1. Andersson GW, Miniscalco C, Gillberg C. {{Preschoolers assessed for autism: Parent and teacher experiences of the diagnostic process}}. {Research in developmental disabilities}. 2014 Sep 4;35(12):3392-402.
Many parents of young children with autism spectrum disorder (ASD) have often been recommended to « wait and see » when they have first expressed concerns. This comparative, descriptive, partly longitudinal questionnaire study aimed to evaluate parent/preschool teacher experiences as regards time of first concern about the child and about the diagnostic process at a specialized Child Neuropsychiatry Clinic. Participants were parents and teachers of 34 preschool children with suspected ASD (26 boys, 8 girls, mean age 37 months) drawn from a general population cohort. Most of the parents, and the teachers, had their first concern about the child’s development before the child’s second birthday. Generally, they were satisfied with the diagnostic process and did not regret their participation in it.
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2. Bejerot S, Eriksson JM, Mortberg E. {{Social anxiety in adult autism spectrum disorder}}. {Psychiatry research}. 2014 Aug 27.
A link has been suggested between Autism Spectrum Disorder (ASD) and anxiety disorders. The aim of the study was to examine the severity of social anxiety measured by the Liebowitz Social Anxiety Scale Self-Report and prevalence of Social Anxiety Disorder (SAD) in adults with ASD, with SAD and a non-ASD comparison group. Individuals with ASD showed significantly higher scores of social anxiety and social avoidance relative to the comparison group, but significantly lower scores relative to the SAD sample.
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3. Cea-Del Rio CA, Huntsman MM. {{The contribution of inhibitory interneurons to circuit dysfunction in Fragile X Syndrome}}. {Frontiers in cellular neuroscience}. 2014;8:245.
Many neurological disorders, including neurodevelopmental disorders, report hypersynchrony of neuronal networks. These alterations in neuronal synchronization suggest a link to the function of inhibitory interneurons. In Fragile X Syndrome (FXS), it has been reported that altered synchronization may underlie hyperexcitability, cognitive dysfunction and provide a link to the increased incidence of epileptic seizures. Therefore, understanding the roles of inhibitory interneurons and how they control neuronal networks is of great importance in studying neurodevelopmental disorders such as FXS. Here, we present a review of how interneuron populations and inhibition are important contributors to the loss of excitatory/inhibitory balance seen in hypersynchronous and hyperexcitable networks from neurodevelopmental disorders, and specifically in FXS.
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4. Ellegood J, Anagnostou E, Babineau BA, Crawley JN, Lin L, Genestine M, DiCicco-Bloom E, Lai JK, Foster JA, Penagarikano O, Geschwind DH, Pacey LK, Hampson DR, Laliberte CL, Mills AA, Tam E, Osborne LR, Kouser M, Espinosa-Becerra F, Xuan Z, Powell CM, Raznahan A, Robins DM, Nakai N, Nakatani J, Takumi T, van Eede MC, Kerr TM, Muller C, Blakely RD, Veenstra-VanderWeele J, Henkelman RM, Lerch JP. {{Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity}}. {Molecular psychiatry}. 2014 Sep 9.
Autism is a heritable disorder, with over 250 associated genes identified to date, yet no single gene accounts for >1-2% of cases. The clinical presentation, behavioural symptoms, imaging and histopathology findings are strikingly heterogeneous. A more complete understanding of autism can be obtained by examining multiple genetic or behavioural mouse models of autism using magnetic resonance imaging (MRI)-based neuroanatomical phenotyping. Twenty-six different mouse models were examined and the consistently found abnormal brain regions across models were parieto-temporal lobe, cerebellar cortex, frontal lobe, hypothalamus and striatum. These models separated into three distinct clusters, two of which can be linked to the under and over-connectivity found in autism. These clusters also identified previously unknown connections between Nrxn1alpha, En2 and Fmr1; Nlgn3, BTBR and Slc6A4; and also between X monosomy and Mecp2. With no single treatment for autism found, clustering autism using neuroanatomy and identifying these strong connections may prove to be a crucial step in predicting treatment response.Molecular Psychiatry advance online publication, 9 September 2014; doi:10.1038/mp.2014.98.
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5. Gabriele S, Lombardi F, Sacco R, Napolioni V, Altieri L, Tirindelli MC, Gregorj C, Bravaccio C, Rousseau F, Persico AM. {{The GLO1 C332 (Ala111) allele confers autism vulnerability: Family-based genetic association and functional correlates}}. {Journal of psychiatric research}. 2014 Aug 8.
Glyoxalase I (GLO1) is a homodimeric Zn2+-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with « unaffected sibling » status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P < 0.05 and P < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N = 38 and 13, respectively) of typically developing C332 allele carriers (P < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels (tau = -0.588, P < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (tau = -0.209, P = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P < 0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects.
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6. Henry CA, Nowinski L, Koesterer K, Ferrone C, Spybrook J, Bauman M. {{Low rates of depressed mood and depression diagnoses in a clinic review of children and adolescents with autistic disorder}}. {Journal of child and adolescent psychopharmacology}. 2014 Sep;24(7):403-6.
Abstract Objectives: The purpose of this study was to investigate the prevalence of depression diagnoses and related clinical data in an outpatient sample of youth with autistic disorder. METHODS: Records of 123 psychiatrically referred children and adolescents with a Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of autistic disorder were examined. Mood disorder diagnoses and chief complaints along with family mood disorder history were the primary variables analyzed. RESULTS: Four subjects (3%) presented with depressed mood. Irritability complaints were frequent (n=78, 63%). Six subjects (5%) received a mood disorder diagnosis; all with mood disorder, not otherwise specified. No subjects received a depressive disorder diagnosis. Family history of mood disorders was common. CONCLUSIONS: Findings raise questions about the appropriate characterization and potential misdiagnoses of depression in youth with autistic disorder.
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7. Huguet G, Contejean Y, Doyen C. {{[Autism spectrum disorder and suicidality.]}}. {L’Encephale}. 2014 Sep 4.
INTRODUCTION: Most studies on suicide exclude subjects with autism spectrum disorders, yet there is a risk group. The purpose of this article is to present the data in the literature regarding the clinical and epidemiological characteristics of suicidality in subjects with autism spectrum disorders and to identify the factors that promote the transition to action. METHODS: This review was carried out using the data set collected in Medline PubMed, items with « autism spectrum disorder », « pervasive developmental disorder », « Asperger’s syndrome », « suicide », « suicide attempt », and « suicide behavior ». RESULTS: In all subjects from our research on PubMed, 21.3% of subjects with autism spectrum disorder reported suicidal ideation, have attempted suicide or died by suicide (115 out of 539 subjects) and 7.7% of subjects supported for suicidal thoughts or attempted suicide exhibited an autism spectrum disorder (62 out of 806 subjects), all ages combined. Suicidal ideation and morbid preoccupation are particularly common in adolescents and young adults. Suicide attempts are accompanied by a willingness for death and can lead to suicide. They are more common in high-functioning autism and Asperger subjects. The methods used are often violent and potentially lethal or fatal in two cases published. Suicide risk depends on many factors that highlight the vulnerability of these subjects, following autistic and developmental symptoms. Vulnerability complicating the diagnosis of comorbid depressive and anxiety disorders are major factors associated with suicidality. Vulnerability but also directly related to suicidality, since the origin of physical and sexual abuse and victimization by peers assigning them the role of « scapegoat » are both responsible for acting out. CONCLUSION: Given the diversity of factors involved in the risk of suicide in this population, this does not validate « a » program of intervention, but the intervention of « customized programs ». Their implementation should be as early as possible in order to treat while the brain has the greatest plasticity. The aim is to provide the necessary access to the greatest possible autonomy. Hence, including working communication skills and interaction, these subject will have independent means of protection, an essential complement to measures to protect vulnerable subjects; the vulnerability of direct and indirect suicidality. Comorbid diagnoses must take into account the specificities of these patients, their difficulties in communicating their mental state, and adapted and innovative therapeutic strategies must be offered and validated.
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8. Kalkbrenner AE, Schmidt RJ, Penlesky AC. {{Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence}}. {Current problems in pediatric and adolescent health care}. 2014 Sep 4.
In the past decade, the number of epidemiological publications addressing environmental chemical exposures and autism has grown tremendously. These studies are important because it is now understood that environmental factors play a larger role in causing autism than previously thought and because they address modifiable risk factors that may open up avenues for the primary prevention of the disability associated with autism. In this review, we covered studies of autism and estimates of exposure to tobacco, air pollutants, volatile organic compounds and solvents, metals (from air, occupation, diet, dental amalgams, and thimerosal-containing vaccines), pesticides, and organic endocrine-disrupting compounds such as flame retardants, non-stick chemicals, phthalates, and bisphenol A. We included studies that had individual-level data on autism, exposure measures pertaining to pregnancy or the 1st year of life, valid comparison groups, control for confounders, and adequate sample sizes. Despite the inherent error in the measurement of many of these environmental exposures, which is likely to attenuate observed associations, some environmental exposures showed associations with autism, especially traffic-related air pollutants, some metals, and several pesticides, with suggestive trends for some volatile organic compounds (e.g., methylene chloride, trichloroethylene, and styrene) and phthalates. Whether any of these play a causal role requires further study. Given the limited scope of these publications, other environmental chemicals cannot be ruled out, but have not yet been adequately studied. Future research that addresses these and additional environmental chemicals, including their most common routes of exposures, with accurate exposure measurement pertaining to several developmental windows, is essential to guide efforts for the prevention of the neurodevelopmental damage that manifests in autism symptoms.
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9. Mari-Bauset S, Llopis-Gonzalez A, Zazpe-Garcia I, Mari-Sanchis A, Morales-Suarez-Varela M. {{Nutritional Status of Children with Autism Spectrum Disorders (ASDs): A Case-Control Study}}. {J Autism Dev Disord}. 2014 Sep 7.
Children with autism spectrum disorder (ASD) have problems of food selectivity, implying risks of nutritional deficiencies. The aim was to compare intakes of macro and micronutrients and body mass index in ASD and typically developing (TD) children. In a case-control study, 3-day food diaries and anthropometric measurements were completed for ASD (n = 40) and TD (n = 113) children (aged 6-10 years) living in the same area. Body mass indices were below the 5th percentile in 20 % of ASD versus 8.85 % of TD children. We found intakes were lower for fluoride (p = 0.017) and higher for vitamin E (p = 0.001). There was limited food variety and inadequacy of some intakes suggests that routine monitoring of ASD children should include assessment of their dietary habits, as well as anthropometric measurements.
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10. Matson JL, Jang J. {{Treating aggression in persons with autism spectrum disorders: A review}}. {Research in developmental disabilities}. 2014 Sep 3;35(12):3386-91.
Aggression is one of the most frequent and debilitating problems observed among persons with autism spectrum disorders (ASD). It is common and can be more problematic than many core symptoms of ASD. Thus, treating the behavior is a high priority. A surprisingly limited number of studies have addressed treatment when taken in the context of the vast ASD literature. This paper reviews many of these papers and describes the types of interventions that have been used and the characteristics of the people who have been studied.
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11. Metsu S, Rainger JK, Debacker K, Bernhard B, Rooms L, Grafodatskaya D, Weksberg R, Fombonne E, Taylor MS, Scherer SW, Kooy RF, FitzPatrick DR. {{A CGG-Repeat Expansion Mutation in ZNF713 Causes FRA7A: Association with Autistic Spectrum Disorder in two Families}}. {Human mutation}. 2014 Sep 4.
We report de novo occurrence of the 7p11.2 folate-sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG-repeat expansion mutation ( approximately 450 repeats) in a 5′ intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband-derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated pre-mutation (85 repeats). This CGG-repeat showed length polymorphism in control samples (5-22 repeats). In a second unrelated family three siblings with ASD and their unaffected father were found to carry FRA7A pre-mutations, which were partially or mosaically methylated. In one of the affected siblings mitotic instability of the pre-mutation was observed. ZNF713 expression in LCLs in this family was increased in 3 of these 4 premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed. This article is protected by copyright. All rights reserved.
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12. Mizuno M, Matsumoto A, Hamada N, Ito H, Miyauchi A, Jimbo EF, Momoi MY, Tabata H, Yamagata T, Nagata KI. {{Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders}}. {Journal of neurochemistry}. 2014 Sep 6.
Using comparative genomic hybridization (CGH) analysis for an autism spectrum disorder (ASD) patient, a 73 Kb duplication at 19q13.33 (nt. 49 562 755-49 635 956) including LIN7B and 5 other genes was detected. We then identified a novel frameshift mutation in LIN7B in another ASD patient. Since LIN7B encodes a scaffold protein essential for neuronal function, we analyzed the role of Lin-7B in the development of cerebral cortex. Acute knockdown of Lin-7B with in utero electroporation caused a delay in neuronal migration during corticogenesis. When Lin-7B was knocked down in cortical neurons in one hemisphere, their axons failed to extend efficiently into the contralateral hemisphere after leaving the corpus callosum. Meanwhile, enhanced expression of Lin-7B had no effects on both cortical neuron migration and axon growth. Notably, silencing of Lin-7B did not affect the proliferation of neuronal progenitors and stem cells. Taken together, Lin-7B was found to play a pivotal role in corticogenesis through the regulation of excitatory neuron migration and interhemispheric axon growth, while further analyses are required to directly link functional defects of Lin-7B to ASD pathophysiology. This article is protected by copyright. All rights reserved.
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13. Orosco LA, Ross AP, Cates SL, Scott SE, Wu D, Sohn J, Pleasure D, Pleasure SJ, Adamopoulos IE, Zarbalis KS. {{Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology}}. {Nature communications}. 2014;5:4692.
Autism spectrum disorders (ASDs) are complex and heterogeneous developmental disabilities affecting an ever-increasing number of children worldwide. The diverse manifestations and complex, largely genetic aetiology of ASDs pose a major challenge to the identification of unifying neuropathological features. Here we describe the neurodevelopmental defects in mice that carry deleterious alleles of the Wdfy3 gene, recently recognized as causative in ASDs. Loss of Wdfy3 leads to a regionally enlarged cerebral cortex resembling early brain overgrowth described in many children on the autism spectrum. In addition, affected mouse mutants display migration defects of cortical projection neurons, a recognized cause of epilepsy, which is significantly comorbid with autism. Our analysis of affected mouse mutants defines an important role for Wdfy3 in regulating neural progenitor divisions and neural migration in the developing brain. Furthermore, Wdfy3 is essential for cerebral expansion and functional organization while its loss-of-function results in pathological changes characteristic of ASDs.
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14. Palermo MT, Bogaerts S. {{The Dangers of Posthumous Diagnoses and the Unintended Consequences of Facile Associations: Jeffrey Dahmer and Autism Spectrum Disorders}}. {International journal of offender therapy and comparative criminology}. 2014 Sep 10.
Posthumous diagnoses are not uncommonly given to notorious public and historical figures by applying retrospectively, and typically in the absence of the individual being diagnosed, contemporary diagnostic criteria. Although this may be relatively easy and free of consequences when it concerns clear-cut medical conditions, it may have unintended repercussions in the case of psychiatric disorders by creating myths and perpetuating stigma. The case of serial killer Jeffrey Dahmer is a typical example where a somewhat facile and almost syllogistic application of perhaps over-inclusive criteria may have contributed to the legend of solitary murderers as possibly suffering from an autism spectrum condition. Although there may be an understandable human need to explain abominable and heinous behaviors, the lack of the possibility to verify a diagnostic theory and the ill-advised attempt to make a diagnosis fit may de facto be the basis of prejudice and profiling that do not correspond to clinical reality. Although there is no doubt that the brain is the organ of behavior, the authors caution against a budding neo-Lombrosian approach to crime and criminality and against the all too common use of widely differing terms in the study of deviance, such as crime, delinquency, and aggression, the operational use of which, often used interchangeably even in association studies, often erroneously leads to further confusion.
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15. Pitskel NB, Bolling DZ, Kaiser MD, Pelphrey KA, Crowley MJ. {{Neural systems for cognitive reappraisal in children and adolescents with autism spectrum disorder}}. {Developmental cognitive neuroscience}. 2014 Aug 19;10C:117-28.
Despite substantial clinical and anecdotal evidence for emotion dysregulation in individuals with autism spectrum disorder (ASD), little is known about the neural substrates underlying this phenomenon. We sought to explore neural mechanisms for cognitive reappraisal in children and adolescents with ASD using functional magnetic resonance imaging (fMRI). We studied 16 youth with ASD and 15 age- and IQ-matched typically developing (TD) comparison youth. Participants were instructed in the use of cognitive reappraisal strategies to increase and decrease their emotional responses to disgusting images. Participants in both groups displayed distinct patterns of brain activity for increasing versus decreasing their emotions. TD participants showed downregulation of bilateral insula and left amygdala on decrease trials, whereas ASD participants showed no modulation of insula and upregulation of left amygdala. Furthermore, TD youth exhibited increased functional connectivity between amygdala and ventrolateral prefrontal cortex compared to ASD participants when downregulating disgust, as well as decreased functional connectivity between amygdala and orbitofrontal cortex. These findings have important implications for our understanding of emotion dysregulation and its treatment in ASD. In particular, the relative lack of prefrontal-amygdala connectivity provides a potential target for treatment-related outcome measurements.
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16. Rossignol DA, Frye RE. {{The use of medications approved for Alzheimer’s disease in autism spectrum disorder: a systematic review}}. {Frontiers in pediatrics}. 2014;2:87.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects 1 in 68 children in the United States. Even though it is a common disorder, only two medications (risperidone and aripiprazole) are approved by the U.S. Food and Drug Administration (FDA) to treat symptoms associated with ASD. However, these medications are approved to treat irritability, which is not a core symptom of ASD. A number of novel medications, which have not been approved by the FDA to treat ASD have been used off-label in some studies to treat ASD symptoms, including medications approved for Alzheimer’s disease. Interestingly, some of these studies are high-quality, double-blind, placebo-controlled (DBPC) studies. This article systematically reviews studies published through April, 2014, which examined the use of Alzheimer’s medications in ASD, including donepezil (seven studies, two were DBPC, five out of seven reported improvements), galantamine (four studies, two were DBPC, all reported improvements), rivastigmine (one study reporting improvements), tacrine (one study reporting improvements), and memantine (nine studies, one was DBPC, eight reported improvements). An evidence-based scale was used to rank each medication. Collectively, these studies reported improvements in expressive language and communication, receptive language, social interaction, irritability, hyperactivity, attention, eye contact, emotional lability, repetitive or self-stimulatory behaviors, motor planning, disruptive behaviors, obsessive-compulsive symptoms, lethargy, overall ASD behaviors, and increased REM sleep. Reported side effects are reviewed and include irritability, gastrointestinal problems, verbal or behavioral regression, headaches, irritability, rash, tremor, sedation, vomiting, and speech problems. Both galantamine and memantine had sufficient evidence ranking for improving both core and associated symptoms of ASD. Given the lack of medications approved to treat ASD, further studies on novel medications, including Alzheimer’s disease medications, are needed.
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17. Silverman L, Hollway JA, Smith T, Aman MG, Arnold LE, Pan X, Li X, Handen BL. {{A Multisite Trial of Atomoxetine and Parent Training in Children with Autism Spectrum Disorders: Rationale and Design Challenges}}. {Res Autism Spectr Disord}. 2014 Jul 1;8(7):899-907.
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18. Timonen-Soivio L, Vanhala R, Malm H, Leivonen S, Jokiranta E, Hinkka-Yli-Salomaki S, Gissler M, Brown AS, Sourander A. {{The association between congenital anomalies and autism spectrum disorders in a Finnish national birth cohort}}. {Developmental medicine and child neurology}. 2014 Sep 8.
AIM: The first aim of this study was to evaluate the association between different subgroups of autism spectrum disorders (ASDs) (childhood autism, Asperger syndrome, and pervasive developmental disorder/pervasive developmental disorder – not otherwise specified [PDD/PDD-NOS]) and congenital anomalies. Second, we assessed the association among intellectually disabled children with ASDs in the subgroups of childhood autism and PDD/PDD-NOS. METHOD: Nationwide population-based register data for children with a diagnosis of ASD (n=4449; 3548 males, 901 females) were collected during years 1987-2000 from the Finnish Hospital Discharge Register. Data on congenital anomalies were derived from the National Register of Congenital Malformations. Conditional logistic regression models were used as a statistical method. The association between ASD subgroups and congenital anomalies was stratified by the presence or absence of intellectual disability. RESULTS: Congenital anomalies occurred more frequently in all subgroups of ASD than in comparison participants (adjusted odds ratio [OR] for major congenital anomalies 1.8, 95% confidence interval [CI] 1.5-2.2, p<0.001). The association between congenital anomalies and childhood autism (OR 2.4, 95% CI 1.6-3.6, p<0.001) and between congenital anomalies and PDD/PDD-NOS (OR 3.7, 95% CI 2.4-5.7, p<0.001) among children with an intellectual disability was strong but remained significant also without intellectual disability (childhood autism: OR 1.7, 95% CI 1.3-2.3, p<0.001; PDD/PDD-NOS: OR 2.3, 95% CI 1.9-2.8, p<0.001). INTERPRETATION: The results suggest a significant association between ASDs and congenital anomalies regardless of the ASD subgroup. The association between childhood autism and PDD/PDD-NOS and congenital anomalies is stronger among children with intellectual disability is stronger than among those without intellectual disability. These results may have relevance in examining early risk factors in autism during fetal neurodevelopment.
