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1.
Cytogenet Genome Res ; 158(4): 192-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31394532

RESUMO

Prader-Willi syndrome (PWS) and recurrent 15q13.3 microdeletion syndrome can be caused by genomic rearrangements in the complex 15q11q13 chromosomal region. Here, we describe the first female child with PWS and 15q13.3 microdeletion syndrome resulting from an unusual 10.7-Mb deletion from 15pter to 15q13.3 due to an unbalanced de novo 15;19 translocation. The patient presents with hypotonia, microcephaly, developmental delay with lack of speech, intellectual disability, happy demeanor, clinodactyly of the 4th and 5th fingers, and dysmorphic facial features discordant for PWS and consistent with an atypical phenotype.


Assuntos
Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Convulsões/complicações , Convulsões/genética , Translocação Genética/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Feminino , Humanos , Recém-Nascido
2.
Medicine (Baltimore) ; 98(32): e16782, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393404

RESUMO

INTRODUCTION: Over the past 10 years, epilepsy genetics has made dramatic progress. This study aimed to analyze the knowledge structure and the advancement of epilepsy genetics over the past decade based on co-word analysis of medical subject headings (MeSH) terms. METHODS: Scientific publications focusing on epilepsy genetics from the PubMed database (January 2009-December 2018) were retrieved. Bibliometric information was analyzed quantitatively using Bibliographic Item Co-Occurrence Matrix Builder (BICOMB) software. A knowledge social network analysis and publication trend based on the high-frequency MeSH terms was built using VOSviewer. RESULTS: According to the search strategy, a total of 5185 papers were included. Among all the extracted MeSH terms, 86 high-frequency MeSH terms were identified. Hot spots were clustered into 5 categories including: "ion channel diseases," "beyond ion channel diseases," "experimental research & epigenetics," "single nucleotide polymorphism & pharmacogenetics," and "genetic techniques". "Epilepsy," "mutation," and "seizures," were located at the center of the knowledge network. "Ion channel diseases" are typically in the most prominent position of epilepsy genetics research. "Beyond ion channel diseases" and "genetic techniques," however, have gradually grown into research cores and trends, such as "intellectual disability," "infantile spasms," "phenotype," "exome," " deoxyribonucleic acid (DNA) copy number variations," and "application of next-generation sequencing." While ion channel genes such as "SCN1A," "KCNQ2," "SCN2A," "SCN8A" accounted for nearly half of epilepsy genes in MeSH terms, a number of additional beyond ion channel genes like "CDKL5," "STXBP1," "PCDH19," "PRRT2," "LGI1," "ALDH7A1," "MECP2," "EPM2A," "ARX," "SLC2A1," and more were becoming increasingly popular. In contrast, gene therapies, treatment outcome, and genotype-phenotype correlations were still in their early stages of research. CONCLUSION: This co-word analysis provides an overview of epilepsy genetics research over the past decade. The 5 research categories display publication hot spots and trends in epilepsy genetics research which could consequently supply some direction for geneticists and epileptologists when launching new projects.


Assuntos
Bibliometria , Epilepsia/genética , Medical Subject Headings/estatística & dados numéricos , Epigenômica/métodos , Humanos , Canais Iônicos/genética , Mutação , Testes Farmacogenômicos/métodos , Fenótipo , Convulsões/genética
3.
Gene ; 711: 143924, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31212050

RESUMO

The MnSOD Ala16Val single nucleotide polymorphism (SNP) has shown to be associated to inflammatory pathways and many metabolic disorders, such as obesity and dyslipidemia. Metabolic syndrome (MetS) is an emergent problem among patients with epilepsy. However, little is known about interaction between MnSOD Ala16Val SNP and metabolic comorbities in epilepsy. Thus, we investigated the relationship between MnSOD Ala16Val SNP with epilepsy and its influence on MetS, inflammation, apoptosis and DNA damage parameters. Ninety subjects were evaluated (47 epilepsy patients and 43 healthy controls) by questionnaires and laboratorial exams. Levels of inflammatory, apoptotic and DNA damage markers, as well as MnSOD polymorphism were assessed. An increased proportion of VV genotype in epilepsy group when compared to control group was observed. Tumor Necrosis Factor-α (TNF-α), Acetylcholinesterase, caspase-8, and Picogreen levels were increased in VV epilepsy group. An important correlation between TNF-α vs caspase-8, and Cholesterol vs. Triglycerides was observed in the epilepsy group with VV genotype. Our findings suggest that the MnSOD Ala16Val SNP might have an important role in epilepsy, mainly in patients with generalized seizures and particularly with VV genotype. The metabolic parameters also presented significant results in epilepsy group with VV genotype, which applying attention in view of further consequences and disorders that could be developed.


Assuntos
Substituição de Aminoácidos , Colesterol/metabolismo , Convulsões/genética , Superóxido Dismutase/genética , Triglicerídeos/metabolismo , Acetilcolinesterase/genética , Adulto , Estudos de Casos e Controles , Caspase 8/genética , Dano ao DNA , Feminino , Proteínas Ligadas por GPI/genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Estresse Oxidativo , Fator de Necrose Tumoral alfa/genética
4.
Biomed Pharmacother ; 114: 108683, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30947016

RESUMO

OBJECTIVE: This study is conducted to explore the role of microRNA-223 (miR-223) in brain injury and apoptosis of hippocampal neurons through the NLRP3-Caspase-1 signaling pathway in febrile seizure (FS) rats. METHODS: The models of FS were induced in rats by hot water-bath, which were stereotactically injected with miR-223 mimics and mimics negative control (NC) to perturb the expression of miR-223. A series of experiments was conducted to find out the potential mechanisms of miR-223 on convulsion attack, learning and memory ability, pathological injury of hippocampal neurons, inflammatory injury, apoptosis of hippocampal neurons in FS rats. Besides, the targeting relationship between miR-223 and NLRP3 was also verified. RESULTS: Low expression of miR-223 was found in hippocampus tissues of FS rats. Up-regulation of miR-223 alleviated convulsion attack and improved learning and memory ability, while inhibiting pathological injury of hippocampal neurons and inflammatory injury in FS rats. Up-regulation of miR-223 promoted the survival of hippocampal neurons and inhibited their apoptosis in FS rats. MiR-223 inhibited the activation of NLRP3-Caspase-1 signaling pathway in hippocampus tissues of FS rats by inhibiting NLRP3. CONCLUSION: The inhibited expression of miR-223 after FS may participate in the activation of the NLRP3-Caspase-1 signaling pathway, resulting in brain injury and apoptosis of hippocampal neurons in rat models of FS.


Assuntos
Apoptose/genética , Lesões Encefálicas/genética , Caspase 1/genética , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Convulsões Febris/genética , Regulação para Cima/genética , Animais , Lesões Encefálicas/patologia , Hipocampo/patologia , Aprendizagem/fisiologia , Memória/fisiologia , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Convulsões/genética , Convulsões/patologia , Transdução de Sinais/genética , Ativação Transcricional/genética
5.
Nat Commun ; 10(1): 1917, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015467

RESUMO

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.


Assuntos
Corpo Estriado/metabolismo , Proteínas Munc18/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Neocórtex/metabolismo , Convulsões/genética , Transmissão Sináptica , Potenciais de Ação/efeitos dos fármacos , Animais , Anticonvulsivantes/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Dioxóis/farmacologia , Eletroencefalografia , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/metabolismo , Epilepsia Tipo Ausência/fisiopatologia , Etossuximida/farmacologia , Regulação da Expressão Gênica , Haploinsuficiência , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Interneurônios/patologia , Camundongos , Camundongos Knockout , Proteínas Munc18/deficiência , Canal de Sódio Disparado por Voltagem NAV1.2/deficiência , Neocórtex/efeitos dos fármacos , Neocórtex/patologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Piperidinas/farmacologia , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Convulsões/metabolismo , Convulsões/fisiopatologia , Convulsões/prevenção & controle , Transdução de Sinais , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
6.
Gene ; 704: 97-102, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978478

RESUMO

In the current study, we report three cases of Asparagine Synthetase (ASNS) Deficiency from two consanguineous families. Family 1 had two early neonatal deaths due to a novel mutation in the ASNS gene c.788C > T (p.S263F) and both the children presented with microcephaly and one of them had severe intracranial haemorrhage. The proband from the second family was homozygous for c.146G > A (p.R49Q) and manifested myoclonic seizures, developmental delay, coarse hair and diffuse cortical atrophy. Molecular docking studies of both the mutations revealed alteration in the ligand binding site. Till date, 26 mutations were reported in ASNS gene in 29 affected children indicating high degree of genetic heterogeneity and high mortality. Although asparagine depletion is not of diagnostic utility, multiple linear regression model suggested that asparagine levels vary to the extent of 20.6% based on glutamine and aspartate levels and ASNS deficiency results in depletion of asparagine synthesis. ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy.


Assuntos
Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Grupo com Ancestrais do Continente Asiático , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/deficiência , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Família , Feminino , Humanos , Índia , Lactente , Recém-Nascido , Hemorragias Intracranianas/congênito , Hemorragias Intracranianas/genética , Masculino , Microcefalia/patologia , Técnicas de Diagnóstico Molecular , Morte Perinatal , Convulsões/complicações , Convulsões/genética
7.
Rinsho Shinkeigaku ; 59(3): 144-148, 2019 Mar 28.
Artigo em Japonês | MEDLINE | ID: mdl-30814447

RESUMO

A 21-year-old woman presented with a chief complaint of generalized tonic-clonic seizures occurring once a month at night since the age of 14. The patient was treated with clonazepam plus levetiracetam, but seizure frequency was not reduced. After the detailed re-examination of her history of illness, it was revealed that she has been suffering from transient and recurrent choreoathetoid attacks triggered by sudden voluntary movements since she was a junior high school student, and it recently increased in frequency. Neither she nor her family recognize that it was significant to describe to the doctors. She was diagnosed as a complex of paroxysmal kinesigenic choreoathetosis (PKC) and its related conditions. Direct sequencing of proline-rich transmembrane protein 2 (PRRT2) revealed the most frequently described gene mutation, (NM_145239.2:c.649dupC), among PRRT2-related paroxysmal disorders. PKC and seizures were readily controlled with small dose of carbamazepine. Given the broad spectrum of PRRT2-related paroxysmal disorders, assessment of potential clinical complication of paroxysmal disorders including PKC might therefore be critical.


Assuntos
Distonia/genética , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Convulsões/genética , Carbamazepina/administração & dosagem , Distonia/diagnóstico , Distonia/tratamento farmacológico , Distonia/etiologia , Eletroencefalografia , Feminino , Humanos , Convulsões/tratamento farmacológico , Privação do Sono/complicações , Resultado do Tratamento , Adulto Jovem
8.
Medicine (Baltimore) ; 98(8): e14524, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813157

RESUMO

RATIONALE: Trio family-based whole exome sequencing (WES) is a powerful tool in the diagnosis of rare neurodevelopmental diseases, even in patients with the unclear diagnosis. There have been previous reports of variants in the phosphatidylinositol glycan anchor biosynthesis class T (PIGT) gene associated with multiple congenital anomalies, with a total of 14 affected individuals across 8 families. PATIENT CONCERNS: An 18-month-old boy of Greek ancestry presented with global developmental delay, generalized tonic-clonic seizures, hypotonia, renal cysts, esotropia, bilateral undescended testes, bilateral vesicoureteric reflux, marked cardiac dextroposition, bilateral talipes equinovarus, and dysmorphic features. DIAGNOSIS: WES revealed 2 compound heterozygous variants in the PIGT gene, c.[494-2A>G]; [547A>C]/p.[Asp122Glyfs*35]; [Thr183Pro]. The splicing mutation was demonstrated to lead to the skipping of exon 4. INTERVENTIONS: Seizures, infections, and other main symptoms were treated. OUTCOMES: The patient died at 2 years of age before the molecular diagnosis was achieved. Genetic counseling has been offered to the family. LESSONS: Most of the clinical features of the patient are in agreement with the previously described PIGT cases corroborating the usefulness of WES as a diagnostic tool.


Assuntos
Anormalidades Múltiplas/genética , Aciltransferases/genética , Técnicas de Cultura de Células , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Evolução Fatal , Humanos , Lactente , Masculino , Hipotonia Muscular/genética , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Convulsões/genética , Síndrome , Sequenciamento Completo do Exoma/métodos
9.
Brain ; 142(2): 412-425, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649209

RESUMO

Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy in which brainstem spreading depolarization may play a pivotal role, as suggested by animal studies. However, patiotemporal details of spreading depolarization occurring in relation to fatal seizures have not been investigated. In addition, little is known about behavioural and neurophysiological features that may discriminate spontaneous fatal from non-fatal seizures. Transgenic mice carrying the missense mutation S218L in the α1A subunit of Cav2.1 (P/Q-type) Ca2+ channels exhibit enhanced excitatory neurotransmission and increased susceptibility to spreading depolarization. Homozygous Cacna1aS218L mice show spontaneous non-fatal and fatal seizures, occurring throughout life, resulting in reduced life expectancy. To identify characteristics of fatal and non-fatal spontaneous seizures, we compared behavioural and electrophysiological seizure dynamics in freely-behaving homozygous Cacna1aS218L mice. To gain insight on the role of brainstem spreading depolarization in SUDEP, we studied the spatiotemporal distribution of spreading depolarization in the context of seizure-related death. Spontaneous and electrically-induced seizures were investigated by video monitoring and electrophysiological recordings in freely-behaving Cacna1aS218L and wild-type mice. Homozygous Cacna1aS218L mice showed multiple spontaneous tonic-clonic seizures and died from SUDEP in adulthood. Death was preceded by a tonic-clonic seizure terminating with hindlimb clonus, with suppression of cortical neuronal activity during and after the seizure. Induced seizures in freely-behaving homozygous Cacna1aS218L mice were followed by multiple spreading depolarizations and death. In wild-type or heterozygous Cacna1aS218L mice, induced seizures and spreading depolarization were never followed by death. To identify temporal and regional features of seizure-induced spreading depolarization related to fatal outcome, diffusion-weighted MRI was performed in anaesthetized homozygous Cacna1aS218L and wild-type mice. In homozygous Cacna1aS218L mice, appearance of seizure-related spreading depolarization in the brainstem correlated with respiratory arrest that was followed by cardiac arrest and death. Recordings in freely-behaving homozygous Cacna1aS218L mice confirmed brainstem spreading depolarization during spontaneous fatal seizures. These data underscore the value of the homozygous Cacna1aS218L mouse model for identifying discriminative features of fatal compared to non-fatal seizures, and support a key role for cortical neuronal suppression and brainstem spreading depolarization in SUDEP pathophysiology.


Assuntos
Tronco Encefálico/fisiopatologia , Canais de Cálcio Tipo N/genética , Córtex Cerebral/fisiopatologia , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Convulsões/genética , Convulsões/fisiopatologia , Animais , Morte Súbita , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
11.
J Hum Genet ; 64(4): 347-350, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30626896

RESUMO

We report the second case of early infantile epileptic encephalopathy (EIEE) arising from a homozygous truncating variant of NECAP1. The boy developed infantile-onset tonic-clonic and tonic seizures, then spasms in clusters. His electroencephalogram (EEG) showed a burst suppression pattern, leading to the diagnosis of Ohtahara syndrome. Whole-exome sequencing revealed the canonical splice-site variant (c.301 + 1 G > A) in NECAP1. In rodents, Necap1 protein is enriched in neuronal clathrin-coated vesicles and modulates synaptic vesicle recycling. cDNA analysis confirmed abnormal splicing that produced early truncating mRNA. There has been only one previous report of a mutation in NECAP1 in a family with EIEE; this was a nonsense mutation (p.R48*) that was cited as EIEE21. Decreased mRNA levels and the loss of the WXXF motif in both the families suggests that loss of NECAP1 function is a common pathomechanism for EIEE21. This study provided additional support that synaptic vesicle recycling plays a key role in epileptogenesis.


Assuntos
Subunidades alfa do Complexo de Proteínas Adaptadoras/genética , Convulsões/genética , Espasmos Infantis/genética , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Homozigoto , Humanos , Lactente , Masculino , Mutação , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/fisiopatologia
12.
Arch Pediatr ; 26(2): 102-107, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30638765

RESUMO

BACKGROUND AND OBJECTIVES: Sanjad-Sakati syndrome (SSS; OMIM 241410) is a rare autosomal recessive disorder found almost exclusively in people of Arab origin. It is characterized by congenital hypoparathyroidism, severe prenatal and postnatal growth retardation, and distinct facial dysmorphism. The molecular pathology of this syndrome was shown to be due to a mutation in the tubulin-specific chaperone E (TBCE) gene in chromosomal area 1q42-q43. We aimed to detect and confirm the common mutation responsible for SSS in Tunisian patients and review the literature in order to create a set of clinical diagnostic criteria that might provide appropriate indications for molecular testing. METHODS: Three Tunisian patients with clinical feature of SSS were examined via direct Sanger sequencing of exon 3 of the TBCE gene. RESULTS: Mutation analysis of the TBCE gene revealed the common 12-bp (155-166del) deletion in three new patients, thus raising the number of reported SSS patients to 73. Reviewing the literature, we suggest a scoring system that assigns one point each for major criteria and one half point for minor criteria. INTERPRETATION AND CONCLUSIONS: SSS is an autosomal recessive disorder found in the Middle Eastern population with an estimated incidence of 1 per 40,000-100,000 live births in Saudi Arabia. Reviewing the literature on both its clinical and biochemical characteristics, we suggest for the first time, based on defined major and minor SSS criteria, a clinical scoring system for the diagnosis of SSS. On the one hand, an established scoring system will provide appropriate indications for molecular testing and, on the other hand, reviewed data on SSS will help delineate the phenotype and draw a distinction between differential diagnoses.


Assuntos
Anormalidades Múltiplas/diagnóstico , Transtornos do Crescimento/diagnóstico , Hipoparatireoidismo/diagnóstico , Deficiência Intelectual/diagnóstico , Chaperonas Moleculares/genética , Osteocondrodisplasias/diagnóstico , Convulsões/diagnóstico , Anormalidades Múltiplas/genética , Consenso , Feminino , Marcadores Genéticos , Transtornos do Crescimento/genética , Humanos , Hipoparatireoidismo/genética , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Osteocondrodisplasias/genética , Convulsões/genética , Deleção de Sequência , Tunísia
13.
J Hum Genet ; 64(4): 313-322, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30655572

RESUMO

Casein kinase 2 (CK2) is a serine threonine kinase ubiquitously expressed in eukaryotic cells and involved in various cellular processes. In recent studies, de novo variants in CSNK2A1 and CSNK2B, which encode the subunits of CK2, have been identified in individuals with intellectual disability syndrome. In this study, we describe four patients with neurodevelopmental disorders possessing de novo variants in CSNK2A1 or CSNK2B. Using whole-exome sequencing, we detected two de novo variants in CSNK2A1 in two unrelated Japanese patients, a novel variant c.571C>T, p.(Arg191*) and a recurrent variant c.593A>G, p.(Lys198Arg), and two novel de novo variants in CSNK2B in Japanese and Malaysian patients, c.494A>G, p.(His165Arg) and c.533_534insGT, p.(Pro179Tyrfs*49), respectively. All four patients showed mild to profound intellectual disabilities, developmental delays, and various types of seizures. This and previous studies have found a total of 20 CSNK2A1 variants in 28 individuals with syndromic intellectual disability. The hotspot variant c.593A>G, p.(Lys198Arg) was found in eight of 28 patients. Meanwhile, only five CSNK2B variants were identified in five individuals with neurodevelopmental disorders. We reviewed the previous literature to verify the phenotypic spectrum of CSNK2A1- and CSNK2B-related syndromes.


Assuntos
Caseína Quinase II/genética , Deficiências do Desenvolvimento/genética , Convulsões/genética , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Convulsões/complicações , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
14.
Epilepsy Res ; 150: 70-77, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30660939

RESUMO

Epilepsy with myoclonic-atonic seizures (EMAS) accounts for 1-2% of all childhood-onset epilepsies. EMAS has been shown to have an underlying genetic component, however the genetics of this disorder is not yet well understood. The purpose of this study was to review genetic testing results for a cohort of EMAS patients. A retrospective chart review was conducted for 77 patients evaluated at Children's Hospital Colorado with a potential diagnosis of EMAS. Genetic testing and biochemical testing was reviewed. Family history data was also collected. Seventy-seven percent of the cohort had at least one genetic test performed, and a molecular diagnosis was reached for six patients. Thirty-seven patients had a microarray, six of which identified a copy number variant. Only one was felt to contribute to the phenotype (2p16.3 deletion including NRXN1). Fifty-one patients had an epilepsy panel, two of which were positive (likely pathogenic variant in SCN1A, pathogenic variant in GABRG2). Of the six patients who had whole exome sequencing, two were negative, three were positive or likely positive, and one had multiple variants not felt to explain the phenotype. While EMAS is widely accepted to have a strong genetic component, the diagnostic yield of genetic testing remains low. This may be because several genes now thought to be associated with EMAS are not included on the more commonly ordered epilepsy panels, or have only recently been added to them.


Assuntos
Epilepsia/complicações , Epilepsia/genética , Convulsões/complicações , Convulsões/genética , Moléculas de Adesão Celular Neuronais/genética , Estudos de Coortes , Polimerase do DNA Mitocondrial/genética , Proteínas de Ligação a DNA/genética , Eletroencefalografia , Saúde da Família , Feminino , Testes Genéticos , Transportador de Glucose Tipo 1/genética , Humanos , Masculino , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Proteínas do Tecido Nervoso/genética , Receptores de GABA-A/genética , Sequenciamento Completo do Exoma
15.
Neurol Sci ; 40(3): 523-528, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30564963

RESUMO

OBJECTIVE: This study aims to describe the associations between genetic polymorphisms and therapeutic effect of valproic acid (VPA) in children with focal seizures. METHODS: Eighty-nine children with focal seizures on VPA therapy were enrolled. Patients' basic information, dosage regimens, and plasma concentrations were recorded. A 1-year follow-up was performed to evaluate the treatment response. Sixty-six single nucleotide polymorphisms involved in the metabolism, transport, and target receptor of VPA were identified, and their associations with VPA response were analyzed using logistic regression adjusted by various influence factors. Selected polymorphisms involved in the metabolism, transport, and target receptor of VPA were not associated with treatment effect in children with focal seizures. RESULTS: Three variants, rs9313892 (GABRA6, G > A, OR = 2.73, 95% CI 1.00 to 7.48, P = 0.051), rs4921195 (GABRA6, T > C, OR = 2.71, 95% CI 0.99 to 7.42, P = 0.053), and rs424740 (GABRG2, A > T, OR = 0.39, 95% CI 0.15 to 1.01, P = 0.053) had the potential to be associated with the VPA response. CONCLUSION: Selected genetic polymorphisms were not significantly associated with VPA response in children with focal seizures. However, three GABR variants showed potential to be associated with the response to VPA. Further and larger studies are warranted to confirm the results.


Assuntos
Anticonvulsivantes/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Receptores de GABA-A/genética , Convulsões/tratamento farmacológico , Convulsões/genética , Ácido Valproico/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Modelos Logísticos , Masculino
16.
Epilepsy Behav ; 90: 217-227, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578097

RESUMO

OBJECTIVE: Behavior problems in Dravet syndrome (DS) are common and can impact the lives of patients tremendously. The current study aimed to give more insight into (1) the prevalence of a wide range of specific behavior difficulties and aspects of health-related quality of life (HRQoL) in patients with DS compared with the general population (gp) and patients with epilepsy without DS, (2) the relations between these behavior problems and different aspects of HRQoL, and (3) the associations between seizure frequency, cognitive impairment (CI), behavior problems, and HRQoL, based on a conceptual model. METHODS: One hundred and sixteen patients (aged between 2 and 67 years), affected by SCN1A-related seizures, were included in the study. Eighty-five were patients with DS, 31 were patients with epilepsy without DS. Behavior problems were measured using the Child/Adult Behavior Checklist (C/ABCL), HRQoL was measured using the Pediatric Quality of Life Inventory (PedsQL) Measurement Model. Other characteristics were obtained by clinical assessments, medical records, and semi-structured telephone interviews with parents. Comparisons between patients with DS, patients without DS, and the gp were calculated by the exact goodness of fit χ2 analyses, relations between subscales were analyzed using Pearson's correlations, and the conceptual model was tested in a path analysis. RESULTS: (1) Patients with DS show significantly more behavior problems compared with the gp and patients with epilepsy without DS. A total of 56.5% of patients with DS scored in the borderline and clinical ranges for total behavior problems. Problems with attention were most prevalent; 62.3% of patients with DS scored in the borderline and clinical ranges. Health-related quality of life was significantly lower for patients with DS compared with the gp and patients without DS. Physical and social functioning scores were especially low and decreased even more in the older age categories. (2) Problems with attention, aggression, and withdrawn behavior were most related to social functioning. Somatic problems and anxiety/depression were most related to emotional functioning. (3) Cognitive impairment and behavior problems were both independent predictors of poorer HRQoL in patients with DS, with behavior problems being the strongest predictor. Seizure frequency was only indirectly related to HRQoL, mediated by cognitive impairment. IMPLICATIONS: The high prevalence of behavior problems in DS and the significant impact on quality of life (QoL), independent of epilepsy-related factors, emphasize the need for active management and treatment of these problems and should be considered as part of the management plan.


Assuntos
Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/psicologia , Comportamento Problema/psicologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Depressão/diagnóstico , Depressão/genética , Depressão/psicologia , Epilepsias Mioclônicas/diagnóstico , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/psicologia , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/genética , Síndromes Epilépticas/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Síndrome de Rett/psicologia , Convulsões/diagnóstico , Convulsões/genética , Convulsões/psicologia , Ajustamento Social , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Espasmos Infantis/psicologia , Inquéritos e Questionários , Adulto Jovem
17.
Epileptic Disord ; 20(6): 530-534, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530430

RESUMO

Williams-Beuren syndrome is rarely associated with epilepsy. One previously reported case showed an association with apnoeic seizures while a few other cases showed an association with infantile epileptic spasms and generalized and focal seizures. We report the case of a 13-month-old boy with a deletion typically associated with Williams-Beuren syndrome, who presented with isolated apnoeic seizures which were refractory to multiple antiepileptic drugs but partially responsive to the ketogenic diet. The diagnosis was challenging due to a complex cardiac history, gastroesophageal reflux, and normal interictal EEG findings. This case highlights the importance of prolonged EEG monitoring in suspected cases of apnoeic seizures. Further, given the reported cases of unexplained sudden death in Williams-Beuren syndrome, this case raises the possibility of an association between apnoeic seizures and unexplained sudden death. [Published with video sequence on www.epilepticdisorders.com].


Assuntos
Epilepsia Resistente a Medicamentos/genética , Convulsões/genética , Encéfalo/fisiopatologia , Diagnóstico Diferencial , Dieta Cetogênica , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/dietoterapia , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletroencefalografia , Humanos , Lactente , Masculino , Convulsões/diagnóstico , Convulsões/dietoterapia , Convulsões/fisiopatologia , Deleção de Sequência , Síndrome de Williams/diagnóstico , Síndrome de Williams/genética
18.
Epileptic Disord ; 20(6): 541-544, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530441

RESUMO

A male neonate presented with seizures at 18 hours of life, characterized by tonic posturing with eye deviation to the right, apnoea, bradycardia, and oxygen desaturation. Initial structural, metabolic, and infectious work-up was unremarkable. He continued to have seizures refractory to a variety of antiepileptic medications. A phenobarbital coma was trialled, leading to cessation of clinical seizures but continuation of electrographic status epilepticus. On EEG, ictal discharges originated from both the right and left hemispheres, migrating to the opposite hemisphere, consistent with encephalopathy of infancy with migrating focal seizures. At this time, he developed septic shock and was trialled on a ketamine infusion and ketogenic diet. Due to his poor prognosis, a goals of care discussion was carried out with the family, leading to withdrawal of care and his subsequent death at one month and seven days. A posthumous genetic panel revealed a de novo KCNQ2 p.Ser247Leu variant, considered likely to be pathogenic. This is the third reported case of a KCNQ2 mutation associated with an encephalopathy of infancy with migrating focal seizures phenotype. We discuss potential cellular mechanisms underlying this unique KCNQ2 phenotype, as well as future therapeutic considerations.


Assuntos
Canal de Potássio KCNQ2/genética , Mutação , Convulsões/genética , Espasmos Infantis/genética , Encéfalo/fisiopatologia , Análise Mutacional de DNA , Eletroencefalografia , Humanos , Recém-Nascido , Masculino , Prognóstico , Convulsões/fisiopatologia , Espasmos Infantis/fisiopatologia
19.
Medicine (Baltimore) ; 97(50): e13675, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30558073

RESUMO

Glioma is the most common malignant tumor in the central nervous system (CNS). Lower-grade gliomas (LGG) refer to Grade II and III gliomas. In LGG patients, seizure often appears as an initial symptom and play an important role in clinical performance and quality of life of the patients. To date, the relationship between the onset of seizures and the molecular pathology in gliomas is still poorly investigated. In this study, we investigate the potential relationship between isocitrate dehydrogenase (IDH)/telomerase reverse transcriptase promoter (TERTp) mutations and preoperative seizures in patients with LGG. 289 adult LGG patients were enrolled in this study. Data of clinical characteristics and molecular pathology were acquired. Sanger sequencing was used to detect IDH/TERTp mutations. Chi-square test was performed to determine if the IDH/TERTp mutations were associated with seizures and seizure types. In 289 LGG patients, preoperative seizures accounted for 25.3% (73/289), IDH mutations accounted for 34.3%(99/289), and TERTp mutations accounted for 44.3% (128/289). The correlation analysis demonstrated that IDH mutation is a significant factor influencing the occurrence of tumor-related epilepsy (P <.001, chi-square test). On the other hand, the statistical analysis revealed no significant correlation between TERTp mutations and seizure in LGG patients (P = .102, chi-square test). The tumor-related epilepsy rates vary among different subgroups according to IDH/TERTp mutations. However, there is no definite correlation between the IDH (P = 1.000, chi-square test)/TERTp (P = .613, chi-square test) mutations and the types of epileptic seizure. IDH mutations are more common in preoperative LGG patients with epileptic symptoms, suggesting that this mutation is positively correlated with seizures. However, there was no significant correlation between TERTp mutations and seizures. Different molecular pathologic types based on IDH/TERTp have different incidences of tumor-associated epilepsy in LGGs.


Assuntos
Glioma/genética , Isocitrato Desidrogenase/genética , Convulsões/genética , Telomerase/genética , Neoplasias Encefálicas/patologia , Sistema Nervoso Central/patologia , Feminino , Glioma/classificação , Glioma/patologia , Glioma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Convulsões/etiologia , Análise de Sequência de DNA/métodos
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