Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 991
Filtrar
1.
Ann Clin Transl Neurol ; 6(4): 655-668, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31019990

RESUMO

Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. Methods: We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. Results: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. Interpretation: Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.


Assuntos
Encéfalo/anormalidades , Encéfalo/patologia , Fatores de Transcrição Forkhead/genética , Proteínas do Tecido Nervoso/genética , Animais , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/patologia , Feminino , Genótipo , Humanos , Deficiência Intelectual/genética , Camundongos Transgênicos , Microcefalia/genética , Fenótipo , Síndrome de Rett/genética
2.
Mol Psychiatry ; 24(11): 1720-1731, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-29875476

RESUMO

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) controversially combined previously distinct subcategories of autism spectrum disorder (ASD) into a single diagnostic category. However, genetic convergences and divergences between different ASD subcategories are unclear. By retrieving 1725 exonic de novo mutations (DNMs) from 1628 subjects with autistic disorder (AD), 1873 from 1564 subjects with pervasive developmental disorder not otherwise specified (PDD-NOS), 276 from 247 subjects with Asperger's syndrome (AS), and 2077 from 2299 controls, we found that rates of putative functional DNMs (loss-of-function, predicted deleterious missense, and frameshift) in all three subcategories were significantly higher than those in control. We then investigated the convergences and divergences of the three ASD subcategories based on four genetic aspects: whether any two ASD subcategories (1) shared significantly more genes with functional DNMs, (2) exhibited similar spatio-temporal expression patterns, (3) shared significantly more candidate genes, and (4) shared some ASD-associated functional pathways. It is revealed that AD and PDD-NOS were broadly convergent in terms of all four genetic aspects, suggesting these two ASD subcategories may be genetically combined. AS was divergent to AD and PDD-NOS for aspects of functional DNMs and expression patterns, whereas AS and AD/PDD-NOS were convergent for aspects of candidate genes and functional pathways. Our results indicated that the three ASD subcategories present more genetic convergences than divergences, favouring DSM-5's new classification. This study suggests that specifically defined genotypes and their corresponding phenotypes should be integrated analyzed for precise diagnosis of complex disorders, such as ASD.


Assuntos
Transtorno do Espectro Autista/classificação , Transtorno do Espectro Autista/genética , Adolescente , Síndrome de Asperger/genética , Transtorno Autístico/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Bases de Dados Genéticas , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Genótipo , Humanos , Masculino , Fenótipo
3.
BMC Psychiatry ; 18(1): 369, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30463616

RESUMO

BACKGROUND: A substantial genetic component accounts for Autism Spectrum Disorders (ASD) aetiology, with some rare and common genetic risk factors recently identified. Large collections of DNAs from thoroughly characterized ASD families are an essential step to confirm genetic risk factors, identify new variants and investigate genotype-phenotype correlations. The Italian Autism Network aimed at constituting a clinical database and a biorepository of samples derived from ASD subjects and first-degree relatives extensively and consistently characterized by child psychiatry centers in Italy. METHODS: The study was approved by the ethical committee of the University of Verona, the coordinating site, and by the local ethical committees of each recruiting site. Certified staff was specifically trained at each site for the overall study conduct, for clinical protocol administration and handling of biological material. A centralized database was developed to collect clinical assessment and medical records from each recruiting site. Children were eligible for recruitment based on the following inclusion criteria: age 4-18 years, at least one parent or legal guardian giving voluntary written consent, meeting DSM-IV criteria for Autistic Disorder or Asperger's Disorder or Pervasive Developmental Disorder NOS. Affected individuals were assessed by full psychiatric, neurological and physical examination, evaluation with ADI-R and ADOS scales, cognitive assessment with Wechsler Intelligence Scale for Children or Preschool and Primary, Leiter International Performance Scale or Griffiths Mental Developmental Scale. Additional evaluations included language assessment, the Krug Asperger's Disorder Index, and instrumental examination such as EEG and structural MRI. DNA, RNA and plasma were collected from eligible individuals and relatives. A central laboratory was established to host the biorepository, perform DNA and RNA extraction and lymphocytes immortalisation. DISCUSSION: The study has led to an extensive collection of biological samples associated with standardised clinical assessments from a network of expert clinicians and psychologists. Eighteen sites have received ADI/ADOS training, thirteen of which have been actively recruiting. The clinical database currently includes information on 812 individuals from 249 families, and the biorepository has samples for 98% of the subjects. This effort has generated a highly valuable resource for conducting clinical and genetic research of ASD, amenable to further expansion.


Assuntos
Síndrome de Asperger , Transtorno do Espectro Autista , Bancos de Espécimes Biológicos/organização & administração , Transtornos Globais do Desenvolvimento Infantil , Bases de Dados como Assunto/organização & administração , Adolescente , Síndrome de Asperger/sangue , Síndrome de Asperger/genética , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/genética , Biomarcadores/sangue , Criança , Transtornos Globais do Desenvolvimento Infantil/sangue , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Feminino , Recursos em Saúde , Humanos , Itália , Masculino , Registros Médicos
4.
Br J Psychiatry ; 212(5): 287-294, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29693535

RESUMO

BACKGROUND: Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.AimsTo determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders. METHOD: A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites. RESULTS: The yield of pathogenic CNVs was high - 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations. CONCLUSIONS: In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.Declaration of interestNone.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Variações do Número de Cópias de DNA/genética , Deficiência Intelectual/genética , Transtornos Mentais/genética , Esquizofrenia/genética , Adulto , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Comorbidade , Europa (Continente)/epidemiologia , Feminino , Humanos , Deficiência Intelectual/epidemiologia , Masculino , Transtornos Mentais/epidemiologia , Análise em Microsséries , Pessoa de Meia-Idade , Esquizofrenia/epidemiologia
5.
J Child Psychol Psychiatry ; 59(4): 299-302, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29574739

RESUMO

The Journal of Child Psychology and Psychiatry's Annual Research Review (ARR) is a must-read special issue of the journal that presents a series of major reviews of key topics in the field. This year the ARR consists of eight reviews, each accompanied by a commentary from a leading expert in the field, on a diverse range of topics addressing, in complementary ways, the key role of the environment in child psychopathology and in leveraging change in the service of prevention and intervention. Topics include epigenetics, stress physiology, neonatal imaging, interparental conflict, bullying, autism treatments and suicide. The papers considered together represent the very best of contemporary child psychology and psychiatry research.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Interação Gene-Ambiente , Psicologia do Desenvolvimento , Criança , Humanos
6.
Neurosci Biobehav Rev ; 89: 132-150, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29391184

RESUMO

Clinical and molecular genetics have advanced current knowledge on genetic disorders associated with autism. A review of diverse genetic disorders associated with autism is presented and for the first time discussed extensively with regard to possible common underlying mechanisms leading to a similar cognitive-behavioral phenotype of autism. The possible role of interactions between genetic and environmental factors, including epigenetic mechanisms, is in particular examined. Finally, the pertinence of distinguishing non-syndromic autism (isolated autism) from syndromic autism (autism associated with genetic disorders) will be reconsidered. Given the high genetic and etiological heterogeneity of autism, autism can be viewed as a behavioral syndrome related to known genetic disorders (syndromic autism) or currently unknown disorders (apparent non-syndromic autism), rather than a specific categorical mental disorder. It highlights the need to study autism phenotype and developmental trajectory through a multidimensional, non-categorical approach with multivariate analyses within autism spectrum disorder but also across mental disorders, and to conduct systematically clinical genetic examination searching for genetic disorders in all individuals (children but also adults) with autism.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Psicóticos/genética , Transtorno do Espectro Autista/etiologia , Epigênese Genética/genética , Humanos , Fenótipo , Transtornos Psicóticos/complicações
7.
Eur J Med Genet ; 61(5): 280-283, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29307791

RESUMO

22q11.2 microduplication (22q11.2DupS) is associated with a broad spectrum of phenotypes, including normality. Psychiatric disorders are described in 13% of these patients, including Attention Deficit and Hyperactivity Disorder (ADHD), Intellectual Deficiency (ID), and Autism Spectrum Disorder (ASD), but not schizophrenia. We report changes in the psychiatric symptom profile in the course of development of a young boy with a 22q11.2DupS syndrome, from early childhood to adolescence. The boy's psychiatric presentation was characterized by features of Pervasive Developmental Disorder (PDD), with ADHD in early childhood, a single psychotic episode in mid-infancy, and executive impairment in adolescence. We discuss the importance of an in-depth assessment of cognitive functions in children with22q11.2DupS throughout their development.


Assuntos
Anormalidades Múltiplas/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Síndrome de DiGeorge/diagnóstico , Transtornos Psicóticos/diagnóstico , Anormalidades Múltiplas/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Função Executiva , Humanos , Masculino , Linhagem , Transtornos Psicóticos/genética
8.
Mol Psychiatry ; 23(2): 263-270, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28044064

RESUMO

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children, N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors influencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic influences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms.


Assuntos
Transtorno do Espectro Autista/genética , Esquizofrenia/genética , Comportamento Verbal/fisiologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/fisiopatologia , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Comunicação , Feminino , Estudo de Associação Genômica Ampla , Humanos , Idioma , Estudos Longitudinais , Masculino , Herança Multifatorial/genética , Fatores de Risco , Esquizofrenia/fisiopatologia , Comportamento Social
9.
Turk Psikiyatri Derg ; 28(2): 89-94, 2017.
Artigo em Turco | MEDLINE | ID: mdl-29192941

RESUMO

OBJECTIVE: Methylphenidate is the first-choice medication for the Pervasive Developmental Disorders (PDDs), and comorbid Attention Deficit Hyperactivity Disorder (ADHD). But this approach generally results with poor outcomes, and increased adverse effects. It is aimed to investigate the comparison of cases who diagnosed with PDDs and Mild Mental Retardation (MR) and cases with pure ADHD in terms of the clinical response to MPH. Also we aimed to investigate the relations between CES-1 polymorphism gene and the clinical response to MPH. METHODS: For clarifying this we searched for three polymorphisms (Arg199/His, Ser75/Asn, and Ile49/Val) in carboxylesterase-1 gene (CES-1) in the saliva of patients diagnosed with PDD+ADHD. Also, we assessed the clinical response to MPH by dimensional approach using the Attention Deficit Hyperactivity Disorder Rating Scale IV and Clinical Global Impression-Improvement scale. RESULTS: PDD+ADHD groups had significantly higher Arg199/His polymorphism, and clinically responded poorer with symptoms sometimes even worsening to the MPH treatment compared with "pure" ADHD and ADHD+MR groups. CONCLUSION: This is the first study that an association between Arg199/His polymorphism in CES1 and altered treatment response to MPH in patients with PDD that presents with symptoms of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Hidrolases de Éster Carboxílico/genética , Estimulantes do Sistema Nervoso Central/uso terapêutico , Transtornos Globais do Desenvolvimento Infantil/tratamento farmacológico , Metilfenidato/uso terapêutico , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estimulantes do Sistema Nervoso Central/administração & dosagem , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Feminino , Humanos , Masculino , Metilfenidato/administração & dosagem , Variantes Farmacogenômicos , Polimorfismo Genético , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
10.
Neurología (Barc., Ed. impr.) ; 32(9): 568-578, nov.-dic. 2017. tab
Artigo em Espanhol | IBECS | ID: ibc-169036

RESUMO

Introducción: El retraso global del desarrollo (RGD) y la discapacidad intelectual (DI) son un motivo de consulta frecuente en la consulta de Neuropediatría. Actualmente, la hibridación genómica comparada constituye una de las principales técnicas aplicadas al diagnóstico de esta patología. Resulta útil determinar qué características fenotípicas se asocian a obtener un resultado etiológico en el test genético. Métodos: Se llevó a cabo un estudio ciego pormenorizado de las características clínicas, antropométricas y morfológicas de 80 individuos afectos de DI no explicada y se analizó cuales estaban asociadas a obtener un resultado etiológico en el array-CGH. Resultados: El resultado del array fue patológico en un 27,5% de los casos. Los factores que se asociaron estadísticamente a tener una prueba de array-CGH patológica fueron los antecedentes familiares de DI/RGD (OR: 12,1), la presencia de malformaciones congénitas (OR: 5,33), más de 3 rasgos dismórficos faciales (OR: 20,9) y la hipotonía periférica (OR: 3,25). Conclusiones: Nuestros hallazgos coinciden con otras series publicadas. Por lo tanto, asumimos que la probabilidad de encontrar variación en el número de copias de significado patológico mediante array-CGH aumenta si alguna de las características anteriores está presentes en individuos afectos de DI/RGD (AU)


Introduction: Global developmental delay (GDD) and intellectual disability (ID) are frequent reasons for consultation in paediatric neurology departments. Nowadays, array comparative genomic hybridisation (array-CGH) is one of the most widely used techniques for diagnosing these disorders. Our purpose was to determine the phenotypic features associated with pathological results in this genetic test. Methods: We conducted a blind study of the epidemiological, clinical, anthropometric, and morphological features of 80 patients with unexplained ID to determine which features were associated with pathological results in array-CGH. Results: Pathological results were found in 27.5% of the patients. Factors associated with pathological results in array-CGH were a family history of GDD/ID (OR = 12.1), congenital malformations (OR = 5.33), having more than 3 facial dysmorphic features (OR = 20.9), and hypotonia (OR = 3.25). Conclusions: Our findings are consistent with those reported by other published series. We therefore conclude that the probability of having pathological results in array-CGH increases with the presence of any of the features mentioned above in patients with ID/GDD (AU)


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Deficiência Intelectual/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Hibridização Genômica Comparativa/métodos , Fenótipo , Marcadores Genéticos/genética , Facies
11.
Behav Brain Res ; 331: 92-101, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28499914

RESUMO

Autism spectrum disorders (ASD) are common heterogeneous neurodevelopmental disorders with typical triad of symptoms: impaired social interaction, language and communication abnormalities and stereotypical behavior. Despite extensive research, the etiology and pathogenesis of ASD remain largely unclear. The lack of solid knowledge on the mechanisms of these disorders decreases the opportunities for pathogenetic treatment of autism. Various theories where proposed in order to explain the pathophysiology underlying ASD. Despite the fact that none of them is able to completely explain the impairments in the nervous system of ASD patients, these hypotheses were instrumental in highlighting the most important mechanisms in the development of this complex disorder. Some new theories are based on neurovisualization studies, others on the data from genomic studies, which become increasingly available worldwide. As the research in this field is largely dependent on the animal models, there is an ongoing discussion and search for the most appropriate one adequately reproducing the pathology. Here we provide an overview of current theories of the origin and development of ASD discussed in the context of existing and proposed rodent models of ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Transtorno Autístico/fisiopatologia , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Modelos Animais de Doenças , Rede Nervosa/fisiopatologia , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Comportamento/fisiologia , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/patologia , Humanos
12.
Nat Rev Neurosci ; 18(3): 147-157, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28179641

RESUMO

Several large-scale genomic studies have supported an association between cases of autism spectrum disorder and mutations in the genes SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2 and SHANK3, which encode a family of postsynaptic scaffolding proteins that are present at glutamatergic synapses in the CNS. An evaluation of human genetic data, as well as of in vitro and in vivo animal model data, may allow us to understand how disruption of SHANK scaffolding proteins affects the structure and function of neural circuits and alters behaviour.


Assuntos
Transtorno do Espectro Autista/metabolismo , Transtornos Globais do Desenvolvimento Infantil/metabolismo , Neurônios/metabolismo , Sinapses/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Humanos , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo
13.
Proc Natl Acad Sci U S A ; 113(52): 15054-15059, 2016 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-27956632

RESUMO

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.


Assuntos
Transtorno do Espectro Autista/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Deleção de Genes , Genes Essenciais , Mutação , Alelos , Animais , Encéfalo/metabolismo , Éxons , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Risco , Irmãos , Comportamento Social
14.
PLoS Genet ; 12(11): e1006425, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27846226

RESUMO

Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.


Assuntos
Transtorno do Espectro Autista/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Cromossomos Humanos X/genética , Transtorno do Espectro Autista/patologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Transtornos Globais do Desenvolvimento Infantil/patologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Caracteres Sexuais
16.
Psychiatr Pol ; 50(3): 543-54, 2016.
Artigo em Inglês, Polonês | MEDLINE | ID: mdl-27556113

RESUMO

Autism spectrum disorders (ASD) are caused by disruptions in early stages of central nervous system development and are usually diagnosed in first years of life. Despite common features such as impairment of socio-communicative development and stereotypical behaviours, ASD are characterised by heterogeneous course and clinical picture. The most important aetiological factors comprise genetic and environmental influences acting at prenatal, perinatal and neonatal period. The role of rare variants with large effect i.e. copy number variants in genes regulating synapse formation and intrasynaptic connections is emphasised. Common variants with small effect may also be involved, i.e. polymorphisms in genes encoding prosocial peptides system - oxytocin and vasopressin. The environmental factors may include harmful effects acting during pregnancy and labour, however their specificity until now is not confirmed, and in some of them a primary genetic origin cannot be excluded. In several instances, especially with comorbid disorders - intellectual disability, epilepsy and dysmorphias - a detailed molecular diagnostics is warranted, which currently may elucidate the genetic background of disorder in about 20% of cases.


Assuntos
Asfixia Neonatal/epidemiologia , Transtorno do Espectro Autista/epidemiologia , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Complicações na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Asfixia Neonatal/genética , Transtorno do Espectro Autista/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Comorbidade , Feminino , Humanos , Masculino , Gravidez , Nascimento Prematuro/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética
17.
JAMA Psychiatry ; 73(6): 622-9, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27145529

RESUMO

IMPORTANCE: Previous research has focused on examining the familial clustering of schizophrenia, bipolar disorder, and autism spectrum disorders (ASD). Little is known about the clustering of other psychiatric and neurodevelopmental disorders among siblings of persons with ASD. OBJECTIVE: To examine the risk for psychiatric and neurodevelopmental disorders among full siblings of probands with ASD. DESIGN, SETTING, AND PARTICIPANTS: The Finnish Prenatal Study of Autism and Autism Spectrum Disorders used a population-based cohort that included children born from January 1, 1987, to December 31, 2005, who received a diagnosis of ASD by December 31, 2007. Each case was individually matched to 4 control participants by sex and date and place of birth. The siblings of the cases and controls were born from January 1, 1977, to December 31, 2005, and received a diagnosis from January 1, 1987, to December 31, 2009. This nested case-control study included 3578 cases with ASD with 6022 full siblings and 11 775 controls with 22 127 siblings from Finnish national registers. Data were analyzed from March 6, 2014, to February 12, 2016. MAIN OUTCOMES AND MEASURES: The adjusted risk ratio (RR) for psychiatric and neurodevelopmental disorders among siblings of probands with ASD vs siblings of matched controls. Additional analyses were conducted separately for ASD subgroups, including childhood autism, Asperger syndrome, and pervasive developmental disorders not otherwise specified. Analyses were further stratified by sex and intellectual disability among the probands. RESULTS: Among the 3578 cases with ASD (2841 boys [79.4%]) and 11 775 controls (9345 boys [79.4%]), 1319 cases (36.9%) and 2052 controls (17.4%) had at least 1 sibling diagnosed with any psychiatric or neurodevelopmental disorder (adjusted RR, 2.5; 95% CI, 2.3-2.6). The largest associations were observed for childhood-onset disorders (1061 cases [29.7%] vs 1362 controls [11.6%]; adjusted RR, 3.0; 95% CI, 2.8-3.3), including ASD (374 cases [10.5%] vs 125 controls [1.1%]; adjusted RR, 11.8; 95% CI, 9.4-14.7), tic disorders (28 cases [0.8%] vs 24 controls [0.2%]; adjusted RR, 4.3; 95% CI, 2.3-8.2), attention-deficit/hyperactivity disorder (189 cases [5.3%] vs 180 controls [1.5%]; adjusted RR, 3.7; 95% CI, 2.9-4.7), learning and coordination disorders (563 cases [15.7%] vs 697 controls [5.9%]; adjusted RR, 3.2; 95% CI, 2.8-3.6), intellectual disability (104 cases [2.9%] vs 137 controls [1.2%]; adjusted RR, 3.1; 95% CI, 2.3-4.2), conduct and oppositional disorders (180 cases [5.0%] vs 221 controls [1.9%]; adjusted RR, 2.8; 95% CI, 2.2-3.5), and emotional disorders with onset specific to childhood (126 cases [3.5%] vs 157 controls [1.3%]; adjusted RR, 2.6; 95% CI, 1.9-3.4). Autism spectrum disorders were also associated with schizophrenia spectrum disorders, affective disorders, anxiety disorders, and other neurotic and personality disorders among siblings. CONCLUSIONS AND RELEVANCE: Psychiatric and neurodevelopmental disorders cluster among siblings of probands with ASD. For etiologic research, these findings provide further evidence that several psychiatric and neurodevelopmental disorders have common risk factors.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Transtornos Mentais/genética , Transtornos do Neurodesenvolvimento/genética , Irmãos , Adolescente , Análise de Variância , Síndrome de Asperger/diagnóstico , Síndrome de Asperger/genética , Síndrome de Asperger/psicologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/psicologia , Estudos de Casos e Controles , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/psicologia , Estudos de Coortes , Comorbidade , Feminino , Finlândia , Seguimentos , Humanos , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologia , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/psicologia , Risco , Irmãos/psicologia , Adulto Jovem
18.
Nat Med ; 22(4): 345-61, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27050589

RESUMO

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.


Assuntos
Transtorno do Espectro Autista/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Predisposição Genética para Doença , Terapia de Alvo Molecular , Animais , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/terapia , Transtornos Globais do Desenvolvimento Infantil/patologia , Transtornos Globais do Desenvolvimento Infantil/terapia , Modelos Animais de Doenças , Humanos
19.
J Am Acad Child Adolesc Psychiatry ; 55(2): 106-13.e4, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26802777

RESUMO

OBJECTIVE: Recent studies have highlighted the impact of coexisting mental health problems in autism spectrum disorders (ASD). No twin studies to date have reported on individuals meeting diagnostic criteria of ASD. This twin study reports on the etiological overlap between the diagnosis of ASD and emotional symptoms, hyperactivity, and conduct problems measured with the Strengths and Difficulties Questionnaire. METHOD: Genetic and environmental influences on the covariance between ASD and coexisting problems were estimated, in line with the correlated risks model prediction. Phenotypic causality models were also fitted to explore alternative explanations of comorbidity: namely, that coexisting problems are the result of or result in ASD symptoms; that they increase recognition of ASD; or that they arise due to an over-observation bias/confusion when differentiating between phenotypes. RESULTS: More than 50% of twins with broad spectrum/ASD met the borderline/abnormal levels cut-off criteria for emotional symptoms or hyperactivity, and approximately 25% met these criteria for the 3 reported problems. In comparison, between 13% and 16% of unaffected twins scored above the cut-offs. The phenotypic correlation between ASD and emotional symptoms was explained entirely by genetic influences and accompanied by a moderate genetic correlation (0.42). The opposite was true for the overlap with conduct problems, as nonshared-environmental factors had the strongest impact. For hyperactivity, the best-fitting model suggested a unidirectional phenotypic influence of hyperactivity on ASD. CONCLUSION: Our findings suggest a possible effect of hyperactivity on identification of ASD. The lack of genetic influences on conduct problems-ASD overlap further supports the genetic independence of these 2 phenotypes. Finally, the co-occurrence of emotional symptoms in ASD, compared to other co-occurring problems, is completely explained by common genetic effects.


Assuntos
Transtorno do Espectro Autista/etiologia , Agitação Psicomotora/etiologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtorno do Espectro Autista/psicologia , Criança , Transtornos Globais do Desenvolvimento Infantil/etiologia , Transtornos Globais do Desenvolvimento Infantil/genética , Comorbidade , Emoções , Feminino , Genética Comportamental , Humanos , Masculino , Saúde Mental , Fenótipo , Agitação Psicomotora/genética , Agitação Psicomotora/psicologia , Gêmeos/genética , Gêmeos/psicologia
20.
Pediatr. aten. prim ; 17(68): 309-315, oct.-dic. 2015. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-146928

RESUMO

Introducción: se realiza una revisión del número de trastornos del neurodesarrollo en la población pediátrica de un centro de Atención Primaria de la ciudad de Zaragoza (España), con el objetivo de conocer la prevalencia y la importancia creciente del diagnóstico genético. Material y métodos: se realiza una búsqueda de casos en el programa de historia clínica informatizada OMI6 con los siguientes términos: 'retraso mental', 'retraso del desarrollo', 'trastorno del desarrollo', 'autismo'. Resultados: se han obtenido 76 casos de trastornos del neurodesarrollo, que son el 2,19% de la población. Los diagnósticos principales fueron: 23 trastornos del lenguaje, 17 trastornos del aprendizaje, 11 de retraso mental, 10 casos de trastorno del espectro autista (TEA), 8 de retraso del desarrollo, 5 casos de dislexia, un caso de síndrome de Asperger y un caso de dispraxia motora. Se solicitó estudio genético en 21 casos, el 27,63% de los niños, siendo mucho más frecuente su realización en casos de retraso mental o TEA. Las pruebas genéticas proporcionaron el diagnóstico en 12 pacientes de los estudiados, un 57,14% de los casos. En general, se encuentra una causa genética en el 75% de los casos con diagnóstico establecido. Conclusiones: este estudio muestra que los trastornos del neurodesarrollo aparecen en nuestra población con una frecuencia similar a la descrita en la bibliografía médica. Los estudios genéticos permiten cada vez más un diagnóstico etiológico preciso (AU)


Introduction: we review the number of neurodevelopmental disorders in the pediatric population of a primary care center in Zaragoza, in order to determine the prevalence and the growing importance of genetic diagnosis. Material and methods: the research was carried out in the computerized medical record programme OMI6 with the following terms: 'mental retardation', 'development delay', 'development disorders' and 'autism spectrum disorders'. Results: 76 cases of neurodevelopment disorders have been got, which mean 2.19% of the population of study. The main diagnoses were: 23 language disorders, 17 learning disorders, 11 mental retardation, 10 cases of autism, 8 development delay, 5 cases of dyslexia, 1 case of Asperger´s syndrome and 1 case of dyspraxia. A genetic study was requested in 21 cases, which supposed the 27.63% of children, being more frequent implementation in cases of mental retardation or autism. Genetic test provided diagnosis in 12 patients of the study, which means the 57.14% of the cases. A genetic cause was found in the 75% of the cases with an established diagnosis. Conclusion: this study shows that neurodevelopmental disorders appear in our population with a similar frequency described in the literature. Genetic studies increasingly allow precise etiological diagnosis (AU)


Assuntos
Humanos , Retardo Mental Ligado ao Cromossomo X/epidemiologia , Deficiência Intelectual/genética , Técnicas Genéticas , Transtorno Autístico/genética , Transtornos Globais do Desenvolvimento Infantil/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA