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1.
Nat Commun ; 11(1): 5236, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067431

RESUMO

The etiology of major neurodevelopmental disorders such as schizophrenia and autism is unclear, with evidence supporting a combination of genetic factors and environmental insults, including viral infection during pregnancy. Here we utilized a mouse model of maternal immune activation (MIA) with the viral mimic PolyI:C infection during early gestation. We investigated the transcriptional changes in the brains of mouse fetuses following MIA during the prenatal period, and evaluated the behavioral and biochemical changes in the adult brain. The results reveal an increase in RNA editing levels and dysregulation in brain development-related gene pathways in the fetal brains of MIA mice. These MIA-induced brain editing changes are not observed in adulthood, although MIA-induced behavioral deficits are observed. Taken together, our findings suggest that MIA induces transient dysregulation of RNA editing at a critical time in brain development.


Assuntos
Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/genética , Complicações na Gravidez/imunologia , Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/genética , Edição de RNA , Animais , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Encéfalo/imunologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Imunidade Materno-Adquirida , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/psicologia , Poli I-C/efeitos adversos , Poli I-C/imunologia , Complicações na Gravidez/etiologia , Complicações na Gravidez/genética , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/psicologia
2.
Medicine (Baltimore) ; 99(34): e21847, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846834

RESUMO

RATIONALE: Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder presenting with uric acid overproduction, neurocognitive disability, and behavioral disturbances. Inhalational anesthesia has been frequently used in LNS patients undergoing surgery. Characteristic compulsive self-injurious behavior and high risk of emesis may hinder inhalational induction. Propofol may be beneficial for these patients because of its easy and rapid titration for anesthetic depth during induction, early recovery from anesthesia, and antiemetic effect as well as uricosuric effect. PATIENT CONCERNS: A 16-year-old male adolescent was scheduled for percutaneous nephrolithotomy. He exhibited poorly controlled muscle, self-injurious behaviors and intellectual disability. DIAGNOSIS: The patient presented with neurodevelopmental delay in the first year of life, and was diagnosed with LNS, with a substitution of phenylalanine to leucine in hypoxanthine-guanine phosphoribosyltransferase (HPRT) 1 gene on the X-chromosome at 3 years of age. INTERVENTIONS: Total intravenous anesthesia was used for induction and maintenance of anesthesia with propofol and remifentanil using target-controlled infusion. OUTCOMES: Time to recovery of consciousness was prolonged after uneventful surgery. Serum uric acid levels gradually increased during postoperative period. LESSONS: Propofol anesthesia using target-controlled infusion does not provide significant clinical advantages in rapid emergence from anesthesia and management of hyperuricemia in LNS patients undergoing urological surgery.


Assuntos
Anestesia Geral/efeitos adversos , Hipoxantina Fosforribosiltransferase/genética , Síndrome de Lesch-Nyhan/psicologia , Propofol/administração & dosagem , Administração Intravenosa , Adolescente , Período de Recuperação da Anestesia , Anestesia Geral/métodos , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/etiologia , Deficiência Intelectual/etiologia , Cálculos Renais/cirurgia , Síndrome de Lesch-Nyhan/sangue , Síndrome de Lesch-Nyhan/diagnóstico , Síndrome de Lesch-Nyhan/genética , Masculino , Nefrolitotomia Percutânea/métodos , Transtornos do Neurodesenvolvimento/etiologia , Comportamento Autodestrutivo/etiologia , Resultado do Tratamento , Ácido Úrico/sangue , Vômito/induzido quimicamente
3.
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
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
5.
J Pediatr ; 221: 39-46.e5, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32446491

RESUMO

OBJECTIVE: To evaluate the hypothesis that early-onset sepsis increases risk of death or neurodevelopmental impairment (NDI) among preterm infants; and that among infants without early-onset sepsis, prolonged early antibiotics alters risk of death/NDI. STUDY DESIGN: Retrospective cohort study of infants born at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers (2006-2014) at 22-26 weeks of gestation and birth weight 401-1000 g. Early-onset sepsis defined as growth of a pathogen from blood or cerebrospinal fluid culture ≤72 hours after birth. Prolonged early antibiotics was defined as antibiotics initiated ≤72 hours and continued ≥5 days without culture-confirmed infection, necrotizing enterocolitis, or spontaneous perforation. Primary outcome was death before follow-up or NDI assessed at 18-26 months corrected age. Poisson regression was used to estimate adjusted relative risk (aRR) and CI for early-onset sepsis outcomes. A propensity score for receiving prolonged antibiotics was derived from early clinical factors and used to match infants (1:1) with and without prolonged antibiotic exposure. Log binomial models were used to estimate aRR for outcomes in matched infants. RESULTS: Among 6565 infants, those with early-onset sepsis had higher aRR (95% CI) for death/NDI compared with infants managed with prolonged antibiotics (1.18 [1.06-1.32]) and to infants without prolonged antibiotics (1.23 [1.10-1.37]). Propensity score matching was achieved for 4362 infants. No significant difference in death/NDI (1.04 [0.98-1.11]) was observed with or without prolonged antibiotics among the matched cohort. CONCLUSIONS: Early-onset sepsis was associated with increased risk of death/NDI among extremely preterm infants. Among matched infants without culture-confirmed infection, prolonged early antibiotic administration was not associated with death/NDI.


Assuntos
Antibacterianos/administração & dosagem , Sepse/tratamento farmacológico , Sepse/mortalidade , Idade de Início , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente Extremamente Prematuro , Masculino , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Estudos Retrospectivos , Medição de Risco , Sepse/complicações , Taxa de Sobrevida , Fatores de Tempo
6.
Neurología (Barc., Ed. impr.) ; 35(4): 226-232, mayo 2020. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-194073

RESUMO

INTRODUCCIÓN: Los niños con hipotiroidismo congénito (HC) están en riesgo de presentar déficit cognitivos sutiles, a pesar de tener un rendimiento intelectual global dentro de rangos normales. Estos déficits pueden ser consecuencia de condiciones inherentes a la enfermedad y a factores relacionados con el tratamiento. El presente estudio explora el efecto de las desviaciones del estado de eutiroidismo durante los primeros 3 años de vida en el rendimiento atencional durante la edad escolar. MÉTODOS: Fueron evaluados 49 niños con HC diagnosticado y bajo tratamiento, de ellos 14 fueron niños (9,5 ± 2,8 años de edad) y 35 niñas (9,6 ± 2,6 años de edad). Se calculó el total de episodios de sobre, infra y normotratamiento a partir de los valores de TSH durante los primeros 3 años de vida (medidos a los 12, 18, 24, 30 y 36 meses de edad). Los niños fueron evaluados mediante una versión computarizada del Test de atención sostenida. Se calcularon los modelos lineales generales usando el índice de atención como variable dependiente y el género, la etiología y los episodios de sobre, infra y normotratamiento como independientes. RESULTADOS: El número de episodios de sobretratamiento (TSH baja) se asoció a un peor rendimiento atencional en la edad escolar (p = 0,005, r = -0,45). CONCLUSIÓN: Debe realizarse un seguimiento estrecho en los 3 primeros años en pacientes con HC para evitar no solo el hipotiroidismo, sino también los efectos adversos de episodios de hipertratamiento que pueden comprometer el procesamiento atencional en edad escolar


INTRODUCTION: Children with congenital hypothyroidism (CH) are at risk of developing mild cognitive impairment despite normal overall intellectual performance. These deficits may be caused by disease-related and treatment-related factors. This study explores the impact of abnormal thyroid function during the first 3 years of life on attention performance at school age. METHODS: We included 49 children diagnosed with CH and receiving treatment for the condition: 14 boys (mean age 9.5 ± 2.8 years) and 35 girls (9.6 ± 2.6 years). The number of episodes of normal, under-, and overtreatment were estimated based on TSH levels during their first 3 years of life (at 12, 18, 24, 30, and 36 months). Children were assessed using a computerised version of a Sustained attention test. General linear models were calculated with the attention index as the dependent variable and sex, aetiology, and number of episodes of normal, under-, and overtreatment as independent variables. RESULTS: Higher numbers of episodes of overtreatment (low TSH level) were associated with poorer attention performance at school age (P = .005, r = -0.45). CONCLUSIONS: Children with CH should be monitored closely during the first 3 years of life in order to prevent not only hypothyroidism but also any adverse effects of overtreatment that may affect attentional function at school age


Assuntos
Humanos , Masculino , Feminino , Criança , Hipotireoidismo Congênito/terapia , Hipotireoidismo Congênito/complicações , Transtornos do Neurodesenvolvimento/etiologia , Disfunção Cognitiva/etiologia , Deficiências da Aprendizagem/etiologia , Sobremedicalização , Seguimentos
7.
Eur J Paediatr Neurol ; 27: 78-85, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32327390

RESUMO

BACKGROUND: Neurodevelopmental follow-up in Neonatal Hypoxic Ischaemic Encephalopathy (HIE) typically focusses on major neuromotor (cerebral palsy, CP) and severe cognitive impairment. Outcomes in those without major neuromotor impairment are less well explored. OBJECTIVES: To examine behavioural, cognitive and neurological outcomes after neonatal HIE, in a clinical cohort of children without CP, at age 2 years. METHODS: Clinical routine outcome data from children admitted to a tertiary centre with neonatal HIE for hypothermia treatment between 05/08/09-30/05/2016. Children were assessed for neuromotor status - particularly minor neurological signs (MNS), with Bayley Scales of Infant and Toddler Development III (Bayley III) or Ages and Stages Questionnaire-3 (ASQ), Child Behavior Checklist 1.5-5 (CBCL), Quantitative Checklist for Autism in Toddlers (Q-CHAT). RESULTS: Of 107 children, 75.5% had normal neurology, 12.1% CP, 12.1% MNS. Children with CP were excluded from analyses. For those without CP, Bayley-III scores were in the average range for the majority; mild cognitive delay observed in 5%, 4.2% language, 1.3% motor development; severe delay in 1.3% for cognitive, 4.2% for language. More than in the normative population scored in clinical ranges for CBCL externalising, sleep, and other problems. No significant difference was seen for Q-CHAT. Children with MNS were significantly more likely to have impaired Bayley-III scores, parent-reported internalising, sleep, and other problems. CONCLUSIONS: In this clinical cohort, the majority of children had favourable outcome at 2 years. However, children with MNS were at risk for cognitive and behavioural difficulties and will benefit from enhanced clinical follow-up and support.


Assuntos
Hipóxia-Isquemia Encefálica/complicações , Transtornos do Neurodesenvolvimento/etiologia , Asfixia Neonatal/complicações , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Recuperação de Função Fisiológica , Inquéritos e Questionários , Tempo
8.
BMC Neurol ; 20(1): 115, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228505

RESUMO

BACKGROUND: Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls. METHOD: Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1ß, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF ß, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin). RESULTS: GM-CSF, TNF-ß, IL-2 IL-6 and IL-8 were significantly elevated at school age following NE (n = 40) compared to controls (n = 37). A rise in GM-CSF, IL-8, TNF-α, IL-1ß, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-ß. Elevated TNF-ß was associated with low gross motor scores on assessment at school age. CONCLUSION: School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-ß was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for neuroprotection therapies.


Assuntos
Asfixia Neonatal/complicações , Asfixia Neonatal/imunologia , Citocinas/sangue , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/imunologia , Encefalopatias/etiologia , Encefalopatias/imunologia , Criança , Feminino , Humanos , Recém-Nascido , Masculino
9.
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
10.
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
11.
Sci Rep ; 10(1): 4697, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170216

RESUMO

Previous studies demonstrate an association between activation of the maternal immune system during pregnancy and increased risk of neurodevelopmental psychiatric conditions, such as schizophrenia and autism, in the offspring. Relatively recent findings also suggest that the gut microbiota plays an important role in shaping brain development and behavior. Here we show that maternal immune activation (MIA) accomplished by infection with a mouse-adapted influenza virus during pregnancy induced up-regulation of frontal cortex serotonin 5-HT2A receptor (5-HT2AR) density in the adult offspring, a phenotype previously observed in postmortem frontal cortex of schizophrenic subjects. 5-HT2AR agonist-induced head-twitch behavior was also augmented in this preclinical mouse model. Using the novel object recognition (NOR) test to evaluate cognitive performance, we demonstrate that MIA induced NOR deficits in adult offspring. Oral antibiotic treatment of prepubertal mice prevented this cognitive impairment, but not increased frontal cortex 5-HT2AR density or psychedelic-induced head-twitch behavior in adult MIA offspring. Additionally, gut microbiota transplantation from MIA mice produced behavioral deficits in antibiotic-treated mock mice. Adult MIA offspring displayed altered gut microbiota, and relative abundance of specific components of the gut microbiota, including Ruminococcaceae, correlated with frontal cortex 5-HT2AR density. Together, these findings provide a better understanding of basic mechanisms by which prenatal insults impact offspring brain function, and suggest gut-brain axis manipulation as a potential therapeutic approach for neurodevelopmental psychiatric conditions.


Assuntos
Comportamento Animal , Suscetibilidade a Doenças , Microbioma Gastrointestinal , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/psicologia , Comportamento Problema , Maturidade Sexual , Fatores Etários , Animais , Antibacterianos/administração & dosagem , Modelos Animais de Doenças , Memória , Camundongos , Fenótipo , Reconhecimento Psicológico , Esquizofrenia/etiologia
12.
Sci Adv ; 6(4): eaax0021, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010779

RESUMO

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação a DNA/metabolismo , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Aminoácidos , Animais , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Linhagem Celular , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Suscetibilidade a Doenças , Predisposição Genética para Doença , Histona Acetiltransferases/genética , Humanos , Imagem por Ressonância Magnética , Camundongos , Camundongos Knockout , Modelos Biológicos , Complexos Multiproteicos/metabolismo , Mutação , Neoplasias/diagnóstico , Transtornos do Neurodesenvolvimento/diagnóstico , Fenótipo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Processamento de Proteína Pós-Traducional , Síndrome
13.
JAMA Netw Open ; 3(2): e1920787, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32031649

RESUMO

Importance: Maternal obesity, pregestational type 1 and 2 diabetes, and gestational diabetes have been reported to increase the risk of autism spectrum disorder and attention-deficit/hyperactivity disorder in the mothers' offspring. However, the associations of maternal diabetes disorders and body mass index jointly with psychiatric disorders among offspring are less well documented, especially for type 2 diabetes. Objective: To examine the associations of different types of maternal diabetes, separately and together with maternal obesity, with psychiatric disorders in the mothers' offspring. Design, Setting, and Participants: This population-based cohort study used data from nationwide registries in Finland encompassing all 649 043 live births occurring between 2004 and 2014. The study and data analysis were conducted from January 1, 2019, to July 5, 2019. Exposures: Maternal prepregnancy body mass index, insulin-treated pregestational diabetes, and pregestational type 2 diabetes and gestational diabetes without insulin treatment. Main Outcomes and Measures: Psychiatric diagnoses and prescription of psychotropic drugs among the mothers' offspring. Cox proportional hazards models were adjusted for birth year, sex, mode of delivery, maternal age, number of fetuses, parity, mother's country of birth, mother's marital status, maternal smoking, maternal psychiatric disorder, and maternal systemic inflammatory disease. Results: The mean (SD) age of mothers was 30.20 (5.37) years; 357 238 of 394 302 mothers (90.6%) were born in Finland. Of the 647 099 births studied, 4000 fetuses (0.62%) were exposed to maternal insulin-treated pregestational diabetes, 3724 (0.57%) were exposed to type 2 diabetes, and 98 242 (15.18%) were exposed to gestational diabetes; 34 892 offspring (5.39%) later received a diagnosis of a mild neurodevelopmental or psychiatric disorder. Non-insulin-treated type 2 diabetes in severely obese mothers, compared with normal-weight mothers without diabetes, was associated with psychiatric disorders in the offspring (hazard ratio, 1.97; 95% CI, 1.64-2.37), although with a lower effect size than that for severely obese mothers with insulin-treated pregestational diabetes (hazard ratio, 2.71; 95% CI, 2.03-3.61). The largest effect sizes were found for mood disorders, attention-deficit/hyperactivity disorder and conduct disorders, and autism. Gestational diabetes in severely obese mothers had a lower overall effect size (hazard ratio, 1.61; 95% CI, 1.50-1.72). Diabetes in normal-weight mothers was not associated with psychopathologic disorders in the offspring. Conclusions and Relevance: Severe obesity in mothers with diabetes was associated with an increased overall risk for psychiatric disorders in their offspring. The risk was highest for those exposed to insulin-treated pregestational diabetes, followed by non-insulin-treated type 2 diabetes and gestational diabetes. These findings may have implications for managing pregnancies.


Assuntos
Índice de Massa Corporal , Diabetes Gestacional/fisiopatologia , Exposição Materna/efeitos adversos , Transtornos do Neurodesenvolvimento/epidemiologia , Gravidez em Diabéticas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Feminino , Finlândia/epidemiologia , Humanos , Transtornos do Neurodesenvolvimento/etiologia , Obesidade/complicações , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Modelos de Riscos Proporcionais , Sistema de Registros
14.
Am J Hum Genet ; 106(2): 246-255, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004447

RESUMO

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.


Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Proteínas Ativadoras de GTPase/genética , Hipotonia Muscular/etiologia , Mutação , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/etiologia , Espasmos Infantis/etiologia , Alelos , Movimento Celular , Proliferação de Células , Pré-Escolar , Família , Transtornos da Alimentação e da Ingestão de Alimentos/patologia , Feminino , Humanos , Lactente , Masculino , Hipotonia Muscular/patologia , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Espasmos Infantis/patologia
15.
Brain Dev ; 42(4): 342-347, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32019687

RESUMO

OBJECTIVE: The effect of complex febrile seizures (FS), specifically focal FS, on long-term neurodevelopmental outcome is not well known. The aim of this study was to assess the association between complex FS and neurodevelopmental outcome. METHODS: A single-center, retrospective, cohort study was performed. The study included 282 children aged 6-60 months who experienced FS. Of these, 61 (22%) experienced recurrent FS, 33 (12%) prolonged FS, and 17 (6%) focal FS. The effect of these complex FS on subsequent need for special neurodevelopmental support was investigated. The neurodevelopmental status after FS was evaluated by a questionnaire. RESULTS: During a median follow-up period of 3 years post FS, 12 children (4.3%) required special neurodevelopmental support. Univariate analysis demonstrated a significant association between focal FS and the need for subsequent special neurodevelopmental support, as well as a correlation between prolonged FS and pre-existing neurodevelopmental abnormality. Multiple logistic regression analysis demonstrated that focal FS (odds ratio [OR]: 12.27; 95% confidence interval [CI]: 2.11-71.22) and pre-existing neurodevelopmental abnormality (OR: 262; 95% CI: 17-3944) were significantly associated with the need for subsequent special support. CONCLUSION: An association was found between focal FS and subsequent neurodevelopmental impairment; therefore, close follow-up with particular attention to neurodevelopmental status is required for children who experience focal FS.


Assuntos
Transtornos do Neurodesenvolvimento/epidemiologia , Convulsões Febris/epidemiologia , Desenvolvimento Infantil , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtornos do Neurodesenvolvimento/etiologia , Estudos Retrospectivos , Fatores de Risco , Convulsões Febris/complicações
16.
PLoS One ; 15(2): e0229434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32109947

RESUMO

The main goal of this manuscript was to investigate the neurodevelopment of children exposed by Zika virus in the intrauterine period who are asymptomatic at birth. Newborns with documented Zika virus exposure during the intrauterine period who were asymptomatic at birth were followed in the first two years of life for neurodevelopment using Bayley III test. Children were classified as having normal or delayed neurodevelopment for age based on most recent Bayley III evaluation results. Eighty-four infants were included in the study. The first Bayley III evaluation was performed at a mean chronological age of 9.7±3.1 month; 13 children (15%) had a delay in one of the three domains, distributed as follow: 10 (12%) in the language domain and 3 (3.5%) in the motor domain. The most recent Bayley III evaluation was performed at a mean age 15.3±3.1 months; 42 children (50%) had a delay in one of the three domains: 4 (5%) in cognition, 31 (37%) in language, and 20 (24%) in motor performance. There were no statistical differences in Gender, Gestational Age, Birth Weight and Head Circurference at birth between children with normal and delayed neurodevelopment for age. A very high proportion of children exposed ZIKV during pregnancy who were asymptomatic at birth demonstrated a delay in neurodevelopment, mainly in the language domain, the first two years of life.


Assuntos
Transtornos do Neurodesenvolvimento/etiologia , Complicações Infecciosas na Gravidez/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Útero/virologia , Infecção por Zika virus/complicações , Zika virus/isolamento & purificação , Adolescente , Adulto , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/patologia , Parto , Gravidez , Complicações Infecciosas na Gravidez/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Adulto Jovem , Infecção por Zika virus/virologia
17.
J Perinatol ; 40(4): 633-639, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32051541

RESUMO

OBJECTIVE: To study the association between perinatal sentinel events (PSE) and brain MRI/neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia (TH). DESIGN: This is a retrospective single-center study. Data collection included perinatal history, brain MRI, and neurodevelopmental outcome. RESULTS: Out of the 182 neonates, 53 (29%) neonates had PSE and 129 (71%) neonates did not have PSE. Neonates with PSE had more normal MRIs (76%) compared with neonates without PSE (55%), p = 0.01. PSE was associated with favorable motor (p = 0.02), language outcome (p = 0.03), and trend to better cognitive scores (p = 0.13). In PSE, favorable motor outcome persisted (OR for impairment 0.15 (0.003-0.84), p = 0.03) after adjusting for the degree of encephalopathy and brain MRI injury. Injury on brain MRI despite TH after PSE was associated with unfavorable neurodevelopmental outcome (p < 0.001). CONCLUSION: Neonates with HIE receiving TH after PSE had less severe injury on brain MRI after rewarming, and improved motor and language outcomes at 18-36 months.


Assuntos
Encéfalo/patologia , Hipotermia Induzida , Hipóxia-Isquemia Encefálica/terapia , Transtornos do Neurodesenvolvimento/prevenção & controle , Descolamento Prematuro da Placenta , Encéfalo/diagnóstico por imagem , Pré-Escolar , Feminino , Seguimentos , Humanos , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/patologia , Lactente , Recém-Nascido , Modelos Logísticos , Imagem por Ressonância Magnética , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/etiologia , Testes Neuropsicológicos , Complicações do Trabalho de Parto , Gravidez , Estudos Retrospectivos , Distocia do Ombro
18.
Arch. argent. pediatr ; 118(1): 52-56, 2020-02-00. tab, ilus
Artigo em Inglês, Espanhol | LILACS, BINACIS | ID: biblio-1095588

RESUMO

El amplio espectro de aberraciones cromosómicas observable en los trastornos del neurodesarrollo no siempre puede ser caracterizado por análisis cromosómico. El objetivo del trabajo fue determinar la etiología genética de estos trastornos en pacientes con afecciones neurológicas congénitas y sospecha clínica de un síndrome genético, aplicando un algoritmo de estudio clínico-molecular. En 71 de 111 niños analizados, se hallaron aberraciones submicroscópicas asociadas a síndromes de microdeleción-microduplicación: DiGeorge (22 casos), Prader-Willi (26 casos), Angelman (2 casos), Williams-Beuren (17 casos), Smith-Magenis (1 caso), Miller-Dieker (1 caso) y síndrome cri du chat (1 caso). Adicionalmente, se detectó una inserción desbalanceada de novo de la región 17p12p11.2, en el punto 5p13.1, en un niño de tres años. La utilización del método clínico unido a técnicas moleculares, como hibridación fluorescente in situ, ha permitido, en la mayoría de los casos, el diagnóstico certero de pacientes y/o familias con trastornos del neurodesarrollo.


The wide range of chromosome aberrations seen in neurodevelopmental disorders may not always be characterized by means of a chromosome analysis. The objective of this study was to determine the genetic etiology of these disorders in patients with congenital neurological conditions and clinical suspicion of a genetic disorder using a clinical and molecular testing algorithm. Among 111 studied children, 71 showed submicroscopic chromosome aberrations associated with microdeletion/microduplication syndromes: DiGeorge (22 cases), Prader-Willi (26 cases), Angelman (2 cases), Williams-Beuren (17 cases), Smith-Magenis (1 case), Miller-Dieker (1 case), and cri du chat syndrome (1 case). Additionally, a de novo trisomy 17p12p11.2 due to an unbalanced insertion into 5p13.1 was identified in a 3-year-old child. In most cases, the use of a clinical method together with molecular techniques, such as fluorescence in situ hybridization, has allowed to make an accurate diagnosis in patients and/or families with neurodevelopmental disorders.


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Transtornos do Neurodesenvolvimento/diagnóstico , Doenças Genéticas Inatas/diagnóstico , Síndrome , Algoritmos , Deficiências do Desenvolvimento , Estudos Retrospectivos , Hibridização in Situ Fluorescente , Procedimentos Clínicos , Transtornos do Neurodesenvolvimento/etiologia , Aconselhamento Genético
19.
J Pediatr ; 218: 22-27.e2, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31926665

RESUMO

OBJECTIVE: To identify factors associated with neurodevelopmental impairment (NDI) in patients with bronchopulmonary dysplasia (BPD). STUDY DESIGN: We identified 151 patients with moderate to severe BPD from 2010 to 2014 with complete Bayley Scales of Infant Development (BSID) scores at 24 months corrected age. We defined NDI as any diagnosis of cerebral palsy or ≥1 BSID composite scores of <80. RESULTS: The mean corrected age at BSID was 23 ± 1 months; 18% had a cognitive score of <80, 37% had a communication score of <80, and 26% had a motor score of <80. Cerebral palsy was diagnosed in 22 patients (15%); 84 (56%) patients did not have NDI. Patients with NDI had lower birth weight, but there was no difference in gestational age at birth, severe intraventricular hemorrhage (IVH), necrotizing enterocolitis, or patent ductus arteriosus ligation compared with patients with no NDI. Ventilator days were greater in patients with NDI than in patients without NDI. More patients with NDI received furosemide and systemic corticosteroids and the hospital length of stay was longer than in patients with no NDI. Logistic regression modeling demonstrated that for every additional 100 g of birth weight the odds of NDI decreased by 35% and for every additional hospital day the odds of NDI increased by 1.3%. CONCLUSIONS: In our cohort of patients with moderate to severe BPD, the majority had no NDI, and low birth weight and length of hospital stay were associated with increased risk of developing NDI. This finding suggests that there are potentially modifiable factors associated with better neurodevelopmental outcomes in patients with BPD that deserve further study.


Assuntos
Displasia Broncopulmonar/complicações , Recém-Nascido Prematuro , Transtornos do Neurodesenvolvimento/etiologia , Medição de Risco/métodos , Pré-Escolar , Feminino , Seguimentos , Idade Gestacional , Humanos , Incidência , Lactente , Masculino , Transtornos do Neurodesenvolvimento/epidemiologia , Ohio/epidemiologia , Estudos Retrospectivos , Fatores de Risco
20.
J Pediatr ; 220: 86-92.e3, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31982088

RESUMO

OBJECTIVE: To develop an accurate understanding of outcomes for necrotizing enterocolitis (NEC) to inform parental counseling, clinical care, and research agendas. STUDY DESIGN: A systematic review of recent (January 2010-January 2018) large cohort studies reporting outcomes of infants who developed NEC. Only studies reporting national, regional, or multicenter outcomes of NEC in high income countries were included. Outcomes assessed were mortality, neurodevelopmental outcome, and intestinal failure. Meta-analyses were used to generate summary statistics for these outcomes. RESULTS: Of 1375 abstracts, 38 articles were included. Overall mortality was 23.5% in all neonates with confirmed NEC (Bell stage 2a+) (95% CI 18.5%-28.8%), 34.5% (30.1%-39.2%) for neonates that underwent surgery for NEC, 40.5% (37.2%-43.8%) for extremely low birthweight infants (<1000 g), and 50.9% (38.1%-63.5%) for extremely low birthweight infants with surgical NEC. Studies examining causes of neonatal mortality showed NEC is responsible for around 1 in 10 of all neonatal deaths. Neurodevelopmental disability was reported in 4 studies at between 24.8% and 61.1% (1209 total NEC cases). Three studies reported intestinal failure with an incidence of 15.2%-35.0% (n = 1370). The main limitation of this review is the lack of an agreed definition for diagnosing NEC and the differences in the way that outcomes are reported. CONCLUSIONS: Mortality following NEC remains high. These contemporary data inform clinical care and justify ongoing research efforts. All infants with NEC should have long-term neurodevelopmental assessment. Data on the long-term risk of intestinal failure are limited. TRIAL REGISTRATION: CRD42018094791.


Assuntos
Enterocolite Necrosante/complicações , Enterocolite Necrosante/mortalidade , Enterocolite Necrosante/cirurgia , Humanos , Lactente , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido de Baixo Peso , Recém-Nascido , Transtornos do Neurodesenvolvimento/etiologia
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