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1.
Medicina (B Aires) ; 79 Suppl 3: 37-41, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31603842

RESUMO

Around 15% of childhood epilepsies are resistant to antiepileptic drugs, 40% of which are caused by malformations of cortical development (MCD). The current classification scheme for MCD is based on the primary developmental steps of cell proliferation, neuronal migration, and cortical organization. Considering the clinic and molecular alterations, a classification based on main pathways disruption and imaging phenotype has been proposed. MCD were divided into four groups: megalencephaly and focal cerebral dysplasia; tubulinopathies and lissencephalies; polymicrogyria syndromes and heterotopia syndromes. More than 100 genes have been reported to be associated with different types of MCD. Genetic and biological mechanisms include different stages of cell cycle regulation - especially cell division -, apoptosis, cell-fate specification, cytoskeletal structure and function, neuronal migration, and basement-membrane function. The associated epileptic syndromes are varied ranging from early-onset epileptic encephalopathies to focal epilepsies. As MCD are common causes of refractory epilepsy, a prompt diagnosis and the development of different therapeutic options in order to improve the outcome of the patients are essential.


Assuntos
Epilepsia/etiologia , Malformações do Desenvolvimento Cortical/complicações , Criança , Pré-Escolar , Eletroencefalografia , Humanos , Imagem por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/classificação , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/genética
2.
Nat Commun ; 10(1): 2129, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086189

RESUMO

De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1Y92C/+ mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1Y92C/+ animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.


Assuntos
Malformações do Desenvolvimento Cortical/genética , Microtúbulos/metabolismo , Neurogênese/genética , Neurônios/fisiologia , Tubulina (Proteína)/genética , Animais , Comportamento Animal , Movimento Celular/genética , Centrossomo/metabolismo , Córtex Cerebral/anormalidades , Córtex Cerebral/citologia , Córtex Cerebral/diagnóstico por imagem , Modelos Animais de Doenças , Embrião de Mamíferos , Epilepsia/genética , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Técnicas de Introdução de Genes , Predisposição Genética para Doença , Células HeLa , Humanos , Microscopia Intravital , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Microscopia Eletrônica , Microtúbulos/genética , Mutação de Sentido Incorreto
3.
Eur J Paediatr Neurol ; 23(3): 410-417, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30837194

RESUMO

AIM: The COL4A1 gene (13q34) encodes the α1 chain of type IV collagen, a crucial component of the basal membrane. COL4A1 mutations have been identified as a cause of a multisystem disease. Brain MRI in COL4A1-mutated patients typically shows vascular abnormalities and white matter lesions. Cortical malformations (specifically schizencephaly) have also recently been described in these patients, suggesting that these, too, could be part of the phenotypic spectrum of COL4A1 mutations. The aim of our work was to retrospectively evaluate COL4A1-mutated subjects diagnosed at our centers in order to assess the frequency and define the type of cortical malformations encountered in these individuals. METHOD: We retrospectively reviewed MRI data of 18 carriers of COL4A1 mutations diagnosed in our centers between 2010 and 2016. RESULTS: We identified polymicrogyria in two patients, and schizencephaly in the mother of a further patient. INTERPRETATION: Our findings confirm that cortical malformations should be considered to fall within the phenotypic spectrum of COL4A1 mutations and show that not only schizencephaly but also polymicrogyria can also be found in mutated individuals. Although further studies are needed to clarify the underlying pathogenetic mechanism, independently of this, the timing of the brain damage could be the crucial factor determining the type of lesion.


Assuntos
Colágeno Tipo IV/genética , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia , Adulto , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação , Estudos Retrospectivos
4.
Neuron ; 101(6): 1117-1133.e5, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30709655

RESUMO

Neural progenitors with distinct potential to generate progeny are associated with a spatially distinct microenvironment. Neocortical intermediate progenitors (IPs) in the subventricular zone (SVZ) of the developing brain generate neurons for all cortical layers and are essential for cortical expansion. Here, we show that spatial control of IP positioning is essential for neocortical development. We demonstrate that HDAC1 and HDAC2 regulate the spatial positioning of IPs to form the SVZ. Developmental stage-specific depletion of both HDAC1 and HDAC2 in radial glial progenitors results in mispositioning of IPs at the ventricular surface, where they divide and differentiate into neurons, thereby leading to the cortical malformation. We further identified the proneural gene Neurogenin2 as a key target of HDAC1 and HDAC2 for regulating IP positioning. Our results demonstrate the importance of the spatial positioning of neural progenitors in cortical development and reveal a mechanism underlying the establishment of the SVZ microenvironment.


Assuntos
Células Ependimogliais/metabolismo , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Ventrículos Laterais/embriologia , Malformações do Desenvolvimento Cortical/genética , Neocórtex/embriologia , Células-Tronco Neurais/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Movimento Celular/genética , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Malformações do Desenvolvimento Cortical/embriologia , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Neurogênese
5.
Epileptic Disord ; 21(1): 65-77, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30782578

RESUMO

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


Assuntos
Epilepsias Parciais/diagnóstico , Malformações do Desenvolvimento Cortical/diagnóstico , Adolescente , Adulto , Eletrocorticografia , Epilepsias Parciais/genética , Epilepsias Parciais/patologia , Epilepsias Parciais/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia , Malformações do Desenvolvimento Cortical/fisiopatologia , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Avaliação de Resultados (Cuidados de Saúde) , Adulto Jovem
6.
Neuroradiol J ; 32(2): 148-150, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30704335

RESUMO

Patients with mutations in tubulin-related genes usually present with brain malformations, intellectual disability, epilepsy, microcephaly and ocular abnormalities. In these patients the diagnosis can be suggested by neuroimaging findings. We report a 5-year-old patient with characteristic magnetic resonance imaging findings including malformation of cortical development, fused basal ganglia, large head of the caudate nuclei, absent anterior limbs of the internal capsules, corpus callosum dysgenesis and dysplastic cerebellar vermis. Sequencing of the TUBB2B gene confirmed a heterozygous mutation: c. 260C>A (p. Pro87Gln).


Assuntos
Imagem por Ressonância Magnética/métodos , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/genética , Tubulina (Proteína)/genética , Pré-Escolar , Humanos , Masculino , Mutação , Fenótipo
7.
PLoS Genet ; 14(12): e1007535, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30586385

RESUMO

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


Assuntos
Proteínas de Membrana/genética , Transtornos Mentais/genética , Proteínas do Tecido Nervoso/genética , Transtorno do Espectro Autista/genética , Transtorno Bipolar/genética , Anormalidades Craniofaciais/genética , Variações do Número de Cópias de DNA , Bases de Dados de Ácidos Nucleicos , Epilepsias Parciais/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Masculino , Malformações do Desenvolvimento Cortical/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/genética , Deleção de Sequência
8.
Brain Dev ; 40(6): 480-483, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29501407

RESUMO

INTRODUCTION: Recently recessive mutations in sphingosine-1-phosphate lyase (SGPL1) have been published as a cause of syndromic congenital nephrotic syndrome with adrenal insufficiency. We have identified a case with fetal hydrops and brain malformations due to a mutation in SGPL1. CASE REPORT: We report a patient presenting with severe fetal hydrops, congenital nephrotic syndrome and adrenal calcifications. MRI imaging showed generalized cortical atrophy with simplified gyral pattern and hypoplastic temporal lobes as well as cerebellar hypoplasia and hyperintensity in the pons. The boy deceased at 6 weeks of age. Via whole exome sequencing, we identified a novel homozygous frameshift mutation c.1233delC (p.Phe411Leufs∗56) in SGPL1. CONCLUSION: In our patient, we describe a novel mutation in sphingosine-1-phosphate lyase (SGPL1) leading to severe brain malformation. Neurodevelopmental phenotypes have been reported earlier, but not described in detail. To this end, we present a review on all published SGPL1-mutations and genotype-phenotype correlations focusing on neurodevelopmental outcomes. We hypothesized on the severe neurological phenotypes, which might be due to disruption of neuronal autophagy. Mutations in SGPL1 shall be considered in the differential diagnosis of fetal hydrops as well as congenital brain malformations and neuropathies.


Assuntos
Aldeído Liases/genética , Mutação da Fase de Leitura , Hidropisia Fetal/genética , Malformações do Desenvolvimento Cortical/genética , Síndrome Nefrótica/genética , Evolução Fatal , Homozigoto , Humanos , Hidropisia Fetal/diagnóstico por imagem , Hidropisia Fetal/patologia , Lactente , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/patologia , Síndrome Nefrótica/complicações , Síndrome Nefrótica/diagnóstico por imagem , Síndrome Nefrótica/patologia
9.
N Engl J Med ; 378(11): 1018-1028, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29539279

RESUMO

BACKGROUND: In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. METHODS: Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick. RESULTS: A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia. CONCLUSIONS: Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).


Assuntos
Mutação , Epilepsia Mioclônica Juvenil/genética , Proteínas Serina-Treonina Quinases/genética , Adolescente , Animais , Teorema de Bayes , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromossomos Humanos Par 6 , Modelos Animais de Doenças , Eletroencefalografia , Feminino , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Malformações do Desenvolvimento Cortical/genética , Camundongos , Camundongos Knockout , Epilepsia Mioclônica Juvenil/fisiopatologia , Análise de Sequência de DNA , Adulto Jovem
10.
Neuroradiology ; 60(2): 137-150, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29279945

RESUMO

The current classification of malformations of cortical development is based on the type of disrupted embryological process (cell proliferation, migration, or cortical organization/post-migrational development) and the resulting morphological anomalous pattern of findings. An ideal classification would include knowledge of biological pathways. It has recently been demonstrated that alterations affecting the mechanistic target of rapamycin (mTOR) signaling pathway result in diverse abnormalities such as dysplastic megalencephaly, hemimegalencephaly, ganglioglioma, dysplastic cerebellar gangliocytoma, focal cortical dysplasia type IIb, and brain lesions associated with tuberous sclerosis. We review the neuroimaging findings in brain abnormalities related to alterations in the mTOR pathway, following the emerging trend from morphology towards genetics in the classification of malformations of cortical development. This approach improves the understanding of anomalous brain development and allows precise diagnosis and potentially targeted therapies that may regulate mTOR pathway function.


Assuntos
Imagem por Ressonância Magnética/métodos , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Neuroimagem/métodos , Humanos
11.
Mol Genet Genomic Med ; 6(1): 92-98, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29222831

RESUMO

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects. METHODS: We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS. RESULTS: We reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region-specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS. CONCLUSION: Our study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.


Assuntos
Encéfalo/fisiopatologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Anormalidades Múltiplas/genética , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Pré-Escolar , Cromossomos Humanos Par 12/genética , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética , Cariotipagem , Masculino , Malformações do Desenvolvimento Cortical/genética , Megalencefalia/genética , Mosaicismo , Tetrassomia/genética
12.
Neurosci Lett ; 667: 40-46, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28111355

RESUMO

Approximately 50 million people have epilepsy, making it the most common chronic and severe neurological disease worldwide, with increased risk of mortality and psychological and socioeconomic consequences impairing quality of life. More than 30% of patients with epilepsy have inadequate control of their seizures with drug therapy. Any structural brain lesion can provoke epilepsy. However, progression of seizure activity as well as the development of drug-resistance remains difficult to predict, irrespective of the underlying epileptogenic condition, i.e., traumatic brain injury, developmental brain lesions, brain tumors or genetic inheritance. Mutated DNA sequences in genes encoding for ion channels or neurotransmitter receptors have been identified in hereditary focal or generalized epilepsies, but genotype-phenotype correlations are poor, arguing for additional factors determining the effect of a genetic predisposition. The dynamics of epigenetic mechanisms (e.g. DNA methylation, histone modifications, chromatin remodelling, and non-coding RNAs) provide likely explanations for common features in epilepsy and other complex diseases, including late onset, parent-of-origin effects, discordance of monozygotic twins, and fluctuation of symptoms. In addition, many focal epilepsies, including focal cortical dysplasias (FCDs), glio-neuronal tumors (e.g. ganglioglioma), or temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), do not seem to primarily associate with hereditary traits, suggesting other pathogenic mechanisms. Herein we will discuss the many faces of the epigenetic machinery, which provides powerful tools and mechanisms to propagate epileptogenicity and likely also contribute to the epileptogenic memory in chronic and difficult-to-treat epilepsies.


Assuntos
Epigênese Genética/genética , Epigenômica , Epilepsia/genética , Malformações do Desenvolvimento Cortical/genética , Animais , Encéfalo/patologia , Metilação de DNA/genética , Humanos , Malformações do Desenvolvimento Cortical/patologia , Neurônios/patologia
13.
Clin EEG Neurosci ; 49(3): 187-191, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28762286

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal-dominant inheritable neurocutaneous disease due to mutations within the TSC1 and TSC2 genes. Many patients present with West syndrome, a severe epilepsy syndrome characterized by the triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia (continuous slow activity with an amplitude higher than 300 µV and multiregional spikes/polyspikes/sharp waves) and developmental regression. In this study, we report on a previously healthy patient with positive family history of epilepsy with new-onset epileptic encephalopathy at the age of 9 years. Clinical signs alone were not sufficient to establish the diagnosis of TSC but epilepsy panel screening revealed a novel frameshift mutation (c.90delA; p.Glu31Argfs*12) within the TSC1 gene. Segregation gene analysis detected the same mutation in the mother. Cranial magnetic resonance imaging (MRI) studies from the index patient and his mother revealed a similar pattern of isolated subcortical white matter lesions resembling most likely focal cortical dysplasia (FCD) type IIb. In summary, in these 2 related patients, a novel TSC1 frameshift mutation was associated with an isolated FCD type IIb in the absence of further CNS abnormalities usually encountered in patients with TSC, fostering our understanding of the broad mutation spectra in the TSC1 gene and the close relationship between cortical tubers and FCD type IIb.


Assuntos
Epilepsia/fisiopatologia , Mutação em Linhagem Germinativa/genética , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Adulto , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Eletroencefalografia/métodos , Epilepsia/genética , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/genética , Esclerose Tuberosa/fisiopatologia , Proteína 1 do Complexo Esclerose Tuberosa
14.
Dev Med Child Neurol ; 60(1): 100-105, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29064093

RESUMO

In this case report we assess the occurrence of cortical malformations in children with early infantile epilepsy associated with variants of the gene protocadherin 19 (PCDH19). We describe the clinical course, and electrographic, imaging, genetic, and neuropathological features in a cohort of female children with pharmacoresistant epilepsy. All five children (mean age 10y) had an early onset of epilepsy during infancy and a predominance of fever sensitive seizures occurring in clusters. Cognitive impairment was noted in four out of five patients. Radiological evidence of cortical malformations was present in all cases and, in two patients, validated by histology. Sanger sequencing and Multiplex Ligation-dependent Probe Amplification analysis of PCDH19 revealed pathogenic variants in four patients. In one patient, array comparative genomic hybridization showed a microdeletion encompassing PCDH19. We propose molecular testing and analysis of PCDH19 in patients with pharmacoresistant epilepsy, with onset in early infancy, seizures in clusters, and fever sensitivity. Structural lesions are to be searched in patients with PCDH19 pathogenic variants. Further, PCDH19 analysis should be considered in epilepsy surgery evaluation even in the presence of cerebral structural lesions. WHAT THIS PAPER ADDS: Focal cortical malformations and monogenic epilepsy syndromes may coexist. Structural lesions are to be searched for in patients with protocadherin 19 (PCDH19) pathogenic variants with refractory focal seizures.


Assuntos
Caderinas/genética , Epilepsia , Malformações do Desenvolvimento Cortical , Adolescente , Criança , Pré-Escolar , Comorbidade , Epilepsia/epidemiologia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Humanos , Imagem por Ressonância Magnética , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/epidemiologia , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia
15.
J Child Neurol ; 33(1): 55-63, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29246093

RESUMO

Malformations of cortical development represent a common cause of epileptic encephalopathies and drug-resistant epilepsy in children. As current treatments are often ineffective, new therapeutic targets are needed for epileptic encephalopathies associated with cortical malformations. The mechanistic/mammalian target of rapamycin (mTOR) pathway constitutes a signaling pathway that drives cellular and molecular mechanisms of epileptogenesis in a variety of focal cortical malformations. mTOR inhibitors prevent epilepsy and associated pathogenic mechanisms of epileptogenesis in mouse models of tuberous sclerosis complex and are currently in clinical trials for drug-resistant seizures in these patients. A recent explosion of genetic studies has linked mutations in various genes regulating the mTOR pathway to other cortical malformations, such as focal cortical dysplasia and hemimegalencephaly. Thus, mTOR inhibitors represent promising candidates as novel antiseizure and antiepileptogenic therapies for epilepsy associated with a spectrum of cortical malformations.


Assuntos
Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Malformações do Desenvolvimento Cortical/tratamento farmacológico , Malformações do Desenvolvimento Cortical/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Epilepsia/etiologia , Epilepsia/genética , Humanos , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/genética
16.
Am J Hum Genet ; 101(6): 1021-1033, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29220674

RESUMO

ACTB encodes ß-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, ß-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic ß-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, ß-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência/genética , Actinas/biossíntese , Adolescente , Adulto , Idoso , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Coloboma/genética , Facies , Feminino , Mutação da Fase de Leitura/genética , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Malformações do Desenvolvimento Cortical/genética , Camundongos , Interferência de RNA , RNA Interferente Pequeno/genética , Adulto Jovem
17.
J Vis Exp ; (130)2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29286390

RESUMO

Birth defects that involve the cerebral cortex - also known as malformations of cortical development (MCD) - are important causes of intellectual disability and account for 20-40% of drug-resistant epilepsy in childhood. High-resolution brain imaging has facilitated in vivo identification of a large group of MCD phenotypes. Despite the advances in brain imaging, genomic analysis and generation of animal models, a straightforward workflow to systematically prioritize candidate genes and to test functional effects of putative mutations is missing. To overcome this problem, an experimental strategy enabling the identification of novel causative genes for MCD was developed and validated. This strategy is based on identifying candidate genomic regions or genes via array-CGH or whole-exome sequencing and characterizing the effects of their inactivation or of overexpression of specific mutations in developing rodent brains via in utero electroporation. This approach led to the identification of the C6orf70 gene, encoding for a putative vesicular protein, to the pathogenesis of periventricular nodular heterotopia, a MCD caused by defective neuronal migration.


Assuntos
Encéfalo/patologia , Hibridização Genômica Comparativa/métodos , Eletroporação/métodos , Malformações do Desenvolvimento Cortical/genética , Sequenciamento Completo do Exoma/métodos , Animais , Química Encefálica , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Modelos Animais de Doenças , Feminino , Humanos , Malformações do Desenvolvimento Cortical/sangue , Malformações do Desenvolvimento Cortical/patologia , Gravidez , Ratos
18.
Int J Mol Sci ; 18(11)2017 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-29109381

RESUMO

Malformations of the cerebral cortex are an important cause of developmental disabilities and epilepsy. Neurological disorders caused by abnormal neuronal migration have been observed to occur with mutations in tubulin genes. The α- and ß-tubulin genes encode cytoskeletal proteins, which play a role in the developing brain. TUBA1A mutations are associated with a wide spectrum of neurological problems, which are characterized by peculiar clinical details and neuroradiologic patterns. This manuscript describes the case of a nine-year-old girl with microcephaly, mild facial dysmorphisms, epileptic seizures, and severe developmental delay, with a de novo heterozygous c.320A>G [p.(His 107 Arg)] mutation in TUBA1A gene, and the clinical aspects and neuroimaging features of "lissencephaly syndrome" are summarized. This case shows that TUBA1A mutations lead to a variety of brain malformations ranging from lissencephaly with perisylvian pachygyria to diffuse posteriorly predominant pachygyria, combined with internal capsule dysgenesis, cerebellar dysplasia, and callosal hypotrophy. This peculiar neuroradiological pattern, in combination with the usually severe clinical presentation, suggests the need for future molecular studies to address the mechanisms of TUBA1A mutation-induced neuropathology.


Assuntos
Epilepsia/genética , Malformações do Desenvolvimento Cortical/genética , Mutação de Sentido Incorreto , Tubulina (Proteína)/genética , Criança , Epilepsia/diagnóstico , Feminino , Heterozigoto , Humanos , Malformações do Desenvolvimento Cortical/diagnóstico , Síndrome
19.
Am J Med Genet A ; 173(12): 3127-3131, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29048727

RESUMO

The clinical diagnosis of malformations of cortical development (MCDs) is often challenging due to the complexity of the brain malformation by neuroimaging, the rarity of individual malformation syndromes, and the rapidly evolving genetic landscape of these disorders facilitated with the use of Next Generation Sequencing (NGS) methods. While the clinical and molecular diagnosis of severe cortical malformations, such as classic lissencephaly, is often straightforward, the diagnosis of more subtle and complex types of cortical malformations, such as pachygyria and polymicrogyria (PMG), can be more challenging due to limited knowledge regarding their genetic etiologies. Here, we report two individuals with the same de novo KIF5C mutation who present with subtle MCDs, early onset epilepsy and significant neurodevelopmental and behavioral issues including absent language. Our data, combined with the limited literature on KIF5C mutations, to date, support that KIF5C mutations are associated with a neurodevelopmental disorder characterized by infantile onset epilepsy, and subtle but recognizable types of brain malformations. We also show that the spectrum of KIF5C mutations is narrow, as five out of the six identified individuals have mutations affecting amino acid Glu237. Therefore, the identification of the clinical and neuroimaging features of this disorder may strongly facilitate rapid and efficient molecular diagnosis.


Assuntos
Epilepsia/genética , Deficiência Intelectual/genética , Cinesina/genética , Malformações do Desenvolvimento Cortical/genética , Transtornos do Neurodesenvolvimento/genética , Córtex Cerebral/anormalidades , Epilepsia/diagnóstico por imagem , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Linguagem , Lisencefalia/diagnóstico por imagem , Lisencefalia/genética , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Mutação , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Polimicrogiria/diagnóstico por imagem , Polimicrogiria/genética
20.
Am J Med Genet A ; 173(9): 2534-2538, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28742248

RESUMO

Vascular Ehlers-Danlos syndrome (type IV) is an autosomal dominant disorder caused by heterozygous variants of COL3A1. We identified biallelic COL3A1 variants in two unrelated families. In a 3-year-old female with developmental delay the nonsense variant c.1282C>T, p.(Arg428*) was detected in combination the c.2057delC, p.(Pro686Leufs*105) frame shift variant. Both compound heterozygous variants were novel. This patient was born with bilateral clubfoot, joint laxity, and dysmorphic facial features. At the age of 2 years she developed an aneurysmal brain hemorrhage. Cerebral MRI showed a peculiar pattern of profound cerebral abnormalities including bilateral frontoparietal polymicrogyria of the cobblestone variant. In the second family, the two affected siblings were homozygous for the missense variant c.145C

Assuntos
Colágeno Tipo III/genética , Deficiências do Desenvolvimento/genética , Síndrome de Ehlers-Danlos/genética , Malformações do Desenvolvimento Cortical/genética , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Pré-Escolar , Códon sem Sentido , Tecido Conjuntivo/diagnóstico por imagem , Tecido Conjuntivo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Síndrome de Ehlers-Danlos/diagnóstico por imagem , Síndrome de Ehlers-Danlos/fisiopatologia , Feminino , Heterozigoto , Humanos , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/fisiopatologia , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Receptores Acoplados a Proteínas-G/genética
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