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1.
Medicina (B Aires) ; 79 Suppl 3: 33-36, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31603841

RESUMO

The development and establishment of the normal sleep patterns are very important processes in the final anatomical and physiological architecture of the central nervous system. The relationship between sleep disturbances during childhood with neurodevelopmental disorders is complex and potentially synergistic. Sleep patterns are present since the fetal period but their structure and physiology is modified according with the maturation of the central nervous system. Sleep disorders and their relationship with attention deficit hyperactivity disorders(ADHD), autism spectrum disorders(ASD) and other neurodevelopmental disorders (TDN) are not well understood yet, but significant progresses have been made in understanding associations and potential etiological correlations. We reviewed sleep disturbances in NDT, in ADHD and in ASD. A greater understanding of the pleiotropic functions of the genes involved in sleepwake cycle disorders and deviations from neurological developme nt could lead to new diagnostic and therapeut ic strategies in an early stage in order to improve the quality of life of the patient, relatives and caregivers.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Espectro Autista/complicações , Transtornos do Sono-Vigília/complicações , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Pré-Escolar , Ritmo Circadiano , Humanos , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/genética
2.
Nat Neurosci ; 22(7): 1066-1074, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209380

RESUMO

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.


Assuntos
Abuso de Maconha/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Nicotínicos/fisiologia , Idade de Início , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Cognição/fisiologia , Estudos de Coortes , Fatores de Confusão (Epidemiologia) , Dinamarca , Escolaridade , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Transcriptoma
3.
Lancet Psychiatry ; 6(6): 493-505, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31056457

RESUMO

BACKGROUND: Several copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders (referred to as ND-CNVs). We aimed to characterise the effect of ND-CNVs on childhood development and investigate whether different ND-CNVs lead to distinct and specific patterns of cognitive and behavioural outcomes. METHODS: In this case-control study, we used data from the Intellectual Disability and Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study. Children aged 4 years and older with pathogenic CNV or single nucleotide variants were recruited via the UK National Health Service (NHS) medical genetic clinic network and via patient support groups to complete broad online phenotyping, from whom children aged 6-19 years with at least one of a specific group of ND-CNVs (1q21.1 [proximal duplication, and distal deletion and duplication], 2p16.3 deletion, 9q34.3 deletion, 15q11.2 deletion, 15q13.3 deletion and duplication, 16p11.2 [proximal deletion and duplication, and distal deletion], and 22q11.2 deletion and duplication) and their families were approached for a deep phenotyping, home-based assessment, and we report on this sample here. We invited siblings of index children to participate as controls, for whom the presence of ND-CNVs was excluded by use of microarray results and also medical records where possible. We systematically assessed the children for psychiatric disorders and broader traits of neurodevelopmental, cognitive, and psychopathological origin and compared results of ND-CNV carriers with control siblings to test the hypothesis that phenotypes would differ by genotype, both quantitatively in terms of severity and qualitatively in the pattern of associated impairments. FINDINGS: Between Oct 1, 2014, and Dec 31, 2018, of 2819 children recruited, 258 (9%) had one ND-CNV of interest, with 13 CNVs across nine loci, and underwent a home-based assessment. 106 control siblings were enrolled. 186 (80%) of ND-CNV carriers met criteria for one or more psychiatric disorder (odds ratio [OR] 13·8, 95% CI 7·2-26·3, compared with controls). The risk of attention-deficit hyperactivity disorder (OR 6·9, 3·2-15·1), oppositional defiant disorder (OR 3·6, 1·4-9·4), any anxiety disorder (OR 2·9, 1·2-6·7), and autism spectrum disorder traits (OR 44·1, 15·3-127·5) was particularly high compared with controls. ND-CNV carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits compared with controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. Overall, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, with rank-based analyses showing moderate qualitative and quantitative profile differences between ND-CNVs; however, the specific genotype accounted for a low proportion of variance in cognitive and behavioural outcomes (approximately 5-20% depending on the trait). INTERPRETATION: The 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits and indicates that future research should avoid being narrowly focused on single phenotypes. FUNDING: UK Medical Research Council and Medical Research Foundation.


Assuntos
Transtornos de Ansiedade/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/genética , Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Irmãos , Reino Unido
4.
Atten Defic Hyperact Disord ; 11(1): 91-105, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30927234

RESUMO

Na+/H+ Exchanger 9 (NHE9) is an endosomal membrane protein encoded by the Solute Carrier 9A, member 9 gene (SLC9A9). SLC9A9 has been implicated in attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), epilepsy, multiple sclerosis and cancers. To better understand the function of NHE9 and the effects of disease-associated variants on protein-protein interactions, we conducted a quantitative analysis of the NHE9 interactome using co-immunoprecipitation and isobaric labeling-based quantitative mass spectrometry. We identified 100 proteins that interact with NHE9. These proteins were enriched in known functional pathways for NHE9: the endocytosis, protein ubiquitination and phagosome pathways, as well as some novel pathways including oxidative stress, mitochondrial dysfunction, mTOR signaling, cell death and RNA processing pathways. An ADHD-associated mutation (A409P) significantly altered NHE9's interactions with a subset of proteins involved in caveolae-mediated endocytosis and MAP2K2-mediated downstream signaling. An ASD nonsense mutation in SLC9A9, R423X, produced no-detectable amount of NHE9, suggesting the overall loss of NHE9 functional networks. In addition, seven of the NHE9 interactors are products of known autism candidate genes (Simons Foundation Autism Research Initiative, SFARI Gene) and 90% of the NHE9 interactome overlap with SFARI protein interaction network PIN (p < 0.0001), supporting the role of NHE9 interactome in ASDs molecular mechanisms. Our results provide a detailed understanding of the functions of protein NHE9 and its disrupted interactions, possibly underlying ADHD and ASDs. Furthermore, our methodological framework proved useful for functional characterization of disease-associated genetic variants and suggestion of druggable targets.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Mutação , Mapas de Interação de Proteínas/genética , Trocadores de Sódio-Hidrogênio/genética , Humanos
5.
Atten Defic Hyperact Disord ; 11(1): 107-111, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30927235

RESUMO

Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for α-synuclein (SNCA). α-Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the α-synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, pnom = 1 padj = 1) and rs356219 (OR 1.28; pnom = 0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, pnom = 0.020), which survived Bonferroni correction (padj = 0.039); again, no association for NACP-Rep1 (OR 0.8, p = 0.317, padj = 0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect α-synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Predisposição Genética para Doença/genética , alfa-Sinucleína/genética , Alelos , Criança , Repetições de Dinucleotídeos/genética , Feminino , Genótipo , Humanos , Masculino , Projetos Piloto , Polimorfismo de Nucleotídeo Único/genética
6.
Behav Brain Res ; 363: 126-134, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30707907

RESUMO

To explore the associations between stress response genes and attention deficit hyperactivity disorder (ADHD) in children, we conducted a case-control study consisting of 406 newly diagnosed ADHD cases and 432 controls in Wuhan, China. We genotyped the candidate genes, nuclear receptor subfamily 3 group C member 1(NR3C1) and solute carrier family 6 member 4(SLC6A4), using the Sequenom MassARRAY technology. After correction by Bonferroni (α' = 0.05/6 = 0.008), the rs6191 SNP was found to be associated with a reduced risk of ADHD in the dominant model (OR = 0.564, 95% CI = 0.389-0.819, P = 0.003) while the rs25531 SNP was associated with an increased risk of ADHD in the multiplicative model (OR = 1.380, 95% CI = 1.111-1.714, P = 0.004). Additionally, both the rs6191 and rs25531 SNPs were significantly associated with the attention deficit factor (P = 0.006, P = 0.003, respectively) but not with the hyperactivity/impulsivity factor in the Swanson, Nolan and Pelham-IV Questionnaire (SNAP-IV) scale. Furthermore, we found that these two SNPs were significantly associated with pure ADHD, and not affected by the comorbidities (P = 0.001, P = 0.007, respectively). Besides, there was an interaction between these two SNPs. This study demonstrated the role of NR3C1 and SLC6A4 polymorphisms in ADHD, yet independent replication of the findings of this study in multi-center and multi-stage studies with large samples is warranted in the future.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Receptores de Glucocorticoides/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Estudos de Casos e Controles , Criança , China , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptores de Glucocorticoides/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estresse Fisiológico/genética
7.
Psychiatr Genet ; 29(3): 63-78, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30741787

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder. In recent years, genetic studies have revealed several risk gene variants associated with ADHD; however, these variants could only be partly replicated and are responsible for only a fraction of the whole heritability of ADHD estimated from family and twin studies. One factor that could potentially explain the 'missing heritability' of ADHD is that childhood and adult or persistent ADHD could be genetically distinct subtypes, which therefore need to be analyzed separately. Another approach to identify this missing heritability could be combining the investigation of both common and rare gene risk variants as well as polygenic risk scores. Finally, environmental factors are also thought to play an important role in the etiology of ADHD, acting either independently of the genetic background or more likely in gene-environment interactions. Environmental factors might additionally convey their influence by epigenetic mechanisms, which are relatively underexplored in ADHD. The aforementioned mechanisms might also influence the response of patients with ADHD to stimulant and other ADHD medication. We conducted a selective review with a focus on risk genes of childhood and adult ADHD, gene-environment interactions, and pharmacogenetics studies on medication response in childhood and adult ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Interação Gene-Ambiente , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
8.
Neurosci Biobehav Rev ; 100: 9-18, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30779935

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a common, debilitating neurodevelopmental disorder associated with inattentiveness, pathological hyperactivity and impulsivity. Despite the mounting human and animal evidence, the neurological pathways underlying ADHD remain poorly understood. Novel translational model organisms, such as the zebrafish (Danio rerio), are becoming important tools to investigate genetic and pathophysiological mechanisms of various neuropsychiatric disorders. Here, we discuss ADHD etiology, existing animal models and their limitations, and emphasize the advantages of using zebrafish to model ADHD. Overall, the growing utility of zebrafish models may improve our understanding of ADHD and facilitate drug discovery to prevent or treat this disorder.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Pesquisa Médica Translacional , Animais , Comportamento Animal , Peixe-Zebra/genética
9.
J Affect Disord ; 246: 633-639, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611060

RESUMO

BACKGROUND: Studying the phenotypic manifestations of increased genetic liability for Bipolar Disorder (BD) can increase understanding of this disorder. AIMS: We assessed whether genetic risk for BD was associated with childhood psychopathology and features of hypomania in young adulthood within a large population-based birth cohort. METHODS: We used data from the second Psychiatric Genetics Consortium Genome Wide Association Study (GWAS) for Bipolar Disorder to construct a polygenic risk score (PRS) for each individual in the Avon Longitudinal Study of Parents and Children (ALSPAC). Linear and logistic regression models were used to assess associations between the BD-PRS and emotional/behavioural difficulties, attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) traits in childhood, as well as hypomania in early adulthood (sample sizes from 2654 to 6111). RESULTS: The BD-PRS was not associated with total hypomania score, but was weakly associated with a binary measure of hypomania (OR = 1.13, 95%CI 0.98,1.32; p = 0.097), and particularly at higher hypomania symptom thresholds (strongest evidence OR = 1.33, 95%CI 1.07, 1.65; p = 0.01). The BD-PRS was also associated with ADHD (OR = 1.31, 95%CI 1.10, 1.57; p = 0.018), but not with other childhood psychopathology. LIMITATIONS: The PRS only captures common genetic variation and currently explains a relatively small proportion of the variance for BD. CONCLUSIONS: The BD-PRS was associated with ADHD in childhood, and weakly with adult hypomania, but not with other psychopathology examined. Our findings suggest that genetic risk for BD does not appear to manifest in childhood to the same extent as schizophrenia genetic risk has been reported to do.


Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno da Personalidade Borderline/genética , Criança , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Herança Multifatorial , Fenótipo , Psicopatologia , Medição de Risco , Esquizofrenia/genética , Adulto Jovem
10.
Transl Psychiatry ; 9(1): 35, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679418

RESUMO

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10-8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10-5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10-6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Escolaridade , Linguagem , Alfabetização , Herança Multifatorial , Adolescente , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Inteligência , Masculino , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Análise de Regressão , Medição de Risco , Reino Unido
11.
Transl Psychiatry ; 9(1): 8, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30664628

RESUMO

Deletion and duplication of 16p11.2 (BP4-BP5) have been associated with an increased risk of intellectual disability and psychiatric disorder. This is the first study to compare the frequency of a broad spectrum of psychiatric disorders in children with 16p11.2 deletion and duplication. We aimed to evaluate (1) the nature and prevalence of psychopathology associated with copy number variation (CNV) in children with 16p11.2 by comparing deletion and duplication carriers with family controls; (2) whether deletion and duplication carriers differ in frequency of psychopathology. 217 deletion carriers, 77 deletion family controls, 114 duplication carriers, and 32 duplication family controls participated in the study. Measures included standardized research diagnostic instruments. Deletion carriers had a higher frequency of any psychiatric disorder (OR = 8.9, p < 0.001), attention deficit hyperactivity disorder (ADHD) (OR = 4.0, p = 0.01), and autism spectrum disorder (ASD) (OR = 39.9, p = 0.01) than controls. Duplication carriers had a higher frequency of any psychiatric diagnosis (OR = 5.3, p = 0.01) and ADHD (OR = 7.0, p = 0.02) than controls. The prevalence of ASD in child carriers of deletions and duplications was similar (22% versus 26%). Comparison of the two CNV groups indicated a higher frequency of ADHD in children with the duplication than deletion (OR = 2.7, p = 0.04) as well as a higher frequency of overall psychiatric disorders (OR = 2.8, p = 0.02) and psychotic symptoms (OR = 4.7, p = 0.02). However, no differences between deletion and duplications carriers in the prevalence of ASD were found. Both deletion and duplication are associated with an increased risk of psychiatric disorder, supporting the importance of early recognition, diagnosis, and intervention in these groups.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Deleção de Sequência , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Espectro Autista/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Heterozigoto , Humanos , Masculino
12.
J Pediatr Endocrinol Metab ; 32(2): 203-206, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30681972

RESUMO

Background Resistance to thyroid hormone (RTH) commonly presents with goiter, attention deficit hyperactivity disorder (ADHD), short stature and tachycardia. However, due to its variable presentation with subtle clinical features, a third of the cases are mistreated, typically as hyperthyroidism. Case presentation A 15-year-old female with ADHD and oligomenorrhea was initially diagnosed as Hashimoto's thyroiditis but found to have a rare heterozygous mutation in c803 C>G (p Ala 268 Gly) in the THRß gene, confirming resistance to thyroid hormone. Conclusions Fluctuating thyroid function tests in addition to thyroid peroxidase antibody (TPO Ab) positivity complicated the diagnosis of RTH, initially diagnosed as Hashimoto's thyroiditis. A high index of suspicion is needed to prevent misdiagnosis and mistreatment.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Doença de Hashimoto/diagnóstico , Oligomenorreia/diagnóstico , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Diagnóstico Diferencial , Feminino , Genes erbA/genética , Doença de Hashimoto/genética , Doença de Hashimoto/metabolismo , Humanos , Mutação , Oligomenorreia/genética , Oligomenorreia/metabolismo , Prognóstico , Testes de Função Tireóidea , Síndrome da Resistência aos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/metabolismo
14.
J Clin Psychopharmacol ; 39(1): 28-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30566416

RESUMO

PURPOSE/BACKGROUND: Interventions for attention-deficit/hyperactivity disorder (ADHD) may be inadequate for some patients. There is evidence that supplementation with L-methylfolate augments antidepressant agent effects and thus might also augment ADHD treatment effects by a common catecholaminergic mechanism. METHODS: Forty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of ADHD participated in a randomized, double-blind, placebo-controlled, 12-week trial of 15 mg of L-methylfolate in combination with osmotic-release oral system methylphenidate. Osmotic-release oral system methylphenidate was dose optimized over the first 6 weeks. We evaluated the effects on ADHD symptoms, self-report on the Behavior Rating Inventory of Executive Function of executive function, methylphenidate dosing, neuropsychological test measures, the Adult ADHD Self-report scale, emotional dysregulation, social adjustment, and work productivity, as well as moderating effects of body mass index, autoantibodies to folate receptors, and select genetic polymorphisms. RESULTS: L-Methylfolate was well tolerated, with no significant effect over placebo except improvement from abnormal measures on the mean adaptive dimension of the ASR scale (χ = 4.36, P = 0.04). Methylphenidate dosing was significantly higher in individuals on L-methylfolate over time (χ = 7.35, P = 0.007). Exploratory analyses suggested that variation in a guanosine triphosphate cyclohydrolase gene predicted association with higher doses of methylphenidate (P < 0.001). CONCLUSIONS: L-Methylfolate was associated with no change in efficacy on measures relevant to neuropsychiatric function in adults with ADHD, other than suggestion of reduced efficacy of methylphenidate. Further investigation would be required to confirm this effect and its mechanism and the genotype prediction of effects on dosing.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Metilfenidato/uso terapêutico , Tetra-Hidrofolatos/uso terapêutico , Administração Oral , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Preparações de Ação Retardada/uso terapêutico , Dietoterapia , Suplementos Nutricionais , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Função Executiva/efeitos dos fármacos , Feminino , Receptor 1 de Folato/imunologia , GTP Cicloidrolase/genética , Humanos , Masculino , Metilfenidato/administração & dosagem , Testes Neuropsicológicos , Projetos Piloto , Tetra-Hidrofolatos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
15.
Behav Brain Res ; 360: 279-285, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30550949

RESUMO

The energy deficit hypothesis of attention-deficit/hyperactivity disorder (ADHD) suggests that low lactate production by brain astrocytes causes the symptoms of the disorder. Astrocytes are the main producers of lactate in the brain; however, skeletal muscles can produce the most lactate in the body. The lactate production by skeletal muscles increases with physical activity, as does the expression of the lactate transporter monocarboxylate transporter 1 (MCT1) at the blood-brain barrier (BBB). We hypothesise that children with ADHD, by being hyperactive, increase lactate production by skeletal muscles and transport it into the brain to compensate for low supply by astrocytes. The aim of this study was to explore whether the level of MCT1 is altered in the brain in an animal model of ADHD. The MCT1 expression was quantified on hippocampal brain sections from the best available rat model of ADHD, i.e., the spontaneously hypertensive rat (SHR) (n = 12), and the relevant control, the Wistar Kyoto rat (WKY) (n = 12), by the use of quantitative immunofluorescence laser scanning microscopy and postembedding immunogold electron microscopy. The results revealed significantly higher levels of hippocampal MCT1 immunoreactivity in SHR compared to WKY, particularly at the BBB. These results indicate that lactate flux through MCT1 between the body and the brain could be upregulated in children with ADHD. This study adds to previous research suggesting hyperactivity may be beneficial in ADHD; Children with ADHD possibly display a hyperactive behaviour in order to raise skeletal muscle lactate production, MCT1 expression and flux over the BBB to supply the brain with lactate.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/patologia , Barreira Hematoencefálica/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Regulação para Cima/fisiologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Barreira Hematoencefálica/ultraestrutura , Modelos Animais de Doenças , Masculino , Microscopia Confocal , Microscopia Imunoeletrônica , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/ultraestrutura , Neurópilo/metabolismo , Neurópilo/ultraestrutura , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Análise de Regressão , Especificidade da Espécie , Regulação para Cima/genética
16.
Behav Brain Res ; 360: 209-215, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30552946

RESUMO

Glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) carry the bulk of excitatory synaptic transmission. Their modulation plays key roles in synaptic plasticity, which underlies hippocampal learning and memory. A dysfunctional glutamatergic system may negatively affect learning abilities and underlie symptoms of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate whether the expression and function of AMPARs were altered in ADHD. We recorded AMPAR mediated synaptic transmission at hippocampal excitatory synapses and quantified immunogold labelling density of AMPAR subunits GluA1 and GluA2/3 in a rat model for ADHD; the spontaneously hypertensive rat (SHR). Electrophysiological recordings showed significantly reduced AMPAR mediated synaptic transmission at the CA3-to-CA1 pyramidal cell synapses in stratum radiatum and stratum oriens in SHRs compared to control rats. Electronmicroscopic immunogold quantifications did not show any statistically significant changes in labelling densities of the GluA1 subunit of the AMPAR on dendritic spines in stratum radiatum or in stratum oriens. However, there was a significant increase of the GluA2/3 subunit intracellularly in stratum oriens in SHR compared to control, interpreted as a compensatory effect. The proportion of synapses lacking AMPAR subunit labelling was the same in the two genotypes. In addition, electronmicroscopic examination of tissue morphology showed the density of this type of synapse (i.e., asymmetric synapses on spines), and the average size of the synaptic membranes, to be the same. AMPAR dysfunction, possibly involving molecular changes, in hippocampus may in part reflect altered learning in individuals with ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/patologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Receptores de AMPA/metabolismo , Animais , Animais Recém-Nascidos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Espinhas Dendríticas , Modelos Animais de Doenças , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Microscopia Eletrônica , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Células Piramidais/ultraestrutura , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores de AMPA/ultraestrutura , Membranas Sinápticas/metabolismo , Membranas Sinápticas/ultraestrutura
17.
J Affect Disord ; 242: 234-243, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30212762

RESUMO

BACKGROUND: Genome-wide association studies have been extensively applied in identifying SNP associated with major psychiatric disorders. However, the SNPs identified by the prevailing univariate approach only explain a small percentage of the genetic variance of traits, and the extensive data have shown the major psychiatric disorders have common biological mechanisms and the overlapping pathophysiological pathways. METHODS: We applied the genetic pleiotropy-informed metaCCA method on summary statistics data from the Psychiatric Genomics Consortium Cross-Disorder Group to examine the overlapping genetic relations between the five major psychiatric disorders. Furthermore, to refine all genes, we performed gene-based association analyses for the five disorders respectively using VEGAS2. Gene enrichment analysis was applied to explore the potential functional significance of the identified genes. RESULTS: After metaCCA analysis, 1147 SNPs reached the Bonferroni corrected threshold (p < 1.06 × 10-6) in the univariate SNP-multivariate phenotype analysis, and 246 genes with a significance threshold (p < 3.85 × 10-6) were identified as potentially pleiotropic genes in the multivariate SNP-multivariate phenotype analysis. By screening the results of gene-based p-values, we identified 37 putative pleiotropic genes which achieved significance threshold in metaCCA analyses and were also associated with at least one disorder in the VEGAS2 analyses. LIMITATIONS: Alternative approaches and experimental studies may be applied to check whether novel genes could still be identified/substantiated with these methods. CONCLUSIONS: The metaCCA method identified novel variants associated with psychiatric disorders by effectively incorporating information from different GWAS datasets. Our analyses may provide insights for some common therapeutic approaches of these five major psychiatric disorders based on the pleiotropic genes and common mechanisms identified.


Assuntos
Pleiotropia Genética/genética , Transtornos Mentais/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Autístico/genética , Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Humanos , Masculino , Análise Multivariada , Fenótipo , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética
18.
Artigo em Inglês | MEDLINE | ID: mdl-30217770

RESUMO

BACKGROUND: Intent-to-treat analyses from a randomized controlled trial showed significant between-group differences favouring micronutrient treatment on the Clinical Global Impression-Improvement, but no group differences on clinician, parent and teacher ratings of overall ADHD symptoms. There was an advantage of micronutrients over placebo in improving overall function, emotional regulation, aggression, and reducing impairment as well as improving inattention based on clinician but not parent observation. No group differences were observed on hyperactive-impulsive symptoms. We investigated predictors of response defined by pre-treatment variables. METHOD: We conducted analyses of data from a clinical trial of children (7-12 years) with ADHD, whereby participants were randomized to receive micronutrients or placebo for 10 weeks followed by a 10 week open-label (OL) phase. We included only children who had been exposed to micronutrients for a full 10 week period and demonstrated satisfactory adherence, either in RCT phase (n = 40) or OL phase (those who received placebo during RCT phase; n = 31). Seven outcomes were examined: change in ADHD symptoms (clinician/parent), ADHD responder, overall responder, change in mood, change in functioning, and change in aggression. Demographic, developmental variables, current clinical and physical characteristics, MTHFR genotype at two common variants, and pre-treatment serum/plasma levels (vitamin D, B12, folate, zinc, copper, iron, ferritin, potassium, calcium, magnesium, and homocysteine) were all considered as putative predictors. RESULTS: Substantial nutrient deficiencies pre-treatment were observed only for vitamin D (13%) and copper (15%), otherwise most children entered the trial with nutrient levels falling within expected ranges. Regression analyses showed varying predictors across outcomes with no one predictor being consistently identified across different variables. Lower pre-treatment folate and B12 levels, being female, greater severity of symptoms and co-occurring disorders pre-treatment, more pregnancy complications and fewer birth problems were identified as possible predictors of greater improvement for some but not all outcome measures although predictive values were weak. Lower IQ and higher BMI predicted greater improvement in aggression. CONCLUSIONS: This study replicates Rucklidge et al. (2014b) showing the limited value of using serum nutrient levels to predict treatment response although we cannot rule out that other non-assayed nutrient levels may be more valuable. Additionally, no specific demographic or clinical characteristics, including MTHFR genetic status, were identified that would preclude children with ADHD from trying this treatment approach.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/terapia , Suplementos Nutricionais , Micronutrientes/uso terapêutico , Vitaminas/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Biomarcadores/sangue , Índice de Massa Corporal , Criança , Feminino , Humanos , Inteligência , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Transtornos Nutricionais/sangue , Transtornos Nutricionais/diagnóstico , Transtornos Nutricionais/genética , Transtornos Nutricionais/terapia , Polimorfismo de Nucleotídeo Único , Prognóstico , Índice de Gravidade de Doença
19.
Artigo em Inglês | MEDLINE | ID: mdl-30053573

RESUMO

Attention Deficit and Hyperactivity Disorder (ADHD) is one of the most common psychiatric disorders in childhood and causes significant functional impairments in children. Behavioral genetic and molecular genetic studies have provided significant evidence in terms of highlighting the etiology of ADHD. Folate deficiency during pregnancy is an established risk factor for ADHD. Polymorphisms in the Methyltetrahydrofolate Reductase (MTHFR) encoding gene, such as A1298C and C667T, are associated with the decreased bioavailability of folate, and this condition can act like folate deficiency. In the literature, no study has investigated MTHFR polymorphisms in mothers of children with ADHD. Sixty-four children diagnosed with ADHD and their mothers as well as 40 healthy children and their mothers participated in this study. MTHFR polymorphisms were investigated in all participants. Comparison of the C677C and A1298C MTHFR polymorphisms in children with and without ADHD revealed no significant differences. We found that the maternal C677C_CT genotype counts, both observed and expected values, were significantly different from those based on Hardy-Weinberg Principle Analysis in the ADHD group. The most important result of this study was that maternal C677C MTHFR gene polymorphisms are significant risk factors in for ADHD, and we argue that children with ADHD are exposed to folate deficiency, even if their mothers received a sufficient amount of folate during pregnancy. This result also highlights one of the genetic factors of ADHD. Further studies should be performed to confirm this finding.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Relações Mãe-Filho , Polimorfismo Genético/genética , Adolescente , Lista de Checagem , Distribuição de Qui-Quadrado , Criança , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Análise de Componente Principal , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos
20.
Psychiatry Res ; 270: 780-785, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30551325

RESUMO

The aim of the study is to explore the impact of Generalized Anxiety Disorder (GAD) comorbidity in children with Attention Deficit Hyperactivity Disorder (ADHD). Six hundred children with ADHD (mean age = 9.12 years), recruited from 2013 to 2017, participated in the study. A total of 96 (16%) children with ADHD displayed a comorbidity with GAD. ADHD + GAD were compared to 504 ADHD children without GAD in terms of cognitive and psychiatric profile, ADHD subtype and family psychiatric history. The ADHD + GAD, predominantly represented from ADHD combined (72.6%), displayed higher psychiatry comorbidity, in particular with depressive disorders, and were associated with higher rates of maternal depression, of ADHD in fathers, and bipolar disorders in second degree relatives. Moreover, younger preschool-primary school age children with ADHD + GAD showed significant higher frequency of depressive disorders versus younger preschool-primary children with ADHD without GAD. ADHD + GAD comorbidity represents a more complex clinical condition compared to ADHD without GAD, characterized by the higher frequency of multiple comorbidities and by a psychiatric family with higher rates of mood and disruptive disorders.


Assuntos
Transtornos de Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Adolescente , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Criança , Pré-Escolar , Comorbidade , Estudos Transversais , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/genética , Transtorno Depressivo/psicologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Prevalência
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