las entrevistas fueron grabadas, transcriptas, y si era necesario, traducidas al inglés para análisis temáticos. Se evaluó la saturación conceptual y los resultados se compararon con el modelo conceptual de enfermedad francés, desarrollado previamente. RESULTADOS: Los tipos más comunes de convulsión reportados por los cuidadores fueron la tónico-clónica, las ausencias o las focales con alteración de la conciencia (localizadas/parciales). La fiebre y las actividades físicas fueron los desencadenantes más comúnmente reportados. Los impactos reportados en los pacientes fueron alteraciones en la cognición, habilidades motrices, comunicación, habilidades sociales y funcionamiento conductual. Los cuidadores informaron sistemáticamente sobre los impactos negativos a nivel social, físico y familiar. Los conceptos identificados en las entrevistas mostraron similitud con el modelo conceptual francés. Es probable que las diferencias menores entre países reflejen variaciones en los sistemas de atención de salud. INTERPRETACIÓN: Los hallazgos en Italia, Australia, Reino Unido y EEUU confirman que las alteraciones claves del síndrome de Dravet en niños y cuidadores identificados en Francia son generalizables en todos los países. Los síntomas claves y las alteraciones relevantes para los niños y los padres deben ser considerados como objetivos críticos de evolución cuando se evalúan el diseño de nuevas terapias.
PERCEPÇÃO DO IMPACTO DA SÍNDROME DE DRAVET EM CRIANÇAS E CUIDADORES EM MÚLTIPLOS PAÍSES: OLHANDO PARA ALÉM DAS CONVULSÕES: OBJETIVO: Avaliar a relevância e generalizabilidade entre países dos conceitos sobre o impacto da síndrome de Dravet para além das convulsões, com base no reconhecimento das famílias. MÉTODO: Cuidadores de crianças com síndrome de Dravet em quatro países (Australia [n=8]; EUA, Reino Unido, e Itália [all n=4]) participaram de entrevistas qualitativas por telefone com duração de 1 hora, identificando conceitos chave da síndrome de Dravet. As entrevistas foram gravadas, transcritas, e quando necessário, traduzidas para o inglês para análise temática. A saturação conceitual foi avaliada e os resultados comparados com o modelo conceitual francês da doença desenvolvido previamente. RESULTADOS: Os tipos mais comuns de convulsões reportados pelos cuidadores eram tônico-clônico, ausência, ou redução focal da consciência (localizada/parcial). Febre e atividade física foram os gatilhos mais comumente reportados. Os impactos relevantes para os pacientes incluíram deficiências na cognição, habilidades motoras, comunicação, habilidades sociais, e funcionamento comportamental. Os cuidadores reportaram impactos negativos sociais, físicos e familares. Os conceitos identificados nas entrevistas mostraram similaridades com o modelo conceitural francês. Diferenças pequenas entre países provavelmente refletem variações nos sistemas de cuidado à saúde. INTERPRETAÇÃO: Achados na Itália, Austrália, Reino unido e EUA confirmam que os impactos principais da síndrome de Dravet em crianças e cuidadores identificados na Franca são generalizáveis entre países. Os principais sintomas e conceitos de impacto relevantes para crianças e pais devem ser visados como desfechos críticos na avaliação de novas terapias.
Assuntos
Cuidadores/psicologia , Epilepsias Mioclônicas/psicologia , Adolescente , Adulto , Austrália , Criança , Pré-Escolar , Comparação Transcultural , Epilepsias Mioclônicas/complicações , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Relações Pais-Filho , Pesquisa Qualitativa , Qualidade de Vida , Reino Unido , Estados UnidosRESUMO
AIM: Many children with severe developmental and epileptic encephalopathies experience significant sleep disturbance, causing major disruption to the family's quality of life. We aimed to determine the frequency and nature of sleep problems in individuals with Dravet syndrome. METHODS: The Sleep Disturbance Scale for Children and a seizure questionnaire were distributed to the parents/guardians of 96 patients with Dravet syndrome. Sixteen patients had two nights of home oximetry. RESULTS: Fifty-seven out of 96 questionnaires were completed. Forty-three out of 57 (75%) individuals had sleep problems. Twenty-five out of 57 (44%) individuals had an abnormal total sleep score, with difficulty initiating and maintaining sleep (22 out of 57, 39%), sleep-wake transition disorders (20 out of 57, 35%), and sleep breathing disorders (19 out of 57, 33%). Twenty-two out of 57 (39%) individuals took medication to assist sleep, predominantly melatonin (n=14). Thirty out of 57 (53%) recently had nocturnal seizures. Overnight oximetry showed 14 out of 16 (88%) had a higher oxygen desaturation index (>3%), and six out of 16 (38%) had higher mean pulse rates than normative values. Home oximetry was normal or inconclusive in all patients. INTERPRETATION: Seventy-five per cent of individuals with Dravet syndrome had sleep problems, highlighting the importance of routinely assessing sleep and initiating appropriate behavioural and pharmacological interventions to improve the patient and family's quality of life. A high oxygen desaturation index and mean pulse rates on pulse oximetry may reflect unrecognized nocturnal seizures. WHAT THIS PAPER ADDS: More than 70% of patients with Dravet syndrome have sleep problems. Difficulty initiating and maintaining sleep was most common, particularly in those older than 20 years. Second most common were sleep-wake transition disorders, affecting more than 50% of those younger than 5 years. Sleep breathing disorders were a frequent problem across all age groups. Oximetry was not diagnostic of sleep-disordered breathing or obvious seizures.
Assuntos
Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Masculino , Oximetria , Qualidade de Vida , Inquéritos e Questionários , Adulto JovemAssuntos
Epilepsia/genética , Mosaicismo , Mutação , Convulsões/genética , Feminino , Humanos , Masculino , PaisRESUMO
Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.
Assuntos
Proteínas de Ligação a DNA/genética , Epilepsia Reflexa/genética , Predisposição Genética para Doença , Mutação/genética , Animais , Eletroencefalografia , Técnicas de Silenciamento de Genes/métodos , Humanos , Estimulação Luminosa/métodos , Fatores de Risco , Peixe-ZebraRESUMO
Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.
Assuntos
Variações do Número de Cópias de DNA , Metilação de DNA , Epilepsia , Humanos , Metilação de DNA/genética , Feminino , Criança , Masculino , Epilepsia/genética , Epilepsia/diagnóstico , Variações do Número de Cópias de DNA/genética , Pré-Escolar , Proteínas de Ligação a DNA/genética , Adolescente , Testes Genéticos/métodos , LactenteRESUMO
BACKGROUND AND OBJECTIVES: The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the rates of convulsive status epilepticus (CSE), nonconvulsive status epilepticus (NCSE), and sudden unexplained death in epilepsy (SUDEP) in these diseases are not well understood. We aimed to describe the proportions of patients with frequently observed genetic DEEs who developed CSE, NCSE, mortality, and SUDEP. Understanding the risks of these serious presentations in each genetic DEE will enable earlier diagnosis and appropriate management. METHODS: In this retrospective analysis of patients with a genetic DEE, we estimated the proportions with CSE, NCSE, and SUDEP and the overall and SUDEP-specific mortality rates for each genetic diagnosis. We included patients with a pathogenic variant in the genes SCN1A, SCN2A, SCN8A, SYNGAP1, NEXMIF, CHD2, PCDH19, STXBP1, GRIN2A, KCNT1, and KCNQ2 and with Angelman syndrome (AS). RESULTS: The cohort comprised 510 individuals with a genetic DEE, in whom we observed CSE in 47% and NCSE in 19%. The highest proportion of CSE occurred in patients with SCN1A-associated DEEs, including 181/203 (89%; 95% CI 84-93) patients with Dravet syndrome and 8/15 (53%; 95% CI 27-79) non-Dravet SCN1A-DEEs. CSE was also notable in patients with pathogenic variants in KCNT1 (6/10; 60%; 95% CI 26-88) and SCN2A (8/15; 53%; 95% CI 27-79). NCSE was common in patients with non-Dravet SCN1A-DEEs (8/15; 53%; 95% CI 27-79) and was notable in patients with CHD2-DEEs (6/14; 43%; 95% CI 18-71) and AS (6/19; 32%; 95% CI 13-57). There were 42/510 (8%) deaths among the cohort, producing a mortality rate of 6.1 per 1,000 person-years (95% CI 4.4-8.3). Cases of SUDEP accounted for 19/42 (48%) deaths. Four genes were associated with SUDEP: SCN1A, SCN2A, SCN8A, and STXBP1. The estimated SUDEP rate was 2.8 per 1,000 person-years (95% CI 1.6-4.3). DISCUSSION: We showed that proportions of patients with CSE, NCSE, and SUDEP differ for commonly encountered genetic DEEs. The estimates for each genetic DEE studied will inform early diagnosis and management of status epilepticus and SUDEP and inform disease-specific counseling for patients and families in this high-risk group of conditions.
Assuntos
Síndrome de Angelman , Epilepsias Mioclônicas , Síndromes Epilépticas , Estado Epiléptico , Morte Súbita Inesperada na Epilepsia , Humanos , Estudos Retrospectivos , Morte Súbita Inesperada na Epilepsia/epidemiologia , Estado Epiléptico/epidemiologia , Estado Epiléptico/genética , Estado Epiléptico/diagnóstico , Epilepsias Mioclônicas/genética , Síndromes Epilépticas/genética , Morte Súbita/epidemiologia , Protocaderinas , Canais de Potássio Ativados por Sódio , Proteínas do Tecido NervosoRESUMO
BACKGROUND AND OBJECTIVES: To determine the frequency and spectrum of complications of influenza infection in individuals with SCN1A-positive Dravet syndrome (SCN1A-DS). METHODS: Individuals with SCN1A-DS were identified in neurologists' care at 2 hospitals in Melbourne, Australia, with additional searches of EEG databases, the Victorian PAEDS FluCan influenza database, and the University of Melbourne Epilepsy Genetics Research Program database. Medical records were searched and families questioned to identify individuals who had an influenza infection; reported infections were confirmed by pathology report. For these individuals, we obtained baseline clinical characteristics and clinical details of the influenza infection. RESULTS: Twenty-one of 82 individuals (26%) had 24 documented influenza infections (17 influenza A and 7 influenza B) at age 0.5-25 years (median 4 years). All presented to hospital, 18/24 (75%) for status epilepticus or seizure exacerbations. Recovery was prompt in 18/24 (75%) infections, delayed but complete in 1/24 (4%) and incomplete in 5/24 (21%). One child died from influenza pneumonia, and long-term neurologic sequelae were seen with 4 infections. These individuals were poorly responsive after termination of status epilepticus. Brain imaging in 2 showed cerebral edema and 1 also having imaging features of laminar necrosis. All have ongoing neurologic deficits compared with their baseline, 1 having profound global impairment. DISCUSSION: Our data show that patients with SCN1A-DS are highly susceptible to neurologic complications during and severe sequelae after influenza infection, including moderate to severe persistent neurologic impairments and death. Safe administration of the seasonal influenza vaccine should be prioritized for this population.