Autism Diagnostic Interview-Revised Research Articles

Anomalies in uncinate fasciculus development and social defects in preschoolers with autism spectrum disorder

BackgroundIndividuals with autism spectrum disorder (ASD) have social interaction deficits and difficulties in emotional regulation. The neural substrates for these socio-affective deficits are not yet clear, but one potential candidate is maldevelopment of the uncinate fasciculus (UF), a white matter tract thought to be involved in socio-affective processing. However, the developmental trajectory of the UF in young children with social interaction deficits has not been examined. The present study was designed to describe the developmental growth trajectory of the UF and the relationships between UF development and social deficits in ASD.MethodsEigenvalues of the UF were measured by diffusion tensor imaging (DTI)-based tractography in 37 children with ASD and 27 matched 2–3-year-old subjects with developmental delay (DD) at baseline (time 1) and at 2-year follow-up (time 2). Growth rates of the UF were compared between groups and associations with social deficit scores according to the Autism Diagnostic Interview-Revised (ADI-R) analyzed by Pearson’s correlations.ResultsAt time 1, axial diffusivity (AD) of the left UF was significantly larger in the ASD group than the DD group. At time 2, left UF fractional anisotropy (FA) was significantly higher and radial diffusivity (RD) significantly lower in the ASD group than the DD group. The rate of UF growth during this 2-year interval was faster in children with ASD than DD. Significant negative correlations were found between the rise in ADI-R social deficit measures and both right UF RD and left UF mean diffusivity (MD).ConclusionsYoung children with ASD demonstrate UF overgrowth during the 2-year development period between 2 and 3 and 4–5 years of age, and this white matter abnormality is directly associated with the progression of social deficits.Trial registrationWorld Health Organization class I registered international clinical trial platform, ChiCTR-ROC-17012877.

Affected Sib-Pair Analyses Identify Signaling Networks Associated With Social Behavioral Deficits in Autism.

Autism spectrum disorders (ASDs) are characterized by deficits in three core behavioral domains: reciprocal social interactions, communication, and restricted interests and/or repetitive behaviors. Several hundreds of risk genes for autism have been identified, however, it remains a challenge to associate these genes with specific core behavioral deficits. In multiplex autism families, affected sibs often show significant differences in severity of individual core phenotypes. We hypothesize that a higher mutation burden contributes to a larger difference in the severity of specific core phenotypes between affected sibs. We tested this hypothesis on social behavioral deficits in autism. We sequenced synaptome genes (n = 1,886) in affected male sib-pairs (n = 274) in families from the Autism Genetics Research Exchange (AGRE) and identified rare (MAF ≤ 1%) and predicted functional variants. We selected affected sib-pairs with a large (≥10; n = 92 pairs) or a small (≤4; n = 108 pairs) difference in total cumulative Autism Diagnostic Interview-Revised (ADI-R) social scores (SOCT_CS). We compared burdens of unshared variants present only in sibs with severe social deficits and found a higher burden in SOCT_CS≥10 compared to SOCT_CS ≤ 4 (SOCT_CS≥10: 705.1 ± 16.2; SOCT_CS ≤ 4, 668.3 ± 9.0; p = 0.025). Unshared SOCT_CS≥10 genes only in sibs with severe social deficits are significantly enriched in the SFARI gene set. Network analyses of these genes using InWeb_IM, molecular signatures database (MSigDB), and GeNetMeta identified enrichment for phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) (Enrichment Score [eScore] p value = 3.36E−07; n = 8 genes) and Nerve growth factor (NGF) (eScore p value = 8.94E−07; n = 9 genes) networks. These studies support a key role for these signaling networks in social behavioral deficits and present a novel approach to associate risk genes and signaling networks with core behavioral domains in autism.

Evaluation on Machine Learning Algorithms for Classification of Autism Spectrum Disorder (ASD)

Autism Spectrum Disorder (ASD) was characterized by delay in social interactions development, repetitive behaviors and narrow interest, which usually diagnosed with standard diagnostic tools such as Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADIR-R). Previous work has implemented machine-learning methods for the classification of ASD, however they used different types of dataset such as brain images for MRI and EEG, risk genes in genetic profiles and behavior evaluation based on ADOS and ADI-R. Here a trial on using Autism Spectrum Questions (AQ) to build models that have higher potential to classify ASD was developed. In this research, Chi-square and Least Absolute Shrinkage and Selection Operator (LASSO) have been selected as feature selection methods to select the most important features for 3 supervised machine learning algorithms, which are Random Forest, Logistic Regression and K-Nearest Neighbors with K-fold cross validation. The performance was evaluated in which results Logistic Regression scored the highest accuracy with 97.541% using model with 13 selected features based on Chi-square selection method.

L’ADI-R et l’ADOS face au diagnostic différentiel des troubles du spectre autistique : intérêts, limites et ouvertures

IntroductionCurrent developments in international public health are leading qualified authorities to release clinical practice guidelines for Autism Spectrum Disorders (ASD) assessment and diagnosis. Such documents incorporate procedures that rely on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) which are considered to be the “gold standard” assessment measures in the evaluation of ASD. Although these tools do prove their effectiveness in the evaluation of autistic symptomatology, they nevertheless stumble whenever the situation becomes more complex and reveal differential diagnostic issues in infantile and adult autism cases. This differential diagnostic issue remains significant in the clinical practice of daily life and has strong implications for the course of therapeutic treatment. ObjectivesOur objective is to underline and nuance the metrological qualities of the ADI-R and the ADOS in the differential diagnosis of autistic disorders by presenting a synthesis of recent studies, thus supporting the interest of maintaining an open debate on diagnostic practices. MethodsOur selective review of the recent literature focuses on studies that confront the ADI-R and the ADOS — used either independently or in a combination — with various differential issues in adulthood and childhood autism in order to highlight their qualities and limits. ResultsThe ADI-R is a semi-structured interview applied by trained examiners and applied to relatives and/or caregivers who collect developmental information about the patient's first years of life on a variety of behaviors and skills. It is therefore relatively dependent on the availability and personal bias of the interviewed third parties. Metric features highlighted by the reviewed studies straightforwardly reveal a certain effectiveness of the tool and a good discrimination of childhood disorders. At the same time, the tool's discriminatory capacity seems insufficient when applied to toddlers, very young children, and adults alike. The latter seems particularly true when it comes to differentiating between autistic and schizophrenic spectrum disorders. The ADOS is a semi-structured standardized observation assessment tool that has experienced several successive developments, such as optimizations concerning the sensitivity of its cutoffs. Many works have contributed to building such a tool with reliable and solid metric qualities which nevertheless retain important biases such as the subjectivity of the caregiver or the evaluator during the scoring process. For assessments of autistic children the tool still has a good diagnostic validity but seems to retain cases of incorrect diagnosis of ASD (false positives). In other words, disorders or developmental disabilities of some children and adolescents could not be distinguished from ASD when relying on this test alone. The ADOS Module 4, designed for the diagnosis of adolescents and adults with fluent speech, has undergone less updating. This revisited algorithm has metrological qualities useful for clinicians and remains one of the few available tools for this population. Unfortunately, its diagnostic accuracy is lower when applied to women, the elderly, people with personality disorders or higher intellectual abilities, or for the discrimination between ASD and schizophrenia. Overall, scores from these two instruments bring strong evidence of their usefulness in the diagnostic process of ASD, provided that they are used with caution and a critical clinical perspective, and only as a secondary technical support. Their use in combination is effective since they are complementary and compensate for each other's limitations. However, their globalized hegemony as “gold-standard” tools constitutes a setback insofar as it constrains the diagnosis of ASD to a set of stereotyped items. The latter in turn sets a normative model of autism that excludes other phenotypic forms, especially in the case of women and the elderly. Finally, the discrimination between autism and psychosis for children seems to remain an insoluble task even for the ADI-R/ADOS combination. ConclusionsThe problematics of differential diagnosis remain critical for clinical approaches to autism. Therefore, formalizations of the diagnostic procedures must be able to remain open-minded and accompanied by a creative clinical approach, especially in the case of complex situations that are not soluble by means of conventional diagnostic tools. One possibility may lie in the deepening of the phenomenological approach to autism as an attempt to model the subjective phenomena of autistic subjects and thus operationalize elements that serve the diagnostic process. In the same way, a psychodynamic epistemology could help clinicians to go beyond the consideration of observable behaviors and scores, introducing a psychoanalytic point of view that interfaces objective behaviors with the individual's dynamic intrapsychic functioning. This project could be articulated with projective methodologies — notably the Rorschach test — which respects the needs for standardization and quantification of conventionally used diagnostic tools.

ASD Phenotype-Genotype Associations in Concordant and Discordant Monozygotic and Dizygotic Twins Stratified by Severity of Autistic Traits.

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by impaired social communication coupled with stereotyped behaviors and restricted interests. Despite the high concordance rate for diagnosis, there is little information on the magnitude of genetic contributions to specific ASD behaviors. Using behavioral/trait severity scores from the Autism Diagnostic Interview-Revised (ADI-R) diagnostic instrument, we compared the phenotypic profiles of mono- and dizygotic twins where both co-twins were diagnosed with ASD or only one twin had a diagnosis. The trait distribution profiles across the respective twin populations were first used for quantitative trait association analyses using publicly available genome-wide genotyping data. Trait-associated single nucleotide polymorphisms (SNPs) were then used for case-control association analyses, in which cases were defined as individuals in the lowest (Q1) and highest (Q4) quartiles of the severity distribution curves for each trait. While all of the ASD-diagnosed twins exhibited similar trait severity profiles, the non-autistic dizygotic twins exhibited significantly lower ADI-R item scores than the non-autistic monozygotic twins. Case-control association analyses of twins stratified by trait severity revealed statistically significant SNPs with odds ratios that clearly distinguished individuals in Q4 from those in Q1. While the level of shared genomic variation is a strong determinant of the severity of autistic traits in the discordant non-autistic twins, the similarity of trait profiles in the concordantly autistic dizygotic twins also suggests a role for environmental influences. Stratification of cases by trait severity resulted in the identification of statistically significant SNPs located near genes over-represented within autism gene datasets.

Association between Interictal Epileptiform Discharges and Autistic Spectrum Disorder.

It has been reported that bioelectric alterations in an electroencephalogram (EEG) may play an etiological role in neurodevelopmental disorders. The clinical impact of interictal epileptiform discharges (IEDs) in association with autistic spectrum disorder (ASD) is unknown. The Autism Diagnostic Interview-Revised (ADI-R) is one of the gold standards for the diagnosis of autistic spectrum disorder. Some studies have indicated high comorbidity of IED and ASD, while other studies have not supported an association between the central symptoms of autism and IED. This review examines the high comorbidity and clinical impact of IED; patients with epilepsy are excluded from the scope of this review. ASD can be disabling and is diagnosed at an average age of 5 years old, at which point the greatest neurological development has occurred. If an association between IED and ASD is identified, a clinical tool that entails an innocuous procedure could enable diagnosis in the first years of life. However, in the absence of reports that prove an association between IED and ASD, patients should not be subjected to expensive treatments, such as the administration of anticonvulsant therapies.

Behavioral characteristics of autism spectrum disorder in very preterm birth children

BackgroundLower gestational age may increase autism spectrum disorder (ASD) vulnerability; however, the incidence of ASD diagnosis through a direct assessment on every very preterm birth child on the population base remains unclear. Moreover, the behavioral characteristics of preterm birth ASD are unknown.MethodsEvery very preterm birth child (gestational age < 32 weeks; birth weight < 1500 g) who was discharged from neonatal intensive care units in Southern Taiwan and prospectively followed to 5 years of age was evaluated using the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R). The term birth (gestational age > 37 weeks) ASD children characterized by ADOS and ADI-R were group matched to the preterm birth ASD by age at examination for comparison. ADOS severity scores were calculated by the Mann–Whitney U test and ADI-R by multivariate analysis of variance and canonical discriminant analysis.ResultsTwo hundred forty-six (87%) of the 283 very preterm survivors were followed prospectively to 5 years of age. Nineteen (7.7%) of the 246 children fulfilled the diagnostic criteria of ASD. After excluding 1 patient with cerebral palsy and profound mental disability, 18 preterm ASD children were compared with 44 term birth ASD children. The two ASD groups were comparable for age at examination, gender, and intelligence quotient. The two groups showed comparable ADOS severity scores in social affect deficits, restricted repetitive behaviors, and total score, but had differences in qualitative abnormalities in reciprocal social interaction (Wilks lambda F value = 6.2, P < 0.001) of ADI-R. Compared to term birth ASD children, preterm birth ASD children exhibited worse nonverbal behaviors that regulate social interaction (OR 2.59, 95% CI 1.41–4.73, P = 0.002) but more favorable peer relationships (OR 0.58, 95% CI 0.38–0.90, P = 0.01) and socioemotional reciprocity (OR 0.55, 95% CI 0.33–0.92, P = 0.02). In contrast to the heterogeneous severity of social reciprocity in the term ASD group, the behavioral characteristics of the preterm ASD group showed a homogeneous reciprocal social interaction pattern.ConclusionsThe 5-year incidence rate of ASD was high in very preterm birth children. Preterm birth ASD exhibited a specific behavioral phenotype of reciprocal social interaction.

Investigating the natural history and prognostic factors of ASD in children: the multicEntric Longitudinal study of childrEN with ASD - the ELENA study protocol

IntroductionThere is global concern about the increasing prevalence of autism spectrum disorders (ASDs), which are early-onset and long-lasting disorders. Although ASDs are considered to comprise a unique syndrome, their clinical...

Télémédecine et troubles du spectre de l’autisme de l’enfant et de l’adolescent : guide théorique et pratique

ObjectivesThe development of telemedicine for children and adolescents is a real need because of difficult accessibility of mental health and the paucity of childhood psychiatrists. Thus the American Academy for Child and Adolescent Psychiatry (AACAP) published in 2008 good practice recommendations for telepsychiatry in children and adolescents based on clinical consensus and scientific evidence. In France the legal framework defines four practical modalities according to the presence or not of a health professional or a psychologist with the practitioner accomplishing the teleconsultation act. Data exist about the outcome of children and adolescents who benefited from therapeutic interventions with technological media. Effect size is modest but it doesn’t justify ruling out these techniques. Children who present with a developmental disorder or who cannot cooperate are evaluated with a certain degree of uncertainty. By contrast, some children with severe Attention Deficit with or without Hyperactivity (ADHD), social anxiety or Autism Spectrum Disorders (ASD) can be more easily engaged within a teleconsultation model. Teleconsultations in autism spectrum disorders (ASD) are feasible because of the nature of diagnosis and the type of care recommended in this disorder. The behavioral nature of the disorder and the behavioral therapeutic approaches recommended in North America culture highlight the potential interest of telemedicine because these disorders are easily observable. Literature suggests new opportunities in order to facilitate the care process for the ASD person and his family: the first one is diagnosis with use of validated instruments such as the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview (ADI). Parental accompaniment is the second opportunity. Development of telemedicine for ASD could be a complementary approach for diagnosis and medical care. MethodSince 2015, a program called PROMETTED (PROgramme MEdical de Télépsychiatrie pour enfants et adolescents présentant un Trouble Envahissant du Développement) was supported by Regional Health Agency of Île-de-France. It was developed and managed by the team of a Diagnosis Center Evaluation for Autism (DCEA) of Paris area in collaboration with a DCEA of Île-de-France region. Five medico-social structures for children and adolescents with autistic disorders and the two diagnosis centers of evaluation for autism co-elaborated a scheme of intervention with telemedicine. The remote evaluation is a 4-step process: a first teleconsultation structured around the medical history of the subject in order to complete his medical file and the observation of the young subject; a second teleconsultation structured around the ADI-R interview with parents; the third teleconsultation is a mixed teleconsultation associating the medical expert of the DCEA and a psychologist trained in the use of the Childhood Autism Rating Scale (CARS) and the Vineland Adaptive Behavior Scales (VABS). The fourth teleconsultation consists of the psychiatrist giving feed-back to parents about the results of the observations of the DCEA team. ResultsThe four-step program is well-accepted and the use of validated instruments for diagnosis or functional evaluation appears feasible. Medical data were completed for 44% of cases; complementary genetic or medical investigations were prescribed for 50% of cases; medical advice about psychotropic or vitaminic medication was given for 31% of cases. Mean duration of evaluation was 11.1 weeks±9.4. ConclusionsThe PROMETTED program empirically validates the concept of remote evaluation for children and adolescents with ASD. The need to extend the use of telemedicine to tele-expertise for medicine monitoring or behavioral disorder management has been noted.

Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations.

Autism spectrum disorder (ASD) is a childhood neuropsychiatric disorder with a complex genetic architecture. The diagnostic potential of a targeted panel of ASD genes has only been evaluated in small cohorts to date and is especially understudied in the Chinese population. Here, we designed a capture panel with 358 genes (111 syndromic and 247 nonsyndromic) for ASD and sequenced a Chinese cohort of 539 cases evaluated with the Autism Diagnostic Interview‐Revised (ADI‐R) and the Autism Diagnostic Observation Schedule (ADOS) as well as 512 controls. ASD cases were found to carry significantly more ultra‐rare functional variants than controls. A subset of 78 syndromic and 54 nonsyndromic genes was the most significantly associated and should be given high priority in the future screening of ASD patients. Pathogenic and likely pathogenic variants were detected in 9.5% of cases. Variants in SHANK3 and SHANK2 were the most frequent, especially in females, and occurred in 1.2% of cases. Duplications of 15q11–13 were detected in 0.8% of cases. Variants in CNTNAP2 and MEF2C were correlated with epilepsy/tics in cases. Our findings reveal the diagnostic potential of ASD genetic panel testing and new insights regarding the variant spectrum. Genotype–phenotype correlations may facilitate the diagnosis and management of ASD.

Effects of Lactobacillus plantarum PS128 on Children with Autism Spectrum Disorder in Taiwan: A Randomized, Double-Blind, Placebo-Controlled Trial.

This four-week, randomized, double-blind, placebo-controlled study investigated the effects of Lactobacillus plantarum PS128 (PS128) on boys with autism spectrum disorder (ASD) aged 7–15 in Taiwan. All subjects fulfilled the criteria for ASD diagnosis of DSM-V and the Autism Diagnostic Interview-Revised (ADI-R). Questionnaires used for the primary outcome measure include the Autism Behavior Checklist-Taiwan version (ABC-T), the Social Responsiveness Scale (SRS) and the Child Behavior Checklist (CBCL). The Swanson, Nolan, and Pelham-IV-Taiwan version (SNAP-IV) and the Clinical Global Impression-improvement (CGI-I) were used for the secondary outcome measure. The results showed that PS128 ameliorated opposition/defiance behaviors, and that the total score of SNAP-IV for younger children (aged 7−12) improved significantly compared with the placebo group. Additionally, several elements were also notably improved in the PS128 group after 28-day consumption of PS128. Further studies are needed to better clarify the effects of PS128 for younger children with ASD on broader symptoms.

Autism spectrum disorder (ASD) symptom profiles of children with comorbid Down syndrome (DS) and ASD: A comparison with children with DS-only and ASD-only

BackgroundDown syndrome (DS) is associated with increased rates of autism spectrum disorder (ASD), characterized by social−communicative impairments (SOC−COM) and repetitive behaviors and interests (RBI). However, little is known about the ASD symptom presentation in children with DS + ASD. AimsThe current study sought to describe parent-report of SOC−COM and RBI symptoms on the Autism Diagnostic Interview -Revised (ADI-R) in children with DS (n = 22), DS + ASD (n = 11), and ASD (n = 66). MethodSOC−COM and RBI scores from the ADI-R were compared across the groups whose autism status was ascertained using the Autism Diagnostic Observation Schedule. ResultsDifferences in SOC−COM and RBI symptom severity was observed. The general pattern of findings was ASD > DS+ASD > DS. Dissimilar ASD symptom profiles were observed across groups. In ASD, SOC−COM scores were higher than RBI scores; in DS + ASD, similar SOC−COM and RBI scores were observed. Lastly, SOC−COM impairments were highly related to verbal cognition in youth with DS + ASD but not in those with DS or ASD. Conclusions and ImplicationsThese findings suggest that children with DS + ASD have a distinct profile of ASD symptoms that differs from peers with either disorder in isolation. Thus, care should be taken in evaluating and designing treatments for this group.

Phenotypic subgrouping and multi-omics analyses reveal reduced diazepam-binding inhibitor (DBI) protein levels in autism spectrum disorder with severe language impairment.

BackgroundThe mechanisms underlying autism spectrum disorder (ASD) remain unclear, and clinical biomarkers are not yet available for ASD. Differences in dysregulated proteins in ASD have shown little reproducibility, which is partly due to ASD heterogeneity. Recent studies have demonstrated that subgrouping ASD cases based on clinical phenotypes is useful for identifying candidate genes that are dysregulated in ASD subgroups. However, this strategy has not been employed in proteome profiling analyses to identify ASD biomarker proteins for specific subgroups.MethodsWe therefore conducted a cluster analysis of the Autism Diagnostic Interview-Revised (ADI-R) scores from 85 individuals with ASD to predict subgroups and subsequently identified dysregulated genes by reanalyzing the transcriptome profiles of individuals with ASD and unaffected individuals. Proteome profiling of lymphoblastoid cell lines from these individuals was performed via 2D-gel electrophoresis, and then mass spectrometry. Disrupted proteins were identified and compared to the dysregulated transcripts and reported dysregulated proteins from previous proteome studies. Biological functions were predicted using the Ingenuity Pathway Analysis (IPA) program. Selected proteins were also analyzed by Western blotting.ResultsThe cluster analysis of ADI-R data revealed four ASD subgroups, including ASD with severe language impairment, and transcriptome profiling identified dysregulated genes in each subgroup. Screening via proteome analysis revealed 82 altered proteins in the ASD subgroup with severe language impairment. Eighteen of these proteins were further identified by nano-LC-MS/MS. Among these proteins, fourteen were predicted by IPA to be associated with neurological functions and inflammation. Among these proteins, diazepam-binding inhibitor (DBI) protein was confirmed by Western blot analysis to be expressed at significantly decreased levels in the ASD subgroup with severe language impairment, and the DBI expression levels were correlated with the scores of several ADI-R items.ConclusionsBy subgrouping individuals with ASD based on clinical phenotypes, and then performing an integrated transcriptome-proteome analysis, we identified DBI as a novel candidate protein for ASD with severe language impairment. The mechanisms of this protein and its potential use as an ASD biomarker warrant further study.

Interaction of glutathione S-transferase polymorphisms and tobacco smoking during pregnancy in susceptibility to autism spectrum disorders

Autism spectrum disorders (ASD) are a group of complex psychiatric disorders, with a proposed gene-environment interaction in their etiology. One mechanism that could explain both the genetic and environmental component is oxidative stress. The aim of our study was to investigate the potential role of common polymorphisms in genes for glutathione transferase A1, M1, T1 and P1 in susceptibility to ASD. We also aimed to explore the possible oxidative stress - specific gene-environment interaction, regarding GST polymorphisms, maternal smoking tobacco during pregnancy (TSDP) and the risk of ASD. This case-control study included 113 children with ASD and 114 age and sex-matched controls. The diagnosis was made based on ICD-10 criteria and verified by Autism Diagnostic Interview – Revised (ADI-R). We investigated GSTA1, GSTM1, GSTP1 and GSTT1 genotypes and explored their individual and combined effects in individuals with ASD. Individual effect of GST genotypes was shown for GSTM1 active genotype decreasing the risk of ASD (OR = 0.554, 95%CI: 0.313–0.983, p = 0.044), and for GSTA1 CC genotype, increasing susceptibility to ASD (OR = 4.132, 95%CI: 1.219–14.012, p = 0.023); the significance was lost when genotype-genotype interactions were added into the logistic regression model. The combination of GSTM1 active and GSTT1 active genotype decreased the risk of ASD (OR = 0.126, 95%CI: 0.029–0.547, p = 0.006), as well as combination of GSTT1 active and GSTP1 llelle (OR = 0.170, 95%CI: 0.029–0.992, p = 0.049). Increased risk of ASD was observed if combination of GSTM1 active and GSTP1 llelle was present (OR = 11.088, 95%CI: 1.745–70.456, p = 0.011). The effect of TSDP was not significant for the risk of ASD, neither individually, nor in interaction with specific GST genotypes. Specific combination of GST genotypes might be associated with susceptibility to ASD, while it appears that maternal smoking during pregnancy does not increase the risk of ASD.

Cognitive and behavioral differences in toddlers with autism spectrum disorder from multiplex and simplex families.

Prospective, longitudinal designs utilizing "high-risk" infant siblings of children diagnosed with Autism Spectrum Disorder (ASD-sibs) have provided unique and valuable insights regarding the early ASD phenotype. However, it remains unclear whether these cases are representative of all children with ASD. The objective in the present study was to investigate whether the early development of toddlers with ASD from multiplex (MPX) families, who have an affected older sibling, is similar or different to toddlers with ASD from simplex (SPX) families, where there is no affected sibling. A further aim was to examine patterns of association between autism symptom severity and cognitive functioning within each group to inform possible mechanisms for group similarities/differences. Behavioral and cognitive assessment data from a sample of toddlers with ASD was utilized, comprising 45 MPX, 127 first-born SPX, and 72 later-born SPX toddlers. Participants in the MPX group had significantly higher developmental quotients on the Mullen Scales of Early Learning compared to those in the SPX groups, who did not differ from each other. However, all three groups were similar on their autism severity scores (measured using the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview), and the pattern of relationships between cognitive ability and autism symptom severity. The results suggest that caution be exercised in generalizing findings from ASD-sib samples to other samples of children with ASD. The higher cognitive abilities in the MPX group, in addition to biological differences, may also be an outcome of family environmental factors, which deserves further investigation. Autism Research 2019, 12: 682-693. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We sought to establish whether toddlers with autism from families where there is more than one affected child, called multiplex families, are different to children from simplex families, where there is only one affected child, and no other members within the immediate family with an autism diagnosis. We found that while toddlers from multiplex families were similar to those from simplex families in their autism symptoms, they were more developmentally advanced than children in the latter group.

Epilepsy and interictal epileptiform activity in patients with autism spectrum disorders

PurposeThe purpose of this study was to determine the prevalence of epilepsy and subclinical epileptiform abnormalities in children with autism spectrum disorder (ASD), and to investigate its effects on core autistic symptoms and adaptive behavior skills. MethodsPatients with diagnosis of ASD who met full criteria on Autism Diagnostic Interview-Revised (ADI-R) were included in the study. Adaptive behavior skills were assessed by Vineland Adaptive Behavior Scale-II (VABS-II). Clinical assessment for epilepsy and video electroencephalography (EEG) (v-EEG) examinations during wakefulness and/or sleep were prospectively performed in all patients. ResultsA total of 112 patients with diagnosis of ASD of mean age 6.58 ± 3.72 were included in the study. Based on clinical and v-EEG assessments, three groups of patients were defined: 1) patients with epilepsy (n = 17; 15.2%); 2) patients with epileptiform discharges in absence of clinical seizures (n = 14; 12.5%); 3) patients without epilepsy and without epileptiform discharges (n = 81; 72.3%). There were no significant differences between three groups of patients on ADI-R subscores. Speech development was also not significantly related to epilepsy. There was a slight tendency of the VABS-II motor skills score to be higher in the group of patients with autism without clinical diagnosis of epilepsy and without subclinical epileptiform discharges (p < 0.05) in comparison with the two other groups. According to this tendency, we might claim that patients with higher scores on motor skills could have 0.88 times lower odds for having epileptiform EEG activity. ConclusionsAccording to our results, we were not able to detect differences in the ADI-R between the three populations with ASD, all with unknown etiology. Epilepsy, as well as subclinical epileptic discharges, showed small effects on Motor Skills in patients with autism, and had no effect on adaptive behavior Communication/Socialization/Daily Living Skills.

7 - A GENETIC FIRST APPROACH TO DISSECTING THE HETEROGENEITY OF AUTISM: PHENOTYPIC COMPARISON OF AUTISM RISK COPY NUMBER VARIANTS

Background Autism is a heterogeneous condition and there is growing evidence that different features are dissociable and may be underpinned by different risk factors. Several autism risk copy number variants (CNVs) have been identified. It remains unclear whether these CNVs differentially impact autism presentation. This study aimed to contrast autism symptomatology and the clinical profile of different autism risk CNVs. Methods Patients were recruited at several international sites based on genotype, not autism phenotype. This work represents the efforts of several consortia; the ECHO study, IMAGINE-ID consortium, International 22q11.2DS Brain Behaviour Consortium, 16p11.2 European Consortium and Simons VIP. Patients were all assessed using the Autism Diagnostic Interview-Revised (ADI-R) and underwent IQ testing. We focused on 16p11.2 deletion (n=96), 16p11.2 duplication (n=47), 22q11.2 deletion (n=383) and 22q11.2 duplication (n=22) carriers. Patients were aged 4–27 years. We examined autism prevalence based on ADI-R criteria, ADI-R domain scores, whether carriers with autism had additional IQ deficits and autism male-to-female ratio. Results Autism prevalence differed by syndrome (p Discussion Autism risk genetic variants have specific genotype-phenotype correlations. This indicates that autism is dissociable at the genetic level, and supports the view that different biological pathways underpin distinct symptom domains.

Autism spectrum disorder and cognitive profile in children with Dravet syndrome: Delineation of a specific phenotype.

SummaryObjectiveWe aimed to assess a cohort of young patients with Dravet syndrome (DS) for intellectual disability (ID) and autism spectrum disorder (ASD) using standardized tools and parental questionnaires to delineate their specific profiles.MethodsWe included 35 patients with DS aged 24 months to 7 years, excluding patients with a developmental age (DA) <18 months (n = 5). We performed specific tests adapted for ID (Psychoeducational Profile, Third Edition [PEP‐3]), in addition to the Child Development Inventory (CDI) and Vineland Adaptive Behavior Scales, Second Edition (VABS‐II) questionnaires. We used 2 standardized tools for ASD: the Autism Diagnostic Observation Schedule, Second Edition (ADOS‐2) and the Autism Diagnostic Interview‐Revised (ADI‐R). We compared the with parental questionnaires and the VABS‐II, and with ASD characteristics.Results PEP‐3 subscales showed pathologic development in all but one patient (97%): ID in 23 of 30 (77%), and borderline cognitive functioning in 6 of 30 (22%). Eleven patients (39%) had ASD and 2 (7%) had a Social Communication Disorder (SCD) diagnosis. We found no difference between PEP‐3 and CDI categorization except for fine motor skills. We found significant negative correlations between ADOS‐2 and PEP‐3 for the majority of scores. For patients aged older than 50 months, 2 groups emerged (ASD/no ASD) with significant difference in DA. The logistic regression for ASD diagnosis explained by VABS‐II showed a significant effect for Socialization, Motor Skills, and Adaptive Behavior.SignificanceWe found a high prevalence of ID in patients with DS. ID is characterized by expressive and comprehensive communication deficits in addition to visuospatial difficulties. ASD showed a specific profile with a relative preservation of social skills, emphasizing a possible underdiagnosis. Parental questionnaires can provide a good assessment of cognitive profile and might allow the difficulty of addressing cognitive scales in DS to be overcome. The profile of ID and ASD should help to establish early adapted rehabilitation programs and emphasizes the global need for care beyond seizures in DS and other developmental epileptic encephalopathies.

Association of Prenatal Exposure to Air Pollution With Autism Spectrum Disorder

The etiology of autism spectrum disorder (ASD) is poorly understood, but prior studies suggest associations with airborne pollutants. To evaluate the association between prenatal exposures to airborne pollutants and ASD in a large population-based cohort. This population-based cohort encompassed nearly all births in Metro Vancouver, British Columbia, Canada, from 2004 through 2009, with follow-up through 2014. Children were diagnosed with ASD using a standardized assessment with the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Monthly mean exposures to particulate matter with a diameter less than 2.5 µm (PM2.5), nitric oxide (NO), and nitrogen dioxide (NO2) at the maternal residence during pregnancy were estimated with temporally adjusted, high-resolution land use regression models. The association between prenatal air pollution exposures and the odds of developing ASD was evaluated using logistic regression adjusted for child sex, birth month, birth year, maternal age, maternal birthplace, and neighborhood-level urbanicity and income band. Data analysis occurred from June 2016 to May 2018. Mean monthly concentrations of ambient PM2.5, NO, and NO2 at the maternal residence during pregnancy, calculated retrospectively using temporally adjusted, high-resolution land use regression models. Autism spectrum disorder diagnoses based on standardized assessment of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. The hypothesis being tested was formulated during data collection. In a cohort of 132 256 births, 1307 children (1.0%) were diagnosed with ASD by the age of 5 years. The final sample size for the PM2.5-adjusted model was 129 439 children, and for NO and NO2, it was 129 436 children; of these, 1276 (1.0%) were diagnosed with ASD. Adjusted odds ratios for ASD per interquartile range (IQR) were not significant for exposure to PM2.5 during pregnancy (1.04 [95% CI, 0.98-1.10] per 1.5 μg/m3 increase [IQR] in PM2.5) or NO2 (1.06 [95% CI, 0.99-1.12] per 4.8 ppb [IQR] increase in NO2) but the odds ratio was significant for NO (1.07 [95% CI, 1.01-1.13] per 10.7 ppb [IQR] increase in NO). Odds ratios for male children were 1.04 (95% CI, 0.98-1.10) for PM2.5; 1.09 (95% CI, 1.02-1.15) for NO; and 1.07 (95% CI, 1.00-1.13) for NO2. For female children, they were for 1.03 (95% CI, 0.90-1.18) for PM2.5; 0.98 (95% CI, 0.83-1.13) for NO; and 1.00 (95% CI, 0.86-1.16) for NO2. In a population-based birth cohort, we detected an association between exposure to NO and ASD but no significant association with PM2.5 and NO2.

Psychiatric disorders and autism in young children with 22q11.2 deletion syndrome compared to children with idiopathic autism

Background: The 22q11.2 deletion syndrome (22q11DS) is a neurogenetic condition characterized by high rates of psychiatric disorders. To our knowledge, this is the first study to assess psychiatric disorders in young children with 22q11DS using a structured psychiatric diagnostic interview, and one of few studies to use the complete gold standard diagnostic evaluation to examine the prevalence of autism spectrum disorder (ASD) in young children with 22q11DS and compare it to a matched control group with iASD.Methods: We identified the psychiatric disorders and autistic phenotype of young children with 22q11DS (age 3–8 years) and compared them with those of age and sex-matched children with idiopathic autism (iASD). We used the gold standard psychiatric and ASD assessments including the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS) and a clinical examination by a child psychiatrist.Results: Eighty-four percent of the children with 22q11DS had at least one psychiatric disorder, including anxiety disorders and ADHD, and 16% met strict criteria for ASD. Children with 22q11DS and ASD symptoms had less severe overall ASD symptoms than those with iASD. Children with 22q11DS, regardless of ASD diagnosis, were characterized by repetitive restricted behaviors.Conclusions: Our results highlight the need to screen for psychiatric disorders in 22q11DS and treat them already in preschool years.