Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 301
Filtrar
1.
Am J Hum Genet ; 107(4): 753-762, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32910914

RESUMO

Lamin B1 plays an important role in the nuclear envelope stability, the regulation of gene expression, and neural development. Duplication of LMNB1, or missense mutations increasing LMNB1 expression, are associated with autosomal-dominant leukodystrophy. On the basis of its role in neurogenesis, it has been postulated that LMNB1 variants could cause microcephaly. Here, we confirm this hypothesis with the identification of de novo mutations in LMNB1 in seven individuals with pronounced primary microcephaly (ranging from -3.6 to -12 SD) associated with relative short stature and variable degree of intellectual disability and neurological features as the core symptoms. Simplified gyral pattern of the cortex and abnormal corpus callosum were noted on MRI of three individuals, and these individuals also presented with a more severe phenotype. Functional analysis of the three missense mutations showed impaired formation of the LMNB1 nuclear lamina. The two variants located within the head group of LMNB1 result in a decrease in the nuclear localization of the protein and an increase in misshapen nuclei. We further demonstrate that another mutation, located in the coil region, leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts. Our findings collectively indicate that de novo mutations in LMNB1 result in a dominant and damaging effect on nuclear envelope formation that correlates with microcephaly in humans. This adds LMNB1 to the growing list of genes implicated in severe autosomal-dominant microcephaly and broadens the phenotypic spectrum of the laminopathies.


Assuntos
Nanismo/genética , Deficiência Intelectual/genética , Lamina Tipo B/genética , Microcefalia/genética , Mutação , Lâmina Nuclear/genética , Sequência de Aminoácidos , Sequência de Bases , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Nanismo/diagnóstico por imagem , Nanismo/metabolismo , Nanismo/patologia , Feminino , Expressão Gênica , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Lamina Tipo B/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Imagem por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/metabolismo , Microcefalia/patologia , Lâmina Nuclear/metabolismo , Lâmina Nuclear/patologia
2.
Am J Hum Genet ; 107(3): 564-574, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32822602

RESUMO

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.


Assuntos
Atrofia/genética , Doenças Cerebelares/genética , Deficiência Intelectual/genética , Lisina Acetiltransferase 5/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Atrofia/diagnóstico por imagem , Atrofia/fisiopatologia , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/fisiopatologia , Pré-Escolar , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Reparo do DNA/genética , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Histonas/genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Processamento de Proteína Pós-Traducional/genética
3.
Eur J Med Genet ; 63(10): 104004, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32688057

RESUMO

De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions. All individuals presented developmental delay with a median age of 2.5 years for independent walking and of 3 years for first spoken words. GATAD2B variant carriers showed very little subsequent speech progress, two patients over 30 years of age remaining non-verbal. ID was mostly moderate to severe, with one profound and one mild case, which shows a wider spectrum of disease severity than previously reported. We confirm macrocephaly as a major feature in GAND (53%). Most common dysmorphic features included broad forehead, deeply set eyes, hypertelorism, wide nasal base, and pointed chin. Conversely, prenatal abnormalities, non-cerebral malformations, epilepsy, and autistic behavior were uncommon. Other features included feeding difficulties, behavioral abnormalities, and unspecific abnormalities on brain MRI. Improving our knowledge of the clinical phenotype is essential for correct interpretation of the molecular results and accurate patient management.


Assuntos
Fatores de Transcrição GATA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Face/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Megalencefalia/diagnóstico por imagem , Megalencefalia/genética , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Gravidez , Deleção de Sequência , Distúrbios da Fala/genética
4.
Eur J Med Genet ; 63(10): 104019, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32712214

RESUMO

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been described as an autosomal-dominant disorder caused by mutations in the NR2F1 gene, whose common characteristics include developmental delay, intellectual disability, optic nerve atrophy, hypotonia, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity and thinning of the corpus callosum. Missense mutations in NR2F1 have been reported to be the major cause of BBSOAS. A possible genotype-phenotype correlation has been considered with missense mutations affecting the ligand-binding domain of NR2F1 as well as whole-gene deletions of NR2F1 showing a milder phenotype of BBSOAS. Here we report on a patient with a novel frameshift mutation in NR2F1 showing the full spectrum of BBOAS indicating an expanded clinical spectrum and a reconsideration of the observed genotype-phenotype correlation.


Assuntos
Transtorno do Espectro Autista/genética , Fator I de Transcrição COUP/genética , Deficiência Intelectual/genética , Atrofias Ópticas Hereditárias/genética , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/fisiopatologia , Sequência de Bases , Criança , Mutação da Fase de Leitura , Estudos de Associação Genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Hipotonia Muscular/genética , Mutação de Sentido Incorreto , Atrofias Ópticas Hereditárias/diagnóstico por imagem , Atrofias Ópticas Hereditárias/fisiopatologia , Fenótipo , Mutação Puntual , Convulsões/genética
5.
Epilepsia ; 61(7): e71-e78, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32645220

RESUMO

Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Fatores de Crescimento de Fibroblastos/genética , Deficiência Intelectual/genética , Fenótipo , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsia/diagnóstico por imagem , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Estudos Retrospectivos , Adulto Jovem
6.
Brain Topogr ; 33(5): 618-635, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32623611

RESUMO

Head motion is a significant barrier to functional MRI (fMRI) in patients who are unable to tolerate awake scanning, including young children or those with cognitive and behavioural impairments. General anaesthesia minimises motion and ensures patient comfort, however the optimal anaesthesia regimen for fMRI in the paediatric setting is unknown. In this study, we tested the feasibility of anaesthetised fMRI in 11 patients (mean age = 9.8 years) with Lennox-Gastaut syndrome, a severe form of childhood-onset epilepsy associated with intellectual disability. fMRI was acquired during clinically-indicated MRI sessions using a synergistic anaesthesia regimen we typically administer for epilepsy neurosurgery: combined low-dose isoflurane (≤ 0.8% end-tidal concentration) with remifentanil (≤ 0.1 mcg/kg/min). Using group-level independent component analysis, we assessed the presence of resting-state networks by spatially comparing results in the anaesthetised patients to resting-state network templates from the 'Generation R' study of 536 similarly-aged non-anaesthetised healthy children (Muetzel et al. in Hum Brain Mapp 37(12):4286-4300, 2016). Numerous resting-state networks commonly studied in non-anaesthetised healthy children were readily identifiable in the anaesthetised patients, including the default-mode, sensorimotor, and frontoparietal networks. Independent component time-courses associated with these networks showed spectral characteristics suggestive of a neuronal origin of fMRI signal fluctuations, including high dynamic range and temporal frequency power predominantly below 0.1 Hz. These results demonstrate the technical feasibility of anaesthetised fMRI in children, suggesting that combined isoflurane-remifentanil anaesthesia may be an effective strategy to extend the emerging clinical applications of resting-state fMRI (for example, neurosurgical planning) to the variety of patient groups who may otherwise be impractical to scan.


Assuntos
Anestesia , Epilepsia , Deficiência Intelectual , Isoflurano , Criança , Epilepsia/diagnóstico por imagem , Humanos , Deficiência Intelectual/diagnóstico por imagem , Isoflurano/farmacologia , Imagem por Ressonância Magnética , Remifentanil
7.
Eur J Med Genet ; 63(10): 104005, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32693209

RESUMO

9p duplication syndrome is a common congenital anomaly syndrome with specific facial features, mental and developmental retardations, and characteristic fingers. Pure 9p duplication without other chromosomal structural variations is very rare. It has recently been reported that cases with partial 9p duplication including SMARCA2 have phenotypes overlapping with Coffin-Siris syndrome (CSS). Herein, we present a family with pure 9p duplication syndrome in which phenotypes partially characteristic of CSS were identified. In one of two siblings, X-ray examination revealed hypoplasia of the distal phalanges of the fifth fingers, aplasia of the middle phalanges of the fifth fingers, and aplasia of the distal phalanges of the second to fifth toes. In pure 9p duplication together with our one affected case, 9 out of 14 cases (64.3%), excluding cases whose clinical data were unavailable, presented the absence or hypoplasia of the middle phalanges of fingers or toes. Interestingly, there are no reports on CSS with aplasia or hypoplasia of the middle phalanx. Therefore, this family might suggest that the aplasia or hypoplasia of the middle phalanges of the fifth fingers or toes is a distinct finding that can distinguish between pure 9p duplication and CSS.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Falanges dos Dedos da Mão/anormalidades , Dedos/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Dedos do Pé/anormalidades , Fatores de Transcrição/genética , Trissomia/genética , Anormalidades Múltiplas/diagnóstico por imagem , Cromossomos Humanos Par 9/genética , Face/diagnóstico por imagem , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Recém-Nascido , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Micrognatismo/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Fenótipo , Gravidez , Irmãos
8.
Eur J Med Genet ; 63(7): 103951, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32439618

RESUMO

BACKGROUND: Genetic factors represent a considerable part of the etiologies of intellectual disability; however, the identification of causal genetic anomaly has long been complicated by the great clinical and genetic heterogeneity of this type of disease. With advances in next-generation sequencing technologies and functional studies, the identification of genes involved in intellectual development has led to more accurate diagnostics and better understanding of the underlying biological pathways. CASE REPORT: We report on the case of two Moroccan siblings presenting mild intellectual disability with minimal dysmorphic features in which whole exome sequencing analysis revealed homozygous mutation in the METTL23 gene. Mutations in this gene have been reported to cause autosomal recessive mild intellectual disability but the association with dysmorphic features remains controversial. CONCLUSION: Hereby, we highlight the similarity of the dysmorphic traits and the characteristic facial features in patients with METTL23-related intellectual disability, suggesting the consideration of a distinct clinical entity associating mild intellectual deficiency with specific facial dysmorphy for an efficient diagnosis orientation and a better phenotype-genotype correlation in intellectual disability disorders.


Assuntos
Transtornos Dismórficos Corporais/genética , Exoma/genética , Homozigoto , Deficiência Intelectual/genética , Metiltransferases/genética , Mutação , Transtornos Dismórficos Corporais/diagnóstico por imagem , Criança , Feminino , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Marrocos , Linhagem , Sequenciamento Completo do Exoma
9.
Eur J Med Genet ; 63(5): 103868, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32004679

RESUMO

Pathogenic variants in NKX6-2 gene causing autosomal recessive spastic ataxia type 8 with hypomyelinating leukodystrophy have been reported in few families around the world. In this study, we performed Whole Exome Sequencing and identified a novel missense variant, c.501C > G; p.(Phe167Leu), in two affected siblings with main manifestations of global developmental delay, motor regression, hypotonia, clonus in lower limbs and muscle bulk atrophy especially in the upper limbs, spasticity and contracture, scoliosis, hip dislocation, oculomotor apraxia, horizontal and vertical nystagmus. In addition, wrist and foot drop due to peripheral axonal neuropathy were observed in these patients as a new clinical finding and cerebellar white matter involvement in brain Magnetic Resonance Imaging (MRI) as new imaging finding. Therefore, we expanded the manifestations of NKX6-2-related disorders in this manuscript.


Assuntos
Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Espasticidade Muscular/genética , Atrofia Óptica/genética , Fenótipo , Ataxias Espinocerebelares/genética , Cerebelo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Imagem por Ressonância Magnética , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/patologia , Mutação de Sentido Incorreto , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/patologia , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/patologia , Substância Branca/diagnóstico por imagem
10.
Clin Dysmorphol ; 29(1): 46-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31205051
11.
J Clin Ultrasound ; 48(4): 235-239, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31859376

RESUMO

Dandy-Walker malformation (DWM) may occur as part of Mendelian disorders such as Walker-Warburg and Meckel-Gruber syndromes. We report a novel association with type III lissencephaly in a 22-week male fetus. Ultrasound showed fetal akinesia deformation sequence, single umbilical artery, microlissencephaly, hydranencephaly with cerebral lamination, DWM, and pontocerebellar hypoplasia. These abnormalities were confirmed by magnetic resonance imaging and autopsy, which also revealed pulmonary and adrenal hypoplasia, common mesentery and bilateral uretero-pyelo-calyceal dilatation. Neuropathological examination showed brain calcifications and diffuse neuronal degeneration. We conclude that DWM may be a feature of type III lissencephaly and that this association can be easily diagnosed by ultrasound.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Síndrome de Dandy-Walker/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Lisencefalia/diagnóstico por imagem , Microcefalia/diagnóstico por imagem , Ultrassonografia Pré-Natal , Feminino , Idade Gestacional , Humanos , Imagem por Ressonância Magnética , Gravidez , Diagnóstico Pré-Natal/métodos
12.
Am J Med Genet A ; 182(1): 93-103, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622028

RESUMO

White matter (WM) signal abnormalities are demonstrated in various neurodevelopmental disorders on brain magnetic resonance imaging (MRI). The pattern of WM abnormalities can aid in the diagnostic process. This study aims to characterize the WM changes found in microdeletion/microduplication syndromes. Thirteen patients with neurodevelopmental disorders due to copy number variations were collected from a cohort of children with evidence of WM abnormalities on brain MRI, in two medical centers. A pediatric neuroradiologist blindly interpreted the MRI scans. Clinical and genetic findings were retrospectively extracted from the medical records. WM changes included: multifocal (10/13) periventricular (12/13) and subcortical (5/13) signal abnormalities and WM volume loss (6/13). Dysgenesis of the corpus callosum was depicted in 12/13. The main clinical features were: global developmental delay (13/13), hypotonia (11/13), epilepsy (10/13), dysmorphic features (9/13), microcephaly (6/13), short stature (6/13), and systemic involvement (6/13). We showed that different chromosomal micro-rearrangement syndromes share similar MRI patterns of nonspecific multifocal predominantly periventricular WM changes associated with corpus callosum dysgenesis with or without WM and gray matter loss. Hence, the association of these features in a patient evaluated for global developmental delay/intellectual disability suggests a chromosomal micro-rearrangement syndrome, and a chromosomal microarray analysis should be performed.


Assuntos
Encéfalo/metabolismo , Cromossomos/genética , Variações do Número de Cópias de DNA/genética , Leucoencefalopatias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adolescente , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Transtornos Dismórficos Corporais/diagnóstico por imagem , Transtornos Dismórficos Corporais/genética , Transtornos Dismórficos Corporais/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Catarata/congênito , Catarata/diagnóstico por imagem , Catarata/genética , Catarata/patologia , Criança , Estudos de Coortes , Córnea/anormalidades , Córnea/diagnóstico por imagem , Córnea/patologia , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Epilepsia/patologia , Feminino , Predisposição Genética para Doença , Humanos , Hipogonadismo/diagnóstico por imagem , Hipogonadismo/genética , Hipogonadismo/patologia , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Imagem por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/genética , Microcefalia/patologia , Hipotonia Muscular/diagnóstico por imagem , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Atrofia Óptica/diagnóstico por imagem
13.
Neurobiol Dis ; 136: 104709, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31843706

RESUMO

Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two "severe" G424R and K389N variants (responsible for severe ID and CCA) and the "mild" A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.


Assuntos
Agenesia do Corpo Caloso/genética , Movimento Celular/fisiologia , Deficiência Intelectual/genética , Mutação/genética , Índice de Gravidade de Doença , Quinases Ativadas por p21/genética , Agenesia do Corpo Caloso/complicações , Agenesia do Corpo Caloso/diagnóstico por imagem , Sequência de Aminoácidos , Animais , Células COS , Criança , Chlorocebus aethiops , Células HEK293 , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Masculino , Linhagem , Estrutura Secundária de Proteína , Quinases Ativadas por p21/química
14.
Am J Med Genet A ; 182(3): 441-445, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31846209

RESUMO

Kabuki syndrome is a rare, multi-systemic disorder of chromatin regulation due to mutations in either KMT2D or KDM6A that encode a H3K4 methyltransferase and an H3K27 demethylase, respectively. The associated clinical phenotype is a direct result of temporal and spatial changes in gene expression in various tissues including the brain. Although mild to moderate intellectual disability is frequently recognized in individuals with Kabuki syndrome, the identification of brain anomalies, mostly involving the hippocampus and related structures remains an exception. Recently, the first two cases with alobar holoprosencephaly and mutations in KMT2D have been reported in the medical literature. We identified a de novo, pathogenic KMT2D variant (c.6295C > T; p.R2099X) using trio whole-exome sequencing in a 2-year-old female with lobar holoprosencephaly, microcephaly and cranio-facial features of Kabuki syndrome. This report expands the spectrum of brain anomalies associated with Kabuki syndrome underscoring the important role of histone modification for early brain development.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Holoprosencefalia/genética , Deficiência Intelectual/genética , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Pré-Escolar , Face/diagnóstico por imagem , Face/patologia , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/diagnóstico por imagem , Doenças Hematológicas/patologia , Holoprosencefalia/diagnóstico , Holoprosencefalia/diagnóstico por imagem , Holoprosencefalia/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Mutação/genética , Fenótipo , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/diagnóstico por imagem , Doenças Vestibulares/patologia , Sequenciamento Completo do Exoma
15.
Cerebellum ; 18(5): 972-975, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31410782

RESUMO

Spinocerebellar Ataxia 23 (SCAR23) is a newly described condition caused by mutations in TDP2 gene. To date, only four patients from two families have been reported, all carrying the same homozygous mutation. We describe a fifth patient, carrying a novel mutation in the same gene, thus confirming the role of TDP2 mutations in determining the disease and defining the main features SCAR23: pediatric onset ataxia and drug-resistant epilepsy and intellectual disability. We further show the clinical presentation which is associated with the neuroradiological evidence of progressive cerebellar atrophy, giving the evidence that SCAR23 can be classified as a degenerative condition.


Assuntos
Proteínas de Ligação a DNA/genética , Epilepsia Resistente a Medicamentos/genética , Deficiência Intelectual/genética , Mutação/genética , Diester Fosfórico Hidrolases/genética , Ataxias Espinocerebelares/genética , Adolescente , Epilepsia Resistente a Medicamentos/complicações , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Feminino , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico por imagem , Sequenciamento Completo do Exoma/métodos
16.
Nat Commun ; 10(1): 2966, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273213

RESUMO

Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors. The mechanisms leading to the development of these two disease entities alone or in combination remain unclear. We generated mice with a heterozygous nervous system-specific partial loss-of-function mutation in a BAF core component gene, Smarcb1. These Smarcb1 mutant mice show various brain midline abnormalities that are also found in individuals with Coffin-Siris syndrome (CSS) caused by SMARCB1, SMARCE1, and ARID1B mutations and in SMARCB1-related intellectual disability (ID) with choroid plexus hyperplasia (CPH). Analyses of the Smarcb1 mutant animals indicate that one prominent midline abnormality, corpus callosum agenesis, is due to midline glia aberrations. Our results establish a novel role of Smarcb1 in the development of the brain midline and have important clinical implications for BAF complex-related ID/neurodevelopmental disorders.


Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/genética , Corpo Caloso/crescimento & desenvolvimento , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteína SMARCB1/genética , Anormalidades Múltiplas/diagnóstico por imagem , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/patologia , Alelos , Animais , Criança , Pré-Escolar , Corpo Caloso/citologia , Corpo Caloso/diagnóstico por imagem , Modelos Animais de Doenças , Embrião de Mamíferos , Face/diagnóstico por imagem , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Micrognatismo/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Neuroglia/patologia , Cultura Primária de Células
17.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(6): 541-546, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31208506

RESUMO

OBJECTIVE: To study the value of fast spin-echo diffusion weighted imaging (TSE-DWI) apparent diffusion coefficient (ADC) in children aged 2-12 years with intellectual disability (ID)/global developmental delay (GDD) who have normal conventional brain MRI findings. METHODS: A total of 578 children with normal conventional brain MRI findings who met the diagnostic criteria for ID/GDD and 375 normal children were enrolled. Their imaging and clinical data were collected. All children underwent scanning with brain TSE-DWI sequence and routine sequence. ADC values of each brain region were compared between normal children with different ages, as well as between children with different degrees of ID/GDD in each age group. The influence of Adaptive Behavior Assessment System-II (ABAS-II) score on ADC values of each brain region was analyzed. RESULTS: For the normal children, the ADC values of the frontal and temporal white matter, the corpus callosum, the inner capsule, the centrum semiovale, the cerebellar dentate nucleus, the optic radiation, the thalamus, the lenticular nucleus, and the caudate nucleus gradually decreased with age (P<0.05). ADC values of the deep white matter, the shallow white matter, the deep gray matter nuclei, and the shallow gray matter increased with the increase in the degree of ID/GDD in the ID/GDD children aged 4-6 years (P<0.05). In the children with ID/GDD, the ADC values of the deep white matter, the shallow white matter, and the deep gray matter nuclei decreased with age (P<0.05). The ADC values of the children with ID/GDD decreased with the increase in ABAS-II score (P<0.05). CONCLUSIONS: ADC can reflect the subtle structural changes of brain regions in children with ID/GDD who have normal conventional brain MRI findings. It may be associated with social adaptation. It can provide an objective basis for the quantitative diagnosis of ID/GDD in children.


Assuntos
Deficiência Intelectual , Substância Branca , Encéfalo , Criança , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética
18.
Eur J Med Genet ; 62(8): 103691, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176769

RESUMO

Mutations in the chromatin regulator gene BRPF1 were recently associated with the Intellectual Developmental Disorder With Dysmorphic Facies And Ptosis (IDDDFP). Up till now, clinical data of 22 patients are reported. Besides intellectual disability (ID), ptosis and blepharophimosis are frequent findings, with refraction problems, amblyopia and strabism as other reported ophthalmological features. Animal studies indicate BRPF1 as an important mediator in brain development. However, only 5 of 22 previously reported patients show structural brain abnormalities. We report on an additional patient harboring a novel de novo nonsense mutation p.(Glu219*) in BRPF1. He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum. Our findings support previous findings of brain abnormalities in BRPF1-mutations and indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Agenesia do Corpo Caloso/genética , Coloboma/genética , Paralisia Facial/genética , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/fisiopatologia , Animais , Pré-Escolar , Cromatina/genética , Códon sem Sentido/genética , Coloboma/diagnóstico por imagem , Coloboma/fisiopatologia , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Nervo Facial/patologia , Paralisia Facial/diagnóstico por imagem , Paralisia Facial/fisiopatologia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação
19.
Seizure ; 66: 81-85, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30818181

RESUMO

PURPOSE: Mutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly. METHODS: We use family-based whole-exome sequencing to identify candidate variants. RESULTS: We report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein. CONCLUSION: Variable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling.


Assuntos
Epilepsia/genética , Saúde da Família , Deficiência Intelectual/genética , Megalencefalia/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Adulto , Análise Mutacional de DNA , Epilepsia/complicações , Epilepsia/diagnóstico por imagem , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Megalencefalia/complicações , Megalencefalia/diagnóstico por imagem , Sequenciamento Completo do Exoma , Adulto Jovem
20.
J Hum Genet ; 64(4): 341-346, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692597

RESUMO

The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1 (c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows. Magnetic resonance imaging delineated anterior pituitary hypoplasia, ectopic posterior pituitary, invisible pituitary stalk, thinning of the corpus callosum, and hypoplasia of the pons and midbrain. The phenotypically normal parents (first cousins) were heterozygous for the mutation. The results provide further evidence of ROBO1 being involved in the development of the pituitary gland. A recessive mutation of ROBO1 is a potential novel cause of a syndromic disorder associated with combined pituitary hormone deficiency.


Assuntos
Perda Auditiva Neurossensorial/genética , Hipopituitarismo/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Receptores Imunológicos/genética , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/fisiopatologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Hipopituitarismo/complicações , Hipopituitarismo/diagnóstico por imagem , Hipopituitarismo/fisiopatologia , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação , Sítios de Splice de RNA/genética , Sequenciamento Completo do Exoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA