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AIM: Children born extremely preterm frequently have developmental coordination disorder (DCD). We aimed to evaluate perinatal risk factors for DCD. METHODS: Swedish national cohort study including 226 children born before 27 gestational weeks without major neurodevelopmental disabilities at 6.5 years. Outcome was DCD, defined as ≤5th percentile on the Movement Assessment Battery for Children-Second Edition. Perinatal risk factors were evaluated using multivariable logistic regression. RESULTS: DCD was present in 84/226 (37.2%) children. Of the risk factors known at 40 weeks gestation, independent and significant risk factors for DCD were: mother's age at delivery (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.07-2.80); pre-eclampsia (2.79, 1.14-6.80); mother born in a non-Nordic country (2.23, 1.00-4.99); gestational age per week increase (0.70, 0.50-0.99) and retinopathy of prematurity (2.48, 1.26-4.87). Of factors known at discharge, postnatal steroids exposure (2.24, 1.13-4.46) and mechanical ventilation (1.76, 1.06-2.09) were independent risk factors when added to the model in separate analyses. CONCLUSION: The risk of DCD in children born extremely preterm was multifactorial and associated with gestational age largely mediated by ROP, maternal factors, pre-eclampsia, administration of postnatal steroids and mechanical ventilation. These risk factors are common among children born extremely preterm, contributing to their high risk of DCD.
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Transtornos das Habilidades Motoras , Pré-Eclâmpsia , Recém-Nascido , Gravidez , Feminino , Humanos , Criança , Estudos de Coortes , Lactente Extremamente Prematuro , Idade Gestacional , Fatores de Risco , MãesRESUMO
AIM: To determine the prevalence of neurobehavioral symptoms at 6.5 years in children born extremely preterm (EPT, <27 weeks' gestation). METHODS: Population-based cohort study of infants born EPT in Sweden from 2004 to 2007. Of 486 survivors 375 were assessed and compared with 369 matched term-born controls. EPT children free from neurosensory and intellectual disabilities (neurodevelopmental disabilities [NDD]-free, n = 236) were compared separately. Standardised questionnaires were used to assess parental ratings of hyperactivity and attention, emotional, peer-relation, conduct and social problems; and deficits in perception, language and memory. RESULTS: EPT children had more reported problems in all assessed neurobehavioral domains than controls, with more than three times greater odds for most outcomes. Except for conduct problems, increased problems were identified also in NDD-free children. The odds of having neurobehavioral problems in ≥3 co-occurring domains were five (whole EPT group) and three (NDD-free group) times higher than in controls. CONCLUSION: EPT children with or without NDD have more neurobehavioral problems in multiple domains than term peers. Ongoing assessments of behaviour until school age or beyond should recognise early symptoms of attention, everyday social problems, perceptual, emotional or language difficulties.
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Lactente Extremamente Prematuro , Parto , Recém-Nascido , Lactente , Gravidez , Feminino , Criança , Humanos , Suécia/epidemiologia , Estudos de Coortes , Idade GestacionalRESUMO
We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.
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Actinas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Dendritos/patologia , Epilepsia/etiologia , Células-Tronco Pluripotentes Induzidas/patologia , Mutação , Transtornos do Neurodesenvolvimento/etiologia , Neurônios/patologia , Adulto , Criança , Pré-Escolar , Cromatina/genética , Cromatina/metabolismo , Dendritos/metabolismo , Epilepsia/patologia , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lactente , Masculino , Transtornos do Neurodesenvolvimento/patologia , Neurônios/metabolismo , Adulto JovemRESUMO
AIM: To identify the aetiology and outcome of seizure-like events leading to hospital referrals in infants and to identify early predictors of epilepsy and delayed neurodevelopment. METHODS: This Norwegian population-based study focused on all children born in Sør-Trøndelag county, who were up to one year of age in 2014-2015. They were identified by diagnostic codes for seizure-like events and electroencephalography (EEG) examinations. Hospital records were examined up to 1.5 years of age. RESULTS: The one-year prevalence of seizure-like events was 1.5% (114/7430). Epilepsy was diagnosed in 17%, 57% had non-epileptic paroxysmal events (NEPE), 16% had febrile seizures, and 10% had other acute symptomatic epileptic seizures. Neurodevelopmental delay occurred in 21%. The cumulative incidence was 0.22% for epilepsy and 0.79% for NEPE. Abnormal brain magnetic resonance imaging, abnormal first EEGs and neonatal care increased the likelihood of epilepsy and delayed development. Identifying situation-related factors decreased the epilepsy risk. Occurrence at a younger age increased the risk of delayed development. Absence of unambiguous motor symptoms was less common in epilepsy than in NEPE. CONCLUSION: Seizure-like events were common in infants and most were not caused by epilepsy. Specific anamnestic clues, and detailed descriptions of the entire event, helped to predict adverse outcomes.
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Epilepsia , Convulsões , Criança , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Humanos , Lactente , Recém-Nascido , Encaminhamento e Consulta , Estudos Retrospectivos , Convulsões/epidemiologia , Convulsões/etiologiaRESUMO
AIM: To evaluate sex differences in infants born at term with metabolic acidosis with regard to perinatal health and symptomatology, and developmental outcome. METHODS: From a population-based cohort of infants born at term (n = 14 687), 78 were prospectively identified as having metabolic acidosis at birth. Two matched controls per case were selected. Sex differences in perinatal characteristics and in neurodevelopmental outcome at 6.5 years of age were analysed. Subgroup analysis was made based on need of neonatal care and planned follow-up. RESULTS: Acidotic boys who appeared healthy, that is with no need of specialised neonatal care respectively only followed at ordinary health care service, have worse perinatal symptoms and less favourable neurodevelopmental outcome compared to girls. The male disadvantage concerning neurodevelopmental outcome was also indicated in children without acidosis. Outcome at 6.5 years was associated with Apgar at 10 minutes (p = 0.03), need of neonatal care (p = 0.04) and sex (p = 0.02) but not acidosis per se (p = 0.54). CONCLUSION: Sex affected immediate symptomatology in term acidotic infants and neurodevelopmental outcome at the age of 6.5 years. The findings were seen in those who appeared healthy in the neonatal period. The results suggest that sex should be considered in assessment of acidotic children.
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Acidose/complicações , Transtornos do Neurodesenvolvimento/etiologia , Acidose/epidemiologia , Criança , Feminino , Seguimentos , Humanos , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/epidemiologia , Caracteres Sexuais , Suécia/epidemiologiaRESUMO
De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.
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Subunidades beta da Proteína de Ligação ao GTP/genética , Estudos de Associação Genética , Mutação/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/genética , Feminino , Subunidades beta da Proteína de Ligação ao GTP/química , Humanos , Masculino , Sistema Nervoso/crescimento & desenvolvimento , Fenótipo , Gravidez , Estrutura Terciária de ProteínaRESUMO
INTRODUCTION: Preconditions for good pain treatment in children include education and guidelines. This study investigated whether the guidelines on acute pain treatment of children in Danish emergency departments reflected the national guideline, examined the knowledge and use of guidelines, and explored the approach adopted to treating pain in children. METHODS: This cross-sectional study consisted of two parts. Part I compared the guidelines in each emergency department with a national guideline; Part II was a structured interview with the emergency department doctors regarding their approach to treating pain in children. RESULTS: Several guidelines did not include pain assessment, dose schedules and non-pharmacological methods as recommended in the national guideline. The doctors knew where to find the guidelines, but a considerable share of them did not use the guidelines. Most doctors felt competent in treating children, but reported a reluctance to using opioids and reported using pain assessment irregularly. CONCLUSION: The Danish guidelines on acute pain treatment of children in many emergency departments vary compared with the national guideline. We found that several doctors do not use the guidelines, are reluctant to use opioids and do not use pain assessment. We suggest a thorough implementation of a national guideline in emergency departments to standardise pain treatment. FUNDING: none. TRIAL REGISTRATION: not relevant.
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Dor Aguda , Criança , Humanos , Dor Aguda/tratamento farmacológico , Estudos Transversais , Manejo da Dor , Serviço Hospitalar de Emergência , Analgésicos Opioides , DinamarcaRESUMO
Importance: There are concerns that apparently healthy extremely preterm children face a risk of developing motor impairments, such as developmental coordination disorder. Objective: To evaluate the prevalence of developmental coordination disorder and associated comorbidities in a national cohort of apparently healthy children born at 22 to 26 gestational weeks, compared alongside term-born peers. Design, Setting, and Participants: This prospective, population-based cohort study included all children who were consecutively born at 22 to 26 gestational weeks in Sweden from April 1, 2004, through March 31, 2007. At 6.5 years, 441 preterm children were evaluated alongside 371 controls. A total of 275 preterm children (62.4%) and 359 term-born children (96.8%) did not have neurodevelopmental disabilities. Motor assessments were completed for 229 of 275 preterm children (83.3%) and 344 of 359 (95.8%) term-born children, who composed the final study sample. Main Outcomes and Measures: Developmental coordination disorder was defined as a score of the fifth percentile or lower on the Movement Assessment Battery for Children-Second Edition scale, using control group scores. Assessment tools included the Wechsler Intelligence Scale for Children-Fourth Edition, the Brown Attention-Deficit Disorder Scales, the Five to Fifteen questionnaire, and the Strengths and Difficulties questionnaire. Results: Of the 229 extremely preterm children and 344 term-born controls who underwent motor assessments, 115 (50.2%) and 194 (56.4%) were boys, respectively. Developmental coordination disorder was present in 85 of 229 (37.1%) preterm children and in 19 of 344 controls (5.5%) (adjusted odds ratio [OR], 7.92; 99% CI, 3.69-17.20). When preterm children with developmental coordination disorder were compared with term-born peers, the risk was increased for total behavioral problems, internalizing, externalizing, attentional problems, hyperactivity, perceptual problems, executive dysfunction, and poor social skills, with adjusted ORs varying from 2.66 (99% CI, 1.09-6.48) for time concepts to 9.06 (99% CI, 3.60-22.8) for attentional problems (all P < .01). When preterm children with and without developmental coordination disorder were compared, preterm children with developmental coordination disorder had more behavioral problems; the adjusted OR for total behavioral problems was 2.71 (99% CI, 1.15-6.37); for externalizing problems, 2.80 (99% CI, 1.10-7.12); for inattention, 3.38 (99% CI, 1.39-8.18); and for combined attention/hyperactivity problems, 3.68 (99% CI, 1.47-9.16) (all P < .01). Parents underestimated the children's motor problems and only a few of the children had received psychological care or physiotherapy. Conclusions and Relevance: Children who were born extremely preterm faced a high risk for developmental coordination disorder with associated comorbidities. Our findings support the importance of a structured follow-up of motor function, behavior, and cognition.
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Deficiências do Desenvolvimento/complicações , Transtornos das Habilidades Motoras/complicações , Transtornos das Habilidades Motoras/epidemiologia , Criança , Estudos de Coortes , Humanos , Lactente Extremamente Prematuro , PrevalênciaRESUMO
BACKGROUND AND OBJECTIVES: The risk of cerebral palsy (CP) is high in preterm infants and is often accompanied by additional neurodevelopmental comorbidities. The present study describes lifetime prevalence of CP in a population-based prospective cohort of children born extremely preterm, including the type and severity of CP and other comorbidities (ie, developmental delay and/or cognitive impairment, neurobehavioral morbidity, epilepsy, vision and hearing impairments), and overall severity of disability. In this study, we also evaluate whether age at assessment, overall severity of disability, and available sources of information influence outcome results. METHODS: All Swedish children born before 27 weeks' gestation from 2004 to 2007 were included (the Extremely Preterm Infants in Sweden Study). The combination of neonatal information, information from clinical examinations and neuropsychological assessments at 2.5 and 6.5 years of age, original medical chart reviews, and extended chart reviews was used. RESULTS: The outcome was identified in 467 (94.5%) of eligible children alive at 1 year of age. Forty-nine (10.5%) children had a lifetime diagnosis of CP, and 37 (76%) were ambulatory. Fourteen (29%) had CP diagnosed after 2.5 years of age, 37 (76%) had at least 1 additional comorbidity, and 27 (55%) had severe disability. The probability for an incomplete evaluation was higher in children with CP compared with children without CP. CONCLUSIONS: Children born extremely preterm with CP have various comorbidities and often overall severe disability. The importance of long-term follow-up and of obtaining comprehensive outcome information from several sources in children with disabilities is shown.
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Paralisia Cerebral/epidemiologia , Deficiências do Desenvolvimento/epidemiologia , Avaliação da Deficiência , Lactente Extremamente Prematuro , Doenças do Prematuro/epidemiologia , Sistema de Registros , Paralisia Cerebral/diagnóstico , Pré-Escolar , Comorbidade , Deficiências do Desenvolvimento/diagnóstico , Feminino , Seguimentos , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Doenças do Prematuro/diagnóstico , Masculino , Gravidez , Prevalência , Estudos Retrospectivos , Medição de Risco , Suécia/epidemiologia , Fatores de TempoRESUMO
IMPORTANCE: Active perinatal care increases the rate of survival of extremely preterm infants, but there are concerns that improved survival might increase the rate of disabled survivors. OBJECTIVE: To determine the neurodevelopmental outcomes of a national cohort of children 6.5 years of age who had been born extremely preterm (<27 weeks' gestational age) in Sweden. DESIGN, SETTING, AND PARTICIPANTS: Population-based prospective cohort study of consecutively born extremely preterm infants. All of these infants were born in Sweden during the period from April 1, 2004, to March 31, 2007. Of 707 live-born extremely preterm infants, 486 (68.7%) survived to 6.5 years of age. These children were assessed and compared with matched controls who had been born at term. Comparison estimates were adjusted for demographic differences. Assessments ended in February 2014, and analysis started thereafter. MAIN OUTCOMES AND MEASURES: Cognitive ability was measured with the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV), and the mean (SD) scores of the children who had been born extremely preterm were compared with those of the controls. Clinical examinations and parental questionnaires were used for diagnosis of cerebral palsy, hearing and vision impairments, and cognition for the children who were not assessed with the WISC-IV. RESULTS: Of 486 eligible infants who were born extremely preterm, 441 (90.7%) were assessed at 6.5 years of age (59 by medical record review only) alongside 371 controls. The adjusted mean (SD) full-scale WISC-IV score was 14.2 (95% CI, 12.1-16.3) points lower for children who had been born extremely preterm than for controls. Cognitive disability was moderate for 18.8% of extremely preterm children and 2.2% of controls (P < .001), and it was severe for 11.1% of extremely preterm children and 0.3% of controls (P < .001). Cerebral palsy was observed in 9.5% of extremely preterm children and 0.0% of controls (P < .001), blindness was observed in 2.0% of extremely preterm children and 0.0% of controls (P < .001), and hearing impairment was observed in 2.1% of extremely preterm children and 0.5% of controls (P = .07). Overall, 36.1% (95% CI, 31.7%-40.6%) of extremely preterm children had no disability, 30.4% (95% CI 26.3%-34.8%) had mild disability, 20.2% (95% CI, 16.6%-24.2%) had moderate disability, and 13.4% (95% CI, 10.5%-16.9%) had severe disability. For extremely preterm children, moderate or severe overall disability decreased with gestational age at birth (adjusted odds ratio per week, 0.65 [95% CI, 0.54-0.79]; P < .001) and increased from 26.6% to 33.5% (P = .01) for children assessed both at 2.5 and 6.5 years. CONCLUSIONS AND RELEVANCE: Of the 441 extremely preterm infants who had received active perinatal care, 293 (66.4%) had no or mild disability at 6.5 years; of the 371 controls, 11 (3.0%) had moderate or severe disability. Disability rates at 6.5 years increased relative to the rates at 2.5 years. Results are relevant for health care professionals and planners, and for clinicians counseling families facing extremely preterm births.
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Desenvolvimento Infantil/fisiologia , Deficiências do Desenvolvimento/diagnóstico , Crianças com Deficiência/estatística & dados numéricos , Lactente Extremamente Prematuro/fisiologia , Recém-Nascido Prematuro/crescimento & desenvolvimento , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Índice de Gravidade de Doença , SuéciaRESUMO
BACKGROUND: Deletions including chromosome 15q24 have been delineated in recent years as a separate syndrome with phenotypic variability. Here we report a familial 15q24 deletion and further contribute to the phenotypic description of this syndrome. METHODS: Molecular karyotyping and description of the phenotype of three patients in the same family with a 15q24 deletion. RESULTS: Parental transmission of the 15q24 deletion syndrome is described in the same family. The affected, the father and his twin offspring, all exhibit the typical facial features, signs and symptoms consistent with the syndromic phenotype. A distinct phenotypic variability is nevertheless noted although they all share the same deletion. CONCLUSIONS: These three patients are to our knowledge the first described cases of 15q24 syndrome in the same family. Urogenital malformations have previously been described as a part of this syndrome. Our adult male patient exhibits no such malformations but has a documented reduced fertility. This fact points to other factors such as haploinsufficiency of one and/or further genes on 15q24 as being responsible for the infertility. Array analysis could be considered as a first hand analysis in the investigation of cases of infertility and intellectual deficiency in adults in analogy to the existing consensus regarding cases of intellectual deficiency in children.
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Deleção Cromossômica , Transtornos Cromossômicos , Deficiência Intelectual , Gêmeos/genética , Adulto , Cromossomos Humanos Par 15 , Pai , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , SíndromeRESUMO
OBJECTIVES: Infants who develop encephalopathy after perinatal asphyxia have an increased risk of death and adverse neurologic outcome. Conflicting results exist concerning outcome in healthy infants with metabolic acidosis at birth. The aim of the current study was to evaluate whether metabolic acidosis at birth in term infants who appear healthy is associated with long-term developmental abnormalities. METHODS: From a population-based cohort (14,687 deliveries), 78 infants were prospectively identified as having metabolic acidosis (umbilical artery pH < 7.05 and base deficit in the extracellular fluid >12.0 mmol/L). Two matched controls per case were selected. The child health and school health care records were scrutinized for developmental abnormalities. RESULTS: Outcome measures at 6.5 years of age for 227 of 234 children (97%) were obtained. No differences were found concerning neurologic or behavioral problems in need of referral action or neurodevelopmental diagnosis in comparison of control children with acidotic children who had appeared healthy at birth, ie, had not required special neonatal care or had no signs of encephalopathy. CONCLUSIONS: Infants born with cord metabolic acidosis and who appear well do not have an increased risk for neurologic or behavioral problems in need of referral actions or special teaching approaches at the age of 6.5 years.