Multistage screening process for neurodevelopmental disorders in siblings of children with autism: the FRATSA protocol study

Objective: To compare the number, frequency, enjoyment and performance in extracurricular activities of siblings of children with autism spectrum disorders (ASD) to their typically developing (TD) peers, and to identify differences between actual and desired participation. Methods: A case-control study with 30 siblings of children with ASD and 30 siblings of TD children was conducted using the Paediatric Interest Profiles and a questionnaire. Results: Siblings of children with ASD participated in fewer extracurricular activities than those with TD siblings. ASD symptoms were significantly associated with the sibling participating in fewer extracurricular activities. Children with TD siblings had higher enjoyment scores in relaxation activities than children with siblings with ASD. Conclusion: While results were mainly positive, some differences indicated that having a sibling with ASD may impact participation in extracurricular activities. Assessments of participation barriers, as well as support to minimise participation restrictions among siblings of children with ASD are required.

Advances in Our Understanding of Genetic Risk Factors for Autism Spectrum Disorders

Background: Autistic traits exist along a continuum that extends into social functioning in the general population, and they aggregate in the family members of children with autism spectrum disorder (ASD). Quantitative measures are therefore essential when investigating the patterns of familiality of these traits. Prior studies have suggested differential inheritance patterns of autistic traits that depend on the cognitive level of the child with ASD as well as the family type. Objective: Our goal was to examine the family patterns of quantitative autism traits (QAT) in a group of simplex autism families of high-functioning children with ASD. Method: We used the Social Responsiveness Scale (SRS) to evaluate QAT in 47 ASD families and 46 control families. SRS assessments (parental/spousal evaluations) were collected for the children with ASD, their siblings, and their parents as well as for the control children and their parents. Results: The SRS was able to distinguish individuals with ASD from the control children and from their unaffected siblings. Significant group differences were also found when comparing the fathers of ASD families to control fathers and when comparing the brothers of individuals with ASD to control boys, with male members of ASD families having higher SRS scores. Gender differences were observed in the group of siblings of children with ASD and the group of parents of children with ASD, with males having higher scores than females. In ASD families, a positive trend between child and father QAT was found, whereas mothers’ scores were not associated with child outcomes. By contrast, in control families, mothers’ QAT correlated more strongly with child QAT. Conclusions: Autistic traits aggregate in the fathers and brothers of children with ASD in simplex autism families. The QAT levels of the family members should be taken into consideration when planning the rehabilitation of the child or adolescent with ASD and when designing family interventions.

To determine the prevalence of autism spectrum disorder (ASD) in Neurofibromatosis Type 1 (NF1). Second-phase population-based epidemiologic study using an allcase NF1 registry in a defined UK 4.1 million population area. A total of 109 (52.7%) of 207 responders from the initial screening phase were grouped by using the parent-rated Social Responsiveness Scale (SRS) as significant ASD (SRS≥76; n = 32), moderate ASD (SRS ≥ 60<76; n = 29), or non-ASD (SRS <60, n = 48). Twenty-three cases from the significant ASD group, 16 from moderate ASD, and 8 from non-ASD (total n = 47), invited proportionately by random selection, were seen for detailed confirmatory ascertainment. Assessments on Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Scale-Generic, and verbal IQ were combined by using standard Collaborative Program for Excellence in Autism criteria into an ASD categorization for each case (ASD, broad ASD with partial features, non-ASD). A preplanned weighted analysis was used to derive prevalence estimates for the whole population. Fourteen (29.5%) of 47 showed ASD, 13 (27.7%) broad ASD, and 20 (42.5%) non-ASD. The ASD/broad ASD group showed male predominance (1.7:1.0), but did not differ significantly from the non-ASD group on IQ, age, socioeconomic status, inheritance, physical severity, or education. The population prevalence estimate is 24.9% ASD (95% confidence interval 13.1%-42.1%) and 20.8% broad ASD (95% confidence interval 10.0%-38.1%); a total of 45.7% showing some ASD spectrum phenotype. Findings indicate high prevalence of ASD in NF1, with implications for clinical practice and further research into NF1 as a single-gene model for autism.

The Social Responsiveness Scale (SRS) is a parent-completed screening questionnaire often used to measure autism spectrum disorders (ASD) severity. Although child characteristics are known to influence scores from other ASD-symptom measures, as well as parent-questionnaires more broadly, there has been limited consideration of how non-ASD-specific factors may affect interpretation of SRS scores. Previous studies have explored effects of behavior problems on SRS specificity, but have not addressed influences on the use of the SRS as a quantitative measure of ASD-symptoms. Raw scores (SRS-Raw) from parent-completed SRS were analyzed for 2,368 probands with ASD and 1,913 unaffected siblings. Regression analyses were used to assess associations between SRS scores and demographic, language, cognitive, and behavior measures. For probands, higher SRS-Raw were associated with greater non-ASD behavior problems, higher age, and more impaired language and cognitive skills, as well as scores from other parent report measures of social development and ASD-symptoms. For unaffected siblings, having more behavior problems predicted higher SRS-Raw; male gender, younger age, and poorer adaptive social and expressive communication skills also showed small, but significant effects. When using the SRS as a quantitative phenotype measure, the influence of behavior problems, age, and expressive language or cognitive level on scores must be considered. If effects of non-ASD-specific factors are not addressed, SRS scores are more appropriately interpreted as indicating general levels of impairment, than as severity of ASD-specific symptoms or social impairment. Additional research is needed to consider how these factors influence the SRS' sensitivity and specificity in large, clinical samples including individuals with disorders other than ASD.

OBJECTIVE: Difficulties in social communication is core syptoms of autism spectrum disorder (ASD), and it is often present in first-degree relatives in varying degrees. However, these subclinical autistic traits, which are thought to be related to genetic susceptibility factors, may be heterogeneous in family members. This prospective, the aim of this study was to compare unaffected siblings of children with ASD in terms of theory of mind, empathy skills, and broad autism phenotype (BAP).METHODS: Fourty-one children who were diagnosed Autistic Disorder, Asperger Disorder and Pervasive Developmental Disorder-not otherwise specified according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition and their unaffected siblings and 43 controls of typically developing children were included. The Schedule for Affective Disorders and Schizophrenia for School-age Children – Present and Lifetime Version was conducted all children with the aim of excluding a psychiatric diagnosis. False-belief tasks and Emotion Recognition Scales were used to evaluate theory of mind and empathy skills. The Social Communication Questionnaire was administered by the clinician in order to evaluate subthreshold autistic symptoms.RESULTS: Unaffected siblings of ASD children exhibited worse performance in theory of mind and emotion recognition tasks. Additionally, these children had more autistic symptoms and there was a correlation with autism symptoms and social cognition tasks.DISCUSSION: In compatible with BAP, the results indicated that the siblings of children with ASD showed a neurocognitive profile associated with ASD at a slight level, and they had more subsyndromal autism symptoms compared with healthy children. The findings also indicated that there was a weakness in skills of empathy and theory of mind ability of siblings of ASD.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Folate has been demonstrated to be associated with ASD. However, current studies on the correlation between folate and symptoms of children with ASD have inconsistent conclusions, use mainly small samples, and lack age-stratified analysis. This study aimed to explore the association between serum folate and symptoms of autistic children at different age groups from a multi-center perspective.Methods: We enrolled 1,300 children with ASD and 1,246 typically developing (TD) children under 7 years old from 13 cities in China. The Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Childhood autism rating scale (CARS) were used to evaluate the symptoms of children with ASD. China neuropsychological and Behavior Scale-Revision 2016 (CNBS-R2016) scale was used to evaluate the neurodevelopment of children with ASD. Serum folate was measured by chemiluminescence assay in the two groups.Results: The serum folate levels of children with ASD were lower than that of TD children. In terms of core symptoms of ASD, we found that the serum folate levels were not associated with ABC, SRS, and CARS scores in ASD children of all ages but negatively associated with communication warning behavior scores of CNBS-R2016 in ASD children aged three and under. Concerning development quotients, it was at the age of three and under that serum folate levels were positively associated with gross motor, fine motor, language, and general quotient of ASD children. These ASD children aged three and under were further divided into two groups according to the median of serum folate (14.33 ng/mL); we found that compared to ASD children with folate ≤ 14.33 ng/mL, those with folate >14.33 ng/mL had lower communication warning behavior score and higher gross motor, fine motor, adaptive behavior, language, person-social, and general development quotients.Conclusion: We found that serum folate status was primarily associated with the neurodevelopment of children with ASD aged three and under. Furthermore, relatively higher serum folate levels may be more beneficial for children with ASD. Our results suggest that folate level should be paid more attention in ASD children, especially in early life, to better promote the intervention of ASD children.

The Social Responsiveness Scale (SRS) is frequently used in research settings to measure characteristics associated with autism spectrum disorders (ASD). A short version has been developed but not yet tested for certain properties of the full SRS, such as familiality. The purpose of this study was to determine if prior familiality findings for the full SRS can be replicated using the short form by measuring the associations ofthe parental Social Responsiveness Scale-Short Form (SRS-SF) scores with child ASD diagnoses and child SRS-SF scores. We used a nested case-control study within a longitudinal cohort study design. Participants were selected from the Nurses' Health Study II (NHS II). Cases were children of study participants who had been diagnosed with ASD, while controls had not been diagnosed with ASD and were frequency matched by year of birth to cases. 2144 out of 3161 eligible participants returned SRS forms for a child and at least one parent. Participants in NHS II completed SRS forms for their spouses and spouses completed SRS forms for NHS II participants. Parental SRS-SF scores were based on a subset of 16 questions from the SRS. ASD diagnosis among children was reported by the mothers and validated in a subset using the Autism Diagnostic Interview-Revised, as well as child SRS-SF scores. Children whose parents both had elevated SRS-SF scores (those in the top 20% of the study distribution) had a higher odds of ASD diagnosis than those who did not have elevated parental scores (OR 2.25; 95% CI 1.41, 3.58). Additionally, children whose fathers had elevated SRS-SF scores had a higher odds of ASD diagnosis (OR 2.18; 95% CI 1.60, 2.97) than those whose fathers scores were not elevated. In sex-stratified analyses, male children with elevated parental SRS-SF scores had a higher odds of ASD diagnosis than those who did not have elevated parental scores. These associations were not as evident among female children. Parental SRS-SF scores also predicted child SRS-SF scores among controls. These findings are similar to prior findings for the full SRS and support the ability of the SRS-SF to capture familiality of ASD-related traits.

IMPULSIVITY AND COMPULSIVITY: TRANSLATIONAL APPROACHES TO COMPULSIVITY IN AUTISM SPECTRUM DISORDERS

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social skills and communication. Forkhead box protein P1 (FOXP1) is involved in the development of the brain and the pathogenesis of ASD. However, the function of FOXP1 within the brain remains unclear. The aim of this case–control study was to evaluate whether FOXP1 could be used as a diagnostic biomarker for ASD. Method: Blood plasma was collected from children with ASD and age-matched controls. The enzyme-linked immunosorbent assay (ELISA) was used to determine the FOXP1 plasma levels in ASD and control groups. The behavioral and social impairments in children with ASD were assessed using the Childhood Autism Rating Scale (CARS) and the Social Responsiveness Scale (SRS). Spearman’s correlation coefficient (r) was used to determine the correlation between different variables. Results: The plasma FOXP1 protein level was significantly decreased in children with ASD compared to the controls (p < 0.001). CARS showed significant differences between the mild-to-moderate and severe subgroups, while the SRS showed no significant difference between the two subgroups. Moreover, both the mild-to-moderate and severe subgroups exhibited a substantial drop in plasma FOXP1 compared to the controls. ASD children older than six years old also showed a significantly decreased FOXP1 level, compared to those aged six years or less. Furthermore, no significant correlation between the FOXP1 level, CARS, and SRS was observed. However, a negative correlation was found between age and FOXP1 plasma level. Conclusions: We suggest that plasma FOXP1 may act as a potential biomarker for the prognosis of ASD severity and social communication impairment. Further research with a larger sample size is needed to clarify these associations and help diagnose or understand the underlying mechanism of ASD.

Fragile X syndrome (FXS) is the leading known genetic cause of autism spectrum disorder (ASD) with 60–74% of males with FXS meeting diagnostic criteria for ASD. Infants with FXS have demonstrated atypical neural responses during face processing that are unique from both typically developing, low-risk infants and infants at high familial risk for ASD (i.e., infants siblings of children with ASD). In the current study, event-related potential (ERP) responses during face processing measured at 12 months of age were examined in relation to ASD symptoms measured at ~48 months of age in participants with FXS, as well as siblings of children with ASD and low-risk control participants. Results revealed that greater amplitude N290 responses in infancy were associated with more severe ASD symptoms in childhood in FXS and in siblings of children with ASD. This pattern of results was not observed for low-risk control participants. Reduced Nc amplitude was associated with more severe ASD symptoms in participants with FXS but was not observed in the other groups. This is the first study to examine ASD symptoms in childhood in relation to infant ERP responses in FXS. Results indicate that infant ERP responses may be predictive of later symptoms of ASD in FXS and the presence of both common and unique pathways to ASD in etiologically-distinct high-risk groups is supported (i.e., syndromic risk vs. familial risk).

The relationship between prenatal exposure to low-level air pollution and child autism spectrum disorder (ASD) is unclear. To examine associations of prenatal air pollution exposure with autism. We analyzed data from 8,035 mother-child pairs from 44 United States cohorts in the Environmental influences on Child Health Outcomes (ECHO) Cohort. Fine particulate matter (PM2.5), nitrogen dioxide (NO2), and 8-hour-max ozone (O3) levels were estimated at residential addresses during pregnancy. Parents rated children's autism-related traits using the Social Responsiveness Scale (SRS) (mean age 9.4 years, SD=3.6) and reported physician-diagnosed ASD. We examined associations of the three air pollutants with SRS scores (10th, 50th, and 90th quantiles) using quantile regression and with ASD diagnosis using logistic regression. Models were run within census divisions, and coefficients were pooled in a meta-analysis. Average (SD) pregnancy exposures were 9.3 µg/m3 (2.7) for PM2.5, 21.8 ppb (8.8) for NO2, and 40.3 ppb (5.5) for O3, with variations across census divisions. The median SRS T-score was 46 (IQR=41 to 52), and 444 children (5.5%) had an ASD diagnosis. Higher PM2.5 was associated with higher SRS scores at the 10th quantile (β=0.74, 95% CI: 0.09, 1.40) but not at the median or highest quantile. The association between PM2.5 and ASD diagnosis was highly heterogeneous, with associations present in the South Central, Mountain, and Pacific census divisions. Heterogeneity was also high in the association between NO2 and SRS at the median and only in the mid-Atlantic, West North Central, and South Atlantic census divisions. Higher O3 was associated with higher SRS scores at the median (β per IQR increment=0.83, 95% CI: 0.05, 1.61) and highest quantile (β=2.19, 95% CI: 0.06, 4.32) in the meta-analysis. Higher O3 also was associated with ASD. Associations with ASD outcomes were present even at low levels of air pollutants. https://doi.org/10.1289/EHP16675.

BackgroundAn individual with autism spectrum disorder (ASD) has social skill, motor skill, and motion perception deficits. However, the relationship among them was not clarified. Therefore, this study aimed to evaluate the effects of motor skills on social skills and motion perception. MethodsFive typically developed children and fourteen children with ASD participated in our study. The N200 component, a brain activity indicating motion perception, was induced in mid-temporal (MT/V5) brain area by watching a random dot kinematograph, and was recorded using a scalp electroencephalogram. Furthermore, the social responsiveness scale (SRS) indicating the social skill deficit, the developmental coordination disorder questionnaire (DCDQ) estimating the developmental coordination disorder (DCD), and the movement assessment battery for children second edition (MABC-2) indicating motor skills were recorded in the children with ASD. A hierarchical multiple regression analysis was conducted to examine the modulation effects of motor skills on the relationship between social skills and motion perception. The dependent variable was the N200 latency, and the independent variables were SRS, MABC-2, and combined MABC-2 and SRS. ResultsThe N200 latency was more delayed in children with ASD relative that in typically developed children. Intact balance ability modulated the relationship between social skills and N200 latency in children with ASD. Within the high balance ability, when the social skills worsened, the N200 latency was shortened. ConclusionsThis is the first report that intact motor skills could modulate the relationship between social skills and motion perception.

Living in the shadows: Correlational analysis of behavioral trajectories and quality of life among siblings of children with neurodevelopmental disorders.

BackgroundResearches have found that alteration of intestinal flora may be closely related to the development of autism spectrum disorder (ASD). However, whether probiotics supplementation has a protective effect on ASD remains controversial. This meta-analysis aimed to analyze the outcome of probiotics in the treatment of ASD children.MethodsThe Pubmed, Cochrane Library, Web of Science and Embase were searched until Sep 2022. Randomized controlled trials (RCTs) relevant to the probiotics and placebo treatment on ASD children were screened. Quality assessment of the included RCTs was evaluated by the Cochrane collaboration’s tool. The primary outcomes were ASD assessment scales, including ABC (aberrant behavior checklist) and CBCL (child behavior checklist) for evaluating the behavior improvement, SRS (social responsiveness scale) for social assessment, DQ (developmental quotient) for physical and mental development and CGI-I (clinical global impression improvement) for overall improvement. The secondary outcome was total 6-GSI (gastrointestinal severity index).ResultsIn total, 6 RCTs from 6 studies with 302 children were included in the systemic review. Total 6-GSI (MD=-0.59, 95%CI [-1.02,-0.17], P < 0.05) decreased significantly after oral administration of probiotics. Whereas, there was no statistical difference in ABC, CBCL, SRS, DQ and CGI-I between probiotics and placebo groups in ASD children.ConclusionProbiotics treatment could improve gastrointestinal symptoms, but there was no significant improvement in ASD.