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1.
Epilepsy Behav ; 99: 106470, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31430660

RESUMO

BACKGROUND: Pure attentional deficits are still underdiagnosed in children with epilepsy. While attention-deficit hyperactivity disorder (ADHD) is historically the most studied cause of attentional disorders, an important number of children with epilepsy and attentional complaints do not fully meet the DSM-V (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition) criteria for ADHD and may be excluded from specific care. Clinical tools currently available are insufficient to detect more subtle but clinically relevant attentional fluctuations. OBJECTIVE/METHODS: The recently developed Bron-Lyon Attention Stability Test (BLAST) was used to evaluate brief attentional fluctuations with a high temporal precision. Drawing on two new attentional indices, we evaluated spontaneous fluctuations of response accuracy and timing, underlying attentional stability. The main objective was to assess attentional stability in children with i) epilepsy with comorbid ADHD, ii) epilepsy without comorbid ADHD, iii) ADHD not medicated and without epilepsy, and iv) normal development. Further objectives were to assess the main determinants of attentional stability in those groups, including the effect of factors related to the epileptic condition. RESULTS: In 122 children with epilepsy (67 with comorbid ADHD), 52 children with ADHD, and 53 healthy controls, we demonstrated lower attentional stability in both the groups with epilepsy and ADHD compared with healthy children. In children with epilepsy, BLAST scores were negatively associated with earlier seizure onset and AED (antiepileptic drug) polytherapy, while the seizure frequency, epilepsy duration, or type did not influence BLAST scores. CONCLUSIONS: This study demonstrates that attentional stability is impaired in children with epilepsy and/or ADHD. Bron-Lyon Attention Stability Test seems to be a sensitive test to detect attentional stability deficit in children with epilepsy and with attentional complaints who did not meet all criteria of ADHD. We propose that BLAST could be a useful clinical neuropsychological tool to assess attentional disorders in children.

2.
Neuropediatrics ; 50(5): 308-312, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31226716

RESUMO

Mutations that disrupt the TBC1D24 presynaptic protein have been implicated in various neurological disorders including epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome, nonsyndromic hearing loss, and myoclonus. We present the case of a 22-month-old male with infantile-onset paroxysmal episodes of facial and limb myoclonus. The episodes were linked to biallelic variants in exon 2 of the TBC1D24 gene that lead to amino acid changes (c.304C >T/p.Pro102Ser and c.410T > C/p.Val137Ala), each variant being inherited from a parent. Follow-up imaging in adolescence revealed widened right cerebellar sulci. We discuss the evolving landscape of TBC1D24 associated phenotypes; this case adds to a growing body of evidence linking this gene to movement disorders in children.

3.
Eur J Paediatr Neurol ; 23(2): 270-279, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30737142

RESUMO

OBJECTIVES: To evaluate the predictive factors for status epilepticus (SE) in neonates and prognostic factors for patient outcomes in newborns suffering either isolated seizures or SE. METHODS: A retrospective single-center study from January 2010 to December 2014, included 91 newborns who had neonatal seizures. Among them, 50 newborns experienced SE and 41 newborns presented isolated seizures only. SE was defined as a single seizure lasting more than 15 min or repeated seizures without return to preictal neurological baseline for more than 15 min. Isolated seizures were defined as one single seizure lasting less than 15 min or more seizures with complete recovery of consciousness between seizures. Perinatal and electroclinical data were recorded. Outcomes were evaluated at one year follow up. RESULTS: In multivariate analysis, the factors identified as being predictive of SE were a severely abnormal initial neurological examination (OR 15.7, 95% CI (3.8-109) p = 0.00075) and hypoglycaemia (OR 6.8, 95% CI (1.5-49.2) p = 0.024), found mostly in newborns with hypoxic-ischemic encephalopathy. When studying our global cohort, SE was found to be a negative prognostic factor for outcome only in univariate analysis. In newborns with isolated seizures only, the postictal clinical examination results were the only independent prognostic factor found, normal results being associated with a more favorable evolution (OR 48.9, 95% CI (7.16-571) p = 0.0003). CONCLUSION: Two independent risk factors for SE in newborns have been identified: a severely abnormal initial neurological examination and hypoglycaemia. In newborns with isolated seizures, the only positive prognostic factor was found to be a normal postictal clinical examination.


Assuntos
Doenças do Recém-Nascido , Fatores de Risco , Estado Epiléptico , Estudos de Coortes , Eletroencefalografia , Feminino , Humanos , Hipoglicemia/complicações , Hipóxia-Isquemia Encefálica/complicações , Recém-Nascido , Masculino , Análise Multivariada , Exame Neurológico , Prognóstico , Estudos Retrospectivos , Convulsões/complicações , Estado Epiléptico/complicações
4.
Brain ; 142(1): 80-92, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544257

RESUMO

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.


Assuntos
Epilepsia/genética , Transtornos do Neurodesenvolvimento/genética , Receptores de N-Metil-D-Aspartato/genética , Adolescente , Adulto , Idoso , Animais , Células Cultivadas , Córtex Cerebelar/metabolismo , Criança , Pré-Escolar , Epilepsia/fisiopatologia , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Adulto Jovem
6.
Epileptic Disord ; 20(4): 289-294, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30078772

RESUMO

SCN8A encephalopathy is a newly defined epileptic encephalopathy caused by de novo mutations of the SCN8A gene. We report herein a four-year-old boy presenting with severe non-epileptic abnormal movements, of possibly antenatal onset, progressively associated with pharmacoresistant epilepsy and regression, associated with a de novo heterozygous missense mutation of SCN8A. This case shows that paroxysmal non-epileptic episodes of severe tremor and hyperekplexia-like startles and a striking vegetative component can be the first early symptoms of severe SCN8A developmental and epileptic encephalopathy. Clinicians should be aware of these symptoms in order to avoid misdiagnosis and ensure early appropriate therapeutic management. [Published with video sequences on www.epilepticdisorders.com].


Assuntos
Encefalopatias , Epilepsia , Hiperecplexia , Doenças do Recém-Nascido , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Tremor , Encefalopatias/diagnóstico , Encefalopatias/genética , Encefalopatias/fisiopatologia , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/fisiopatologia , Humanos , Hiperecplexia/diagnóstico , Hiperecplexia/genética , Hiperecplexia/fisiopatologia , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/fisiopatologia , Masculino , Tremor/diagnóstico , Tremor/genética , Tremor/fisiopatologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-30126759

RESUMO

Christianson syndrome (CS) is a X-linked neurodevelopmental disorder, including severe intellectual disability (ID), progressive microcephaly, ataxia, autistic behaviour (ASD), near absent speech, and epilepsy. Electrical status epilepticus in sleep (ESES) has been reported in two patients. We describe five male patients from three unrelated families with Christianson syndrome caused by a pathogenic nucleotide variation or a copy-number variation involving SLC9A6. ESES was present in three out of the five patients in the critical age window between 4 and 8 years. All patients presented with severe intellectual disability, autistic features, and hyperactivity. Epilepsy onset occurred within the first two years of life. Seizures were of various types. In the two boys with a 20-years follow-up, epilepsy was drug-resistant during childhood, and became less active in early adolescence. Psychomotor regression was noted in two patients presenting with ESES. It was difficult to assess to what extent ESES could have contributed to the pathophysiological process, leading to regression of the already very limited communication skills. The two published case reports and our observation suggests that ESES could be a constitutive feature of Christianson syndrome, as it has already been shown for other Mendelian epileptic disorders, such as GRIN2A and CNKSR2-related developmental epileptic encephalopathies. Sleep EEG should be performed in patients with Christianson syndrome between 4 and 8 years of age. ESES occurring in the context of ID, ASD and severe speech delay, could be helpful to make a diagnosis of CS.

8.
Am J Hum Genet ; 102(5): 995-1007, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656858

RESUMO

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

9.
Am J Hum Genet ; 102(5): 744-759, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656859

RESUMO

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

10.
Am J Hum Genet ; 101(5): 768-788, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100089

RESUMO

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Deficiência Intelectual/genética , Mutação/genética , Animais , Encéfalo/patologia , Linhagem Celular , Exoma/genética , Feminino , Ácido Glutâmico/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Fosforilação/genética , Transdução de Sinais/genética
11.
Epilepsia ; 58(10): 1716-1727, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28762475

RESUMO

OBJECTIVE: We hypothesized that children with benign childhood epilepsy with centrotemporal spikes (BCECTS) might have altered social cognitive skills and underlying neural networks. METHODS: We studied 13 patients with BCECTS and 11 age-matched controls using event-related functional magnetic resonance imaging (fMRI) with an emotional discrimination task consisting of viewing happy, fearful, scrambled, and neutral faces. Behavioral performance measured during the task was correlated with clinical variables and behavioral ratings. RESULTS: In comparison with age-matched controls, children with BCECTS performing a fearful faces detection task showed significantly reduced bilateral fMRI activation in the insular cortex, caudate, and lentiform nuclei, as well as increased response time. The percentage of errors made by children with BCECTS correlated negatively with age, a finding not observed in controls. In patients, accuracy positively correlated with time since the last seizure. The above abnormalities were not observed during happy faces detection task, except for a slower response in children with BCECTS as compared to controls. SIGNIFICANCE: Our study suggests that BCECTS is associated with altered social cognition network and function, particularly for the identification of fearful faces. The age dependency of some of these findings supports the view that a delayed maturation of spiking cortical regions might underlie the cognitive dysfunction observed in BCECTS.


Assuntos
Encéfalo/fisiopatologia , Epilepsia Rolândica/fisiopatologia , Reconhecimento Facial/fisiologia , Medo , Felicidade , Percepção Social , Estudos de Casos e Controles , Núcleo Caudado/fisiopatologia , Córtex Cerebral/fisiopatologia , Criança , Corpo Estriado/fisiopatologia , Epilepsia Rolândica/psicologia , Potenciais Evocados , Expressão Facial , Feminino , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Masculino , Convulsões , Fatores de Tempo
12.
Neurology ; 88(5): 483-492, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28053010

RESUMO

OBJECTIVE: To examine the role of mutations in GABRB3 encoding the ß3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. METHODS: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. RESULTS: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant ß3, together with α5 and γ2s subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. CONCLUSIONS: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism.


Assuntos
Epilepsia/genética , Mutação , Receptores de GABA-A/genética , Animais , Automação Laboratorial , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Potenciais da Membrana/fisiologia , Oócitos , Técnicas de Patch-Clamp , Fenótipo , Receptores de GABA-A/metabolismo , Xenopus laevis
13.
Eur J Hum Genet ; 24(12): 1761-1770, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27352968

RESUMO

Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORß), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia Generalizada/genética , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Adulto , Criança , Pontos de Quebra do Cromossomo , Deleção Cromossômica , Códon sem Sentido , Deficiências do Desenvolvimento/diagnóstico , Epilepsia Generalizada/diagnóstico , Exoma , Éxons , Feminino , Humanos , Masculino , Linhagem , Síndrome , Translocação Genética
14.
Eur J Hum Genet ; 24(7): 1001-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26486472

RESUMO

West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births. To get better insights on the genetic of this pathology, we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings. GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis. The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor. Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments. We suggest a new link between improper assembly of respiratory chain complexes and WS.


Assuntos
GTP Fosfo-Hidrolases/genética , Homozigoto , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto , Fator G para Elongação de Peptídeos/genética , Espasmos Infantis/genética , Sítios de Ligação , Sequência Conservada , Exoma , Feminino , GTP Fosfo-Hidrolases/metabolismo , Teste de Complementação Genética , Humanos , Lactente , Masculino , Proteínas Mitocondriais/metabolismo , Linhagem , Fator 1 de Elongação de Peptídeos , Fator G para Elongação de Peptídeos/metabolismo , Ligação Proteica , Espasmos Infantis/patologia , Leveduras/genética
15.
Epilepsy Res ; 111: 72-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25769375

RESUMO

Mutations in the TBC1D24 gene were first reported in an Italian family with a unique epileptic phenotype consisting of drug-responsive, early-onset idiopathic myoclonic seizures. Patients presented with isolated bilateral or focal myoclonia, which could evolve to long-lasting attacks without loss of consciousness, with a peculiar reflex component, and were associated with generalized tonic-clonic seizures. This entity was named "familial infantile myoclonic epilepsy" (FIME). More recently, TBC1D24 mutations have been shown to cause a variable range of disorders, including epilepsy of various seizure types and severity, non-syndromic deafness, and DOORS syndrome. We report on the electro-clinical features of two brothers, born to first-cousin parents, affected with infantile-onset myoclonic epilepsy. The peculiar epileptic presentation prompted us to perform direct sequencing of the TBC1D24 gene. The patients had very early onset of focal myoclonic fits with variable topography, lasting a few minutes to several hours, without loss of consciousness, which frequently evolved to generalized myoclonus or myoclonic status. Reflex myoclonia were noticed in one patient. Neurological outcome was marked by moderate intellectual disability. Despite the high frequency of seizures, repeated EEG recordings showed normal background rhythm and rare interictal spikes and waves. We found a homozygous missense mutation, c.457G>A/p.Glu153Lys, in the two affected brothers. This observation combined with recent data from the literature, suggest that mutations in TBCD24 cause a pathological continuum, with FIME at the "benign" end and severe drug-refractory epileptic encephalopathy on the severe end. Early-onset myoclonic epilepsy with focal and generalized myoclonic seizures is a common characteristic of this continuum.


Assuntos
Proteínas de Transporte/genética , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Mutação de Sentido Incorreto , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Resistência a Medicamentos , Eletroencefalografia , Epilepsias Mioclônicas/patologia , Face/patologia , Mãos/patologia , Humanos , Deficiência Intelectual/patologia , Masculino , Linhagem , Irmãos
17.
Eur J Med Genet ; 58(2): 51-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25497044

RESUMO

Infantile Spasms syndrome (ISs) is a characterized by epileptic spasms occurring in clusters with an onset in the first year of life. West syndrome represents a subset of ISs that associates spasms in clusters, a hypsarrhythmia EEG pattern and a developmental arrest or regression. Aetiology of ISs is widely heterogeneous including many genetic causes. Many patients, however, remain without etiological diagnosis, which is critical for prognostic purpose and genetic counselling. In the present study, we performed genetic screening of 73 patients with different types of ISs by array-CGH and molecular analysis of 5 genes: CDKL5, STXBP1, KCNQ2, and GRIN2A, whose mutations cause different types of epileptic encephalopathies, including ISs, as well as MAGI2, which was suggested to be related to a subset of ISs. In total, we found a disease-causing mutation or CNV (Copy Number Variation) in 15% of the patients. These included 6 point mutations found in CDKL5 (n = 3) and STXBP1 (n = 3), 3 microdeletions (10 Mb in 2q24.3, 3.2 Mb in 5q14.3 including the region upstream to MEF2C, and 256 kb in 9q34 disrupting EHMT1), and 2 microduplications (671 kb in 2q24.3 encompassing SCN2A, and 11.93 Mb in Xq28). In addition, we discuss 3 CNVs as potential risk factors, including one 16p12.1 deletion, one intronic deletion of the NEDD4 gene, and one intronic deletion of CALN1 gene. The present findings highlight the efficacy of combined cytogenetic and targeted mutation screening to improve the diagnostic yield in patient with ISs.


Assuntos
Espasmos Infantis/genética , Calmodulina/genética , Proteínas de Transporte/genética , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Recém-Nascido , Canal de Potássio KCNQ2/genética , Fatores de Transcrição MEF2/genética , Masculino , Proteínas Munc18/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Ubiquitina-Proteína Ligases Nedd4 , Proteínas Serina-Treonina Quinases/genética , Receptores de N-Metil-D-Aspartato/genética , Síndrome , Ubiquitina-Proteína Ligases/genética
18.
Neurology ; 82(23): 2101-6, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24814846

RESUMO

OBJECTIVE: To study the prevalence of DEPDC5 mutations in a series of 30 small European families with a phenotype compatible with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). METHODS: Thirty unrelated families referred with ADNFLE were recruited in France, Italy, Germany, Belgium, and Norway. Whole-exome sequencing was performed in 10 probands and direct sequencing of the DEPDC5 coding sequence in 20 probands. Testing for nonsense-mediated messenger RNA decay (NMD) was performed in lymphoblastic cells. RESULTS: Exome sequencing revealed a splice acceptor mutation (c.2355-2A>G) in DEPDC5 in the proband of a German family. In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and p.Trp1369*) were detected in the probands of 2 French and one Belgian family. The nonsense mutations p.Arg487* and p.Arg1087* were targeted by NMD, leading to the degradation of the mutated transcripts. At the clinical level, 78% of the patients with DEPDC5 mutations were drug resistant. CONCLUSIONS: DEPDC5 loss-of-function mutations were found in 13% of the families with a presentation of ADNFLE. The rate of drug resistance was high in patients with DEPDC5 mutations. Small ADNFLE pedigrees with DEPDC5 mutations might actually represent a part of the broader familial focal epilepsy with variable foci phenotype.


Assuntos
Mutação/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Cromossomos Humanos Par 22/genética , Resistência a Medicamentos/genética , Epilepsia do Lobo Frontal/genética , Europa (Continente) , Exoma/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
19.
Hum Brain Mapp ; 35(10): 5279-94, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24839121

RESUMO

OBJECTIVES: The aim of our study was to explore the functional connectivity between the insula and other cortical regions, in human, using cortico-cortical evoked potentials (CCEPs) EXPERIMENTAL DESIGN: We performed intra-cerebral electrical stimulation in eleven patients with refractory epilepsy investigated with depth electrodes, including 39 targeting the insula. Electrical stimulation consisted of two series of 20 pulses of 1-ms duration, 0.2-Hz frequency, and 1-mA intensity delivered at each of the 39 insular bipoles. Rates of connectivity were reported whenever a noninsular cortical region was tested by at least ten stimulating/recording electrode pairs in three or more patients RESULTS: Significant CCEPs were elicited in 193 of the 578 (33%) tested connections, with an average latency of 33 ± 5 ms. The highest connectivity rates were observed with the nearby perisylvian structures (59%), followed by the pericentral cortex (38%), the temporal neocortex (28%), the lateral parietal cortex (26%), the orbitofrontal cortex (25%), the mesial temporal structures (24%), the dorsolateral frontal cortex (15%), the temporal pole (14%), and the mesial parietal cortex (11%). No connectivity was detected in the mesial frontal cortex or cingulate gyrus. The pattern of connectivity also differed between the five insular gyri, with greater connectivity rate for the posterior short gyrus (49%), than for the middle short (29%), and two long gyri (28 and 33%) CONCLUSION: The human insula is characterized by a rich and complex connectivity that varies as a function of the insular gyrus and appears to partly differ from the efferences described in nonhuman primates.


Assuntos
Mapeamento Encefálico , Córtex Cerebral/fisiologia , Estimulação Encefálica Profunda/métodos , Epilepsias Parciais/patologia , Estimulação Elétrica , Eletrodos , Eletroencefalografia , Epilepsias Parciais/terapia , Potenciais Evocados/fisiologia , Feminino , Humanos , Masculino , Vias Neurais
20.
Brain ; 137(Pt 4): 1095-106, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24598359

RESUMO

Benign childhood epilepsy with centro-temporal spikes (BCECTS) is a unique form of non-lesional age-dependent epilepsy with rare seizures, focal electroencepalographic abnormalities affecting the same well delineated cortical region in most patients, and frequent mild to moderate cognitive dysfunctions. In this condition, it is hypothesized that interictal electroencepalographic discharges might interfere with local brain maturation, resulting in altered cognition. Diffusion tensor imaging allows testing of this hypothesis by investigating the white matter microstructure, and has previously proved sensitive to epilepsy-related alterations of fractional anisotropy and diffusivity. However, no diffusion tensor imaging study has yet been performed with a focus on BCECTS. We investigated 25 children suffering from BCECTS and 25 age-matched control subjects using diffusion tensor imaging, 3D-T1 magnetic resonance imaging, and a battery of neuropsychological tests including Conner's scale and Wechsler Intelligence Scale for Children (fourth revision). Electroencephalography was also performed in all patients within 2 months of the magnetic resonance imaging assessment. Parametric maps of fractional anisotropy, mean-, radial-, and axial diffusivity were extracted from diffusion tensor imaging data. Patients were compared with control subjects using voxel-based statistics and family-wise error correction for multiple comparisons. Each patient was also compared to control subjects. Fractional anisotropy and diffusivity images were correlated to neuropsychological and clinical variables. Group analysis showed significantly reduced fractional anisotropy and increased diffusivity in patients compared with control subjects, predominantly over the left pre- and postcentral gyri and ipsilateral to the electroencephalographic focus. At the individual level, regions of significant differences were observed in 10 patients (40%) for anisotropy (eight reduced fractional anisotropy, one increased fractional anisotropy, one both), and 17 (56%) for diffusivity (13 increased, one reduced, three both). There were significant negative correlations between fractional anisotropy maps and duration of epilepsy in the precentral gyri, bilaterally, and in the left postcentral gyrus. Accordingly, 9 of 12 patients (75%) with duration of epilepsy>12 months showed significantly reduced fractional anisotropy versus none of the 13 patients with duration of epilepsy≤12 months. Diffusivity maps positively correlated with duration of epilepsy in the cuneus. Children with BCECTS demonstrate alterations in the microstructure of the white matter, undetectable with conventional magnetic resonance imaging, predominating over the regions displaying chronic interictal epileptiform discharges. The association observed between diffusion tensor imaging changes, duration of epilepsy and cognitive performance appears compatible with the hypothesis that interictal epileptic activity alters brain maturation, which could in turn lead to cognitive dysfunction. However, such cross-sectional association does not demonstrate causality, and other hitherto unidentified factors could represent the common cause to part or all of the observed findings.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Epilepsia/patologia , Fibras Nervosas Mielinizadas/patologia , Adolescente , Anisotropia , Encéfalo/fisiopatologia , Criança , Imagem de Tensor de Difusão , Eletroencefalografia , Epilepsia/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino
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