RESUMO
The degree to which genetic factors influence human intelligence remains a matter of some controversy. However, there is little doubt that single gene mutations can significantly alter brain development and function. For example, mutations affecting the FMR1 gene cause the fragile X syndrome, the most prevalent known inherited cause of intellectual dysfunction. The most common mutation occurring in the FMR1 locus involves expansion of a trinucleotide (CGG)n repeat sequence within the promoter region of the gene. Between 6 and 54 repeats are typically observed in individuals from the general population. When > or = 200 CGG repeats are present, the expanded repeat sequence and an adjacent CpG island are usually hypermethylated, Aa phenomenon associated with transcriptional silencing of the gene and commonly referred to as the FMR1 full mutation. The intermediate range of repeats (approximately 50 to 200 CGGs), referred to as the premutation, is characterized by the absence of hypermethylation within the promoter region and normal phenotype. Some individuals have a combination of methylated and unmethylated alleles of differing size and are referred to as having mosaic status. Most males with the FMR1 full mutation function in the mentally retarded range of intelligence; in contrast, females with the FMR1 full mutation show a broader range of intelligence, from mental retardation to normal IQ.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Síndrome do Cromossomo X Frágil/genética , Deficiência Intelectual/genética , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA , Adolescente , Estudos de Casos e Controles , Criança , Mecanismo Genético de Compensação de Dose , Feminino , Proteína do X Frágil da Deficiência Intelectual , Humanos , Inteligência/genética , Testes de Inteligência , Pais , Análise de Regressão , Sequências Repetitivas de Ácido NucleicoRESUMO
Analysis of 84 human X chromosomes for the presence of interrupting AGG trinucleotides within the CGG repeat tract of the FMR1 gene revealed that most alleles possess two interspersed AGGs and that the longest tract of uninterrupted CGG repeats is usually found at the 3' end. Variation in the length of the repeat appears polar. Alleles containing between 34 and 55 repeats, with documented unstable transmissions, were shown to have lost one or both AGG interruptions. These comparisons define an instability threshold of 34-38 uninterrupted CGG repeats. Analysis of premutation alleles in Fragile X syndrome carriers reveals that 70% of these alleles contain a single AGG interruption. These data suggest that the loss of an AGG is an important mutational event in the generation of unstable alleles predisposed to the Fragile X syndrome.
Assuntos
Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA , Cromossomo X , Sequência de Bases , DNA , Proteína do X Frágil da Deficiência Intelectual , Humanos , Masculino , Modelos Genéticos , Dados de Sequência Molecular , Mutação , Sequências Repetitivas de Ácido NucleicoRESUMO
BACKGROUND: Clinical trials of medications to alleviate the cognitive and behavioural symptoms of individuals with fragile X syndrome (FXS) are now underway. However, there are few reliable, valid and/or sensitive outcome measures available that can be directly administered to individuals with FXS. The majority of assessments employed in clinical trials may be suboptimal for individuals with intellectual disability (ID) because they require face-to-face interaction with an examiner, taxing administration periods, and do not provide reinforcement and/or feedback during the test. We therefore examined the psychometric properties of a new computerised 'learning platform' approach to outcome measurement in FXS. METHOD: A brief computerised test, incorporated into the Discrete Trial Trainer©- a commercially available software program designed for children with ID - was administered to 13 girls with FXS, 12 boys with FXS and 15 matched ID controls aged 10 to 23 years (mental age = 4 to 12 years). The software delivered automated contingent access to reinforcement, feedback, token delivery and prompting procedures (if necessary) on each trial to facilitate responding. The primary outcome measure was the participant's learning rate, derived from the participant's cumulative record of correct responses. RESULTS: All participants were able to complete the test and floor effects appeared to be minimal. Learning rates averaged approximately five correct responses per minute, ranging from one to eight correct responses per minute in each group. Test-retest reliability of the learning rates was 0.77 for girls with FXS, 0.90 for boys with FXS and 0.90 for matched ID controls. Concurrent validity with raw scores obtained on the Arithmetic subtest of the Wechsler Intelligence Scale for Children-III was 0.35 for girls with FXS, 0.80 for boys with FXS and 0.56 for matched ID controls. The learning rates were also highly sensitive to change, with effect sizes of 1.21, 0.89 and 1.47 in each group respectively following 15 to 20, 15-min sessions of intensive discrete trial training conducted over 1.5 days. CONCLUSIONS: These results suggest that a learning platform approach to outcome measurement could provide investigators with a reliable, valid and highly sensitive measure to evaluate treatment efficacy, not only for individuals with FXS but also for individuals with other ID.
Assuntos
Síndrome do Cromossomo X Frágil/psicologia , Deficiência Intelectual/diagnóstico , Aprendizagem , Avaliação de Resultados em Cuidados de Saúde/métodos , Adolescente , Criança , Estudos de Viabilidade , Feminino , Síndrome do Cromossomo X Frágil/complicações , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/psicologia , Testes de Inteligência/estatística & dados numéricos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Psicometria , Reprodutibilidade dos Testes , Software , Resultado do Tratamento , Adulto JovemRESUMO
There is increasing evidence that Turner syndrome is associated with a distinct pattern of cognitive and neurophysiological characteristics. Typically this has been characterized by relative strengths in verbal skills, contrasting with relative weaknesses in arithmetic, visuospatial and executive function domains. Potential differences in social cognitive processing have also been identified. More recently, applications of neuroimaging techniques have further elucidated underlying differences in brain structure, function and connectivity in individuals with Turner syndrome. Ongoing research in this area is focused on establishing a unified mechanistic model incorporating genetic influences from the X chromosome, sex hormone contributions, neuroanatomical variation and differences in cognitive processes. This review broadly covers current understanding of how X-monosomy impacts neurocognitive phenotype both from the perspective of cognitive-behavioral and neuroimaging studies. Furthermore, relevant clinical aspects of identifying potential learning difficulties and providing anticipatory guidance for affected individuals with TS, are briefly discussed.
Assuntos
Comportamento , Encéfalo/fisiopatologia , Transtornos Cognitivos/etiologia , Cognição , Deficiências da Aprendizagem/etiologia , Síndrome de Turner/complicações , Síndrome de Turner/psicologia , Função Executiva , Feminino , Humanos , Neuroimagem , Testes NeuropsicológicosRESUMO
To examine the potential mechanisms underlying social deficits in Turner Syndrome, we administered the empathic accuracy task (EAT) -a naturalistic social cognition task- and a (control) visual-motor line-tracking task to 14 girls with TS was compared to 12 age-matched typically developing girls (TD; ages 12 to 17). Empathic accuracy was compared across positive and negative emotionally valanced videos. We found that TS differs from TD on empathic accuracy ratings for negative videos; no differences were detected for the positive videos or for the control line tracking task. Thus, our findings suggest impaired detection of negatively valanced empathic interactions in TS and may help inform the future development of social-cognition treatment strategies for girls with TS.
Assuntos
Transtorno do Espectro Autista , Síndrome de Turner , Adolescente , Criança , Empatia , Feminino , Humanos , Masculino , Desempenho Psicomotor , Síndrome de Turner/psicologiaRESUMO
Brain dysfunction is the most important sequelae of the fragile X (FMR-1) mutation, the most common heritable cause of developmental disability. Using magnetic resonance imaging (MRI) and quantitative morphometry, we have compared the neuroanatomy of 51 individuals with an FMR-1 mutation with matched controls and showed that subjects with an FMR-1 mutation have increased volume of the caudate nucleus and, in males, the lateral ventricle. Both caudate and lateral ventricular volumes are correlated with IQ. Caudate volume is also correlated with the methylation status of the FMR-1 gene. Neuroanatomical differences between two monozygotic twins with an FMR-1 mutation who are discordant for mental retardation are localized to the cerebellum, lateral ventricles and subcortical nuclei. These findings suggest that the FMR-1 mutation causing the fragile X syndrome leads to observable changes in neuroanatomy that may be relevant to the neurodevelopmental disability and behavioural problems observed in affected individuals.
Assuntos
Encéfalo/patologia , Doenças em Gêmeos/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , DNA/metabolismo , Doenças em Gêmeos/psicologia , Feminino , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Deficiência Intelectual/genética , Inteligência , Imageamento por Ressonância Magnética , Masculino , Análise por Pareamento , Metilação , Fatores Sexuais , Gêmeos MonozigóticosRESUMO
In adults, interoception - the sense of the physiological condition of the body - appears to influence emotion processing, cognition, behavior and various somatic and mental health disorders. Adults demonstrate frontal-insula-parietal-anterior cingulate cortex activation during the heartbeat detection task, a common interoceptive measure. Little, however, is known about the functional neuroanatomy underlying interoception in children. The current pilot study examined interoceptive processing in children and adolescents with fMRI while using the heartbeat detection task. Our main findings demonstrate that children as young as the age of six activate the left insula, cuneus, inferior parietal lobule and prefrontal regions. These findings are similar to those in adults when comparing heartbeat and tone detection conditions. Age was associated with increased activation within the dACC, orbital frontal cortex and the mid-inferior frontal gyri. Thus, our pilot study may provide important information about the neurodevelopment of interoceptive processing abilities in children and a task for future interoception neuroimaging studies in children.
Assuntos
Córtex Cerebral/diagnóstico por imagem , Interocepção/fisiologia , Imageamento por Ressonância Magnética , Adolescente , Adulto , Mapeamento Encefálico , Criança , Feminino , Humanos , Masculino , Projetos PilotoRESUMO
The medial temporal lobe (MTL) plays an important role in memory encoding. The development and maturation of MTL and other brain regions involved in memory encoding are, however, poorly understood. We used functional magnetic resonance imaging to examine activation and effective connectivity of the MTL in children and adolescents during encoding of outdoor visual scenes. Here, we show that MTL response decreases with age whereas its connectivity with the left dorsolateral prefrontal cortex (PFC) increases with age. Our findings provide evidence for dissociable maturation of local and distributed memory encoding processes involving the MTL and furthermore suggest that increased functional interactions between the MTL and the PFC may underlie the development of more effective memory encoding strategies.
Assuntos
Mapeamento Encefálico , Memória/fisiologia , Vias Neurais/fisiologia , Lobo Temporal/fisiologia , Adolescente , Adulto , Fatores Etários , Análise de Variância , Criança , Feminino , Lateralidade Funcional/fisiologia , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Modelos Psicológicos , Vias Neurais/irrigação sanguínea , Testes Neuropsicológicos/estatística & dados numéricos , Oxigênio/sangue , Estimulação Luminosa/métodos , Tempo de Reação/fisiologia , Lobo Temporal/irrigação sanguíneaRESUMO
The relationship between fragility (the percentage of cells exhibiting the fragile X chromosome abnormality) and psychopathological conditions was investigated in a sample of 40 obligate female carriers of the fragile X chromosome. Subjects were categorized by those with positive fragility greater than 0% (n = 19) and those with 0% fragility (n = 21). Compared with women with 0% fragility, it was expected that women with positive fragility would have a higher likelihood of manifesting a spectrum of social and psychological disability previously shown to be associated with fragile X syndrome in women. It was also expected that within the group with positive fragility, degree of fragility would be related to severity of symptoms. Results partially supported the hypotheses: women with fragility over 0% were more likely to be assigned a diagnosis of schizotypal features, were rated higher on symptoms associated with the schizophrenia spectrum, and scored lower on IQ, level of healthiest functioning, education, and socioeconomic status than women with 0% fragility. Subsequent comparisons with a control group indicated that the group with 0% fragility and normal controls did not differ on these variables. Within the group with positive fragility, increasing fragility was related to greater severity of symptoms and lower IQ, education, socioeconomic status, and levels of adaptive functioning, as predicted. Contrary to expectations, positive fragility was not associated with proportion of affective disorder diagnoses or ratings on affective disorder symptoms. The results of the study provide evidence that degree of fragility is a potentially important predictor of psychopathology among women with normal IQ who are carriers of the fragile X chromosome abnormality.
Assuntos
Fragilidade Cromossômica , Síndrome do Cromossomo X Frágil/complicações , Heterozigoto , Transtornos Mentais/diagnóstico , Adulto , Escolaridade , Feminino , Síndrome do Cromossomo X Frágil/genética , Humanos , Inteligência , Transtornos Mentais/complicações , Transtornos do Humor/complicações , Transtornos do Humor/diagnóstico , Probabilidade , Escalas de Graduação Psiquiátrica , Esquizofrenia/complicações , Esquizofrenia/diagnóstico , Transtorno da Personalidade Esquizotípica/complicações , Transtorno da Personalidade Esquizotípica/diagnóstico , Fatores Sexuais , Ajustamento Social , Fatores SocioeconômicosRESUMO
Fragile X syndrome, an X-linked genetic condition, is an important genetic cause of mental retardation in males. In addition to mental retardation, hemizygous males with fragile X syndrome appear to have a greater likelihood of displaying behaviors classified under the diagnostic category of pervasive developmental disorder than would be expected on the basis of mental retardation alone. Although the majority of female heterozygotes with the fragile X genetic defect are of normal intelligence, our clinical work with this population and a recent case report have suggested that females with fragile X syndrome have an increased rate of schizophrenia spectrum and affective disorders. In this study, the relationship of the fragile X genetic defect to psychopathology in female heterozygotes is investigated by psychiatric evaluation of 35 obligate female carriers of the fragile X chromosome and a comparison group of 24 fragile X-negative controls. Female fragile X carriers were found to have a greater frequency of psychopathology associated with schizophrenia spectrum diagnoses, particularly schizotypal features. A weaker association between the fragile X genetic defect and chronic affective disorders was detected. The specificity of the neuropsychiatric phenotype occurring in particular genetic conditions such as the fragile X syndrome adds a potentially valuable tool to the study of psychopathology in the general population.
Assuntos
Síndrome do Cromossomo X Frágil/genética , Transtornos Mentais/diagnóstico , Aberrações dos Cromossomos Sexuais/genética , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/genética , Doença Crônica , Feminino , Síndrome do Cromossomo X Frágil/complicações , Humanos , Cariotipagem , Masculino , Transtornos Mentais/genética , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/genética , Cromossomo X/ultraestruturaRESUMO
BACKGROUND: As children with velocardiofacial syndrome (VCFS) develop, they are at increased risk for psychopathology; one third will eventually develop schizophrenia. Because VCFS and the concomitant symptomatology result from a known genetic origin, the biological and behavioral characteristics of the syndrome provide an optimal framework for conceptualizing the associations among genes, brain development, and behavior. The purpose of this study was to investigate the effect of the parental origin of the 22q11.2 microdeletion on the brain development of children and adolescents with VCFS. METHODS: Eighteen persons with VCFS and 18 normal control subjects were matched individually for age and sex. Results of DNA polymorphism analyses determined the parental origin of the deletion. Nine persons with VCFS had a deletion on the maternally derived chromosome 22; 9 persons, on the paternally derived chromosome 22. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of gray and white matter brain tissue. RESULTS: Total brain volume was approximately 11% smaller in the VCFS group than in controls. Comparisons between VCFS subgroups (maternal vs paternal microdeletion 22q11.2) indicated a significant 9% volumetric difference in total volume of cerebral gray matter (volume was greater in patients with paternal microdeletion) but not cerebral white matter. Significant age-related changes in gray matter were detected for subjects whose 22q11.2 deletion was on the maternal chromosome. CONCLUSIONS: Children and adolescents with VCFS experience major alterations in brain volumes. Significant reduction in gray matter development is attributable to presence of 22q11.2 microdeletion on the maternal chromosome.
Assuntos
Anormalidades Múltiplas/genética , Encéfalo/anatomia & histologia , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Anormalidades Craniofaciais/genética , Anormalidades Múltiplas/diagnóstico , Adolescente , Encéfalo/crescimento & desenvolvimento , Criança , Anormalidades Craniofaciais/diagnóstico , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Polimorfismo Genético , Cromossomo X/genética , Cromossomo Y/genéticaRESUMO
Studies have shown that a functional polymorphism of the serotonin transporter gene (5-HTTLPR) impacts performance on memory-related tasks and the hippocampal structures that subserve these tasks. The short (s) allele of 5-HTTLPR has been linked to greater susceptibility for impaired memory and smaller hippocampal volume compared to the long allele (l). However, previous studies have not examined the associations between 5-HTTLPR allele and activation in subregions of the hippocampus. In this study, we used functional magnetic resonance imaging (fMRI) to measure activation in hippocampal and temporal lobe subregions in 36 elderly non-clinical participants performing a face-name encoding and recognition task. Although there were no significant differences in task performance between s allele carriers and l homozygotes, right CA1 and right parahippocampal activation during recognition errors was significantly greater in individuals bearing the s allele. In an exploratory analysis, we determined that these effects were more pronounced in s allele carriers with the apolipoprotein É4 allele. Our results suggest that older individuals with the s allele inefficiently allocate neural resources while making errors in recognizing face-name associations, which could negatively impact memory performance during more challenging tasks.
Assuntos
Envelhecimento/genética , Hipocampo , Transtornos da Memória , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Lobo Temporal/fisiopatologia , Idoso , Mapeamento Encefálico/métodos , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Memória/fisiologia , Transtornos da Memória/diagnóstico , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Transtornos da Memória/psicologia , Testes Neuropsicológicos , Tamanho do Órgão , Polimorfismo Genético , Análise e Desempenho de TarefasRESUMO
Fragile X syndrome is the most important X-linked etiology of mental retardation and developmental disability currently known. Accumulating evidence also indicates that male and female carriers of the fragile X genetic abnormality demonstrate a relatively specific pattern of psychiatric disturbance. Fragile X males frequently manifest behaviors from the autistic spectrum whereas females show dysfunction in social interaction, thought processes, and affective regulation. In this review, an overview of the fragile X syndrome is presented with a focus on the occurrence of particular neuropsychiatric characteristics in males and females. Relevant data from recent genetic and neurobiological research is also described. The ability to study individuals with a specific genetic cause of psychopathology such as fragile X syndrome makes this condition of particular interest to biological psychiatry.
Assuntos
Fragilidade Cromossômica , Síndrome do Cromossomo X Frágil/genética , Aberrações dos Cromossomos Sexuais/genética , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Córtex Cerebelar/patologia , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Linhagem , Fenótipo , Fatores SexuaisRESUMO
Recent reports in the literature have suggested a link between abnormalities of the cerebellar vermis and the behavioral syndrome of autism. Joubert syndrome is an autosomal recessive disorder characterized by partial or complete agenesis of the cerebellar vermis. However, there is little behavioral or psychiatric description of patients with this genetic condition. In this report, the neuropsychiatric characteristics of two children with Joubert syndrome are described in detail. One child met DSM-III-R diagnostic criteria for autistic disorder, while the other displayed autistic features. The female child displayed stereotypic behavior and impairments in social interaction and communication, had a markedly restricted repertoire of interests, and showed distress over changes in the environment. The male child demonstrated perseveration and preoccupation with sounds and textures, but had no abnormalities in social interaction. Although both children showed developmental disabilities, the degree of cognitive delay was significantly less than that described in previous reports of children with Joubert syndrome. This report adds to the growing body of evidence implicating cerebellar involvement in developmental disabilities and autistic behavior.
Assuntos
Transtorno Autístico/genética , Cerebelo/anormalidades , Aberrações Cromossômicas/genética , Genes Recessivos/genética , Deficiência Intelectual/genética , Transtorno Autístico/diagnóstico , Transtorno Autístico/psicologia , Cerebelo/patologia , Criança , Pré-Escolar , Aberrações Cromossômicas/diagnóstico , Aberrações Cromossômicas/psicologia , Transtornos Cromossômicos , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/psicologia , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/psicologia , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , SíndromeRESUMO
BACKGROUND: Velocardiofacial syndrome (VCFS) has been identified as a risk factor for developing schizophrenia. Qualitative neuroimaging studies indicated that VCFS was frequently associated with abnormal development of structures in the posterior fossa of the brain. The objective of this investigation was to identify the specific structures affected in the posterior fossa and investigate the association of these neuroanatomic variations with behaviors potentially related to later-onset psychiatric disorders. METHODS: Twenty-four children and adolescents with VCFS individually matched for age and gender with 24 control subjects received magnetic resonance imaging scans. Analysis of covariance models were used to investigate regional brain differences. Association between brain areas and behaviors measured on the Child Behavior Checklist (CBCL) were assessed using simple regression models. RESULTS: Children with VCFS had significantly smaller size of vermal lobules VI--VII and the pons after adjusting for overall brain size. There were no significant associations between scores on the CBCL and measures of neuroanatomic variation within the VCFS group. CONCLUSIONS: Structural alterations of the posterior fossa in VCFS are specifically limited to cerebellar vermis lobules VI--VII and pons. Previous literature has suggested that the vermis is involved in social cognition, and alteration of lobules VI--VII could therefore partially explain the neurobehavioral profile associated with VCFS.
Assuntos
Fossa Craniana Posterior/anormalidades , Face/anormalidades , Cardiopatias Congênitas/complicações , Deficiências da Aprendizagem/complicações , Imageamento por Ressonância Magnética , Insuficiência Velofaríngea/complicações , Anormalidades Múltiplas , Adolescente , Encéfalo/anormalidades , Criança , Transtornos do Comportamento Infantil/complicações , Transtornos do Comportamento Infantil/diagnóstico , Transtornos Cognitivos/complicações , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Síndrome , Escalas de WechslerRESUMO
BACKGROUND: Volumetric imaging research has shown abnormal brain morphology in adults with posttraumatic stress disorder (PTSD) when compared with matched control subjects. In this article, we present brain imaging findings from a study of children with PTSD symptoms. METHODS: Twenty-four children between the ages of 7 and 14 with a history of trauma and PTSD symptoms were assessed with the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA). The sample underwent magnetic resonance imaging in a 1.5 T scanner. Brain images were analyzed by raters blind to diagnostic status using well-standardized methods, and images were compared with age- and gender-matched healthy control subjects. RESULTS: The clinical group demonstrated attenuation of frontal lobe asymmetry and smaller total brain and cerebral volumes when compared with the control group. There were no statistically significant differences in hippocampal volume between clinical and control subjects. CONCLUSIONS: Frontal lobe abnormalities may occur as a result of PTSD in children or, alternatively, be a risk factor for the development of the syndrome in this age group. The implications of the findings and their consistency with previous research are discussed.
Assuntos
Encéfalo/patologia , Imageamento por Ressonância Magnética , Transtornos de Estresse Pós-Traumáticos/patologia , Sobreviventes/psicologia , Adolescente , Tonsila do Cerebelo/patologia , Análise de Variância , Estudos de Casos e Controles , Criança , Comportamento Infantil , Desenvolvimento Infantil , Cognição , Feminino , Lobo Frontal/patologia , Hipocampo/patologia , Humanos , Inteligência , Masculino , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Escalas de WechslerRESUMO
OBJECTIVE: Velocardiofacial syndrome is a common genetic condition often accompanied by mild cognitive impairment. Children and adolescents with velocardiofacial syndrome also are at greater risk for developing serious neuropsychiatric disorders in adulthood, particularly schizophrenia-like disorders. The purpose of this preliminary study was to 1) elucidate through brain imaging the neurobiological basis of cognitive and neuropsychiatric problems in velocardiofacial syndrome, and 2) consider the association between variations in neuroanatomy in velocardiofacial syndrome subjects and the associated neurobehavioral phenotype. METHOD: Fifteen children and adolescents with velocardiofacial syndrome were matched by age and gender with 15 comparison subjects. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of specified brain tissues and regions. Rater-blind morphometric analyses were conducted to examine tissue volumes of the four lobes and the cerebellum. RESULTS: Total brain volume was approximately 11% smaller in the children with velocardiofacial syndrome. Gray matter volume was reduced to a lesser extent (7.5%) than white matter volume (16.3%). Multivariate analyses of variance indicated a distinct pattern of regional morphological variation among the children with velocardiofacial syndrome. Specifically, frontal lobe tissue tended to be enlarged relative to the overall reduction in brain volume. Normal symmetry of parietal lobe tissue observed in the comparison group was not evident in the velocardiofacial syndrome group. This loss of symmetry was attributable to a significant reduction of gray matter in the left parietal lobe. CONCLUSIONS: Aberrant brain morphology is associated with velocardiofacial syndrome. These changes are potentially related to the language and learning deficits associated with the syndrome and may provide clues about neurodevelopmental pathways associated with schizophrenia.
Assuntos
Anormalidades Múltiplas/diagnóstico , Encéfalo/anatomia & histologia , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Imageamento por Ressonância Magnética , Anormalidades Múltiplas/genética , Adolescente , Cerebelo/anatomia & histologia , Criança , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Feminino , Lobo Frontal/anatomia & histologia , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Humanos , Masculino , Lobo Occipital/anatomia & histologia , Lobo Parietal/anatomia & histologia , Síndrome , Lobo Temporal/anatomia & histologiaRESUMO
OBJECTIVE: Velocardiofacial syndrome results from a microdeletion on chromosome 22 (22q11.2). Clinical studies indicate that more than 30% of children with the syndrome will develop schizophrenia. The authors sought to determine whether neuroanatomical features in velocardiofacial syndrome are similar to those reported in the literature on schizophrenia by measuring the volumes of the temporal lobe, superior temporal gyrus, and mesial temporal structures in children and adolescents with velocardiofacial syndrome. METHOD: Twenty-three children and adolescents with velocardiofacial syndrome and 23 comparison subjects, individually matched for age and gender, received brain magnetic resonance imaging (MRI) scans. Analysis of covariance models were used to compare regional brain volumes. Correlations between residualized brain volumes and age were standardized and compared with the Fisher r-to-z transformation. RESULTS: Children with velocardiofacial syndrome had significantly smaller average temporal lobe, superior temporal gyrus, and hippocampal volumes than normal comparison children, although these differences were commensurate with a lower overall brain size in the affected children. In a cross-sectional analysis, children with velocardiofacial syndrome exhibited aberrant volumetric reductions with age that were localized to the temporal lobe and left hippocampal regions. CONCLUSIONS: Abnormal temporal lobe and hippocampal development in velocardiofacial syndrome is potentially concordant with MRI findings in the schizophrenia literature. Temporal lobe and mesial temporal structures may represent a shared substrate for the effects of the 22q11.2 deletion and for the complex etiological pathways that lead to schizophrenia. Longitudinal research may help determine which children with velocardiofacial syndrome are at risk for serious psychiatric illness in adulthood.
Assuntos
Anormalidades Múltiplas/diagnóstico , Cromossomos Humanos Par 22/genética , Deleção de Genes , Esquizofrenia/diagnóstico , Lobo Temporal/anatomia & histologia , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Adolescente , Adulto , Fatores Etários , Encéfalo/anatomia & histologia , Encéfalo/crescimento & desenvolvimento , Criança , Fissura Palatina/diagnóstico , Fissura Palatina/epidemiologia , Fissura Palatina/genética , Fácies , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Hipocampo/anatomia & histologia , Humanos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Síndrome , Insuficiência Velofaríngea/diagnóstico , Insuficiência Velofaríngea/epidemiologia , Insuficiência Velofaríngea/genéticaRESUMO
OBJECTIVE: Down's syndrome, the most common genetic cause of mental retardation, results in characteristic physical and neuropsychological findings, including mental retardation and deficits in language and memory. This study was undertaken to confirm previously reported abnormalities of regional brain volumes in Down's syndrome by using high-resolution magnetic resonance imaging (MRI), determine whether these volumetric abnormalities are present from childhood, and consider the relationship between neuroanatomic abnormalities and the cognitive profile of Down's syndrome. METHOD: Sixteen children and young adults with Down's syndrome (age range=5-23 years) were matched for age and gender with 15 normal comparison subjects. High-resolution MRI scans were quantitatively analyzed for measures of overall and regional brain volumes and by tissue composition. RESULTS: Consistent with prior imaging studies, subjects with Down's syndrome had smaller overall brain volumes, with disproportionately smaller cerebellar volumes and relatively larger subcortical gray matter volumes. Also noted was relative preservation of parietal lobe gray and temporal lobe white matter in subjects with Down's syndrome versus comparison subjects. No abnormalities in pattern of brain asymmetry were noted in Down's syndrome subjects. CONCLUSIONS: The results largely confirm findings of previous studies with respect to overall patterns of brain volumes in Down's syndrome and also provide new evidence for abnormal volumes of specific regional tissue components. The presence of these abnormalities from an early age suggests that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive and developmental deficits seen in individuals with Down's syndrome.
Assuntos
Encéfalo/anatomia & histologia , Síndrome de Down/diagnóstico , Imageamento por Ressonância Magnética/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Cerebelo/anatomia & histologia , Criança , Pré-Escolar , Feminino , Lobo Frontal/anatomia & histologia , Humanos , Masculino , Lobo Parietal/anatomia & histologia , Lobo Temporal/anatomia & histologiaRESUMO
OBJECTIVE: Fragile X syndrome is a neurogenetic disorder that is the most common known heritable cause of neurodevelopmental disability. This study examined the neural substrates of working memory in female subjects with fragile X syndrome. Possible correlations among behavioral measures, brain activation, and the FMR1 gene product (FMRP expression), as well as between IQ and behavioral measures, were investigated. METHOD: Functional magnetic resonance imaging was used to examine visuospatial working memory in 10 female subjects with fragile X syndrome and 15 typically developing female subjects (ages 10-23 years). Subjects performed standard 1-back and 2-back visuospatial working memory tasks. Brain activation was examined in four regions of the cortex known to play a critical role in visuospatial working memory. Correlations between behavioral, neuroimaging, and molecular measures were examined. RESULTS: Relative to the comparison group, subjects with fragile X syndrome performed significantly worse on the 2-back task but not on the 1-back task. In a region-of-interest analysis focused on the inferior frontal gyrus, middle frontal gyrus, superior parietal lobule, and supramarginal gyrus, comparison subjects showed significantly increased brain activation between the 1-back and 2-back tasks, but subjects with fragile X syndrome showed no change in activation between the two tasks. Significant correlations were found in comparison subjects between activation in the frontal and parietal regions and the rate of correct responses on the 2-back task, but not on the 1-back task. In subjects with fragile X syndrome, significant correlations were found during the 2-back task between FMRP expression and activation in the right inferior and bilateral middle frontal gyri and the bilateral supramarginal gyri. CONCLUSIONS: Subjects with fragile X syndrome are unable to modulate activation in the prefrontal and parietal cortex in response to an increasing working memory load, and these deficits are related to a lower level of FMRP expression in fragile X syndrome subjects than in normal comparison subjects. The observed correlations between biological markers and brain activation provide new evidence for links between gene expression and cognition.