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1.
Epilepsia ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31691264

RESUMO

OBJECTIVE: To determine if routine electroencephalography (EEG) in seizure-naive infants with tuberous sclerosis complex (TSC) can predict epilepsy and subsequent neurocognitive outcomes. METHODS: Forty infants 7 months of age or younger and meeting the genetic or clinical diagnostic criteria for tuberous sclerosis were enrolled. Exclusion criteria included prior history of seizures or treatment with antiseizure medications. At each visit, seizure history and 1-hour awake and asleep video-EEG, standardized across all sites, were obtained until 2 years of age. Developmental assessments (Mullen and Vineland-II) were completed at 6, 12, and 24 months of age. RESULTS: Of 40 infants enrolled (mean age of 82.4 days), 32 completed the study. Two were lost to follow-up and six were treated with antiepileptic drugs (AEDs) due to electrographic seizures and/or interictal epileptiform discharges (IEDs) on their EEG studies prior to the onset of clinical seizures. Seventeen of the 32 remaining children developed epilepsy at a mean age of 7.5 months (standard deviation [SD] = 4.4). Generalized/focal slowing, hypsarrhythmia, and generalized/focal attenuation were not predictive for the development of clinical seizures. Presence of IEDs had a 77.3% positive predictive value and absence a 70% negative predictive value for developing seizures by 2 years of age. IEDs preceded clinical seizure onset by 3.6 months (mean). Developmental testing showed significant decline, only in infants with ongoing seizures, but not infants who never developed seizures or whose seizures came under control. SIGNIFICANCE: IEDs identify impending epilepsy in the majority (77%) of seizure-naive infants with TSC. The use of a 1-hour awake and asleep EEG can be used as a biomarker for ongoing epileptogenesis in most, but not all, infants with TSC. Persistent seizures, but not history of interictal epileptiform activity or history of well-controlled seizures, correlated with low scores on the Vineland and Mullen tests at 2 years of age.

2.
Am Psychol ; 74(3): 356-367, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30945897

RESUMO

The Tuberous Sclerosis Complex Autism Center of Excellence Network (TACERN) is a 6-site collaborative conducting longitudinal research on infants with tuberous sclerosis complex (TSC), focused on identifying early biomarkers for autism spectrum disorder (ASD). A multidisciplinary research team that includes the specialties of psychology, neurology, pediatrics, medical genetics, and speech-language pathology, its members work together to conduct studies on neurological status, brain structure and function, neurodevelopmental phenotype, and behavioral challenges in this population. This article provides insights into the roles of the multidisciplinary multisite team and lessons learned from the collaboration, in terms of research as well as training of future researchers and clinicians. In addition, the authors detail the major findings to date, including those related to the identification and measurement of early symptoms of ASD, relationship between seizures and early development, and early biomarkers for epilepsy and developmental delay in infants and young children with TSC. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

3.
Transl Psychiatry ; 9(1): 107, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837452

RESUMO

One of the co-authors, Marianne B.M. van den Bree has had her name incorrectly abbreviated by citation manager. It was stated as "Bree MBMVD14", but has been updated to "van den Bree, M.B.M." in the HTML, PDF, and XML versions of this article.

4.
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
5.
Am J Med Genet B Neuropsychiatr Genet ; 174(4): 367-380, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28349640

RESUMO

Copy number variation at 16p11.2 is associated with diverse phenotypes but little is known about the early developmental trajectories and emergence of the phenotype. This longitudinal study followed 56 children with the 16p11.2 BP4-BP5 deletion or duplication between the ages of 6 months and 8 years with diagnostic characterization and dimensional assessment across cognitive, adaptive, and behavioral domains. Linear mixed modeling revealed distinct developmental trajectories with deletions showing VIQ gains but declines in motor and social abilities while duplications showed VIQ gains and steady development across other domains. Nonparametric analyses suggest distinct trajectories and early cognitive abilities for deletion carriers who are ultimately diagnosed with intellectual disability and developmental coordination disorder as well as distinct trajectories and early social communication and cognitive abilities for duplication carriers diagnosed with ASD and intellectual disability. Findings provide predictions for patient developmental trajectories, insight into mean functioning of individuals with 16p11.2 at early ages, and highlight the need for ongoing monitoring of social and motor functioning and behavioral symptomatology to improve treatment planning. © 2017 Wiley Periodicals, Inc.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Estudos Longitudinais , Masculino , Fenótipo , Prognóstico
6.
J Autism Dev Disord ; 46(8): 2734-48, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27207092

RESUMO

The 16p11.2 duplication (BP4-BP5) is associated with Autism Spectrum Disorder (ASD), although significant heterogeneity exists. Quantitative ASD, behavioral and neuropsychological measures and DSM-IV diagnoses in child and adult carriers were compared with familial non-carrier controls, and to published results from deletion carriers. The 16p11.2 duplication phenotype ranges widely from asymptomatic presentation to significant disability. The most common diagnoses were intellectual disability, motor delays and Attention Deficit Hyperactivity Disorder in children, and anxiety in adults. ASD occurred in nearly 20 % of child cases, but a majority of carriers did not show the unique social features of ASD. The 16p11.2 duplication phenotype is characterized by wider variability than the reciprocal deletion, likely reflecting contributions from additional risk factors.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Cromossomos Humanos Par 16/genética , Duplicação Gênica/genética , Adolescente , Adulto , Transtorno do Espectro Autista/diagnóstico , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/psicologia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Masculino , Fenótipo
7.
Biol Psychiatry ; 80(2): 129-139, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-26742926

RESUMO

BACKGROUND: Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. METHODS: This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. RESULTS: IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. CONCLUSIONS: The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances.


Assuntos
Transtorno Autístico , Deleção Cromossômica , Transtornos Cromossômicos , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Disfunção Cognitiva , Variações do Número de Cópias de DNA/genética , Função Executiva/fisiologia , Deficiência Intelectual , Inteligência/genética , Linguagem , Memória/fisiologia , Destreza Motora/fisiologia , Adolescente , Adulto , Transtorno Autístico/diagnóstico por imagem , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Criança , Pré-Escolar , Transtornos Cromossômicos/diagnóstico por imagem , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Feminino , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
8.
Res Dev Disabil ; 48: 160-75, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26579706

RESUMO

Repetitive behaviors, restricted interests and other unusual sensory behaviors often significantly impact the lives of many individuals with developmental disabilities, including Autism Spectrum Disorder (ASD). Identifying specific patterns of atypical behaviors across different disorders allows for improved specificity of diagnoses, monitoring response to treatment and elucidating the genetic and neurobiological underpinnings of these disorders. The Behavior and Sensory Interests Questionnaire (BSIQ) is a newly designed, continuous dimensional instrument that comprehensively assesses the type, frequency, intensity, age of onset, and duration of these behaviors. The BSIQ takes 15-40 min to administer to a caregiver in an interview format. Using a large sample of children with either ASD, intellectual disabilities or who were typically developing, the construct validity of the BSIQ was confirmed using a series of multi-group confirmatory factor analysis models. Configural and metric invariance were satisfied, but not scalar invariance, as expected. The BSIQ showed acceptable internal consistency, excellent inter-rater reliability and excellent test-retest reliability.


Assuntos
Transtorno do Espectro Autista , Cognição , Deficiências do Desenvolvimento , Relações Interpessoais , Comportamento Estereotipado , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/psicologia , Sintomas Comportamentais/diagnóstico , Criança , Comportamento Infantil/psicologia , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/psicologia , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensação , Inquéritos e Questionários
9.
Genet Med ; 18(4): 341-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26066539

RESUMO

PURPOSE: To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains. METHODS: Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging. RESULTS: Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers. CONCLUSIONS: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.Genet Med 18 4, 341-349.


Assuntos
Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 1 , Variações do Número de Cópias de DNA , Fenótipo , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Sistema de Registros , Adulto Jovem
10.
JAMA Psychiatry ; 73(1): 20-30, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26629640

RESUMO

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.


Assuntos
Transtorno do Espectro Autista/psicologia , Transtorno Autístico/psicologia , Transtornos Cromossômicos/psicologia , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Cognição , Deficiência Intelectual/psicologia , Esquizofrenia/genética , Adolescente , Adulto , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Transtorno Autístico/epidemiologia , Transtorno Autístico/genética , Estudos de Casos e Controles , Cerebelo/anormalidades , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Estudos de Coortes , Comorbidade , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/genética , Epilepsia/epidemiologia , Epilepsia/genética , Feminino , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Microcefalia/epidemiologia , Microcefalia/genética , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/epidemiologia , Malformações do Sistema Nervoso/genética , Esquizofrenia/epidemiologia , Psicologia do Esquizofrênico , Adulto Jovem
11.
Sleep ; 38(12): 1955-63, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26194566

RESUMO

STUDY OBJECTIVES: Examine the role of sleep in the consolidation of declarative memory in children with autism spectrum disorder (ASD). DESIGN: Case-control study. SETTING: Home-based study with sleep and wake conditions. PARTICIPANTS: Twenty-two participants with ASD and 20 control participants between 9 and 16 y of age. MEASUREMENTS AND RESULTS: Participants were trained to criterion on a spatial declarative memory task and then given a cued recall test. Retest occurred after a period of daytime wake (Wake) or a night of sleep (Sleep) with home-based polysomnography; Wake and Sleep conditions were counterbalanced. Children with ASD had poorer sleep efficiency than controls, but other sleep macroarchitectural and microarchitectural measures were comparable after controlling for age and medication use. Both groups demonstrated better memory consolidation across Sleep than Wake, although participants with ASD had poorer overall memory consolidation than controls. There was no interaction between group and condition. The change in performance across sleep, independent of medication and age, showed no significant relationships with any specific sleep parameters other than total sleep time and showed a trend toward less forgetting in the control group. CONCLUSION: This study shows that despite their more disturbed sleep quality, children with autism spectrum disorder (ASD) still demonstrate more stable memory consolidation across sleep than in wake conditions. The findings support the importance of sleep for stabilizing memory in children with and without neurodevelopmental disabilities. Our results suggest that improving sleep quality in children with ASD could have direct benefits to improving their overall cognitive functioning.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Consolidação da Memória/fisiologia , Sono/fisiologia , Adolescente , Transtorno do Espectro Autista/complicações , Estudos de Casos e Controles , Criança , Cognição/fisiologia , Sinais (Psicologia) , Feminino , Humanos , Masculino , Transtornos da Memória/complicações , Transtornos da Memória/fisiopatologia , Transtornos da Memória/psicologia , Rememoração Mental/fisiologia , Polissonografia , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/fisiopatologia , Transtornos do Sono-Vigília/psicologia , Vigília/fisiologia
12.
JAMA Psychiatry ; 72(2): 119-26, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25493922

RESUMO

IMPORTANCE: Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood. OBJECTIVES: To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs. DESIGN, SETTING, AND PARTICIPANTS: Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project. MAIN OUTCOMES AND MEASURES: We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison. RESULTS: A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD for neuromotor performance (P < .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07). CONCLUSIONS AND RELEVANCE: Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their children's developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders.


Assuntos
Transtorno Autístico/fisiopatologia , Transtornos Cromossômicos/fisiopatologia , Deficiência Intelectual/fisiopatologia , Inteligência/genética , Pais , Fenótipo , Desempenho Psicomotor/fisiologia , Comportamento Social , Adulto , Transtorno Autístico/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Irmãos
13.
Biol Psychiatry ; 77(9): 785-93, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25064419

RESUMO

BACKGROUND: Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. METHODS: To clarify the phenotype of 16p11.2 deletion, we examined the psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. Using an extensive standardized assessment battery across three clinical sites, 85 individuals with the 16p11.2 deletion and 153 familial control subjects were evaluated for symptom presentation and clinical diagnosis. RESULTS: Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonologic processing disorder, expressive and receptive language disorders (71% of individuals >3 years old with a speech and language-related disorder), and autism spectrum disorder. Individuals with the 16p11.2 deletion not meeting diagnostic criteria for autism spectrum disorder had a significantly higher prevalence of autism-related characteristics compared with the familial noncarrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than noncarrier family members on average. CONCLUSIONS: Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 16 , Cognição , Deficiências do Desenvolvimento/genética , Transtornos Mentais/genética , Fenótipo , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/psicologia , Heterozigoto , Humanos , Inteligência/genética , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Adulto Jovem
14.
Clin Pediatr (Phila) ; 53(3): 230-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24391123

RESUMO

BACKGROUND: Dental care is a significant unmet health care need for children with autism spectrum disorders (ASD). Many children with ASD do not receive dental care because of fear associated with dental procedures; oftentimes they require general anesthesia for regular dental procedures, placing them at risk of associated complications. Many children with ASD have a strong preference for visual stimuli, particularly electronic screen media. The use of visual teaching materials is a fundamental principle in designing educational programs for children with ASD. PURPOSE: To determine if an innovative strategy using 2 types of electronic screen media was feasible and beneficial in reducing fear and uncooperative behaviors in children with ASD undergoing dental visits. METHODS: We conducted a randomized controlled trial at Boston Children's Hospital dental clinic. Eighty (80) children aged 7 to 17 years with a known diagnosis of ASD and history of dental fear were enrolled in the study. Each child completed 2 preventive dental visits that were scheduled 6 months apart (visit 1 and visit 2). After visit 1, subjects were randomly assigned to 1 of 4 groups: (1) group A, control (usual care); (2) group B, treatment (video peer modeling that involved watching a DVD recording of a typically developing child undergoing a dental visit); (3) group C, treatment (video goggles that involved watching a favorite movie during the dental visit using sunglass-style video eyewear); and (4) group D, treatment (video peer modeling plus video goggles). Subjects who refused or were unable to wear the goggles watched the movie using a handheld portable DVD player. During both visits, the subject's level of anxiety and behavior were measured using the Venham Anxiety and Behavior Scales. Analyses of variance and Fisher's exact tests compared baseline characteristics across groups. Using intention to treat approach, repeated measures analyses were employed to test whether the outcomes differed significantly: (1) between visits 1 and 2 within each group and (2) between each intervention group and the control group over time (an interaction). RESULTS: Between visits 1 and 2, mean anxiety and behavior scores decreased significantly by 0.8 points (P = .03) for subjects within groups C and D. Significant changes were not observed within groups A and B. Mean anxiety and behavior scores did not differ significantly between groups over time, although group A versus C pairwise comparisons showed a trend toward significance (P = .06). CONCLUSION: These findings suggest that certain electronic screen media technologies may be useful tools for reducing fear and uncooperative behaviors among children with ASD undergoing dental visits. Further studies are needed to assess the efficacy of these strategies using larger sample sizes. Findings from future studies could be relevant for nondental providers who care for children with ASD in other medical settings.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/psicologia , Meios de Comunicação , Ansiedade ao Tratamento Odontológico/psicologia , Ansiedade ao Tratamento Odontológico/terapia , Filmes Cinematográficos , Estimulação Luminosa/métodos , Adolescente , Comportamento do Adolescente/psicologia , Análise de Variância , Boston , Criança , Comportamento Infantil/psicologia , Transtornos Globais do Desenvolvimento Infantil/complicações , Ansiedade ao Tratamento Odontológico/complicações , Medo/psicologia , Estudos de Viabilidade , Feminino , Necessidades e Demandas de Serviços de Saúde , Humanos , Masculino , Projetos Piloto
15.
PLoS One ; 8(9): e75286, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24086496

RESUMO

BACKGROUND AND PURPOSE: Coagulation factor XI (FXI) has an important role in the propagation and stabilization of a thrombus upon vessel injury. High FXI levels have been implicated in thrombotic diseases including ischemic stroke. The aim of our study was to investigate whether FXI gene (F11) variants are associated with ischemic stroke. METHODS: The discovery sample, the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), included 844 patients with ischemic stroke and 668 controls, all aged 18-70 years. Replication was performed in the Lund Stroke Register (LSR) and Malmö Diet and Cancer study (MDC), together including 1213 patients and 788 controls up to 70 years of age, and in total 3145 patients and 1793 controls (18-102 years). Seven F11 single-nucleotide polymorphisms (SNPs) were selected using a tagging approach. RESULTS: The SNPs rs3733403, rs925451, and rs1593 showed independent associations with overall ischemic stroke in SAHLSIS, ORs of 0.74 (95% CI 0.59-0.94), 1.24 (95% CI 1.06-1.46), and 0.70 (95% CI 0.55-0.90), respectively. The association for rs925451 was replicated in the LSR and MDC sample in a pre-specified analysis of subjects aged 70 years or younger, OR of 1.16 (95% CI 1.00-1.34), whereas no SNP was replicated when all ages were included. In line with this, one F11 haplotype was associated with overall ischemic stroke in the discovery sample and in the replication sample ≤70 years. CONCLUSIONS: We found significant associations between F11 variation and overall ischemic stroke up to 70 years of age. These findings motivate further studies on the role of F11 in ischemic stroke, especially in younger individuals.


Assuntos
Fator XI/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Acidente Vascular Cerebral/genética , Adulto , Fatores Etários , Idoso , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Suécia
17.
J Autism Dev Disord ; 43(6): 1459-64, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23065101

RESUMO

Currently, both the DSM-IV-TR and ICD-10 preclude the diagnosis of attention deficit/hyperactivity disorder (ADHD) in cases that present with an autism spectrum disorder (ASD). This criterion will be removed in the upcoming DSM-V, but the relationship between ASD and ADHD, and in particular the prevalence of ADHD among the ASD population, remains controversial. Previous studies have reported clinically significant ADHD symptoms in one-third to three-quarters of ASD-affected individuals (probands). In our sample of 1,838 simplex children and adolescents with ASD, we found that less than 16% met clinically significant levels of ADHD symptoms, per parent report. When both parent and teacher reports were considered, the comorbidity rate was even lower, at 2%.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Adolescente , Criança , Pré-Escolar , Comorbidade , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Prevalência , Sistema de Registros
19.
PLoS One ; 7(12): e49475, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23227143

RESUMO

Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases. Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62-0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65-0.82), but not for female samples (AUC 0.51, 95% CI 0.36-0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58-0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Transcriptoma , Criança , Transtornos Globais do Desenvolvimento Infantil/sangue , Estudos de Coortes , Perfilação da Expressão Gênica , Humanos , Masculino , Modelos Genéticos , Análise de Sequência com Séries de Oligonucleotídeos
20.
J Med Genet ; 49(10): 660-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23054248

RESUMO

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Deleção Cromossômica , Cromossomos Humanos Par 16 , Deficiências do Desenvolvimento/genética , Fenótipo , Adolescente , Adulto , Índice de Massa Corporal , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Deficiências do Desenvolvimento/diagnóstico , Feminino , Ordem dos Genes , Heterozigoto , Humanos , Testes de Inteligência , Masculino , Síndrome , Adulto Jovem
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