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Eric Fombonne - One of the best experts on this subject based on the ideXlab platform.
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epidemiology of pervasive developmental Disorders
Pediatric Research, 2009Co-Authors: Eric FombonneAbstract:This article reviews the results of 43 studies published since 1966 that provided estimates for the prevalence of pervasive developmental Disorders (PDDs), including autistic Disorder, Asperger Disorder, PDD not otherwise specified, and Childhood Disintegrative Disorder. The prevalence of autistic Disorder has increased in recent surveys and current estimates of prevalence are around 20/10,000, whereas the prevalence for PDD not otherwise specified is around 30/10,000 in recent surveys. Prevalence of Asperger Disorder is much lower than that for autistic Disorder and Childhood Disintegrative Disorder is a very rare Disorder with a prevalence of about 2/100,000. Combined all together, recent studies that have examined the whole spectrum of PDDs have consistently provided estimates in the 60-70/10,000 range, making PDD one of the most frequent Childhood neurodevelopmental Disorders. The meaning of the increase in prevalence in recent decades is reviewed. There is evidence that the broadening of the concept, the expansion of diagnostic criteria, the development of services, and improved awareness of the condition have played a major role in explaining this increase, although it cannot be ruled out that other factors might have also contributed to that trend.
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epidemiology of autistic Disorder and other pervasive developmental Disorders
The Journal of Clinical Psychiatry, 2005Co-Authors: Eric FombonneAbstract:Is the incidence of autistic Disorder and other pervasive developmental Disorders (PDDs) increasing? Recent epidemiological surveys of autistic Disorder and other PDDs have heightened awareness of and concern about the prevalence of these Disorders; however, differences in survey methodology, particularly changes in case definition and case identification over time, have made comparisons between surveys difficult to perform and interpret. Recent surveys suggest that the rate of all PDDs is about 60 per 10,000. The prevalence of autism today is estimated at 13 per 10,000, Asperger's Disorder is approximately 3 per 10,000, and Childhood Disintegrative Disorder is very rare at about 0.2 per 10,000. The assessment process, sample size, publication year, and geographic location of studies all have an effect on prevalence estimates. In addition, data from many of these surveys indicate correlates of autistic Disorder and other PDDs with IQ, gender, and other medical Disorders.
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epidemiological surveys of autism and other pervasive developmental Disorders an update
Journal of Autism and Developmental Disorders, 2003Co-Authors: Eric FombonneAbstract:This paper was commissioned by the committee on the Effectiveness of Early Education in Autism of the National Research Council (NRC). It provides a review of epidemiological studies of pervasive developmental Disorders (PDD) which updates a previously published article (The epidemiology of autism: a review. Psychological Medicine 1999; 29: 769–786). The design, sample characteristics of 32 surveys published between 1966 and 2001 are described. Recent surveys suggest that the rate for all forms of PDDs are around 30/10,000 but more recent surveys suggest that the estimate might be as high as 60/10,000. The rate for Asperger Disorder is not well established, and a conservative figure is 2.5/10,000. Childhood Disintegrative Disorder is extremely rare with a pooled estimate across studies of 0.2/10,000. A detailed discussion of the possible interpretations of trends over time in prevalence rates is provided. There is evidence that changes in case definition and improved awareness explain much of the upward trend of rates in recent decades. However, available epidemiological surveys do not provide an adequate test of the hypothesis of a changing incidence of PDDs.
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No evidence for a new variant of measles-mumps-rubella-induced autism.
Pediatrics, 2001Co-Authors: Eric Fombonne, Suniti ChakrabartiAbstract:Objective. A link has been postulated between measles-mumps-rubella (MMR) vaccine and a form of autism that is a combination of developmental regression and gastrointestinal symptoms that occur shortly after immunization. This hypothesis has involved 3 separate claims: 1) that there is new phenotype of autism involving regression and gastrointestinal symptoms, 2) that this new variant is responsible for the alleged rise of autism rates, and 3) that this phenotype is associated with biological findings suggestive of the persistence of measles infection. We tested the first of these claims. If this new “autistic enterocolitis” syndrome had some validity, then 1 or several of the following 6 predictions should be supported by empirical data: 1) Childhood Disintegrative Disorder has become more frequent, 2) the mean age of first parental concern for autistic children who are exposed to MMR is closer to the mean immunization age than in children who are not exposed to MMR, 3) regression in the development of children with autism has become more common in MMR-vaccinated children, 4) the age of onset for autistic children with regression clusters around the MMR immunization date and is different from that of autistic children without regression, 5) children with regressive autism have distinct symptom and severity profiles, and 6) regressive autism is associated with gastrointestinal symptoms and/or inflammatory bowel Disorder. Methods. Three samples were used. Epidemiologic data on 96 children (95 immunized with MMR at a median age of 13.5 months) who were born between 1992 and 1995 and had a pervasive developmental Disorder diagnosis as reported in a recent UK survey (post-MMR sample) were compared with data from 2 previous clinical samples (1 pre-MMR [ n = 98] and 1 post-MMR [ n = 68]) of autistic patients. All patients were assessed with the standardized Autism Diagnostic Interview (ADI), allowing rigorous comparison of age at first parental concerns and rates of regression across samples. Reliability was excellent on ADI scores, age of parental concern, and developmental regression. Furthermore, data on bowel symptoms and Disorders were available in the epidemiologic survey from both pediatric and parental sources, and immunization dates were obtained from computerized records. Results. The prevalence of Childhood Disintegrative Disorder was 0.6/10 000 (95% confidence interval: 0.02–3.6/10 000); this very low rate is consistent with previous estimates and is not suggestive of an increased frequency of this form of pervasive developmental Disorder in samples of children who are immunized with MMR. There was no difference in the mean age at first parental concern between the 2 samples exposed to MMR (19.3 and 19.2 months) and the pre-MMR sample (19.5 months). Thus, MMR immunization was not associated with a shift toward an earlier age for first parental concerns. Similarly, the rate of developmental regression reported in the post-MMR sample (15.6%) was not different from that in the pre-MMR sample (18.4%); therefore, there was no suggestion that regression in the developmental course of autism had increased in frequency since MMR was introduced. In the epidemiologic sample, the subset of autistic children with regression had no other developmental or clinical characteristics, which would have argued for a specific, etiologically distinct phenotype. Parents of autistic children with developmental regression detected the first symptoms at a very similar age (19.8 months) to those of autistic children without regression (19.3 months). Moreover, the mean intervals from MMR immunization to parental recognition of autistic symptoms were comparable in autistic children with or without regression (248 vs 272 days; not significant). In the epidemiologic sample, gastrointestinal symptoms were reported in 18.8% of children. Constipation was the most common symptom (9.4%), and no inflammatory bowel Disorder was reported. Furthermore, there was no association between developmental regression and gastrointestinal symptoms (odds ratio: 0.63; 95% confidence interval: 0.06–3.2; not significant), and only 2.1% of the sample experienced both problems, a rate that did not exceed chance expectations. Conclusions. No evidence was found to support a distinct syndrome of MMR-induced autism or of “autistic enterocolitis.” These results add to the recent accumulation of large-scale epidemiologic studies that all failed to support an association between MMR and autism at population level. When combined, the current findings do not argue for changes in current immunization programs and recommendations.
Jose S Schwartzman - One of the best experts on this subject based on the ideXlab platform.
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Non-autistic pervasive developmental Disorders: Rett syndrome, Disintegrative Disorder and pervasive developmental Disorder not otherwise specified
Revista brasileira de psiquiatria (Sao Paulo Brazil : 1999), 2006Co-Authors: Marcos T Mercadante, Rutger J Van Der Gaag, Jose S SchwartzmanAbstract:The category "Pervasive Developmental Disorders" includes autistic Disorder, Asperger's syndrome, Rett's syndrome, Childhood Disintegrative Disorder, and a residual category, named pervasive developmental Disorder not otherwise specified. In this review, Rett's syndrome and Childhood Disintegrative Disorder, which are well-defined categories, will be discussed, as well as the not well defined categories that have been included in the Pervasive Developmental Disorder Not Otherwise Specified group. Different proposals of categorization have been created, some of which based on descriptive phenomenological approach, and others based upon other theoretical perspectives, such as neuropsychology. Current proposals are presented and discussed, followed by critical appraisals on the clinical advantages and disadvantages of these concepts.
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Transtornos invasivos do desenvolvimento não-autísticos: síndrome de Rett, transtorno desintegrativo da infância e transtornos invasivos do desenvolvimento sem outra especificação Non-autistic pervasive developmental Disorders: Rett syndrome, Disintegrative Disorder and pervasive developmental Disorder not otherwise specified
Associação Brasileira de Psiquiatria (ABP), 2006Co-Authors: Marcos T Mercadante, Rutger J Van Der Gaag, Jose S SchwartzmanAbstract:A categoria "transtorno invasivos do desenvolvimento" inclui o autismo, a síndrome de Asperger, a síndrome de Rett, o transtorno desintegrativo da infância e uma categoria residual denominada transtornos invasivos do desenvolvimento sem outra especificação. Nesta revisão, a síndrome de Rett e o transtorno desintegrativo da infância, que são categorias bem definidas, serão discutidas, assim como as categorias não tão bem definidas que foram incluídas no grupo transtornos invasivos do desenvolvimento sem outra especificação. Diferentes propostas de categorização têm sido feitas, algumas baseadas em abordagem fenomenológica descritiva, outras baseadas em outras perspectivas teóricas, tais como a neuropsicologia. As propostas atuais são apresentadas e discutidas, seguidas por avaliações críticas sobre as vantagens e desvantagens desses conceitos.The category "Pervasive Developmental Disorders" includes autistic Disorder, Asperger's syndrome, Rett's syndrome, Childhood Disintegrative Disorder, and a residual category, named pervasive developmental Disorder not otherwise specified. In this review, Rett's syndrome and Childhood Disintegrative Disorder, which are well-defined categories, will be discussed, as well as the not well defined categories that have been included in the Pervasive Developmental Disorder Not Otherwise Specified group. Different proposals of categorization have been created, some of which based on descriptive phenomenological approach, and others based upon other theoretical perspectives, such as neuropsychology. Current proposals are presented and discussed, followed by critical appraisals on the clinical advantages and disadvantages of these concepts
Marcos T Mercadante - One of the best experts on this subject based on the ideXlab platform.
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Non-autistic pervasive developmental Disorders: Rett syndrome, Disintegrative Disorder and pervasive developmental Disorder not otherwise specified
Revista brasileira de psiquiatria (Sao Paulo Brazil : 1999), 2006Co-Authors: Marcos T Mercadante, Rutger J Van Der Gaag, Jose S SchwartzmanAbstract:The category "Pervasive Developmental Disorders" includes autistic Disorder, Asperger's syndrome, Rett's syndrome, Childhood Disintegrative Disorder, and a residual category, named pervasive developmental Disorder not otherwise specified. In this review, Rett's syndrome and Childhood Disintegrative Disorder, which are well-defined categories, will be discussed, as well as the not well defined categories that have been included in the Pervasive Developmental Disorder Not Otherwise Specified group. Different proposals of categorization have been created, some of which based on descriptive phenomenological approach, and others based upon other theoretical perspectives, such as neuropsychology. Current proposals are presented and discussed, followed by critical appraisals on the clinical advantages and disadvantages of these concepts.
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Transtornos invasivos do desenvolvimento não-autísticos: síndrome de Rett, transtorno desintegrativo da infância e transtornos invasivos do desenvolvimento sem outra especificação Non-autistic pervasive developmental Disorders: Rett syndrome, Disintegrative Disorder and pervasive developmental Disorder not otherwise specified
Associação Brasileira de Psiquiatria (ABP), 2006Co-Authors: Marcos T Mercadante, Rutger J Van Der Gaag, Jose S SchwartzmanAbstract:A categoria "transtorno invasivos do desenvolvimento" inclui o autismo, a síndrome de Asperger, a síndrome de Rett, o transtorno desintegrativo da infância e uma categoria residual denominada transtornos invasivos do desenvolvimento sem outra especificação. Nesta revisão, a síndrome de Rett e o transtorno desintegrativo da infância, que são categorias bem definidas, serão discutidas, assim como as categorias não tão bem definidas que foram incluídas no grupo transtornos invasivos do desenvolvimento sem outra especificação. Diferentes propostas de categorização têm sido feitas, algumas baseadas em abordagem fenomenológica descritiva, outras baseadas em outras perspectivas teóricas, tais como a neuropsicologia. As propostas atuais são apresentadas e discutidas, seguidas por avaliações críticas sobre as vantagens e desvantagens desses conceitos.The category "Pervasive Developmental Disorders" includes autistic Disorder, Asperger's syndrome, Rett's syndrome, Childhood Disintegrative Disorder, and a residual category, named pervasive developmental Disorder not otherwise specified. In this review, Rett's syndrome and Childhood Disintegrative Disorder, which are well-defined categories, will be discussed, as well as the not well defined categories that have been included in the Pervasive Developmental Disorder Not Otherwise Specified group. Different proposals of categorization have been created, some of which based on descriptive phenomenological approach, and others based upon other theoretical perspectives, such as neuropsychology. Current proposals are presented and discussed, followed by critical appraisals on the clinical advantages and disadvantages of these concepts
Brian J Oroak - One of the best experts on this subject based on the ideXlab platform.
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the contribution of de novo coding mutations to autism spectrum Disorder
Nature, 2014Co-Authors: Ivan Iossifov, Brian J Oroak, Stephan J Sanders, Michael Ronemus, Niklas Krumm, Dan Levy, Holly A F Stessman, Kali WitherspoonAbstract:Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum Disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females. Family-based exome sequencing in a large autism study has identified 27 high-confidence gene targets and accurately estimates the contribution of both de novo gene-disrupting and missense mutations to the incidence of simplex autism, with target genes in affected females overlapping those in males of lower but not higher IQ; targets also overlap known targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Autism spectrum Disorder (ASD) is a broad group of brain development Disorders, including autism, Childhood Disintegrative Disorder and Asperger's syndrome, characterized by impaired social interaction and communication, repetitive behaviour and restricted interests. Two groups reporting in this issue of Nature have used large-scale whole-exome sequencing to examine the contribution of inherited and germline de novo mutations to ASD risk. Silvia De Rubeis et al. analysed DNA samples from 3,871 autism cases and 9,937 ancestry-matched or parental controls and identify more than 100 autosomal genes that are likely to affect risk for the disease. De novo loss-of-function mutations were detected in more than 5% of autistic subjects. Many of the associated gene products appear to function in synaptic, transcriptional, and chromatin remodelling pathways. Ivan Iossifov et al. sequenced exomes from more than 2,500 families, each with one child with ASD. They identify 27 high-confidence gene targets and estimate that 13% of de novo missense mutations and 43% of de novo 'likely gene-disrupting' (LGD) mutations contribute to 12% and 9% of diagnoses, respectively.
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molecular cytogenetic analysis and resequencing of contactin associated protein like 2 in autism spectrum Disorders
American Journal of Human Genetics, 2008Co-Authors: Ami Klin, Betul Bakkaloglu, Brian J Oroak, Angeliki Louvi, Abha R Gupta, Jesse F Abelson, Thomas Morgan, Katarzyna Chawarska, Gulhan A ErcansencicekAbstract:demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p ¼ 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonethless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles, 4,5 the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution. The clinical hallmarks of ASD (MIM 209850) are derangements in reciprocal social interaction, abnormal development of speech and language, and the presence of highly restricted interests and stereotyped behaviors. 6 Fundamental impairment in some but not all of these domains defines a spectrum of conditions that includes Asperger syndrome and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). In the DSM-IV, rare developmental Disorders including Rett Syndrome and Childhood Disintegrative Disorder 6 are grouped in the same diagnostic category. A majority of patients with ASD have MR in addition to their social disability and up to one-third suffer from seizures. 6 Individuals with ASD also show an increased burden of chromosomal abnormalities 1 and de novo rare copy number variants. 7
Abha R Gupta - One of the best experts on this subject based on the ideXlab platform.
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Neurogenetic analysis of Childhood Disintegrative Disorder
Molecular Autism, 2017Co-Authors: Abha R Gupta, Alexander Westphal, Daniel Y. J. Yang, Catherine A. W. Sullivan, Jeffrey Eilbott, Samir Zaidi, Avery Voos, Brent C. Vander Wyk, Pam Ventola, Zainulabedin WaqarAbstract:Background Childhood Disintegrative Disorder (CDD) is a rare form of autism spectrum Disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Although there are phenotypic differences between CDD and other forms of ASD, it is unclear if there are neurobiological differences. Methods We pursued a multidisciplinary study of CDD ( n = 17) and three comparison groups: low-functioning ASD ( n = 12), high-functioning ASD ( n = 50), and typically developing ( n = 26) individuals. We performed whole-exome sequencing (WES), copy number variant (CNV), and gene expression analyses of CDD and, on subsets of each cohort, non-sedated functional magnetic resonance imaging (fMRI) while viewing socioemotional (faces) and non-socioemotional (houses) stimuli and eye tracking while viewing emotional faces. Results We observed potential differences between CDD and other forms of ASD. WES and CNV analyses identified one or more rare de novo, homozygous, and/or hemizygous (mother-to-son transmission on chrX) variants for most probands that were not shared by unaffected sibling controls. There were no clearly deleterious variants or highly recurrent candidate genes. Candidate genes that were found to be most conserved at variant position and most intolerant of variation, such as TRRAP , ZNF236 , and KIAA2018 , play a role or may be involved in transcription. Using the human BrainSpan transcriptome dataset, CDD candidate genes were found to be more highly expressed in non-neocortical regions than neocortical regions. This expression profile was similar to that of an independent cohort of ASD probands with regression. The non-neocortical regions overlapped with those identified by fMRI as abnormally hyperactive in response to viewing faces, such as the thalamus, cerebellum, caudate, and hippocampus. Eye-tracking analysis showed that, among individuals with ASD, subjects with CDD focused on eyes the most when shown pictures of faces. Conclusions Given that cohort sizes were limited by the rarity of CDD, and the challenges of conducting non-sedated fMRI and eye tracking in subjects with ASD and significant ID, this is an exploratory study designed to investigate the neurobiological features of CDD. In addition to reporting the first multimodal analysis of CDD, a combination of fMRI and eye-tracking analyses are being presented for the first time for low-functioning individuals with ASD. Our results suggest differences between CDD and other forms of ASD on the neurobiological as well as clinical level.
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molecular cytogenetic analysis and resequencing of contactin associated protein like 2 in autism spectrum Disorders
American Journal of Human Genetics, 2008Co-Authors: Ami Klin, Betul Bakkaloglu, Brian J Oroak, Angeliki Louvi, Abha R Gupta, Jesse F Abelson, Thomas Morgan, Katarzyna Chawarska, Gulhan A ErcansencicekAbstract:demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p ¼ 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonethless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles, 4,5 the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution. The clinical hallmarks of ASD (MIM 209850) are derangements in reciprocal social interaction, abnormal development of speech and language, and the presence of highly restricted interests and stereotyped behaviors. 6 Fundamental impairment in some but not all of these domains defines a spectrum of conditions that includes Asperger syndrome and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). In the DSM-IV, rare developmental Disorders including Rett Syndrome and Childhood Disintegrative Disorder 6 are grouped in the same diagnostic category. A majority of patients with ASD have MR in addition to their social disability and up to one-third suffer from seizures. 6 Individuals with ASD also show an increased burden of chromosomal abnormalities 1 and de novo rare copy number variants. 7