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BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder that causes severe intellectual disability, expressive language deficits, motor impairment, ataxia, sleep problems, epileptic seizures and a happy disposition. People with AS frequently experience gastrointestinal (GI) symptoms. METHOD: This study used data from the Global Angelman Syndrome Registry to explore the relationship between early and current GI symptoms and co-morbidity in children and adolescents with AS (n = 173). Two groups that experienced a high (n = 91) and a low (n = 82) frequency of GI symptoms were examined in relation to feeding and GI history in infancy, sleep and toileting problems, levels of language and communication and challenging behaviours. Predictors of GI symptoms were then investigated using a series of logistic regressions. RESULTS: This analysis found that constipation and gastroesophageal reflux affected 84% and 64%, of the sample, respectively. The high frequency of GI symptoms were significantly associated with: 'refusal to nurse', 'vomiting', 'arching', 'difficulty gaining weight', gastroesophageal reflux, 'solid food transition', frequency of night-time urinary continence and sleep hyperhidrosis during infancy. GI symptoms were not significantly associated with sleep, toileting, language or challenging behaviours. Significant predictors of high frequency GI symptoms were gastroesophageal reflux and sleep hyperhidrosis. CONCLUSIONS: Future research needs to investigate the association between AS and GI co-morbidity in adults with AS.
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Síndrome de Angelman , Refluxo Gastroesofágico , Gastroenteropatias , Hiperidrose , Adolescente , Adulto , Síndrome de Angelman/complicações , Síndrome de Angelman/epidemiologia , Criança , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/epidemiologia , Gastroenteropatias/epidemiologia , Humanos , Hiperidrose/complicações , MorbidadeRESUMO
BACKGROUND: The Compassionate Access Scheme (CAS) being delivered through the Queensland Children's Hospital is designed to allow access to an investigational purified Cannabidiol oral solution to paediatric patients with severe refractory epilepsy. The objectives of this study were to conduct semi-structured interviews to: 1. Understand families' expectations and attitudes about the use of an investigational cannabinoid product for their child's seizures; 2. Understand families' perceptions of Cannabidiol's efficacy for their child's seizures; and other aspects of their child's behaviour, quality of life and/or cognition. METHODS: Children aged 2-18 years had been enrolled in, or were enrolled in a compassionate access scheme for Cannabidiol at the time of the study. Semi-structured interviews (n = 19) with parents or caregivers (n = 23) of children diagnosed with refractory epilepsy were voice-recorded, transcribed and analysed to generate common themes. RESULTS: Key themes emerged relating to seizure activity, family and school engagement, drug safety and legal access, efficacy, clinical support, social acceptance of the medication and program delivery. The use of Cannabidiol was perceived to have benefits in relation to reducing the severity and frequency of seizure activity for almost a third of patients experiencing refractory epilepsy. Participants described other benefits including improved social engagement, wakefulness and a reduction of side effects related to a reduction of conventional medication dosage. CONCLUSION: This study provided unique perspectives of families' experiences managing untreatable epilepsy, their experiences with conventional and experimental pharmacological treatments and health services. Whilst families' perceptions showed the use of Cannabidiol did not provide a therapeutic reduction in the seizure activity for all patients diagnosed with refractory epilepsy, it's use as an additional pharmacological agent was perceived to provide other benefits by some patient families.
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Canabidiol , Epilepsia Resistente a Medicamentos , Adolescente , Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Cuidadores , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Humanos , Pais , Qualidade de VidaRESUMO
BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder affecting between 1 in 15 000 and 1 in 24 000 individuals. The condition results in severe developmental and expressive language delays, motor impairments and a unique behavioural phenotype consisting of excessive laughter, smiling and sociability. While many studies have contributed knowledge about the causes and natural history of the syndrome, large scale longitudinal studies are required to advance research and therapeutics for this rare syndrome. METHOD: This article describes the protocol for the Global Angelman Syndrome Registry, and some initial findings. Due to the rarity of AS and the variability in symptom presentation, the registry team will strive for complete case ascertainment. Parents and caregivers will submit data to the registry via a secure internet connection. The registry consists of 10 modules that cover patient demographics; developmental, diagnostic, medical and surgical history, behaviour and development, epilepsy, medications and interventions and sleep. RESULTS: Since its launch at https://angelmanregistry.info in September 2016, almost 470 individuals with AS have been signed up to the registry worldwide: 59% are from North and South America, 23% are from Europe, 17% are from the Asia Pacific region and 1% are from the Middle East or Africa. The majority of registrants are children, with only 16% aged over 20 years. Most participants indicated a chromosome deletion (76%), with fewer participants indicating a mutation, uniparental disomy or imprinting defect (20%). CONCLUSION: Findings indicate a need to consider recruitment strategies that target caregivers of older children and adults, and parents and caregivers from non-English speaking backgrounds.
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Síndrome de Angelman/diagnóstico , Síndrome de Angelman/terapia , Protocolos Clínicos , Sistema de Registros , Adolescente , Adulto , Síndrome de Angelman/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Internacionalidade , Masculino , Adulto JovemRESUMO
INTRODUCTION: Up to 70% of children with attention-deficit/hyperactivity disorder (ADHD) experience sleep problems. We have demonstrated the efficacy of a brief behavioural intervention for children with ADHD in a large randomised controlled trial (RCT) and now aim to examine whether this intervention is effective in real-life clinical settings when delivered by paediatricians or psychologists. We will also assess the cost-effectiveness of the intervention. METHODS AND ANALYSIS: Children aged 5-12â years with ADHD (n=320) are being recruited for this translational cluster RCT through paediatrician practices in Victoria and Queensland, Australia. Children are eligible if they meet criteria for ADHD, have a moderate/severe sleep problem and meet American Academy of Sleep Medicine criteria for either chronic insomnia disorder or delayed sleep-wake phase disorder; or are experiencing sleep-related anxiety. Clinicians are randomly allocated at the level of the paediatrician to either receive the sleep training or not. The behavioural intervention comprises 2 consultations covering sleep hygiene and standardised behavioural strategies. The primary outcome is change in the proportion of children with moderate/severe sleep problems from moderate/severe to no/mild by parent report at 3â months postintervention. Secondary outcomes include a range of child (eg, sleep severity, ADHD symptoms, quality of life, behaviour, working memory, executive functioning, learning, academic achievement) and primary caregiver (mental health, parenting, work attendance) measures. Analyses will address clustering at the level of the paediatrician using linear mixed effect models adjusting for potential a priori confounding variables. ETHICS AND DISSEMINATION: Ethics approval has been granted. Findings will determine whether the benefits of an efficacy trial can be realised more broadly at the population level and will inform the development of clinical guidelines for managing sleep problems in this population. We will seek to publish in leading international paediatric journals, present at major conferences and through established clinician networks. TRIAL REGISTRATION NUMBER: ISRCTN50834814, Pre-results.
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Terapia Comportamental/métodos , Memória de Curto Prazo/fisiologia , Saúde Mental , Qualidade de Vida , Transtornos do Sono-Vigília/terapia , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Pré-Escolar , Análise por Conglomerados , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Incidência , Masculino , Queensland/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia , Inquéritos e Questionários , Resultado do Tratamento , Vitória/epidemiologiaRESUMO
Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.
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Transtorno do Deficit de Atenção com Hiperatividade/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Adolescente , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estudos de Casos e Controles , Criança , DNA , Feminino , Predisposição Genética para Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Irlanda , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Análise de Sequência de DNA/métodosRESUMO
Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.
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Transtorno do Deficit de Atenção com Hiperatividade/genética , Biologia Computacional/métodos , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Epigenômica , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoAssuntos
Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Transtornos Mentais/genética , Transtornos Mentais/psicologia , Fenótipo , Criança , Avaliação da Deficiência , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/psicologia , Síndrome do Cromossomo X Frágil/terapia , Pesquisa em Genética , Humanos , Deficiência Intelectual/terapia , Transtornos Mentais/terapia , Modelos Psicológicos , Prognóstico , Síndrome de Rett/genética , Síndrome de Rett/psicologia , Síndrome de Rett/terapia , SocializaçãoRESUMO
OBJECTIVE: This study characterises and describes the maturational evolution of the healthy infant sleep electroencephalogram (EEG) longitudinally from 2 weeks to 24 months of age, by means of power spectral analysis. METHODS: A prospective cohort of 34 healthy infants underwent overnight polysomnography (PSG) at 2 weeks, and at 3, 6, 12 and 24 months of age. Sleep epochs were scored as Active Sleep (AS) and Quiet Sleep (QS) at 2 weeks of age and as Rapid Eye Movement (REM) and Non-REM (NREM) stages from 3 months onwards. Representative epochs were used to generate the EEG power spectra, from the central C3 derivation. These were analysed visually and quantitatively in AS/REM and QS/NREM sleep in the following bandwidths: delta (0.5-4 Hz); theta (4-8 Hz); alpha (8-11 Hz); sigma (11-15 Hz) and 0.5-25 Hz. RESULTS: Sleep EEG (central derivation) power spectra changed significantly in the different bandwidths as the infants matured. The emergence of a peak in the sigma bandwidth in NREM N2 sleep corresponded with the development of sleep spindles. Maturational changes were also seen in NREM N3 and in theta and alpha bandwidths in both AS/REM and QS/NREM. CONCLUSIONS: Sleep EEG power spectra characteristics in healthy infants evolve in keeping with maturation and neurodevelopmental milestones. SIGNIFICANCE: This study provides an atlas of healthy infant sleep EEG in the early years of life, providing a basis for association with other neurodevelopmental measures and a normative dataset on which disease may be discriminated.
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Desenvolvimento Infantil/fisiologia , Eletroencefalografia/métodos , Fases do Sono/fisiologia , Pré-Escolar , Estudos de Coortes , Eletroencefalografia/tendências , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Polissonografia/métodos , Polissonografia/tendências , Estudos ProspectivosRESUMO
This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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BACKGROUND: Current genotype-phenotype correlations in Prader-Willi syndrome (PWS) are struggling to give an explanation of the diversity in phenotype and there is a need to move towards a molecular understanding of PWS. A range of functions related to glycoproteins are involved in the pathophysiology of PWS and it may be that abnormal glycosylation is contributing to the biological phenotype. The objective of this study was to investigate the state of N- and O-linked glycosylation in children with Prader-Willi syndrome. METHODS: Twenty-three children with PWS and 20 non-PWS controls were included in the study. Protein N-linked glycosylation was assessed by analysing serum transferrin through mass spectrometry and protein O-linked through isoelectric focusing (IEF) of serum apolipoprotein C-III (apoC-III), confirmed by mass spectrometry. RESULTS: The results of this analysis indicated that the N-linked glycosylation pathway in PWS is normal. A subgroup of PWS individuals was found to have a hyposialylated pattern of apoC-III isoforms. This was independent of the underlying genetic mechanism and is the first report of an apoC-III IEF abnormality in PWS. CONCLUSIONS: This is the first report of apoC-III hyposialylation in PWS. As this field is in its infancy, additional study is required before these findings may be used in clinical settings.
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Glicoproteínas/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/metabolismo , Adolescente , Apolipoproteína C-III/metabolismo , Criança , Pré-Escolar , Genótipo , Glicosilação , Humanos , Lactente , Recém-Nascido , Focalização Isoelétrica , Fenótipo , Síndrome de Prader-Willi/fisiopatologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Transferrina/metabolismo , Adulto JovemRESUMO
Abstract Attention deficit/hyperactivity disorder (ADHD) has long been described in children who demonstrate developmentally inappropriate symptoms of inattention, impulsivity and motor restlessness. In adults, symptoms are known to persist and the validity of adult ADHD as an entity is now recognized. There is an associated high proportion of other serious psychiatric comorbidities, especially substance abuse, mood and anxiety disorders. Advances have been made into the aetiology and management of ADHD. Many of these focus on the dopamine and noradrenaline pathways.
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Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central/uso terapêutico , Terapia Cognitivo-Comportamental , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Criança , Comorbidade , Feminino , Humanos , Deficiências da Aprendizagem , Masculino , Transtornos Mentais , Testes NeuropsicológicosRESUMO
BACKGROUND: Children with chronic illness have increased rates of mental health problems and psychological difficulties often present as physical conditions. This prevalence survey aims to determine whether children attending general paediatric out-patient clinics are at increased risk of suffering from emotional and behavioural disturbance and whether there is an unmet need for psychiatric liaison to paediatric clinics. METHODS: Participants were 307 children aged 5-15 years attending a representative sample of paediatric out-patient clinics in one UK hospital. A national community sample of 10,438 children aged 5-15 years was used as a comparison group. Parental ratings of child behaviour were obtained using the Strengths and Difficulties Questionnaire (SDQ). Doctors rated the extent of any emotional difficulties using a modification of the SDQ 'impact supplement'. RESULTS: Children attending paediatric out-patient clinics were more than twice as likely (OR = 2.3, 95% CI 1.7-3.1) to score in the abnormal range of the SDQ. Of the 60 (20%) children with a probable psychiatric disorder only 15 had received specialist help from Child Mental Health Services. There were no gender differences in the profile of difficulties with emotional symptoms being particularly evident in both boys (OR = 2.85, 95% CI 1.97-4.11) and girls (OR = 3.04, 95% CI 1.92-4.70). The risk of psychiatric disorder was highest among those children with brain disorders attending neurological clinics (OR = 5.8, 95% CI 2.5-11.3). Clinicians only identified emotional or behaviour problems in a quarter of those children with parent-rated disorder. CONCLUSION: There is an increased prevalence of emotional and behavioural disturbance in children attending paediatric out-patient clinics. The SDQ could be added to routine paediatric assessments to aid appropriate referral of children with a possible psychiatric disorder to child mental health services.
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Doença Crônica/psicologia , Transtornos Mentais/epidemiologia , Ambulatório Hospitalar , Adolescente , Sintomas Afetivos/diagnóstico , Sintomas Afetivos/epidemiologia , Criança , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/epidemiologia , Pré-Escolar , Estudos Transversais , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Transtornos Mentais/diagnóstico , Pais , Prevalência , Psicometria , Fatores de Risco , Distribuição por Sexo , Inquéritos e QuestionáriosRESUMO
We isolated 55 coagulase-negative staphylococci (CoNS) over two separate 12-month periods (26 in 1993 and 29 in 1996) from the blood of neonates in a neonatal intensive case unit (NICU) in Melbourne, Australia and compared them by pulse-field gel electrophoresis profile (PFGE), random amplification of polymorphic DNA (RAPD) and antibiogram. The most common species were Staphylococcus epidermidis, S. haemolyticus and S. warneri. The majority of such isolates were resistant to penicillin and to either or both of methicillin and gentamicin. During 1993, there was an increase in the number of CoNS bloodstream infections compared with previous years. S. epidermidis was the most common isolate, with 88% assessed as clinically relevant. Using the three typing systems, we identified one likely epidemic clone of S. epidermidis, the isolates of which were resistant to penicillin, gentamicin and erythromycin and possessed the mecA gene. There was complete correlation between the detection of mecA and the phenotypic expression of resistance when zone diameters in the disc diffusion assay were interpreted according to the latest NCCLS guidelines (1999). Profiles of the remaining 1993 isolates were generally heterogeneous, suggesting independent acquisition with some evidence of cross-infection. The predominant bloodstream isolates in 1996 were heterogeneous multi-resistant strains of S. epidermidis, S. haemolyticus and S. warneri, about half of which were assessed as clinically relevant. These data support the view that CoNS are significant nosocomial pathogens in NICU and that resistant clones may be transmitted between babies. Molecular epidemiological tools are helpful for understanding transmission patterns and sources of infection, and are useful for measuring outcomes of intervention strategies implemented to reduce nosocomial CoNS sepsis. PFGE was found to be more discriminatory than RAPD, but the latter provides results in a more timely manner.
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Bacteriemia/epidemiologia , Proteínas de Bactérias , Coagulase/sangue , Hexosiltransferases , Unidades de Terapia Intensiva Neonatal , Epidemiologia Molecular , Peptidil Transferases , Infecções Estafilocócicas/epidemiologia , Staphylococcus/efeitos dos fármacos , Austrália/epidemiologia , Proteínas de Transporte/genética , Coagulase/genética , Eletroforese em Gel de Campo Pulsado , Humanos , Recém-Nascido , Testes de Sensibilidade Microbiana , Muramilpentapeptídeo Carboxipeptidase/genética , Proteínas de Ligação às Penicilinas , Técnica de Amplificação ao Acaso de DNA Polimórfico , Staphylococcus/genéticaRESUMO
Holoprosencephaly (HPE) is a clinically variable and genetically heterogeneous central nervous system (CNS) malformation. Alobar HPE, which is its most severe form, is associated with a poor prognosis. At the milder end of the HPE spectrum microcephaly, hypotelorism, and single central maxillary incisor may be recognised. Currently, four genes have been identified for this condition. These include Sonic Hedgehog (SHH) on chromosome 7q36, which is thought to be responsible for a significant proportion of autosomal dominant HPE. We report an index case with alobar holoprosencephaly caused by an SHH mutation and six members of his family over two generations with this mutation, with a broad range of clinical presentation, including attention deficit hyperactivity disorder (ADHD). The combination of microcephaly, hypotelorism, subtle midline facial anomalies, and ADHD within a sibship should alert the physician to the possible diagnosis of HPE.
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Transtorno do Deficit de Atenção com Hiperatividade/genética , Holoprosencefalia/genética , Mutação/genética , Transativadores/genética , Adulto , Feminino , Proteínas Hedgehog , Humanos , Lactente , Masculino , LinhagemRESUMO
We describe four children with dysmorphic syndrome with severe learning disability (SLD). Their chromosomes had been normal on conventional cytogenetic examination. However, screening using a multiprobe fluorescence in situ hybridisation (FISH) technique for subtelomeric abnormalities revealed a deletion of the p arm of chromosome 1. The physical features include body asymmetry, microcephaly, distinctive facies with deep-set eyes, sharply defined eye sockets, and mid-face hypoplasia; the neurodevelopmental profile was characterised by SLD, motor delay with hypotonia, markedly delayed visual maturation, and postural asymmetry together with epilepsy. This phenotype is consistent with that described for partial monosomy for 1p36.3.