Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.111
Filtrar
1.
Medicine (Baltimore) ; 99(28): e21194, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664163

RESUMO

The purpose of this study was to investigate the prevalence of neurodevelopmental delay among deformational plagiocephaly (DP) children, and to confirm relationship between neurodevelopmental delay and severity of DP.This study is retrospective study. Five hundred thirteen children who visited for abnormal head shape through outpatient department were recruited. To identify the children with neurodevelopmental delay among the 513 children with DP, Denver Development Screening Test (DDST) was performed in 38 children who suspected of neurodevelopmental delay. Cranial vault asymmetry (CVA) was measured by using caliper, and cranial vault asymmetry index (CVAI) was calculated. Thirty eight children with DP who conducted DDST were divided into 2 groups according to the degree of CVA; group 1 included 21 children with CVA under 10 mm, and group 2 included 17 children with CVA over 10 mm.There was a significant difference in number of neurodevelopmental delay between group 1 (n = 7) and group 2 (n = 14) (P < .05). Mean grade of DP, CVA, and CVAI (1.76 ±â€Š0.44, 5.90 ±â€Š2.21 mm, 4.20 ±â€Š1.51%) in group 1 was smaller than that in group 2 (3.41 ±â€Š0.8, 12.71 ±â€Š3.22 mm, 8.83 ±â€Š2.18%), respectively (P < .05).Our results found that the frequency of developmental delay was significantly increased in children with CVA more than 10 mm. Doctors who take care of children with DP had better keep developmental delays in mild.


Assuntos
Transtornos do Neurodesenvolvimento/epidemiologia , Plagiocefalia não Sinostótica/psicologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtornos do Neurodesenvolvimento/etiologia , Plagiocefalia não Sinostótica/patologia , Prevalência , Estudos Retrospectivos , Índice de Gravidade de Doença
2.
BMJ Open ; 10(7): e038004, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699166

RESUMO

INTRODUCTION: An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in Wuhan, China starting in December 2019. Yet the clinical features and long-term outcomes of neonates with SARS-CoV-2 exposure are lacking. The purpose of this study is to describe the clinical course and prognosis of the neonates exposed to SARS-CoV-2. METHODS AND ANALYSIS: This is a multicentre observational study conducted at the designated children and maternal and child hospitals in the mainland of China. Neonates exposed to SARS-CoV-2 infection will be recruited. The data to be collected via case report forms include demographic details, clinical features, laboratory and imaging results, as well as outcomes. Primary outcomes are the mortality of neonates with COVID-19 and SARS-CoV-2 infection of neonates born to mothers with COVID-19. Secondary outcomes are the birth weight, premature delivery and neurological development of neonates exposed to SARS-CoV-2. The neurological development is assessed by the Chinese standardised Denver Developmental Screening Test at the corrected age of 6 months. ETHICS AND DISSEMINATION: This study has been approved by the Children's Hospital of Fudan University ethics committee (No. (2020)31). The study findings will be disseminated in peer-reviewed journals and presented at national and international conferences in order to improve the understanding of the clinical course among neonates exposed to SARS-CoV-2 and to provide evidence-based treatment and prevention strategies for this group. TRIAL REGISTRATION NUMBER: NCT04279899.


Assuntos
Desenvolvimento Infantil , Infecções por Coronavirus/epidemiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Pneumonia Viral/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Betacoronavirus , China/epidemiologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Feminino , Maternidades , Hospitais Pediátricos , Humanos , Lactente , Recém-Nascido , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Gravidez , Estudos Prospectivos , Índice de Gravidade de Doença
4.
Lancet Diabetes Endocrinol ; 8(7): 594-605, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32559475

RESUMO

BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.


Assuntos
Biomarcadores/análise , Transtornos Mentais/patologia , Transportadores de Ácidos Monocarboxílicos/deficiência , Doenças Musculares/patologia , Transtornos do Neurodesenvolvimento/patologia , Simportadores/deficiência , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Agências Internacionais , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/genética , Doenças Musculares/etiologia , Mutação , Transtornos do Neurodesenvolvimento/etiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Simportadores/genética , Adulto Jovem
6.
Chemosphere ; 255: 126920, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32387734

RESUMO

The pathological traits or diseases susceptibility caused by maternal exposure to environmental adverse insults (infection, malnutrition, environmental toxicants) could be transmitted across generations. It remains uncertain, however, whether the neurodevelopmental disturbances of offspring induced by maternal exposure to PM2.5 during early life can be inherited by subsequent generations without further exposure. In the current study, using transgenerational animal models, we found that F1 female showed poorer performance in Morris Water Maze (MWM), and the deficits in spatial learning and memory similarly presented in F2-F3 female. The transgenerationally-transmitted neurobehavioral disorders were mediated both via maternal and paternal lineage. Since the epigenetic modifications have been reported to be involved in the disturbed neurodevelopment induced by maternal exposure to detrimental environmental factors during early life, we further explored the possible epigenetic mechanism of the transgenerational effects. Intriguingly, the results displayed the significant increase in expression of Dnmt3a in F1 female offspring. And the hypermethylation of Bdnf promoter Ⅳ and downregulated expression of Bdnf in hippocampus were stably transmitted across the generations until the third generation. There was another interesting finding that the transgenerational effects were sex-specific and only emerged in female offspring. Together, our study indicated for the first time that maternal exposure to PM2.5 during early life could detrimentally affect neurobehaviors in multiple generations, and the declined expression of Bdnf induced by hypermethylation of Bdnf promoter Ⅳ mediated by Dnmts might be the potential molecular mechanism.


Assuntos
Exposição Materna/estatística & dados numéricos , Material Particulado/toxicidade , Animais , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Masculino , Exposição Materna/efeitos adversos , Transtornos do Neurodesenvolvimento/epidemiologia , Fenótipo , Gravidez
8.
Am J Physiol Cell Physiol ; 318(6): C1264-C1283, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320288

RESUMO

Plasticity within the neuronal networks of the brain underlies the ability to learn and retain new information. The initial discovery of synaptic plasticity occurred by measuring synaptic strength in vivo, applying external stimulation and observing an increase in synaptic strength termed long-term potentiation (LTP). Many of the molecular pathways involved in LTP and other forms of synaptic plasticity were subsequently uncovered in vitro. Over the last few decades, technological advances in recording and imaging in live animals have seen many of these molecular mechanisms confirmed in vivo, including structural changes both pre- and postsynaptically, changes in synaptic strength, and changes in neuronal excitability. A well-studied aspect of neuronal plasticity is the capacity of the brain to adapt to its environment, gained by comparing the brains of deprived and experienced animals in vivo, and in direct response to sensory stimuli. Multiple in vivo studies have also strongly linked plastic changes to memory by interfering with the expression of plasticity and by manipulating memory engrams. Plasticity in vivo also occurs in the absence of any form of external stimulation, i.e., during spontaneous network activity occurring with brain development. However, there is still much to learn about how plasticity is induced during natural learning and how this is altered in neurological disorders.


Assuntos
Encéfalo/metabolismo , Sinapses Elétricas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Transmissão Sináptica , Animais , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Sinapses Elétricas/patologia , Aprendizagem , Potenciação de Longa Duração , Modelos Neurológicos , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Neurônios/patologia , Potenciais Sinápticos
9.
Neuron ; 106(1): 21-36, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32272065

RESUMO

Since the discovery of ocular dominance plasticity, neuroscientists have understood that changes in visual experience during a discrete developmental time, the critical period, trigger robust changes in the visual cortex. State-of-the-art tools used to probe connectivity with cell-type-specific resolution have expanded the understanding of circuit changes underlying experience-dependent plasticity. Here, we review the visual circuitry of the mouse, describing projections from retina to thalamus, between thalamus and cortex, and within cortex. We discuss how visual circuit development leads to precise connectivity and identify synaptic loci, which can be altered by activity or experience. Plasticity extends to visual features beyond ocular dominance, involving subcortical and cortical regions, and connections between cortical inhibitory interneurons. Experience-dependent plasticity contributes to the alignment of networks spanning retina to thalamus to cortex. Disruption of this plasticity may underlie aberrant sensory processing in some neurodevelopmental disorders.


Assuntos
Dominância Ocular/fisiologia , Plasticidade Neuronal/fisiologia , Retina/fisiologia , Tálamo/fisiologia , Córtex Visual/fisiologia , Animais , Período Crítico Psicológico , Corpos Geniculados/crescimento & desenvolvimento , Corpos Geniculados/fisiologia , Núcleos Laterais do Tálamo/crescimento & desenvolvimento , Núcleos Laterais do Tálamo/fisiologia , Camundongos , Transtornos do Neurodesenvolvimento/fisiopatologia , Retina/crescimento & desenvolvimento , Colículos Superiores/crescimento & desenvolvimento , Colículos Superiores/fisiologia , Núcleo Supraquiasmático/crescimento & desenvolvimento , Núcleo Supraquiasmático/fisiologia , Sinapses/fisiologia , Tálamo/crescimento & desenvolvimento , Visão Binocular/fisiologia , Córtex Visual/crescimento & desenvolvimento , Vias Visuais/crescimento & desenvolvimento , Vias Visuais/fisiologia
10.
J Clin Psychiatry ; 81(2)2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32237297

RESUMO

Many observational studies have found an association between antidepressant drug prescription during pregnancy and neurodevelopmental disorders such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and intellectual disability. The results of such studies cannot be considered conclusive because of the possible presence of inadequately measured, unmeasured, and unknown confounds. In this context, maternal anemia before or at but not after 30 weeks of gestation was recently associated with an increased risk of all 3 of these neurodevelopmental disorders. Additionally, meta-analysis has shown that maternal anemia during pregnancy is associated with other adverse gestational outcomes, as well. Given that anemia is common during pregnancy, and that iron deficiency during pregnancy can compromise neurodevelopment in the offspring, it is clear that maternal anemia during pregnancy should be included as a confound that is adjusted for in analyses in studies of psychotropic drugs in pregnancy. However, many studies that significantly associated gestational exposure to antidepressants with adverse pregnancy outcomes did not adjust for maternal anemia during pregnancy. This issue is not merely academic because studies with such "significant" findings discourage depressed pregnant women from accepting antidepressants; therefore, women and their unborn children may risk experiencing the known harms associated with untreated depression during pregnancy. Additionally, such "significant" findings may provoke unjustified guilt in women who do use antidepressants during pregnancy, especially if the pregnancy is associated with an adverse outcome. Whereas this is not an endorsement of the unquestioning use of antidepressants during pregnancy, it does imply that those who argue against medication use during pregnancy should re-examine the science on which their views are based.


Assuntos
Anemia/complicações , Antidepressivos/efeitos adversos , Transtorno Depressivo/tratamento farmacológico , Transtornos do Neurodesenvolvimento/etiologia , Complicações Hematológicas na Gravidez/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Adolescente , Adulto , Anemia/epidemiologia , Criança , Transtorno Depressivo/epidemiologia , Feminino , Idade Gestacional , Humanos , Masculino , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/epidemiologia , Gravidez , Complicações Hematológicas na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto Jovem
11.
Pediatrics ; 145(5)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32276969

RESUMO

OBJECTIVES: Children born very preterm (VPT) are at an increased risk of developing mental health (MH) disorders. Our aim for this study was to assess rates of MH disorders in children born VPT and term at 13 years of age and stability of MH disorders between ages 7 and 13 years by using a diagnostic measure. METHODS: Participants were from the Victorian Infant Brain Study longitudinal cohort and included 125 children born VPT (<30 weeks' gestational age and/or <1250 g) and 49 children born term (≥37 weeks' gestational age) and their families. Participants were followed-up at both 7 and 13 years, and the Development and Well-Being Assessment was administered to assess for MH disorders. RESULTS: Compared with term peers, 13-year-olds born VPT were more likely to meet criteria for any MH disorder (odds ratio 5.9; 95% confidence interval 1.71-20.03). Anxiety was the most common disorder in both groups (VPT = 14%; term = 4%), whereas attention-deficit/hyperactivity disorder carried the greatest differential elevated risk (odds ratio 5.6; 95% confidence interval 0.71-43.80). Overall rates of MH disorders remained stable between 7 and 13 years, although at an individual level, many participants shifted in or out of diagnostic categories over time. CONCLUSIONS: Children born VPT show higher rates of MH disorders than their term peers, with changing trajectories over time. Findings highlight the importance of early identification and ongoing assessment to support those with MH disorders in this population.


Assuntos
Lactente Extremamente Prematuro/psicologia , Doenças do Prematuro/psicologia , Saúde Mental/tendências , Transtornos do Neurodesenvolvimento/psicologia , Adolescente , Criança , Estudos de Coortes , Feminino , Seguimentos , Humanos , Recém-Nascido , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/epidemiologia , Estudos Longitudinais , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia
12.
Pediatrics ; 145(5)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341177

RESUMO

OBJECTIVES: To determine if in utero selective serotonin reuptake inhibitor (SSRI) or selective serotonin norepinephrine inhibitor (SNRI) exposure is associated with developmental vulnerability in kindergarten among children whose mothers were diagnosed with prenatal mood or anxiety disorder. METHODS: Linkable administrative data were used to create a population-based cohort of 266 479 mother-child dyads of children born in Manitoba, Canada, between 1996 and 2014, with follow-up through 2015. The sample was restricted to mothers who had a mood or anxiety disorder diagnosis between 90 days before conception (N = 13 818). Exposed women had ≥2 SSRI or SNRI dispensations during pregnancy (n = 2055); unexposed mothers did not have a dispensation of an SSRI or SNRI during pregnancy (n = 10 017). The Early Development Instrument (EDI) was used to assess developmental health in kindergarten children. The EDI is a 104-component kindergarten teacher-administered questionnaire, encompassing 5 developmental domains. RESULTS: Of the 3048 children included in the study who met inclusion criteria and had an EDI, 21.43% of children in the exposed group were assessed as vulnerable on 2 or more domains versus 16.16% of children in the unexposed group (adjusted odds ratio = 1.43; 95% confidence interval 1.08-1.90). Children in the exposed group also had a significant risk of being vulnerable in language and/or cognition (adjusted odds ratio = 1.40; 95% confidence interval 1.03-1.90). CONCLUSIONS: Exposure to SSRIs or SNRIs during pregnancy was associated with an increased risk of developmental vulnerability and an increased risk of deficits in language and/or cognition. Replication of results is necessary before clinical implications can be reached.


Assuntos
Antidepressivos/efeitos adversos , Transtorno Depressivo/tratamento farmacológico , Transtornos do Neurodesenvolvimento/induzido quimicamente , Complicações na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Pré-Escolar , Estudos de Coortes , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Manitoba/epidemiologia , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Inibidores de Captação de Serotonina/efeitos adversos , Adulto Jovem
13.
PLoS Genet ; 16(4): e1008653, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32324743

RESUMO

Neural stem cells (NSCs) are crucial for development, regeneration, and repair of the nervous system. Most NSCs in mammalian adult brains are quiescent, but in response to extrinsic stimuli, they can exit from quiescence and become reactivated to give rise to new neurons. The delicate balance between NSC quiescence and activation is important for adult neurogenesis and NSC maintenance. However, how NSCs transit between quiescence and activation remains largely elusive. Here, we discuss our current understanding of the molecular mechanisms underlying the reactivation of quiescent NSCs. We review recent advances on signaling pathways originated from the NSC niche and their crosstalk in regulating NSC reactivation. We also highlight new intrinsic paradigms that control NSC reactivation in Drosophila and mammalian systems. We also discuss emerging evidence on modeling human neurodevelopmental disorders using NSCs.


Assuntos
Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Transdução de Sinais , Animais , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Humanos , Insulina/metabolismo , Transtornos do Neurodesenvolvimento/terapia , Nicho de Células-Tronco
14.
PLoS Genet ; 16(3): e1008625, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32176688

RESUMO

P/Q-type channels are the principal presynaptic calcium channels in brain functioning in neurotransmitter release. They are composed of the pore-forming CaV2.1 α1 subunit and the auxiliary α2δ-2 and ß4 subunits. ß4 is encoded by CACNB4, and its multiple splice variants serve isoform-specific functions as channel subunits and transcriptional regulators in the nucleus. In two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy we identified rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. In silico tools, animal model, clinical, and genetic data suggest the p.(Leu126Pro) CACNB4 variant to be likely pathogenic. To investigate the functional consequences of the CACNB4 variant, we introduced the corresponding mutation L125P into rat ß4b cDNA. Heterologously expressed wild-type ß4b associated with GFP-CaV1.2 and accumulated in presynaptic boutons of cultured hippocampal neurons. In contrast, the ß4b-L125P mutant failed to incorporate into calcium channel complexes and to cluster presynaptically. When co-expressed with CaV2.1 in tsA201 cells, ß4b and ß4b-L125P augmented the calcium current amplitudes, however, ß4b-L125P failed to stably complex with α1 subunits. These results indicate that p.Leu125Pro disrupts the stable association of ß4b with native calcium channel complexes, whereas membrane incorporation, modulation of current density and activation properties of heterologously expressed channels remained intact. Wildtype ß4b was specifically targeted to the nuclei of quiescent excitatory cells. Importantly, the p.Leu125Pro mutation abolished nuclear targeting of ß4b in cultured myotubes and hippocampal neurons. While binding of ß4b to the known interaction partner PPP2R5D (B56δ) was not affected by the mutation, complex formation between ß4b-L125P and the neuronal TRAF2 and NCK interacting kinase (TNIK) seemed to be disturbed. In summary, our data suggest that the homozygous CACNB4 p.(Leu126Pro) variant underlies the severe neurological phenotype in the two siblings, most likely by impairing both channel and non-channel functions of ß4b.


Assuntos
Canais de Cálcio/genética , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Subunidades Proteicas/genética , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo N/genética , Células Cultivadas , Feminino , Regulação da Expressão Gênica/genética , Células HEK293 , Hipocampo/fisiologia , Homozigoto , Humanos , Masculino , Camundongos Endogâmicos BALB C , Neurônios/metabolismo , Terminações Pré-Sinápticas/fisiologia , Isoformas de Proteínas/genética , Ratos , Transmissão Sináptica/genética
15.
Am J Hum Genet ; 106(4): 438-452, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32197073

RESUMO

The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS), previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI. The six variants lead to the same reading frame, adding a common proline rich C-terminal part instead of the last KH RNA binding domain. We detected 41 genes differentially spliced after NOVA2 downregulation in human neural cells. The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events. It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro and to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss-of-function, although a specific contribution of the novel C-terminal extension cannot be excluded.


Assuntos
Mutação da Fase de Leitura/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Neurônios/fisiologia , Processamento de RNA/genética , Proteínas de Ligação a RNA/genética , Processamento Alternativo/genética , Animais , Orientação de Axônios/genética , Sequência de Bases/genética , Células Cultivadas , Pré-Escolar , Regulação para Baixo/genética , Feminino , Heterozigoto , Humanos , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Camundongos , Hipotonia Muscular/genética , Peixe-Zebra/genética
16.
Am J Hum Genet ; 106(4): 484-495, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32220290

RESUMO

Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.


Assuntos
Aciltransferases/genética , Moléculas de Adesão Celular/genética , Doenças Cerebelares/genética , Epilepsia/genética , Variação Genética/genética , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/genética , Alelos , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Malformações do Sistema Nervoso/genética , Linhagem , Síndrome
17.
Brain ; 143(4): 1099-1105, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32168371

RESUMO

A large fraction of rare and severe neurodevelopmental disorders are caused by sporadic de novo variants. Epidemiological disease estimates are not available for the vast majority of these de novo monogenic neurodevelopmental disorders because of phenotypic heterogeneity and the absence of large-scale genomic screens. Yet, knowledge of disease incidence is important for clinicians and researchers to guide health policy planning. Here, we adjusted a statistical method based on genetic data to predict, for the first time, the incidences of 101 known de novo variant-associated neurodevelopmental disorders as well as 3106 putative monogenic disorders. Two corroboration analyses supported the validity of the calculated estimates. First, greater predicted gene-disorder incidences positively correlated with larger numbers of pathogenic variants collected from patient variant databases (Kendall's τ = 0.093, P-value = 6.9 × 10-6). Second, for six of seven (86%) de novo variant associated monogenic disorders for which epidemiological estimates were available (SCN1A, SLC2A1, SALL1, TBX5, KCNQ2, and CDKL5), the predicted incidence estimates matched the reported estimates. We conclude that in the absence of epidemiological data, our catalogue of 3207 incidence estimates for disorders caused by de novo variants can guide patient advocacy groups, clinicians, researchers, and policymakers in strategic decision-making.


Assuntos
Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Doenças Raras/epidemiologia , Doenças Raras/genética , Variação Genética , Humanos , Incidência
18.
Proc Natl Acad Sci U S A ; 117(12): 6836-6843, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32144139

RESUMO

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.


Assuntos
Canais de Cálcio/genética , Córtex Motor/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas/genética , Proteínas com Domínio T/genética , Córtex Visual/fisiopatologia , Adulto , Idoso , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Mapeamento Encefálico , Estudos de Coortes , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/genética , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Desempenho Psicomotor , Percepção Visual
19.
Zhonghua Er Ke Za Zhi ; 58(3): 223-227, 2020 Mar 02.
Artigo em Chinês | MEDLINE | ID: mdl-32135595

RESUMO

Objective: To analyze the clinical , immunological and genetic features of a child with BCL11B mutation induced neurodevelopmental disorder. Methods: The clinical data and genetic test of a child with BCL11B mutation hospitalized in the Department of Rheumatology and Immunology in Children's Hospital of Chongqing Medical University in December 2018 were extracted and analyzed. The literature was searched with "BCL11B mutation" and "immunodeficiency 49" as key words in Chinese databases and Pubmed until January 2019 was reviewed. Results: A male patient aged 3 years and 11 months with facial dysmorphisms and delayed language and motor development was admitted due to neurodevelopmental retardation over two years. Laboratory tests showed normal human immunoglobulin (IgG 12.90 g/L, IgA 1.02 g/L, IgM 1.15 g/L, IgE 532 000 U/L), Trec (228) and proliferation of T and B cells. The lymphocyte subsets revealeda reduced percentage of B cells (0.108) but normal absolute numbers (0.574×10(-3)/L), and an increased percentage (0.828) as well as absolute numbers (4.415×10(-3)/L) of T cells. A heterozygous BCL11B mutation was detected by sanger sequencing, showing a de novo frameshift mutation c.1887_c.1893delCGGCGGG in exon 4. Two papers were found which were all in English, with total of 14 patients(13 patients with complete information). Thirteen mutations were reposed, including 7 frameshift, 2 nonsense, 2 missense, and 2 chromosomal rearrangements; Thirteen patients had heterozygous mutations. All patients had delayed language and motor development and facial dysplasia which were mainly hypertelorism, thin eyebrows and small palpebral fissures. Some patients had dental anomalies, ametropia and allergy, and a few were combined with immune impairment, but without overt signs of immunodeficiency. Only one patient had multisystem anomalies and profound immune deficiency. Conclusions: BCL11B is essential for development of the nervous and the immune system. In this study, the de novo mutation of BCL11B gene resulted in neurodevelopmental and immunological disorders.


Assuntos
Transtornos do Neurodesenvolvimento , Fatores de Transcrição , Proteínas Supressoras de Tumor , Pré-Escolar , Heterozigoto , Humanos , Masculino , Mutação , Transtornos do Neurodesenvolvimento/genética , Proteínas Repressoras , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
20.
Hum Genet ; 139(5): 593-604, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32152699

RESUMO

Gastrointestinal infections can be life threatening, but not much is known about the host's genetic contribution to susceptibility to gastrointestinal infections or the latter's association with psychiatric disorders. We utilized iPSYCH, a genotyped population-based sample of individuals born between 1981 and 2005 comprising 65,534 unrelated Danish individuals (45,889 diagnosed with mental disorders and 19,645 controls from a random population sample) in which all individuals were linked utilizing nationwide population-based registers to estimate the genetic contribution to susceptibility to gastrointestinal infections, identify genetic variants associated with gastrointestinal infections, and examine the link between gastrointestinal infections and psychiatric and neurodevelopmental disorders. The SNP heritability of susceptibility to gastrointestinal infections ranged from 3.7% to 6.4% on the liability scale. Significant correlations were found between gastrointestinal infections and the combined group of mental disorders (OR = 2.09; 95% CI: 1.82-2.4, P = 1.87 × 10-25). Correlations with autism spectrum disorder, attention deficit hyperactivity disorder, and depression were also significant. We identified a genome-wide significant locus associated with susceptibility to gastrointestinal infections (OR = 1.13; 95% CI: 1.08-1.18, P = 2.9 × 10-8), where the top SNP was an eQTL for the ABO gene. The risk allele was associated with reduced ABO expression, providing, for the first time, genetic evidence to support previous studies linking the O blood group to gastrointestinal infections. This study also highlights the importance of integrative work in genetics, psychiatry, infection, and epidemiology on the road to translational medicine.


Assuntos
Gastroenteropatias/epidemiologia , Marcadores Genéticos , Predisposição Genética para Doença , Transtornos Mentais/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Estudos de Casos e Controles , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Gastroenteropatias/genética , Gastroenteropatias/microbiologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Incidência , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA