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1.
Zhonghua Er Ke Za Zhi ; 57(10): 780-785, 2019 Oct 02.
Artigo em Chinês | MEDLINE | ID: mdl-31594065

RESUMO

Objective: To summarize the clinical and genetic characteristics of focal epilepsy in children caused by GATOR1 complex gene variation. Methods: The clinical data, gene variation and treatment outcome of 12 children with focal epilepsy caused by GATOR1 complex gene variation admitted to Beijing Children's Hospital Affiliated to Capital Medical University from June 2016 to October 2018 were retrospectively analyzed. Results: There were 7 males and 5 females in 12 cases. The epilepsy onset age was 5.5 (3.0, 12.0) months, and from 11 days to 16 months of age. The epileptic seizure types were all focal motor seizures, and one case combined with epileptic spasms. The frequency of seizures in all patients was more than one time per day. Seven cases had frontal lobe epilepsy and two cases had lateral temporal lobe epilepsy. One case had a family history of febrile seizures and two had a family history of suspicious epilepsy. Epileptic form discharges were observed in 9 patients during the interictal phase by electroencephalograms (EEG), and all of them were focal discharges. Eight cases had clinical seizures detected by EEG, in 4 of whom the seizures were originated in frontal region. There were no abnormalities in brain magnetic resonance imaging in 11 cases whereas 1 case had malformation of cortical development of left frontal lobe. Eight patients had DEPDC5 gene variation, one had NPRL2 gene variation, three had NPRL3 gene variation. One case had de novo variation and the other 11 had hereditary variation. There were 11 types of gene variation, including 5 nonsense variations, 3 missense variations, 2 frame shift variations and 1 in frame deletion variation. There was no clear relationship between the clinical phenotype and the genotype. During the follow-up period from 6 months to 2 years and 6 months, 6 cases had seizure control, 3 of them were controlled by oxcarbazepine. The other 6 cases had drug-refractory epilepsy, 2 of them failed with vagus nerve stimulation and ketogenic dietary therapy as well, meanwhile combined with mental retardation. Conclusions: GATOR1 complex gene variation can lead to genetic focal epilepsy, which usually has early onset with frequent seizures. Most of the patients have focal epileptic form discharges on EEG, and there is usually no structural lesion in brain imaging. Most of the patients have hereditary loss-of-function variations. Approximately half of cases are drug-resistant epilepsy.


Assuntos
Epilepsias Parciais/genética , Proteínas Ativadoras de GTPase/genética , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/genética , Grupo com Ancestrais do Continente Asiático/genética , Eletroencefalografia , Epilepsias Parciais/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Convulsões/complicações , Convulsões/genética
2.
Epileptic Disord ; 21(2): 185-191, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30977726

RESUMO

Epilepsy with auditory features (EAF) is a focal epilepsy syndrome characterized by prominent auditory ictal manifestations. Two main genes, LGI1 and RELN, have been implicated in EAF, but the genetic aetiology remains unknown in half of families and most sporadic cases. We previously described a pathogenic SCN1A missense variant (p.Thr956Met) segregating in a large family in which the proband and her affected daughter had EAF, thus satisfying the minimum requirement for diagnosis of autosomal dominant EAF (ADEAF). However, the remaining eight affected family members had clinical manifestations typically found in families with genetic epilepsy with febrile seizures plus (GEFS+). We aimed to investigate the role/impact of SCN1A mutations in EAF. We detailed the phenotype of this family and report on SCN1A screening in a cohort of 29 familial and 52 sporadic LGI1 variant-negative EAF patients. We identified two possibly pathogenic missense variants (p.Tyr790Phe and p.Thr140Ile) in sporadic patients (3.8%) showing typical EAF and no antecedent febrile seizures. Both p.Thr956Met and p.Tyr790Phe were previously described in unrelated patients with epilepsies within the GEFS+ spectrum. SCN1A mutations may be involved in EAF within the GEFS+ spectrum, however, the role of SCN1A in EAF without features that lead to a suspicion of underlying GEFS+ remains unclear and should be elucidated in future studies.


Assuntos
Transtornos da Percepção Auditiva , Epilepsias Parciais , Epilepsia Generalizada , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões Febris , Adulto , Idoso , Transtornos da Percepção Auditiva/etiologia , Transtornos da Percepção Auditiva/genética , Transtornos da Percepção Auditiva/fisiopatologia , Epilepsias Parciais/complicações , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/complicações , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Convulsões Febris/complicações , Convulsões Febris/genética , Convulsões Febris/fisiopatologia
3.
Epileptic Disord ; 21(1): 42-47, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30767899

RESUMO

Familial focal epilepsy with variable foci is a relatively rare autosomal disease with an unclear incidence, which is characterized by focal seizures arising from different cortical regions in different family members. We describe three members of a two-generation Argentine family with familial focal epilepsy with variable foci syndrome and a DEPDC5 gene mutation. The mean onset age was nine years old. The father experienced episodes with occipital semiology and both siblings exhibited frontal lobe seizures. Their neurological examination and neuroimaging studies were normal. All three patients are currently seizure-free, in spite of initially experiencing frequent seizures. Complete exome sequencing revealed a new DEPDC5 gene mutation (NM_001242896: c.4718T>C; p.L1573P). This study of a family with clinical characteristics that met all the criteria for familial focal epilepsy with variable foci demonstrates the usefulness of exome sequencing as a diagnostic tool. [Published with video sequence on www.epilepticdisorders.com].


Assuntos
Epilepsias Parciais/fisiopatologia , Síndromes Epilépticas/fisiopatologia , Proteínas Repressoras/genética , Adulto , Idade de Início , Argentina , Criança , Eletroencefalografia , Epilepsias Parciais/genética , Síndromes Epilépticas/genética , Feminino , Genótipo , Humanos , Masculino , Mutação , Linhagem , Fenótipo
4.
Epileptic Disord ; 21(1): 65-77, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30782578

RESUMO

We comprehensively studied the clinical presentation, stereo-EEG and MRI findings, histopathological diagnosis, and brain somatic mutations in a retrospective series of drug-resistant patients with difficult-to-localize epilepsy due to focal cortical dysplasia at the bottom of a sulcus (BOS-FCD). We identified 10 patients with BOS-FCD from the Cleveland Clinic epilepsy surgery database submitted for intracranial video-EEG monitoring. Brain MRI, including voxel-based morphometric analysis and surgical tissue submitted for histopathology, was reviewed. Paraffin tissue samples from five patients were made available for targeted next-generation sequencing. Postsurgical follow-up was available in nine patients. BOS-FCD was identified in the superior frontal sulcus in six patients, inferior frontal sulcus in one patient, central sulcus in one patient, and intraparietal sulcus in two patients. All patients had stereotyped seizures. Intracranial EEG recordings identified ictal onset at the BOS-FCD in all 10 patients, whereas ictal scalp EEG had a localizing value in only six patients. Complete resection was achieved by lesionectomy or focal corticectomy in nine patients. Histopathologically, six patients had FCD type IIb and three had FCD type IIa. Next-generation sequencing analysis of DNA extracted from lesion-enriched (micro-dissected) tissue from five patients with FCD type II led to the identification of a germline frameshift insertion in DEPDC5, introducing a premature stop in one patient. Eight out of nine patients with available follow-up were completely seizure-free (Engel Class IA) after a mean follow-up period of six years. Our results confirm previous studies classifying difficult-to-localize BOS-FCD into the emerging spectrum of FCD ILAE type II mTORopathies. Further studies with large patient numbers and ultra-deep genetic testing may help to bridge the current knowledge gap in genetic aetiologies of FCD.


Assuntos
Epilepsias Parciais/diagnóstico , Malformações do Desenvolvimento Cortical/diagnóstico , Adolescente , Adulto , Eletrocorticografia , Epilepsias Parciais/genética , Epilepsias Parciais/patologia , Epilepsias Parciais/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia , Malformações do Desenvolvimento Cortical/fisiopatologia , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Avaliação de Resultados (Cuidados de Saúde) , Adulto Jovem
5.
J Vet Intern Med ; 33(2): 694-700, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30580458

RESUMO

BACKGROUND: Focal seizures with fear as a primary ictal manifestation, their diagnostic challenges, and impact on quality of life are well described in human medicine. Reports focusing on ictal fear-like behavior in animals are scarce. OBJECTIVE: To describe the clinical and histopathological characteristics of a novel focal epilepsy in Boerboel dogs. ANIMALS: Five client-owned Boerboel littermates presented for evaluation of sudden episodes of severe fear-related behavior. METHODS: Clinical examination, complete blood cell count, routine blood biochemistry, and urinalysis were performed in all dogs. Magnetic resonance imaging (MRI) scans of the brain were performed in 3 affected Boerboels. In addition, in 2 affected Boerboels, metabolic screening, cerebrospinal fluid (CSF) analysis, and necropsy were performed. RESULTS: Onset of signs was 3 months of age in all affected Boerboels. All Boerboels howled loudly, had an extremely fearful facial expression and trembled during seizures. All affected Boerboels also had autonomic or motor signs. Results of laboratory investigations, diagnostic imaging, and metabolic screening were generally unremarkable. Histopathology showed moderate numbers of single large vacuoles in the perikaryon of neurons throughout the brain, specifically in the deeper cerebral cortical regions. Family history, pedigree analysis, and the homogenous phenotype were suggestive of autosomal recessive inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE: The observed paroxysmal fear-related behavior represents a newly recognized hereditary focal epilepsy in dogs with distinctive clinical and histopathologic features. Veterinarians should be aware that sudden episodes of unusual behavior can represent focal epilepsy.


Assuntos
Doenças do Cão/diagnóstico , Epilepsias Parciais/veterinária , Medo/fisiologia , Animais , Doenças do Cão/genética , Doenças do Cão/patologia , Cães , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/genética , Epilepsias Parciais/patologia , Feminino , Masculino , Linhagem
6.
PLoS Genet ; 14(12): e1007535, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30586385

RESUMO

The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin superfamily. CNTNAP2 was first implicated in the cortical dysplasia-focal epilepsy (CDFE) syndrome, a recessive disease characterized by intellectual disability, epilepsy, language impairments and autistic features. Associated SNPs and heterozygous deletions in CNTNAP2 were subsequently reported in autism, schizophrenia and other psychiatric or neurological disorders. We aimed to comprehensively examine evidence for the role of CNTNAP2 in susceptibility to psychiatric disorders, by the analysis of multiple classes of genetic variation in large genomic datasets. In this study we used: i) summary statistics from the Psychiatric Genomics Consortium (PGC) GWAS for seven psychiatric disorders; ii) examined all reported CNTNAP2 structural variants in patients and controls; iii) performed cross-disorder analysis of functional or previously associated SNPs; and iv) conducted burden tests for pathogenic rare variants using sequencing data (4,483 ASD and 6,135 schizophrenia cases, and 13,042 controls). The distribution of CNVs across CNTNAP2 in psychiatric cases from previous reports was no different from controls of the database of genomic variants. Gene-based association testing did not implicate common variants in autism, schizophrenia or other psychiatric phenotypes. The association of proposed functional SNPs rs7794745 and rs2710102, reported to influence brain connectivity, was not replicated; nor did predicted functional SNPs yield significant results in meta-analysis across psychiatric disorders at either SNP-level or gene-level. Disrupting CNTNAP2 rare variant burden was not higher in autism or schizophrenia compared to controls. Finally, in a CNV mircroarray study of an extended bipolar disorder family with 5 affected relatives we previously identified a 131kb deletion in CNTNAP2 intron 1, removing a FOXP2 transcription factor binding site. Quantitative-PCR validation and segregation analysis of this CNV revealed imperfect segregation with BD. This large comprehensive study indicates that CNTNAP2 may not be a robust risk gene for psychiatric phenotypes.


Assuntos
Proteínas de Membrana/genética , Transtornos Mentais/genética , Proteínas do Tecido Nervoso/genética , Transtorno do Espectro Autista/genética , Transtorno Bipolar/genética , Anormalidades Craniofaciais/genética , Variações do Número de Cópias de DNA , Bases de Dados de Ácidos Nucleicos , Epilepsias Parciais/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Masculino , Malformações do Desenvolvimento Cortical/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/genética , Deleção de Sequência
7.
Brain Dev ; 40(8): 728-732, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29699863

RESUMO

A heterozygous mutation in the fibroblast growth factor 12 (FGF12) gene, which elevates the voltage dependence of neuronal sodium channel fast inactivation, was recently identified in some patients with epileptic encephalopathy. Here we report 1 Japanese patient diagnosed with early infantile epileptic encephalopathy (EIEE) and another diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). These 2 patients had an identical heterozygous missense mutation [c.341G>A:p.(Arg114His)] in FGF12 , which was identified with whole-exome sequencing. This mutation is identical to previously reported mutations in cases with early onset epileptic encephalopathy. One of our cases exhibited EIMFS, and this case responded to phenytoin and high-dose phenobarbital (PB). FGF12-related epileptic encephalopathy may exhibit diverse phenotypes and may respond to sodium channel blockers or high-dose PB.


Assuntos
Epilepsias Parciais/genética , Fatores de Crescimento de Fibroblastos/genética , Mutação de Sentido Incorreto , Espasmos Infantis/genética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/fisiopatologia , Humanos , Lactente , Masculino , Fenótipo , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/fisiopatologia
8.
PLoS One ; 13(1): e0191546, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29352316

RESUMO

BACKGROUND: KANSL1 haploinsufficiency causes Koolen-de Vries syndrome (KdVS), characterized by dysmorphic features and intellectual disability; amiable personality, congenital malformations and seizures also commonly occur. The epilepsy phenotypic spectrum in KdVS is broad, but most individuals have focal seizures with some having a phenotype resembling the self-limited focal epilepsies of childhood (SFEC). We hypothesized that variants in KANSL1 contribute to pathogenesis of SFEC. MATERIALS AND METHODS: We screened KANSL1 for single nucleotide variants in 90 patients with SFEC. We then screened a cohort of 208 patients with two specific SFEC syndromes, childhood epilepsy with centrotemporal spikes (CECTS) and atypical childhood epilepsy with centrotemporal spikes (ACECTS) for KANSL1 variants. The second cohort was also used to evaluate minor allelic variants that appeared overrepresented in the initial cohort. RESULTS: One variant, p.Lys104Thr, was predicted damaging and appeared overrepresented in our 90-patient cohort compared to Genome Aggregation Database (gnomAD) allele frequency (0.217 to 0.116, with no homozygotes in gnomAD). However, there was no difference in p.Lys104Thr allele frequency in the follow-up CECTS/ACECTS cohort and controls. Four rare KANSL1 variants of uncertain significance were identified in the CECTS/ACECTS cohort. DISCUSSION: Our data do not support a major role for KANSL1 variants in pathogenesis of SFEC.


Assuntos
Síndromes Epilépticas/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Anormalidades Múltiplas/genética , Substituição de Aminoácidos , Criança , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Estudos de Coortes , Bases de Dados Genéticas , Epilepsias Parciais/genética , Epilepsia Rolândica/genética , Síndromes Epilépticas/etiologia , Frequência do Gene , Variação Genética , Humanos , Deficiência Intelectual/genética
9.
Epilepsia ; 59(2): 389-402, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29315614

RESUMO

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 Jovem
10.
Neurosci Lett ; 667: 4-9, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28499889

RESUMO

In last few years there has been rapid increase in the knowledge of epilepsy genetics. Nowadays, it is estimated that genetic epilepsies include over than 30% of all epilepsy syndromes. Several genetic tests are now available for diagnostic purposes in clinical practice. In particular, next-generation sequencing has proven to be effective in revealing gene mutations causing epilepsies in up to a third of the patients. This has lead also to functional studies that have given insight into disease pathophysiology and consequently to the identification of potential therapeutic targets opening the way of precision medicine for epilepsy patients. This minireview is focused on the most recent advances in genetics of epilepsies. We will also overview the modern genomic technologies and illustrate the diagnostic pathways in patients with genetic epilepsies. Finally, the potential implications for a personalized treatment (precision medicine) are also discussed.


Assuntos
Epilepsias Parciais/genética , Epilepsia/genética , Variação Genética/genética , Mutação/genética , Animais , Testes Genéticos , Humanos , Medicina de Precisão/métodos
11.
Intern Med ; 57(1): 97-99, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29033429

RESUMO

Cowden syndrome is a rare autosomal dominant disorder characterized by multiple hamartomas of the ectoderm and brain. A 36-year-old Japanese man presented with right facial seizure during sleep and was admitted to our hospital. He showed cobblestoning over the tongue and palmar pitting but no neurological abnormalities while he was not having a seizure. Brain magnetic resonance imaging showed focal cortical dysplasia in the left frontal lobe. Electroencephalography showed sharp waves over the left frontal lesion. A genetic analysis revealed a novel mutation of PTEN. The administration of carbamazepine ended the seizures. This is the first Japanese case of Cowden syndrome with a novel PTEN gene mutation and cortical dysplasia.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Síndrome do Hamartoma Múltiplo/tratamento farmacológico , Síndrome do Hamartoma Múltiplo/genética , Malformações do Desenvolvimento Cortical/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/genética , Lobo Frontal/patologia , Síndrome do Hamartoma Múltiplo/diagnóstico , Humanos , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico , Mutação , Resultado do Tratamento
12.
Epileptic Disord ; 19(4): 450-455, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29258966

RESUMO

Somatic mutation of the lissencephaly-1 gene is a cause of subcortical band heterotopia ("double cortex"). The severity of the phenotype depends on the level of mutation in brain tissue. Detecting and quantifying low-level somatic mosaic mutations is challenging. Here, we utilized droplet digital PCR, a sensitive method to detect low-level mutation. Droplet digital PCR was used in concert with classic genotyping techniques (SNaPshot assays and pyrosequencing) to detect and characterize the tissue mosaicism of a somatic mutation (LIS1 c.190A>T; p.K64X) in a patient with posterior bilateral SBH and refractory epilepsy. The high sensitivity of droplet digital PCR and the ability to target individual DNA molecules allowed us to detect the mutation at low level in the brain, despite the low quality of the DNA sample derived from formalin-fixed paraffin-embedded tissue. This low mutation frequency in the brain was consistent with the relatively subtle malformation resolved by magnetic resonance imaging. The presence of the mutation in other tissues from the patient permitted us to predict the timing of mutagenesis. This sensitive methodology will have utility for a variety of other brain malformation syndromes associated with epilepsy for which historical pathological specimens are available and specific somatic mosaic mutations are predicted.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Epilepsia Resistente a Medicamentos/genética , Epilepsias Parciais/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Adulto , Feminino , Humanos , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Reação em Cadeia da Polimerase em Tempo Real
13.
BMC Med Genet ; 18(1): 124, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29096607

RESUMO

BACKGROUND: Defects in the human glycosylphosphatidylinositol anchor biosynthetic pathway are associated with inherited glycosylphosphatidylinositol (GPI)-deficiencies characterized by a broad range of clinical phenotypes including multiple congenital anomalies, dysmorphic faces, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGN, encoding phosphatidylinositol-glycan biosynthesis class N have been recently associated with multiple congenital anomalies hypotonia seizure syndrome. CASE PRESENTATION: Our patient is a 2 year old male with hypotonia, global developmental delay, and focal epilepsy. Trio whole-exome sequencing revealed heterozygous variants in PIGN, c.181G > T (p.Glu61*) and c.284G > A (p.Arg95Gln). Analysis of FLAER and anti-CD59 by flow-cytometry demonstrated a shift in this patient's granulocytes, confirming a glycosylphosphatidylinositol-biosynthesis defect, consistent with PIGN-related disease. CONCLUSIONS: To date, a total of 18 patients have been reported, all but 2 of whom have congenital anomalies and/or obvious dysmorphic features. Our patient has no significant dysmorphic features or multiple congenital anomalies, which is consistent with recent reports linking non-truncating variants with a milder phenotype, highlighting the importance of functional studies in interpreting sequence variants.


Assuntos
Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença/genética , Hipotonia Muscular/genética , Mutação , Fosfotransferases/genética , Pré-Escolar , Análise Mutacional de DNA , Epilepsias Parciais/genética , Exoma/genética , Humanos , Masculino
14.
Seizure ; 53: 51-54, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29125946

RESUMO

PURPOSE: Dishevelled EGL-10 and pleckstrin domain-containing protein 5 (DEPDC5) mutations are found in a wide spectrum of focal epilepsies ranging from epilepsy caused by malformation of cortical development to non-lesional epilepsy, including sleep-related hypermotor epilepsy (SHE). A surgical approach has been anecdotally reported in patients with DEPDC5 mutations, but most of these cases had a lesional etiology. METHODS: We describe a stereo-EEG (SEEG) study in a patient with drug-resistant/non-lesional SHE. Patient was screened for known mutations associated with SHE. RESULTS: SEEG disclosed bilateral synchronous and independent activity prevailing on the right central-anterior cingulate cortex, without a clear spatially defined epileptogenic zone. Due to the lack of a clear epileptogenic zone, surgery was contraindicated. Years later a DEPDC5 mutation was identified. CONCLUSION: We suggest that genetic analysis should be considered before performing SEEG study in a patient with drug resistant non-lesional SHE, in the presence of seizures in wakefulness and unclear anatomo-electroclinical correlation. If DEPDC5 mutations are identified, the presurgical evaluation should be tailored to look for MRI-negative focal cortical dysplasia and a wide epileptogenic network. The appropriate management and potential benefit of surgery for genetic non-lesional epilepsy have yet to be clarified.


Assuntos
Eletroencefalografia/métodos , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Parassonias/genética , Parassonias/fisiopatologia , Proteínas Repressoras/genética , Epilepsia Resistente a Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Técnicas Estereotáxicas
15.
J Pediatr ; 191: 270-274, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28987752

RESUMO

KCNT1 mutations are gain-of-function mutations in potassium channels resulting in severe infantile epilepsy. Herein we describe 3 infants with malignant migrating partial seizures with KCNT1 mutations accompanied by massive systemic to pulmonary collateral arteries with life-threatening hemoptysis and heart failure.


Assuntos
Circulação Colateral , Epilepsias Parciais/genética , Mutação com Ganho de Função , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Artéria Pulmonar/fisiopatologia , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/fisiopatologia , Evolução Fatal , Feminino , Marcadores Genéticos , Humanos , Recém-Nascido , Masculino
16.
Neuron ; 96(2): 387-401.e6, 2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29024662

RESUMO

Because molecular mechanisms underlying refractory focal epilepsy are poorly defined, we performed transcriptome analysis on human epileptogenic tissue. Compared with controls, expression of Circadian Locomotor Output Cycles Kaput (CLOCK) is decreased in epileptogenic tissue. To define the function of CLOCK, we generated and tested the Emx-Cre; Clockflox/flox and PV-Cre; Clockflox/flox mouse lines with targeted deletions of the Clock gene in excitatory and parvalbumin (PV)-expressing inhibitory neurons, respectively. The Emx-Cre; Clockflox/flox mouse line alone has decreased seizure thresholds, but no laminar or dendritic defects in the cortex. However, excitatory neurons from the Emx-Cre; Clockflox/flox mouse have spontaneous epileptiform discharges. Both neurons from Emx-Cre; Clockflox/flox mouse and human epileptogenic tissue exhibit decreased spontaneous inhibitory postsynaptic currents. Finally, video-EEG of Emx-Cre; Clockflox/flox mice reveals epileptiform discharges during sleep and also seizures arising from sleep. Altogether, these data show that disruption of CLOCK alters cortical circuits and may lead to generation of focal epilepsy.


Assuntos
Encéfalo/metabolismo , Proteínas CLOCK/deficiência , Proteínas CLOCK/genética , Epilepsias Parciais/genética , Epilepsias Parciais/metabolismo , Rede Nervosa/metabolismo , Animais , Encéfalo/patologia , Células Cultivadas , Epilepsias Parciais/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/patologia , Estudos Prospectivos
17.
Neurology ; 89(12): 1210-1219, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-28842445

RESUMO

OBJECTIVE: Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum. METHODS: We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years. RESULTS: We identified new phenotypes within the GEFS+ spectrum: focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene. CONCLUSION: As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants.


Assuntos
Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/fisiopatologia , Convulsões Febris/fisiopatologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Epilepsias Parciais/genética , Epilepsia Generalizada/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Convulsões Febris/genética , Adulto Jovem
18.
J Med Genet ; 54(9): 598-606, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28756411

RESUMO

BACKGROUND: Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement 'hotspot' loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained. OBJECTIVE: To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype. METHODS: We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls. RESULTS: When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10-6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10-12, OR 7.45, 95% CI 4.20-13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10-3,OR 2.85, 95% CI 1.62-4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls. CONCLUSIONS: Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE.


Assuntos
Deleção Cromossômica , Epilepsias Parciais/genética , Epilepsia Generalizada/genética , Epilepsia Rolândica/genética , Estudos de Casos e Controles , Estudos de Coortes , Variações do Número de Cópias de DNA , Expressão Gênica , Estudos de Associação Genética , Humanos
19.
J Neurol ; 264(7): 1421-1425, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28620718

RESUMO

Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2-3 years and intellectual disability. Three developed afebrile seizures between age 7-17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy.


Assuntos
Epilepsias Parciais/genética , Deficiência Intelectual/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Convulsões Febris/genética , Adolescente , Adulto , Família , Feminino , Humanos , Masculino , Fenótipo , Adulto Jovem
20.
Neurology ; 89(1): 22-28, 2017 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-28566546

RESUMO

OBJECTIVE: To improve phenotype definition in genetic studies of epilepsy, we assessed the familial aggregation of focal seizure types and of specific seizure symptoms within the focal epilepsies in families from the Epilepsy Phenome/Genome Project. METHODS: We studied 302 individuals with nonacquired focal epilepsy from 149 families. Familial aggregation was assessed by logistic regression analysis of relatives' traits (dependent variable) by probands' traits (independent variable), estimating the odds ratio for each symptom in a relative given presence vs absence of the symptom in the proband. RESULTS: In families containing multiple individuals with nonacquired focal epilepsy, we found significant evidence for familial aggregation of ictal motor, autonomic, psychic, and aphasic symptoms. Within these categories, ictal whole body posturing, diaphoresis, dyspnea, fear/anxiety, and déjà vu/jamais vu showed significant familial aggregation. Focal seizure type aggregated as well, including complex partial, simple partial, and secondarily generalized tonic-clonic seizures. CONCLUSION: Our results provide insight into genotype-phenotype correlation in the nonacquired focal epilepsies and a framework for identifying subgroups of patients likely to share susceptibility genes.


Assuntos
Epilepsias Parciais , Síndrome de Lennox Gastaut , Malformações do Desenvolvimento Cortical , Núcleo Familiar , Espasmos Infantis , Adolescente , Adulto , Criança , Pré-Escolar , Epilepsias Parciais/epidemiologia , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Feminino , Genótipo , Humanos , Lactente , Síndrome de Lennox Gastaut/epidemiologia , Síndrome de Lennox Gastaut/genética , Síndrome de Lennox Gastaut/fisiopatologia , Masculino , Malformações do Desenvolvimento Cortical/epidemiologia , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/fisiopatologia , Pessoa de Meia-Idade , Linhagem , Fenótipo , Espasmos Infantis/epidemiologia , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Adulto Jovem
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