Autism traits in the RASopathies.

BACKGROUND: Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs. METHODS: We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS). RESULTS: Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs. CONCLUSIONS: Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.

The Associations Between Sluggish Cognitive Tempo, Internalizing Symptoms, and Academic Performance in Children With Reading Disorder: A Longitudinal Cohort Study.

OBJECTIVE: To investigate whether sluggish cognitive tempo (SCT) was associated with anxiety, depression, and academic performance (AP) in children with reading disorder (RD), and whether ADHD-Inattention (ADHD-IN) moderated these relationships. METHOD: Parents and teachers of children with RD (N = 147, ages 6-18) completed evaluations of SCT, ADHD, anxiety, depression, and AP, every 3 months for 18 months. Baseline and longitudinal associations between SCT and outcomes, and effect moderation of ADHD-IN, were assessed. RESULTS: Teacher-rated SCT was positively associated with teacher-rated anxiety (p < .001) and negatively associated with AP (p < .001) cross-sectionally and longitudinally, with significant effect modification by ADHD-IN for both outcomes. SCT was not associated with depression in adjusted cross-sectional and longitudinal analyses. There were no significant findings for any parent-reported measures. CONCLUSION: SCT has negative effects on anxiety and AP in children with RD among individuals with low ADHD-IN according to teacher report. Targeted treatment of SCT may provide substantial benefits.

The role of grit and resilience in children with reading disorder: a longitudinal cohort study.

Prior studies have suggested that grit and resilience predict both academic and career success. However, these qualities have not been examined in children with reading disorder (RD). We therefore investigated whether grit and resilience were associated with anxiety, depression, academic performance, and quality of life (QOL) in these students. This 3-year longitudinal cohort study included 163 participants with RD from 3 schools. Evaluations were completed by parents and/or teachers every 3 months. The Grit and Resilience Scale was adapted from the 10-item Connor-Davidson Resilience Scale and the 12-item Grit Scale. Outcome measures included anxiety (School Anxiety Scale - Teacher Report and the 8-item Spence Children's Anxiety Scale), depression (Short Mood and Feelings Questionnaire), academic performance, and QOL (Pediatric QOL Inventory 4.0). Multivariate linear regression models (adjusting for age and sex) assessed the associations at baseline. Repeated measures analysis using mixed-effects models assessed the relationship longitudinally. There were statistically significant associations between grit and resilience and all outcomes at baseline and over time. After adjusting for age and sex, improved grit and resilience was associated with decreased anxiety (ß = - 0.4, p < 0.001) and improved academic performance (ß = 0.5, p < 0.001) when grit and resilience was measured by teachers, as well as decreased depression (ß = - 0.3, p < 0.001) and improved QOL (ß = 0.6, p < 0.001) when grit and resilience was measured by parents. Grit and resilience are significantly related to mental health, academic performance, and QOL in children with RD. This suggests that interventions to improve grit and resilience may lead to positive benefits.

Quality of Life Among School-Age Children With Autism: The Oak Hill School Outcomes Study.

Prior studies have documented a lower quality of life (QOL) in children with autism spectrum disorder (ASD) compared to typically developing peers, but few studies have examined the trajectory of QOL over time in the same population. We conducted a 2-year cohort study in 29 children attending a specialized school for ASD with quarterly measures of parent-rated QOL as well as parent and teacher measures of behavior and social skills to determine the trajectory of change in QOL and predictors of change. The average change in QOL was constant (no change over time), but there was substantial variation with some students showing significant gains and others showing declines. Exploratory analyses revealed that improvements in behavior and social skills were greater (nonsignificantly) among children with improvements in QOL. Children with improved QOL were also younger and had a lower initial symptom burden. This study suggests that early intervention programs that provide social skills and behavioral management strategies may improve QOL in children with ASD. The study also highlights the need to develop and study novel, qualitative measures of QOL in this population.

Improving autism perinatal risk factors: A systematic review.

BACKGROUND: Current understanding of the etiology of autism is based on the interaction of multiple genes with each other and with environmental factors, leading to a neurodevelopmental process that results in the expression of autism spectrum disorder (ASD) in the child. This suggests that it might be possible to strengthen resilience to environmental stressors during the perinatal period to improve outcomes and possibly prevent the development of ASD. METHODS: We searched the MEDLINE database for multiple perinatal factors associated with the development of ASD published between January 1, 2005 and July 1, 2018. The search terms used were "autism" crossed with either "perinatal," "prenatal," "gestational," or "pregnancy," and crossed again with each perinatal risk factor highlighted in this review including topics on parental health, infections, medications, and environmental stressors. We then searched interventions that may improve neurodevelopmental outcome before and during pregnancy, including supplements, breastfeeding, and postpartum stress reduction. We identified recent or unique metanalyses and systematic reviews of the identified focus and on randomized controlled trials and summarized these using the most recent and comprehensive reviews. RESULTS: Folate, omega-3, vitamin D3, environmental toxin avoidance, correcting deficiencies, immune boosting, and prolonged breast feeding are all reported to be linked to the possible reduction of adverse pregnancy outcomes including ASD. CONCLUSIONS: Studies of individual components for improving pregnancy outcomes and several uncontrolled preconception to infancy medical practices suggest that multiple interventions might improve the outcomes of pregnancies where there is risk for developing ASD.

Anterior cingulate volume in pediatric bipolar disorder and autism.

BACKGROUND: An increasing number of studies indicate the anterior cingulate gyrus (ACG) may play a role in the attention deficits associated with pediatric bipolar disorder (BD). Age, medications, and intelligence quotient (IQ) may affect ACG volume; few studies have controlled for these effects. METHODS: We recruited 16 children with BD and 24 children with autism spectrum disorder (ASD); 15 children with no psychiatric diagnosis (NP) were also included. All participants were evaluated with the K-SADS and a DSM-IV Autism/Asperger's Checklist; the ADI-R was also administered to ASD participants shortly after the study began. The participants completed a brain MRI scan on a 1.5Tesla Signa GE scanner. We segmented the ACG and compared left and right ACG volumes between groups. The influence of medications on the ACG volume was assessed while controlling for the effects of age and IQ. RESULTS: The left ACG volume was significantly smaller in the BD group compared to the NP (p=0.004) and ASD (p=0.006) groups. No significant differences were found in the right ACG volume. These differences do not appear to be attributable to medication use or IQ. CONCLUSIONS: Pediatric BD patients have a smaller left ACG volume compared to NP children and children diagnosed with ASD. This replication and extension of previous studies suggest that the ACG volume abnormality may be a biomarker for BD.

Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli.

Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016.

Examining Clinics for Children with Autism: The Autism Translating To Treatment Study.

OBJECTIVES: Certain clinical providers specialize in providing complementary and integrative medicine (CIM) therapies for children with autism spectrum disorder (ASD). Because many of these providers and their patients/families have reported substantial improvement, the authors developed an online platform to carefully examine these clinical practices. The initial goal was to examine the feasibility of prospective data collection in this setting. The larger goals were to characterize the tests and treatments used in these clinics; examine associations between specific treatments, biomarkers, and improved outcomes; and identify promising treatments for future study. DESIGN: Prospective cohort study. SETTING: Four CIM clinics specializing in treating children with ASD. PATIENTS: Children with ASD age 2-8 years. INTERVENTIONS: The study protocol provided no interventions, but all interventions provided by the CIM clinical providers were recorded. OUTCOME MEASURES: Aberrant Behavior Checklist (ABC); Social Responsiveness Scale (SRS); and instruments that assessed sensory sensitivity, language, gastrointestinal (GI) symptoms, pediatric quality of life, and caregiver strain. RESULTS: Fourteen children were enrolled (mean age, 4.4 years). Over 3 months, the total behavior score (ABC) decreased (improved) from 110.8 to 103.8 (change, -7.0; 95% confidence interval [CI], -27.9 to 13.9), and the total social responsiveness score (SRS) decreased (improved) from 133.8 to 127.2 (change, -6.6; 95% CI, -30.5 to 17.3), but these changes were not statistically significant. Similarly, caregiver strain and pediatric quality of life decreased (improved) but by a nonsignificant amount. More severe GI symptoms and more severe ASD symptoms were associated with lower quality of life (p < 0.001). CONCLUSIONS: Barriers to successful data collection were identified. Despite these challenges, this study could confirm interesting associations between data elements, highlighting the future value of similar systems for improving evidence-based care in this population.

Integrating Autism Care through a School-Based Intervention Model: A Pilot Study.

The purpose of this pilot study is to determine the feasibility of monitoring the progress of children with an autism spectrum disorder (ASD) both in school and at home to promote a school-based integrated care model between parents, teachers, and medical providers. This is a prospective cohort study. To monitor progress, outcome measures were administered via an online platform developed for caregivers and teachers of children (n = 30) attending a school specializing in neurodevelopmental disorders and using an integrated medical and education program. Longitudinal analysis showed improvements in a novel scale, the Teacher Autism Progress Scale (TAPS), which was designed to measure key autism-related gains in a school environment (2.1-point improvement, p = 0.004, ES = 0.324). The TAPS showed a strong and statistically significant correlation, with improvement in aberrant behavior (r = -0.50; p = 0.008) and social responsiveness (r = -0.70; p < 0.001). The results also showed non-statistically significant improvements in aberrant behavior, social responsiveness, and quality of life over time at both school and home. To assess feasibility of ongoing progress measurement, we assessed missing data, which showed caregivers were more likely to miss surveys during summer. Results demonstrate the value and feasibility of online, longitudinal data collection in school to assist with individualized education planning and collaborative care for children with ASD. Lessons learned in this pilot will support school outcomes researchers in developing more efficacious, collaborative treatment plans between clinicians, caregivers, and teachers.

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism.

OBJECTIVE: Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress. We sought to determine if methyl B12, a key metabolic cofactor for cellular methylation reactions and antioxidant defense, could improve symptoms of ASD. METHODS: A total of 57 children with ASD were randomly assigned to 8 weeks of treatment with methyl B12 (75 µg/kg) or saline placebo every 3 days in a subcutaneous injection. The primary outcome measure was overall improvement in symptoms of ASD as measured by the Clinical Global Impressions-Improvement (CGI-I) score. Secondary outcome measures included changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Laboratory measures of methionine methylation and antioxidant glutathione metabolism were assessed at baseline and 8 weeks. RESULTS: A total of 50 children (mean age 5.3 years, 79% male) completed the study. The primary outcome measure - the clinician rated CGI-I score - was statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2-0.2, p = 0.005). Clinical improvement among children treated with methyl B12 was positively correlated with increases in plasma methionine (p = 0.05), decreases in S-adenosyl-l-homocysteine (SAH) (p = 0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH (p = 0.007), indicating an improvement in cellular methylation capacity. No improvements were observed in the parent-rated ABC or SRS. CONCLUSIONS: Methyl B12 treatment improved clinician-rated symptoms of ASD that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity. Clinical Trial Registry: Efficacy Study of Subcutaneous Methyl B12 in Children with Autism: NCT01039792 ( clinicaltrials.gov1 ).

Biomarkers in autism.

Autism spectrum disorders (ASDs) are complex, heterogeneous disorders caused by an interaction between genetic vulnerability and environmental factors. In an effort to better target the underlying roots of ASD for diagnosis and treatment, efforts to identify reliable biomarkers in genetics, neuroimaging, gene expression, and measures of the body's metabolism are growing. For this article, we review the published studies of potential biomarkers in autism and conclude that while there is increasing promise of finding biomarkers that can help us target treatment, there are none with enough evidence to support routine clinical use unless medical illness is suspected. Promising biomarkers include those for mitochondrial function, oxidative stress, and immune function. Genetic clusters are also suggesting the potential for useful biomarkers.

Change in plasma cytokine levels during risperidone treatment in children with autism.

BACKGROUND: Atypical antipsychotics decrease irritability in autism. They also affect the cytokine network. Psychological stress, depression, and, possibly, autism spectrum disorder (ASD) are associated with the production of pro-inflammatory cytokines. We sought to determine if risperidone treatment led to changes in plasma cytokine levels. METHODS: Forty-five subjects from an open-label study of risperidone treatment of children and adolescents with ASD, ages 4-18 years, had an analysis of 27 different cytokines at baseline and after 8 weeks of treatment using multiplex assays (Millipore) and read on the Luminex 100(™) platform. We examined changes in each of the cytokine levels in the entire group, and also compared changes in cytokines in responders versus nonresponders. RESULTS: After 8 weeks of risperidone treatment, 2 of the 27 plasma cytokines showed statistically significant decreases in median levels: Eotaxin (p=0.0003) and monocyte chemoattractant protein-1 (MCP-1) (p=0.0024). Six of the 48 subjects met two criteria for responders to risperidone, and the median values of interleukin (IL)-5 were significantly higher (p=0.005) in the overall responder group than in nonresponders. CONCLUSIONS: Two cytokines, eotaxin and MCP-1, which have previously been identified as abnormally elevated in children with autism, decreased during treatment with risperidone. This suggests a possible mechanism of action of risperidone treatment and a balancing of the immune system in affected subjects in this very preliminary study.

Internet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autism.

OBJECTIVE: Preliminary evidence suggests that omega-3 fatty acids may reduce hyperactivity in children with autism spectrum disorder (ASD). We sought to examine the feasibility of a novel, Internet-based clinical trial design to evaluate the efficacy of this supplement. METHOD: E-mail invitations were sent to parents of children aged 5 to 8 years enrolled in the Interactive Autism Network. All study procedures, including screening, informed consent, and collection of outcome measures took place over the Internet. The primary outcome measures were parent- and teacher-rated changes in hyperactivity on the Aberrant Behavior Checklist (ABC-H). RESULTS: During the 6-week recruitment period, 57 children from 28 states satisfied all eligibility criteria and were randomly assigned to 1.3 grams of omega-3 fatty acids or an identical placebo daily for 6 weeks. Outcome assessments were obtained from all 57 participants and 57 teachers, and the study was completed in 3 months. Children in the omega-3 fatty acid group had a greater reduction in hyperactivity (-5.3 points) compared to the placebo group (-2.6 points), but the difference was not statistically significant (1.9-point greater improvement in the omega-3 group, 95% CI = -2.2 to 5.2). Adverse events were rare and not associated with omega-3 fatty acids. Participant feedback was positive. CONCLUSION: Internet-based, randomized controlled trials of therapies in children with ASD are feasible and may lead to marked reductions in the time and cost of completing trials. A larger sample size is required to definitively determine the efficacy of omega-3 fatty acids. Clinical trial registration information-Omega-3 Fatty Acids for Hyperactivity Treatment in Autism Spectrum Disorder; http://clinicaltrials.gov; NCT01694667.

Considering biomedical/CAM treatments.

Complementary and alternative medicine (CAM) is widely used to treat children with psychiatric disorders. In this review, MedLine was searched for various biomedical/CAM treatments in combination with the key words "childre", "adolescents", "psychiatric disorders", and "complementary alternative medicine". The biomedical/CAM treatments most thoroughly researched were omega-3 fatty acids, melatonin, and memantine. Those with the fewest published studies were N-acetylcysteine, vitamin B12, and oxytocin, although many biomedical/CAM treatments have no published studies. Although data are modest, there is evidence to suggest that biomedical/CAM treatments may be helpful for a subgroup of children with psychiatric disorders. Further research and more randomized, controlled trials in children are warranted.