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1.
Nat Commun ; 11(1): 6194, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273479

RESUMO

Genetic mosaicism, a condition in which an organ includes cells with different genotypes, is frequently present in monogenic diseases of the central nervous system caused by the random inactivation of the X-chromosome, in the case of X-linked pathologies, or by somatic mutations affecting a subset of neurons. The comprehension of the mechanisms of these diseases and of the cell-autonomous effects of specific mutations requires the generation of sparse mosaic models, in which the genotype of each neuron is univocally identified by the expression of a fluorescent protein in vivo. Here, we show a dual-color reporter system that, when expressed in a floxed mouse line for a target gene, leads to the creation of mosaics with tunable degree. We demonstrate the generation of a knockout mosaic of the autism/epilepsy related gene PTEN in which the genotype of each neuron is reliably identified, and the neuronal phenotype is accurately characterized by two-photon microscopy.


Assuntos
Corantes Fluorescentes/química , Genes Reporter , Integrases/metabolismo , Mosaicismo , Transtornos do Neurodesenvolvimento/genética , Potenciais de Ação , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Eletroencefalografia , Expressão Gênica , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Transtornos do Neurodesenvolvimento/fisiopatologia , PTEN Fosfo-Hidrolase/metabolismo , Tamoxifeno/farmacologia
2.
PLoS One ; 15(11): e0240694, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33147287

RESUMO

BACKGROUND: Severe anaemia is a common clinical problem among young children in sub-Saharan Africa. However, the effect of severe anaemia on neurodevelopment of these children is not well described. Therefore, we assessed the neurodevelopmental performance of preschool children diagnosed with severe anaemia in Northern Uganda. METHODS: We conducted a prospective cohort study among children < 5 years of age 14 days post discharge after an episode of severe anaemia (Hb < 5.0 g/dl; n = 171; mean Hb = 3.9g/dl) at Lira Regional Referral Hospital, Uganda. Neurodevelopmental outcomes (cognitive, language and motor) were assessed using Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III). Age-adjusted z-scores for each domain were calculated using scores from healthy community control children (n = 88) recruited from the same environment for each age category. Multiple linear regression was used to compare z-scores in the cognitive, language and motor scales between the two groups after adjusting for weight-for-age z-score, socioeconomic status, mother's education, and father's employment on all the scales. RESULTS: The prevalence of neurodevelopmental impairment was 2.3% (95% CI: 0.8-6.1) for cognition, 1.7% (95%: 0.6-5.3) for language and 3.5% (95% CI: 1.6-7.6) for motor scales and 4.6% (95% CI: 2.3-9.1) for deficits in ≥1 area of neurodevelopment. Significant differences were observed between the two groups with the SA group performing worse on cognition [adjusted mean score, (Standard error, SE), P-value] [-0.20, (0.01) vs. 0.00, (0.01), P = 0.02]; language [-0.25, (0.01) vs. 0.00, (0.01), P< 0.001]; and motor [-0.17, (0.01) vs. 0.00, (0.01), P = 0.05] scales. CONCLUSION: In children < 5 years of age, severe anaemia was associated with neurocognitive (cognition, language and motor) deficits in the immediate period post treatment. Further research is needed to identify risk factors and determine the long-term effects of poor neurodevelopment in young children with severe anaemia.


Assuntos
Anemia/fisiopatologia , Cognição/fisiologia , Desenvolvimento da Linguagem , Destreza Motora/fisiologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Anemia/epidemiologia , Anemia/terapia , Pré-Escolar , Comorbidade , Feminino , Hospitais , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Alta do Paciente/estatística & dados numéricos , Prevalência , Estudos Prospectivos , Encaminhamento e Consulta , Índice de Gravidade de Doença , Uganda/epidemiologia
3.
Neurology ; 95(21): 962-972, 2020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-33046609

RESUMO

OBJECTIVE: To contextualize the role of child neurologists and neurodevelopmentalists (CNs/NDDs) in cerebral palsy (CP) care, we review the changing landscape of CP diagnosis and survey stakeholder CNs/NDDs regarding their roles in CP care. METHODS: The optimal roles of the multiple specialties involved in CP care are currently unclear, particularly regarding CP diagnosis. We developed recommendations regarding the role of CNs/NDDs noting (1) increasing complexity of CP diagnosis given a growing number of genetic etiologies and treatable motor disorders that can be misdiagnosed as CP and (2) the views of a group of physician stakeholders (CNs/NDDs from the Child Neurology Society Cerebral Palsy Special Interest Group). RESULTS: CNs/NDDs felt that they were optimally suited to diagnose CP. Many (76%) felt that CNs/NDDs should always be involved in CP diagnosis. However, 42% said that their patients with CP were typically not diagnosed by CNs/NDDs, and 18% did not receive referrals to establish the diagnosis of CP at all. CNs/NDDs identified areas of their expertise critical for CP diagnosis including knowledge of the neurologic examination across development and early identification of features atypical for CP. This contrasts with their views on CP management, where CNs/NDDs felt that they could contribute to the medical team, but were necessary primarily when neurologic coexisting conditions were present. DISCUSSION: Given its increasing complexity, we recommend early referral for CP diagnosis to a CN/NDD or specialist with comparable expertise. This contrasts with current consensus guidelines, which either do not address or do not recommend specific specialist referral for CP diagnosis.


Assuntos
Paralisia Cerebral/diagnóstico , Paralisia Cerebral/fisiopatologia , Transtornos do Neurodesenvolvimento/diagnóstico , Inquéritos e Questionários , Humanos , Transtornos do Neurodesenvolvimento/fisiopatologia , Exame Neurológico/métodos , Medição de Risco , Papel (figurativo)
4.
Res Dev Disabil ; 107: 103790, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33091712

RESUMO

BACKGROUND: While COVID-19 outbreak has had adverse psychological effects in children with special needs, the mental state and burden on their caregivers during this pandemic has yet to be reported. AIMS: The objectives of this study were to describe the mental health status and the change in perceived strain among caregivers during the COVID-19 outbreak. METHODS AND PROCEDURES: Two hundred sixty four caregivers completed an online survey that assessed demographics, use and perspective on tele-rehabilitation, homecare therapy, caregiver's strain and mental health. OUTCOMES AND RESULTS: The prevalence of depression, anxiety and stress symptoms were found to be 62.5 %, 20.5 % and 36.4 % respectively. A significant difference in caregiver strain (p <  0.001, effect size = 0.93) was observed during the outbreak compared to levels pre-outbreak (pre-outbreak strain was measured retrospectively). Caregivers not using tele-rehabilitation along with a perception of it being a poor medium for rehabilitation were at greater risks for poor mental health whereas a negative perception on homecare therapy were strongly associated with higher psychological symptoms and strain. CONCLUSIONS AND IMPLICATIONS: This study identified a high prevalence of depression and significant change in strain displayed by caregivers during the COVID-19 outbreak. We identified several factors associated with poor mental health and perceived strain that can be used to help safeguard caregivers.


Assuntos
Ansiedade/psicologia , Cuidadores/psicologia , Depressão/psicologia , Transtornos do Neurodesenvolvimento/reabilitação , Pais/psicologia , Estresse Psicológico/psicologia , Telerreabilitação , Fatores Etários , Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/reabilitação , Atitude Frente a Saúde , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/reabilitação , Cuidadores/estatística & dados numéricos , Paralisia Cerebral/fisiopatologia , Paralisia Cerebral/reabilitação , Criança , Pré-Escolar , Depressão/epidemiologia , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/reabilitação , Síndrome de Down/fisiopatologia , Síndrome de Down/reabilitação , Feminino , Serviços de Assistência Domiciliar , Humanos , Renda , Índia/epidemiologia , Deficiências da Aprendizagem/fisiopatologia , Deficiências da Aprendizagem/reabilitação , Masculino , Saúde Mental , Transtornos do Neurodesenvolvimento/fisiopatologia , Prevalência , Disrafismo Espinal/fisiopatologia , Disrafismo Espinal/reabilitação , Estresse Psicológico/epidemiologia , Carga de Trabalho
5.
Sci Rep ; 10(1): 15072, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934282

RESUMO

Survivors following very premature birth (i.e., ≤ 32 weeks gestational age) remain at high risk for neurodevelopmental impairments. Recent advances in deep learning techniques have made it possible to aid the early diagnosis and prognosis of neurodevelopmental deficits. Deep learning models typically require training on large datasets, and unfortunately, large neuroimaging datasets with clinical outcome annotations are typically limited, especially in neonates. Transfer learning represents an important step to solve the fundamental problem of insufficient training data in deep learning. In this work, we developed a multi-task, multi-stage deep transfer learning framework using the fusion of brain connectome and clinical data for early joint prediction of multiple abnormal neurodevelopmental (cognitive, language and motor) outcomes at 2 years corrected age in very preterm infants. The proposed framework maximizes the value of both available annotated and non-annotated data in model training by performing both supervised and unsupervised learning. We first pre-trained a deep neural network prototype in a supervised fashion using 884 older children and adult subjects, and then re-trained this prototype using 291 neonatal subjects without supervision. Finally, we fine-tuned and validated the pre-trained model using 33 preterm infants. Our proposed model identified very preterm infants at high-risk for cognitive, language, and motor deficits at 2 years corrected age with an area under the receiver operating characteristic curve of 0.86, 0.66 and 0.84, respectively. Employing such a deep learning model, once externally validated, may facilitate risk stratification at term-equivalent age for early identification of long-term neurodevelopmental deficits and targeted early interventions to improve clinical outcomes in very preterm infants.


Assuntos
Encéfalo , Bases de Dados Factuais , Deficiências do Desenvolvimento , Recém-Nascido Prematuro , Aprendizado de Máquina , Modelos Neurológicos , Transtornos do Neurodesenvolvimento , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Criança , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Recém-Nascido , Doenças do Prematuro/diagnóstico por imagem , Doenças do Prematuro/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/fisiopatologia
6.
Sci Rep ; 10(1): 13375, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770121

RESUMO

Pediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE). Patients might manifest mild to profound neurodevelopmental disabilities. We analysed c.853C > A (P285T) and three mutations that cause KCNQ2 protein changes in the 247 position: c.740C > T (S247L), c.740C > A (S247X), and c.740C > G (S247W). S247L, S247W, and P285T cause neonatal-onset EE and poor neurodevelopmental outcomes; S247X cause BFNC and normal outcome. We investigated the phenotypes correlated with human embryonic kidney 293 (HEK293) cell functional current changes. More cell-current changes and a worse conductance curve were present in the homomeric transfected S247X than in S247L, S247W, and P285T. But in the heteromeric channel, S247L, S247W and P285T had more current impairments than did S247X. The protein expressions of S247X were nonfunctional. The outcomes were most severe in S247L and S247W, and severity was correlated with heteromeric current. Current changes were more significant in cells with homomeric S247X, but currents were "rescued" after heteromeric transfection of KCNQ2 and KCNQ3. This was not the case in cells with S247L, S247W. Our findings support that homomeric current changes are common in KCNQ2 neonatal-onset EE and KCNQ2 BFNC; however, heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes.


Assuntos
Canal de Potássio KCNQ2/metabolismo , Mutação com Perda de Função/genética , Transtornos do Neurodesenvolvimento/genética , Substituição de Aminoácidos/genética , Pré-Escolar , Eletroencefalografia , Epilepsia Neonatal Benigna/genética , Epilepsia Neonatal Benigna/metabolismo , Epilepsia Neonatal Benigna/fisiopatologia , Células HEK293 , Humanos , Lactente , Recém-Nascido , Canal de Potássio KCNQ2/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/fisiopatologia
7.
Am J Hum Genet ; 107(3): 544-554, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32730804

RESUMO

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Fatores de Processamento de Serina-Arginina/genética , Animais , Criança , Drosophila melanogaster/genética , Feminino , Técnicas de Silenciamento de Genes , Variação Genética/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Locomoção/genética , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , RNA Polimerase II/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
8.
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
9.
Neuron ; 107(1): 22-37, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32559416

RESUMO

Neuronal SNAREs and their key regulators together drive synaptic vesicle exocytosis and synaptic transmission as a single integrated membrane fusion machine. Human pathogenic mutations have now been reported for all eight core components, but patients are diagnosed with very different neurodevelopmental syndromes. We propose to unify these syndromes, based on etiology and mechanism, as "SNAREopathies." Here, we review the strikingly diverse clinical phenomenology and disease severity and the also remarkably diverse genetic mechanisms. We argue that disease severity generally scales with functional redundancy and, conversely, that the large effect of mutations in some SNARE genes is the price paid for extensive integration and exceptional specialization. Finally, we discuss how subtle differences in components being rate limiting in different types of neurons helps to explain the main symptoms.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Proteínas SNARE/fisiologia , Humanos , Mutação
10.
Nat Commun ; 11(1): 2441, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415109

RESUMO

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.


Assuntos
Cinesina/genética , Atividade Motora , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Animais , Axônios/metabolismo , Movimento Celular , Proliferação de Células , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Neurônios/metabolismo , Tamanho do Órgão , Organogênese/genética , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/genética
11.
Sci Rep ; 10(1): 7288, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350387

RESUMO

Premature babies are subjected to environmental stresses that can affect brain maturation and cause abnormal neurodevelopmental outcome later in life. Better understanding this link is crucial to developing a clinical tool for early outcome estimation. We defined maturational trajectories between the Electroencephalography (EEG)-derived 'brain-age' and postmenstrual age (the age since the last menstrual cycle of the mother) from longitudinal recordings during the baby's stay in the Neonatal Intensive Care Unit. Data consisted of 224 recordings (65 patients) separated for normal and abnormal outcome at 9-24 months follow-up. Trajectory deviations were compared between outcome groups using the root mean squared error (RMSE) and maximum trajectory deviation (δmax). 113 features were extracted (per sleep state) to train a data-driven model that estimates brain-age, with the most prominent features identified as potential maturational and outcome-sensitive biomarkers. RMSE and δmax showed significant differences between outcome groups (cluster-based permutation test, p < 0.05). RMSE had a median (IQR) of 0.75 (0.60-1.35) weeks for normal outcome and 1.35 (1.15-1.55) for abnormal outcome, while δmax had a median of 0.90 (0.70-1.70) and 1.90 (1.20-2.90) weeks, respectively. Abnormal outcome trajectories were associated with clinically defined dysmature and disorganised EEG patterns, cementing the link between early maturational trajectories and neurodevelopmental outcome.


Assuntos
Eletroencefalografia , Recém-Nascido Prematuro , Transtornos do Neurodesenvolvimento/fisiopatologia , Processamento de Sinais Assistido por Computador , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino
12.
Ann Neurol ; 88(2): 396-406, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32472944

RESUMO

OBJECTIVE: Rett syndrome, CDKL5-deficiency disorder, FOXG1 disorder, and MECP2 duplication disorder are developmental encephalopathies with shared and distinct features. Although they are historically linked, no direct comparison has been performed. The first head-to-head comparison of clinical features in these conditions is presented. METHODS: Comprehensive clinical information was collected from 793 individuals enrolled in the Rett and Rett-Related Disorders Natural History Study. Clinical features including clinical severity, regression, and seizures were cross-sectionally compared between diagnoses to test the hypothesis that these are 4 distinct disorders. RESULTS: Distinct patterns of clinical severity, seizure onset age, and regression were present. Individuals with CDKL5-deficency disorder were the most severely affected and had the youngest age at seizure onset (2 months), whereas children with MECP2 duplication syndrome had the oldest median age at seizure onset (64 months) and lowest severity scores. Rett syndrome and FOGX1 were intermediate in both features. Smaller head circumference correlates with increased severity in all disorders and earlier age at seizure onset in MECP2 duplication syndrome. Developmental regression occurred in all Rett syndrome participants (median = 18 months) but only 23 to 34% of the other disorders. Seizure incidence prior to the baseline visit was highest for CDKL5 deficiency disorder (96.2%) and lowest for Rett syndrome (47.5%). Other clinical features including seizure types and frequency differed among groups. INTERPRETATION: Although these developmental encephalopathies share many clinical features, clear differences in severity, regression, and seizures warrant considering them as unique disorders. These results will aid in the development of disease-specific severity scales, precise therapeutics, and future clinical trials. ANN NEUROL 2020;88:396-406.


Assuntos
Encefalopatias/diagnóstico , Encefalopatias/fisiopatologia , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/fisiopatologia , Síndrome de Rett/diagnóstico , Síndrome de Rett/fisiopatologia , Adolescente , Encefalopatias/genética , Criança , Pré-Escolar , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/genética , Síndromes Epilépticas/fisiopatologia , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Síndrome de Rett/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Adulto Jovem
13.
Neuron ; 107(1): 52-64.e7, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32362337

RESUMO

At neuronal synapses, synaptotagmin-1 (syt1) acts as a Ca2+ sensor that synchronizes neurotransmitter release with Ca2+ influx during action potential firing. Heterozygous missense mutations in syt1 have recently been associated with a severe but heterogeneous developmental syndrome, termed syt1-associated neurodevelopmental disorder. Well-defined pathogenic mechanisms, and the basis for phenotypic heterogeneity in this disorder, remain unknown. Here, we report the clinical, physiological, and biophysical characterization of three syt1 mutations from human patients. Synaptic transmission was impaired in neurons expressing mutant variants, which demonstrated potent, graded dominant-negative effects. Biophysical interrogation of the mutant variants revealed novel mechanistic features concerning the cooperative action, and functional specialization, of the tandem Ca2+-sensing domains of syt1. These mechanistic studies led to the discovery that a clinically approved K+ channel antagonist is able to rescue the dominant-negative heterozygous phenotype. Our results establish a molecular cause, basis for phenotypic heterogeneity, and potential treatment approach for syt1-associated neurodevelopmental disorder.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Neurônios/fisiologia , Transmissão Sináptica/genética , Sinaptotagmina I/genética , 4-Aminopiridina/farmacologia , Animais , Células Cultivadas , Humanos , Camundongos , Transtornos do Neurodesenvolvimento/fisiopatologia , Neurônios/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Sinaptotagmina I/química
14.
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
15.
Dev Med Child Neurol ; 62(7): 784-792, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32227486

RESUMO

Genetic variants in brain-expressed voltage-gated sodium channels (SCNs) have emerged as one of the most frequent causes of Mendelian forms of epilepsy and neurodevelopmental disorders (NDDs). This review explores the biological concepts that underlie sodium channel NDDs, explains their phenotypic heterogeneity, and appraises how this knowledge may inform clinical practice. We observe that excitatory/inhibitory neuronal expression ratios of sodium channels are important regulatory mechanisms underlying brain development, homeostasis, and neurological diseases. We hypothesize that a detailed understanding of gene expression, variant tolerance, location, and function, as well as timing of seizure onset can aid the understanding of how variants in SCN1A, SCN2A, SCN3A, and SCN8A contribute to seizure aetiology and inform treatment choice. We propose a model in which variant type, development-specific gene expression, and functions of SCNs explain the heterogeneity of sodium channel associated NDDs. Understanding of basic disease mechanisms and detailed knowledge of variant characteristics have increasing influence on clinical decision making, enabling us to stratify treatment and move closer towards precision medicine in sodium channel epilepsy and NDDs. WHAT THIS PAPER ADDS: Sodium-channel disorder heterogeneity is explained by variant-specific gene expression timing and function. Gene tolerance and location analyses aid sodium channel variant interpretation. Sodium-channel variant characteristics can contribute to clinical decision making.


Assuntos
Fenômenos Eletrofisiológicos/fisiologia , Epilepsia/fisiopatologia , Expressão Gênica/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.1/fisiologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenômenos Eletrofisiológicos/genética , Epilepsia/genética , Expressão Gênica/genética , Humanos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Transtornos do Neurodesenvolvimento/genética
16.
Dev Med Child Neurol ; 62(7): 778-783, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32277484

RESUMO

This review and synthesis discusses recent work that has utilized brain imaging methods, such as the electroencephalogram (EEG) and magnetoencephalogram, to provide insights into the ways that the body is represented in the infant brain. One aspect of body representation concerns somatotopic maps of the body surface in somatosensory cortex. A good deal is known about the properties of these maps in adults, but there has been relatively little developmental work. Recent studies have provided new insights into the organization of infant neural body maps and have laid the foundations for examining their plasticity in relation to behavioral development. Other work has suggested that neural body maps may be involved in the registration of correspondences between self and other, with implications for early social development. Here, body representations are discussed in the context of preterm birth and autism spectrum disorder, providing novel perspectives relevant to developmental medicine and child neurology. WHAT THIS PAPER ADDS: ●Somatotopic body maps develop prenatally through intrinsic and activity-dependent mechanisms. ●There is increasing interest in understanding postnatal plasticity in body maps. ●Body representations may be involved in the registration of preverbal, interpersonal relationships.


Assuntos
Imagem Corporal , Mapeamento Encefálico , Potenciais Somatossensoriais Evocados/fisiologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Percepção Social , Córtex Somatossensorial/fisiopatologia , Percepção do Tato/fisiologia , Humanos , Lactente , Córtex Somatossensorial/crescimento & desenvolvimento
17.
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
18.
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
19.
Int Rev Neurobiol ; 150: 17-40, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32204831

RESUMO

The impact of stress on brain health begins in the womb. Both animal and human studies have found that prenatal maternal stress affects the brain and behavior of the offspring. Stressful life events, exposure to a natural disaster, and symptoms of maternal anxiety and depression increase the risk for the child having a range of emotional, behavioral and/or cognitive problems in later life. These include depression, anxiety, Attention Deficit Hyperactivity Disorder (ADHD), and/or conduct disorders. There is an increased risk for other outcomes also, including preterm delivery and reduced telomere length, possibly indicative of an accelerated life history. The causal role of prenatal maternal stress on the etiology of the neurodevelopmental disorders is supported by large population cohorts, which have controlled for a wide range of potential confounders, including postnatal maternal mood. More recently, research has begun to explore the biological correlates and mediators of these findings. These studies suggest that the hypothalamic pituitary adrenal (HPA) axis plays a role in mediating the effects of maternal stress on the fetal brain. Further, in vivo brain imaging research reports that maternal stress is associated with changes in limbic and frontotemporal networks, and the functional and microstructural connections linking them. The structural changes include cortical thinning and an enlarged amygdala. While these studies have been conducted on smaller sample sizes and could not control for many confounders, the observed brain changes do plausibly underlie many of the emotional, behavioral and cognitive changes found to be associated with prenatal stress.


Assuntos
Tonsila do Cerebelo , Córtex Cerebral , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário , Transtornos Mentais , Transtornos do Neurodesenvolvimento , Neuroimagem , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/patologia , Animais , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Criança , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Transtornos Mentais/fisiopatologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia
20.
Indian J Tuberc ; 67(1): 136-138, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32192608

RESUMO

Tuberculosis (TB) is a disease of diverse manifestations. In children, neurotuberculosis is the severest form, which when left untreated can have deleterious consequences. There has been reports on pediatric TB meningitis manifesting with fever and seizures, altered sensorium or focal deficits. There are reports on TB meningitis presenting with cognitive decline in adults. We are reporting a eleven month old girl child who presented with acute regression of attained developmental milestones of one month duration as the only presenting complaint and MRI brain revealed basal exudates with hydrocephalus which nailed the diagnosis of tuberculous meningitis. CSF (Cerebro Spinal Fluid) tested by CBNAAT (Cartridge Based Nucleic Acid Amplification Testing) for TB was negative, but gastric aspirate tested for the same, came positive. Tuberculin skin testing was also positive. Chest X-ray was normal. The child had not received BCG (Bacillus Calmette Guerin)vaccine, thereby increasing her risk of complicated TB. The contact couldn't be traced. The child was started on ATT (Anti Tubercular Treatment) as soon as the diagnosis was made and she improved, thus signifying the better outcome with early initiation of ATT. This case reporting is intended to highlight the unusual presentation of TB meningitis in children, which when clinicians are aware of will lead to early treatment and better prognosis.


Assuntos
Hidrocefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Tuberculose Meníngea/fisiopatologia , Acetazolamida/uso terapêutico , Antituberculosos/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/metabolismo , Líquido Cefalorraquidiano/microbiologia , Intervenção Médica Precoce , Etambutol/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/tratamento farmacológico , Lactente , Isoniazida/uso terapêutico , Imagem por Ressonância Magnética , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Técnicas de Amplificação de Ácido Nucleico , Prednisolona/uso terapêutico , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Estômago/microbiologia , Resultado do Tratamento , Tuberculose Meníngea/líquido cefalorraquidiano , Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/tratamento farmacológico
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