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1.
Int J Mol Sci ; 22(17)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34502487

RESUMO

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , COVID-19/tratamento farmacológico , Canabidiol/uso terapêutico , Interações Medicamentosas , Nutrientes/metabolismo , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , COVID-19/virologia , Canabidiol/química , Canabidiol/farmacocinética , Carbamazepina/química , Carbamazepina/farmacocinética , Carbamazepina/uso terapêutico , Clobazam/química , Clobazam/farmacocinética , Clobazam/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Humanos , SARS-CoV-2/isolamento & purificação
2.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34502246

RESUMO

Close to one-third of patients with epilepsies are refractory to current anti-seizure medications; however, trials with cenobamate suggest effectiveness in such patients with focal onset seizures. We searched for data published or otherwise reported on cenobamate and outlined these here. Despite being marketed in the USA, few studies are yet published in full, and trials are ongoing. Nevertheless, cenobamate showed potential for a high degree of efficacy in reducing seizures with an unprecedented seizure-free rate of up to 28%. Rare cases of hypersensitivity reactions seen in early trials seem to be avoided by the current recommended titration schedule. Other adverse events were rated mild-to-moderate and most commonly included dizziness, drowsiness, and headache. If data are confirmed in further published trials, cenobamate will be a welcome new treatment and further analyses may identify those that will benefit the most.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamatos/uso terapêutico , Clorofenóis/uso terapêutico , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Tetrazóis/uso terapêutico , Epilepsia/patologia , Humanos , Convulsões/patologia
3.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445306

RESUMO

Epilepsy is a pathologic condition with high prevalence and devastating consequences for the patient and its entourage. Means for accurate diagnosis of type, patient monitoring for predicting seizures and follow up, and efficacious treatment are desperately needed. To improve this adverse outcome, miRNAs and the chaperone system (CS) are promising targets to understand pathogenic mechanisms and for developing theranostics applications. miRNAs implicated in conditions known or suspected to favor seizures such as neuroinflammation, to promote epileptic tolerance and neuronal survival, to regulate seizures, and others showing variations in expression levels related to seizures are promising candidates as useful biomarkers for diagnosis and patient monitoring, and as targets for developing novel therapies. Components of the CS are also promising as biomarkers and as therapeutic targets, since they participate in epileptogenic pathways and in cytoprotective mechanisms in various epileptogenic brain areas, even if what they do and how is not yet clear. The data in this review should help in the identification of molecular targets among the discussed miRNAs and CS components for research aiming at understanding epileptogenic mechanisms and, subsequently, develop means for predicting/preventing seizures and treating the disease.


Assuntos
Epilepsia/metabolismo , Proteínas de Choque Térmico/metabolismo , MicroRNAs/metabolismo , Animais , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/patologia , Proteínas de Choque Térmico/genética , Humanos , MicroRNAs/genética
4.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360601

RESUMO

Mutations in the SPATA5 gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). While SPATA5 is ubiquitously expressed and is attributed a role within mitochondrial morphogenesis during spermatogenesis, there is only limited knowledge about the associated muscular and molecular pathology. This study reports on a comprehensive workup of muscular pathology, including proteomic profiling and microscopic studies, performed on an 8-year-old girl with typical clinical presentation of EHLMRS, where exome analysis revealed two clinically relevant, compound-heterozygous variants in SPATA5. Proteomic profiling of a quadriceps biopsy showed the dysregulation of 82 proteins, out of which 15 were localized in the mitochondrion, while 19 were associated with diseases presenting with phenotypical overlap to EHLMRS. Histological staining of our patient's muscle biopsy hints towards mitochondrial pathology, while the identification of dysregulated proteins attested to the vulnerability of the cell beyond the mitochondria. Through our study we provide insights into the molecular etiology of EHLMRS and provide further evidence for a muscle pathology associated with SPATA5 deficiency, including a pathological histochemical pattern accompanied by dysregulated protein expression.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Epilepsia/patologia , Perda Auditiva/patologia , Deficiência Intelectual/patologia , Doenças Musculares/patologia , Mutação , Proteoma/metabolismo , ATPases Associadas a Diversas Atividades Celulares/deficiência , Criança , Epilepsia/etiologia , Epilepsia/metabolismo , Feminino , Perda Auditiva/etiologia , Perda Auditiva/metabolismo , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/metabolismo , Doenças Musculares/complicações , Doenças Musculares/metabolismo , Proteoma/análise , Síndrome
5.
Eur J Med Genet ; 64(10): 104310, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34400370

RESUMO

MFSD2A, a member of the major facilitator superfamily (MFS), is a transmembrane transporter responsible for the uptake of specific essential fatty acids through the blood-brain barrier (BBB) to the brain. The transporter is crucial for early embryonic brain development and a major factor in the formation and maintenance of the BBB. Mfsd2a-knockout mice show a leakage of the BBB in early embryonic stages and develop a phenotype characterized by microcephaly, cognitive impairment, and anxiety. So far, homozygous or compound heterozygous MFSD2A mutations in humans have only been reported in 13 different families with a total of 28 affected individuals. The phenotypical spectrum of patients with MFSD2A variants is rather broad but all patients present with microcephaly and severe intellectual disability, absent or limited speech, and walking difficulties. Severely affected patients develop seizures and show brain malformations and have, above all, a profound developmental delay hardly reaching any developmental motor milestones. Here, we report on two unrelated individuals with novel homozygous variants in the MFSD2A gene, presenting with severe primary microcephaly, brain malformations, profound developmental delay, and epilepsy, including hypsarrhythmia. Our findings extend the mutational spectrum of the bi-allelic MFSD2A variants causing autosomal recessive primary microcephaly type 15 and broaden the phenotypic spectrum associated with these pathogenic variants emphasizing the role of MFSD2A in early brain development.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Microcefalia/genética , Fenótipo , Simportadores/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Epilepsia/patologia , Feminino , Humanos , Lactente , Masculino , Microcefalia/patologia , Mutação
6.
Am J Hum Genet ; 108(9): 1692-1709, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34375587

RESUMO

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.


Assuntos
Encéfalo/metabolismo , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Mutação , Receptores de Ácido Caínico/genética , Adolescente , Adulto , Alelos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Epilepsia/diagnóstico por imagem , Epilepsia/metabolismo , Epilepsia/patologia , Potenciais Evocados/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Ativação do Canal Iônico , Masculino , Modelos Moleculares , Neurônios/metabolismo , Neurônios/patologia , Conformação Proteica , Receptores de Ácido Caínico/química , Receptores de Ácido Caínico/metabolismo
7.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445580

RESUMO

CILK1 (ciliogenesis associated kinase 1)/ICK (intestinal cell kinase) is a highly conserved protein kinase that regulates primary cilia structure and function. CILK1 mutations cause a wide spectrum of human diseases collectively called ciliopathies. While several CILK1 heterozygous variants have been recently linked to juvenile myoclonic epilepsy (JME), it remains unclear whether these mutations cause seizures. Herein, we investigated whether mice harboring either a heterozygous null Cilk1 (Cilk1+/-) mutation or a heterozygous loss-of-function Cilk1 mutation (Cilk1R272Q/+) have epilepsy. We first evaluated the spontaneous seizure phenotype of Cilk1+/- and Cilk1R272Q/+ mice relative to wildtype littermates. We observed no electrographic differences among the three mouse genotypes during prolonged recordings. We also evaluated electrographic and behavioral responses of mice recovering from isoflurane anesthesia, an approach recently used to measure seizure-like activity. Again, we observed no electrographic or behavioral differences in control versus Cilk1+/- and Cilk1R272Q/+ mice upon isoflurane recovery. These results indicate that mice bearing a non-functional copy of Cilk1 fail to produce electrographic patterns resembling those of JME patients with a variant CILK1 copy. Our findings argue against CILK1 haploinsufficiency being the mechanism that links CILK1 variants to JME.


Assuntos
Cílios/patologia , Modelos Animais de Doenças , Epilepsia/patologia , Mutação , Fenótipo , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Cílios/metabolismo , Epilepsia/etiologia , Haploinsuficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação
8.
Eur J Med Genet ; 64(9): 104285, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34229114

RESUMO

Recently, an autosomal recessive disorder including the triad of microcephaly, infantile epileptic encephalopathy, and permanent neonatal diabetes syndrome (MEDS, OMIM#614231) has emerged as a new distinguishing syndrome. Eight cases of whom seven from Arab countries, have been reported in association with biallelic variants in the IER3IP1 gene (Immediate early response-3 interacting protein-1). Here, we describe a Tunisian boy who presented with permanent neonatal diabetes, microcephaly, generalized seizures and hypovirilized external genitalia consisting of a small genitalia and unilateral cryptorchidism. Chromosomal analysis indicated a 46, XY karyotype in all metaphases. Exome sequencing identified a homozygous missense variant (c.62 T > G; p. Val21Gly) in the IER3IP1 gene, that is predicted to alter the protein structure within the hydrophobic/transmembrane. This variant was previously reported in two cases associated with MEDS. This is the first reported case of MEDS in Tunisia. Our report focuses on the IER3IP1 related phenotypic spectrum and assumes abnormal genitalia as part of the syndrome. Consequently, we recommend to perform hormonal testing on this topic to understand the effect of the IER3IP1 variant on the male genital pathway.


Assuntos
Proteínas de Transporte/genética , Criptorquidismo/patologia , Diabetes Mellitus/patologia , Epilepsia/patologia , Doenças do Recém-Nascido/patologia , Proteínas de Membrana/genética , Transtornos Psicomotores/patologia , Proteínas de Transporte/química , Criptorquidismo/genética , Diabetes Mellitus/genética , Epilepsia/genética , Humanos , Recém-Nascido , Doenças do Recém-Nascido/genética , Cariótipo , Masculino , Proteínas de Membrana/química , Mutação de Sentido Incorreto , Domínios Proteicos , Transtornos Psicomotores/genética , Síndrome
9.
Neurology ; 97(11): e1141-e1149, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34233939

RESUMO

BACKGROUND AND OBJECTIVES: To determine risk factors associated with clinical relapses and development of chronic epilepsy in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) immunoglobulin G encephalitis. METHODS: Patients with seizures related to LGI1-antibody encephalitis with ≥24 months of follow-up from disease onset were identified in the Mayo Clinic electronic medical record and neuroimmunology laboratory records. Charts were reviewed to determine clinical factors, seizure types, imaging, treatment, occurrence of relapse, and outcome. Binary logistic regression analysis was performed to identify predictors of the development of chronic epilepsy. Univariate Cox proportional hazards regression was used to examine the influence of baseline characteristics on relapse risk. RESULTS: Forty-nine patients with LGI1-antibody encephalitis and acute symptomatic seizures were identified. Almost all patients (n = 48, 98%) were treated with immunotherapy. Eight had definite and 2 had possible chronic epilepsy at the last follow-up (10 of 49, 20.4%). Female sex (p = 0.048) and younger age at disease onset (p = 0.02) were associated with development of chronic epilepsy. Relapses occurred in 20 (40.8%), with a median time to first relapse of 7.5 months (range 3-94 months). Initial treatment with long-term steroid-sparing immunotherapy was associated with reduced risk of relapse (hazard ratio 0.28, 95% confidence interval 0.11-0.73, p = 0.009). DISCUSSION: Chronic epilepsy occurred in 20.4% of our patients with LGI1-antibody encephalitis despite aggressive immunotherapy. Risk factors for chronic epilepsy were female sex and earlier age at onset. Relapses occurred in 40.8% of patients with prolonged follow-up, and long-term steroid-sparing immunotherapy was associated with a lower relapse rate.


Assuntos
Encefalite/patologia , Encefalite/fisiopatologia , Epilepsia/patologia , Epilepsia/fisiopatologia , Convulsões/patologia , Convulsões/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalite/complicações , Encefalite/imunologia , Epilepsia/complicações , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Pessoa de Meia-Idade , Convulsões/complicações
10.
Commun Biol ; 4(1): 680, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083748

RESUMO

Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Local field potential recordings (LFP) were used to screen ∼3300 larvae. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.


Assuntos
Modelos Animais de Doenças , Embrião não Mamífero/metabolismo , Epilepsia/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Criança , Embrião não Mamífero/citologia , Embrião não Mamífero/embriologia , Epilepsia/patologia , Epilepsia/fisiopatologia , Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Larva/genética , Mutação , Fenótipo , Análise de Sobrevida , Sequenciamento Completo do Exoma/métodos , Peixe-Zebra/embriologia
11.
Cell Biochem Funct ; 39(6): 791-801, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34057222

RESUMO

In this study, we established a mouse model of epilepsy and analysed abnormal neuronal damage and inflammation in the hippocampus of mice with kainic acid (KA)-induced epilepsy to provide the basis for the pathogenesis of epilepsy. C57 mice, aged 4 weeks, were injected intraperitoneally in the KA group with 20 mg/kg of KA and in the sham experimental group with normal saline. The whole brain and hippocampus of mice in the sham experimental group and KA epilepsy model group were collected on days 7, 14, 21 and 28 after injection. The difference in the protein expression in the hippocampus was detected using fluorescence immunohistochemistry. The hippocampal tissue was also collected and frozen to detect protein expression by western blot. The results of the haematoxylin and eosin (HE) and Nissl staining showed that the mouse model of temporal lobe epilepsy could be established by intraperitoneal injection of KA, and the success rate of the model was 53.8%. The expression of DCX-, ß-catenin-, GFAP- and Iba-1-labelled glial cells in the KA-induced epilepsy model group were higher than those in the sham group. The results of western blotting showed that the expression of DCX and ß-catenin in the KA-induced epilepsy model group was higher than that in the sham experimental group, while the expression of N-cadherin and Iba-1 on days 14 and 28 was significantly (P < .05) higher than that in the sham experimental group. In KA-induced epilepsy model group, the expression of Bcl-2 was decreased, while the expression of Bad and PUMA was increased.


Assuntos
Epilepsia/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Neurônios/metabolismo , Animais , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/patologia , Hipocampo/patologia , Inflamação/patologia , Ácido Caínico , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia
12.
Ann Neurol ; 90(1): 143-158, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33999436

RESUMO

OBJECTIVE: Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. METHODS: Whole exome sequencing was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. RESULTS: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. INTERPRETATION: Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function. ANN NEUROL 2021;90:149-164.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Hipopituitarismo/genética , Alelos , Encefalopatias/patologia , Pré-Escolar , Epilepsia/patologia , Feminino , Humanos , Hipopituitarismo/patologia , Lactente , Masculino , Hipófise/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
13.
Eur J Med Genet ; 64(7): 104243, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33971351

RESUMO

G-proteins are ubiquitously expressed heterotrimeric proteins consisting of α, ß and γ subunits and mediate G-protein coupled receptor signalling cascades. The ß subunit is encoded by one of five highly similar paralogs (GNB1-GNB5, accordingly). The developmental importance of G-proteins is highlighted by the clinical relevance of variants in genes such as GNB1, which cause severe neurodevelopmental disease (NDD). Recently the candidacy of GNB2 was raised in association with NDD in an individual with a de novo variant affecting a codon conserved across paralogs and recurrently mutated in GNB1-related disease, c.229G>A p.(Gly77Arg), in association with global developmental delay, intellectual disability and dysmorphic features. Here, we report a patient with strikingly similar facial features and NDD in association with a de novo GNB2 variant affecting the same codon, c.229G>T p.(Gly77Trp). In addition, this individual has epilepsy and overgrowth. Our report is the second to implicate a de novo GNB2 variant with a severe yet variable NDD.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Proteínas de Ligação ao GTP/genética , Fenótipo , Adolescente , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Epilepsia/patologia , Feminino , Humanos , Mutação , Síndrome
14.
Eur J Med Genet ; 64(8): 104250, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34022416

RESUMO

ST3GAL3 deficiency is an extremely rare autosomal recessive disorder caused by pathogenic mutations in the ST3GAL3 gene. Epilepsy, motor development delay, severe intellectual disability, and behavioral disorders have been reported to be associated with ST3GAL3 deficiency. In the present study, ST3GAL3 deficiency was caused by a homozygous splice-site mutation (NM_174964.4: c.936+1delG) in ST3GAL3. The patient described in this study was clinically similar to previously reported cases; nevertheless, we were able to detect repetitive behavior, previously not reported manifestations.


Assuntos
Epilepsia/genética , Deficiência Intelectual/genética , Fenótipo , Sialiltransferases/genética , Criança , Epilepsia/patologia , Homozigoto , Humanos , Deficiência Intelectual/patologia , Masculino , Movimento , Mutação , Sítios de Splice de RNA , Sialiltransferases/química , Comportamento Estereotipado , Síndrome
15.
Am J Hum Genet ; 108(6): 965-982, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33932343

RESUMO

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.


Assuntos
Epilepsia/genética , Epilepsia/patologia , Exoma , Marcadores Genéticos , Predisposição Genética para Doença , Variação Genética , Sequenciamento Completo do Exoma/métodos , Estudos de Casos e Controles , Estudos de Coortes , Epilepsia/classificação , Testes Genéticos , Humanos , Fenótipo
16.
J Neuroimmunol ; 355: 577549, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33839521

RESUMO

The pathophysiology of neurological diseases related to potassium-channel dysfunction such as epilepsy is increasingly linked to immune system modulation. However, there are limited reports of which interleukin-4 (IL-4) can act on the neuroinflammatory response after seizure. Hence, we evaluated the effect of IL-4 in murine model of neuroexcitotoxcity using kaliotoxin (KTx), a potassium-channel blocker. Results showed that IL-4 treatment can significantly reduce the neuronal death induced by KTx. Probably by decreasing mitochondria swelling, reversing oxidative damage and enhancing Bcl-2 expression. Furthermore, IL-4 treatment significantly reduced TNF-α expression and enhanced GFAP and IL-10 expressions in the brain. IL-4 can be neuroprotective in epileptogenesis.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Epilepsia/prevenção & controle , Fatores Imunológicos/administração & dosagem , Interleucina-4/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Bloqueadores dos Canais de Potássio/toxicidade , Animais , Córtex Cerebral/imunologia , Córtex Cerebral/patologia , Epilepsia/induzido quimicamente , Epilepsia/imunologia , Epilepsia/patologia , Injeções Intraperitoneais , Injeções Intraventriculares , Camundongos , Venenos de Escorpião/toxicidade
17.
J Neuroimaging ; 31(3): 560-568, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33817887

RESUMO

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) is essential in the diagnosis of pharmacoresistant epilepsy (PRE), because patients with lesions detected by MRI have a better prognosis after surgery. Focal cortical dysplasia (FCD) is one of the most frequent etiologies of PRE but can be difficult to identify by MRI. Voxel-based morphometric analysis programs, like the Morphometric Analysis Program (MAP), have been developed to help improve MRI detection. Our objective was to evaluate the clinical usefulness of MAP in patients with PRE and an apparently normal MRI. METHODS: We studied 70 patients with focal PRE and a nonlesional MRI. The 3DT1 sequence was processed with MAP, obtaining three z-score maps. Patients were classified as MAP+ if one or more z-score maps showed a suspicious area of brightness, and MAP- if the z-score maps did not show any suspicious areas. For MAP+ cases, a second-look MRI was performed with a dedicated inspection based on the MAP findings. The MAP results were correlated with the epileptogenic zone. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Thirty-one percent of patients were classified as MAP+ and 69% were MAP-. Results showed a sensitivity of 0.57, specificity of 0.8, PPV of 0.91, and NPV of 0.35. In 19% of patients, an FCD was found in the second-look MRI after MAP. CONCLUSIONS: MAP was helpful in the detection of lesions in PRE patients with a nonlesional MRI, which could have important repercussions for the clinical management and postoperative prognosis of these patients.


Assuntos
Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia/patologia , Imageamento por Ressonância Magnética/métodos , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Adolescente , Adulto , Pesos e Medidas Corporais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Mapeamento Encefálico/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Epilepsy Behav ; 118: 107936, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33839452

RESUMO

BACKGROUND: Anxiety and depressive symptoms are prevalent in patients with refractory mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) before and after anterior temporal lobectomy (ATL). AIMS: (1) To follow the levels of anxiety and depressive symptoms long-term after ATL among patients with refractory MTLE-HS; (2) To identify pre- and postsurgical variables associated with the levels of anxiety and depressive symptoms after surgery. METHODS: We compared the levels of anxiety and depressive symptoms determined by the Hospital Anxiety and Depression Scale (HADS) before and long after ATL (mean 104 months, range 70-130) in 41 consecutive patients refractory MTLE-HS. The last follow-up was between September 2018 and March 2020. We also determined pre- and postsurgical variables independently associated with the HADS scores after surgery. RESULTS: The scores of HADS and its subdomains related to anxiety and depression decreased significantly (p < 0.01) after ATL. After multiple linear regressions, the HADS-Anxiety scores before surgery (B = 0.47, CI 95% 0.20 to 0.75, p = 0.001) and at follow-up after surgery (B = 0.07, CI 0.00 to 0.14, p = 0.05) remain independently and positively associated with HADS-Anxiety scores after surgery. The HADS-Depression scores after surgery were independently positively associated with HADS-Depression scores before surgery (B = 0.39, CI 95% 0.10 to 0.76, p = 0.01) and worse seizure control after surgery (B = 1.55, CI 95% 0.23 to 2.87, p = 0.02). CONCLUSION: Anxiety and depressive symptoms in patients with MTLE-HS significantly improved after ATL. Presurgical levels of anxiety and depressive symptoms, respectively, were positively associated with the postsurgical levels of those symptoms. Length of follow-up is associated with anxiety, and worse seizure control is associated with depressive symptoms after ATL. The results have implications for the surgical management of MTLE-HS patients.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Lobectomia Temporal Anterior , Ansiedade/etiologia , Depressão/etiologia , Epilepsia/patologia , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/cirurgia , Hipocampo/patologia , Humanos , Estudos Prospectivos , Esclerose/patologia , Resultado do Tratamento
19.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922369

RESUMO

Accumulating evidence has demonstrated that the pathogenesis of epilepsy is linked to neuroinflammation and cerebrovascular dysfunction. Peripheral immune cell invasion into the brain, along with these responses, is implicitly involved in epilepsy. This review explored the current literature on the association between the peripheral and central nervous systems in the pathogenesis of epilepsy, and highlights novel research directions for therapeutic interventions targeting these reactions. Previous experimental and human studies have demonstrated the activation of the innate and adaptive immune responses in the brain. The time required for monocytes (responsible for innate immunity) and T cells (involved in acquired immunity) to invade the central nervous system after a seizure varies. Moreover, the time between the leakage associated with blood-brain barrier (BBB) failure and the infiltration of these cells varies. This suggests that cell infiltration is not merely a secondary disruptive event associated with BBB failure, but also a non-disruptive event facilitated by various mediators produced by the neurovascular unit consisting of neurons, perivascular astrocytes, microglia, pericytes, and endothelial cells. Moreover, genetic manipulation has enabled the differentiation between peripheral monocytes and resident microglia, which was previously considered difficult. Thus, the evidence suggests that peripheral monocytes may contribute to the pathogenesis of seizures.


Assuntos
Astrócitos/patologia , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Epilepsia/patologia , Leucócitos/patologia , Animais , Astrócitos/imunologia , Barreira Hematoencefálica/imunologia , Encéfalo/imunologia , Epilepsia/imunologia , Humanos , Leucócitos/imunologia
20.
Toxicol Lett ; 345: 67-76, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33865920

RESUMO

Trimethyltin chloride (TMT) is a by-product in the synthesis of organotin, a plastic stabilizer. With the rapid development of industry, the occupational hazards caused by TMT cannot be ignored. TMT is a typical neurotoxicant, which mainly damages the limbic system and brainstem of the nervous system. Previous studies have demonstrated that the neurotoxicity induced by TMT is linked to the inhibition of energy metabolism, but the underlying mechanism remains elusive. In order to investigate the mechanism of TMT-induced inhibition of energy metabolism, C57BL/6 male mice were administered by IP injection in different TMT doses (0 mg/kg, 1.00 mg/kg, 2.15 mg/kg and 4.64 mg/kg) and times (1d, 3d and 6d), and then the changes of superoxide dismutase (SOD) activity, malondialdehyde (MDA) level and Na+-K+-ATPase activity in cerebral cortex, cerebellum, hippocampus, pons, medulla oblongata of mice, the expressions of Na+-K+-ATPase protein, AMP-activated protein kinase (AMPK), phosphorylated AMP-activated protein kinase(p-AMPK)and peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) in hippocampus and medulla oblongata were measured; the effects of TMT on the viability, the activity of SOD, glutathione (GSH) and Na+-K+-ATPase, MDA level, and the expression of PGC-1α and Na+-K+-ATPase protein in N2a cells were measured by different TMT doses and times, in order to verify the experiments in vivo. Our results found that most of the mice showed depression, tremor, epilepsy, spasm and other symptoms after TMT exposure. Moreover, with the increase of TMT dose, the activity of Na+-K+-ATPase and the expressions of AMPK protein in the hippocampus and medulla oblongata of mice decreased, and the expressions of p-AMPK protein increased. Peroxidative damage was evident in hippocampus, medulla oblongata of mice and N2a cells, and the expression of PGC-1α and Na+-K+-ATPase protein was significantly down-regulated. Therefore, it is reasonable to believe that TMT-induced neurotoxic symptoms and inhibition of energy metabolism may be related to p-AMPK and down-regulation of PGC-1α in the hippocampus and medulla oblongata.


Assuntos
Encéfalo/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Epilepsia/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Compostos de Trimetilestanho/toxicidade , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Epilepsia/metabolismo , Epilepsia/patologia , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação , ATPase Trocadora de Sódio-Potássio/metabolismo , Superóxido Dismutase/metabolismo
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