Association of Breastfeeding Duration with Neurodevelopmental Outcomes in an Enriched Familial Likelihood Cohort for Autism Spectrum Disorder.

This study aimed to compare the breastfeeding (BF) duration of the younger siblings of children with ASD in an enriched-likelihood cohort for autism spectrum disorder (ASD), and to determine whether longer BF duration was associated with differences in neurodevelopmental outcomes in this cohort. Information on BF practices was collected via surveys in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) study. Developmental evaluations, including the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, were conducted by expert clinicians. Participants' neurodevelopmental outcome was classified by an algorithm into three groups: typical development, ASD, and non-typical development. The median duration of BF was 10.70 months (interquartile range of 12.07 months). There were no significant differences in the distribution of duration of BF among the three neurodevelopmental outcome categories. Children in this enriched-likelihood cohort who were breastfed for > 12 months had significantly higher scores on cognitive testing compared to those who were breastfed for 0-3 months. There was no significant difference in ASD symptomatology or ASD risk based on BF duration.

Untargeted metabolomic, and proteomic analysis identifies metabolic biomarkers and pathway alterations in individuals with 22q11.2 deletion syndrome.

INTRODUCTION: The chromosome 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with a wide range of brain-related phenotypes including schizophrenia spectrum disorders (SCZ), autism spectrum disorders (ASD), anxiety disorders and attention deficit disorders (ADHD). The typically deleted region in 22q11.2DS contains multiple genes which haploinsufficiency has the potential of altering the protein and the metabolic profiles. OBJECTIVES: Alteration in metabolic processes and downstream protein pathways during the early brain development may help to explain the increased prevalence of the observed neurodevelopmental phenotypes in 22q11.2DS. However, relatively little is known about the correlation of dysregulated protein/metabolite expression and neurobehavioral impairments in individuals who developed them over time. METHODS: In this study, we performed untargeted metabolic and proteomic analysis in plasma samples derived from 30 subjects including 16 participants with 22q11.2DS and 14 healthy controls (TD) enrolled in a longitudinal study, aiming to identify a metabolic and protein signature informing about the underlying mechanisms involved in disease development and progression. The metabolic and proteomic profiles were also compared between the participants with 22q11.2DS with and without various comorbidities, such as medical involvement, psychiatric conditions, and autism spectrum disorder (ASD) to detect potential changes among multiple specimens, collected overtime, with the aim to understand the basic underlying mechanisms involved in disease development and progression. RESULTS: We observed a large number of statistically significant differences in metabolites between the two groups. Among them, the levels of taurine and arachidonic acid were significantly lower in 22q11.2DS compared to the TD group. In addition, we identified 16 proteins that showed significant changes in expression levels (adjusted P < 0.05) in 22q11.2DS as compared to TD, including those involved in 70 pathways such as gene expression, the PI3K-Akt signaling pathway and the complement system. Within participants with 22q11.2DS, no significant changes in those with and without medical or psychiatric conditions were observed. CONCLUSION: To our knowledge, this is the first report on plasma metabolic and proteomic profiling and on the identification of unique biomarkers in 22q11.2DS. These findings may suggest the potential role of the identified metabolites and proteins as biomarkers for the onset of comorbid conditions in 22q11.2DS. Ultimately, the altered protein pathways in 22q11.2DS may provide insights of the biological mechanisms underlying the neurodevelopmental phenotype and may provide missing molecular outcome measures in future clinical trials to assess early-diagnosis treatment and the efficacy of response to targeted treatment.

Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.

Pilot Study of Maternal Autoantibody-Related Autism.

OBJECTIVE: The objective of this study was to investigate the presence of maternal autoantibody-related autism spectrum disorder (MAR-ASD) in 2 geographically distinct DBPNet clinical sites (Pennsylvania and Arkansas). MAR-ASD is a biologically defined subtype of ASD that is defined by the presence of autoantibodies specific to proteins in the fetal brain and present in approximately 20% of a Northern California sample but has not been studied in other states. METHODS: Sixty-eight mothers of children with ASD were recruited from 2 DBPNet clinics and provided blood samples. Mothers also completed behavioral questionnaires about their children, and data from the child's clinical diagnostic assessment were abstracted. RESULTS: The mean age of mothers was 38.5 ± 6.1 years, and the mean age of children was 8.3 ± 2.7 years. MAR-ASD was present in 24% of the sample and similar across sites. Children of +MAR mothers had more severe autism symptoms as measured by Autism Diagnostic Observation Schedule comparison scores (W = 3604; p < 0.001) and the Social Communication Questionnaire (W = 4556; p < 0.001). There were no differences in IQ, adaptive function, or aberrant behavior. CONCLUSION: MAR-ASD is a subtype of autism that is present in similar frequencies across 3 states and related to autism severity.

Atypical presentation of Angelman syndrome with intact expressive language due to low-level mosaicism.

BACKGROUND: Angelman syndrome (AS) occurs due to a lack of expression or function of the maternally inherited UBE3A gene. Individuals with AS typically have significant developmental delay, severe speech impairment with absent to minimal verbal language, gait abnormalities including ataxia, and an incongruous happy demeanor. The majority of individuals with AS also have seizures and microcephaly. Some individuals with mosaic AS have been reported to have expressive language and milder levels of developmental delay. CASE REPORT: We report a male patient presenting with mild to moderate intellectual disability, hyperphagia, obesity, and the ability to communicate verbally. His phenotype was suggestive of Prader-Willi syndrome. However, methylation testing was positive for Angelman syndrome and additional methylation specific multiplex ligation-dependent amplification (MS-MLPA) study revealed low-level mosaicism for AS. CONCLUSION: A broader phenotypic spectrum should be considered for AS as patients with atypical presentations may otherwise elude diagnosis.

Comparison of Attention-Deficit Hyperactivity Disorder in Typically Developing Children and Children with Down Syndrome.

OBJECTIVE: This study aimed to evaluate attention-deficit hyperactivity disorder (ADHD) symptom patterns among children with Down syndrome (DS) with or without ADHD and typically developing (TD) children with ADHD. METHODS: Parents and teachers rated symptoms of inattention, hyperactivity, and general behavioral concerns for 22 children with DS and comorbid diagnoses of ADHD (DS + ADHD), 66 gender-matched and age-matched children with DS with no diagnosis of ADHD (DS - ADHD), and 66 gender-matched and age-matched TD children with ADHD (TD + ADHD). Children with DS were recruited from the community. TD children with ADHD were recruited from a specialty clinic evaluating for ADHD. RESULTS: Parents tended to report higher scores of inattention and hyperactivity for TD children with ADHD compared with children with DS and no ADHD. Although mean ADHD symptom summary scores were not significantly different in DS + ADHD and DS - ADHD, specific parent-report items (e.g., distractibility and being "on the go") did tend to differentiate these groups. By contrast, teachers tended to report higher inattention and hyperactivity scores for DS + ADHD compared with both DS - ADHD and TD + ADHD. Specific teacher-reported items tending to differentiate DS + ADHD and DS - ADHD included difficulties following through on tasks, avoiding tasks, leaving one's seat, and excessive talking. CONCLUSION: Variability in response patterns between parent and teacher reports for children with and without DS highlights the need to evaluate ADHD symptoms across environments. Our findings also suggest specific items that may particularly be helpful in distinguishing children with DS who do and do not have ADHD, although replication is needed.

Longitudinal Psychiatric and Developmental Outcomes in 22q11.2 Deletion Syndrome: A Systematic Review.

OBJECTIVE: 22q11.2 deletion syndrome (22q11DS) is a common genetic deletion syndrome associated with psychiatric disorders and developmental delays. A significant amount of 22q11DS research literature is published annually; here, we focus exclusively on longitudinal data that have been published in the past 5 years regarding psychiatric disorders and/or cognitive and social development. After a review, areas for future research consideration and clinical recommendations are presented. METHODS: Articles were reviewed and organized in adherence with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for conducting systematic reviews. The literature search identified 852 studies, and 22 studies met inclusion criteria. RESULTS: Longitudinal study findings indicate that developmental considerations for youth with 22q11DS should focus on the primacy and enduring nature of social and executive functioning deficits, attention-deficit/hyperactivity disorder, anxiety, and negative symptoms of psychosis. CONCLUSION: From the diathesis of physiological conditions and genetic variance, 22q11DS and its associated phenotype of persistent cognitive deficits, comorbid psychiatric disorders, and social impairments likely conspire to increase the risk for stress in adolescence. The diathesis-stress framework, along with chronic stress, increases psychosis risk in individuals with 22q11DS. The existing literature has a heavy focus on the impact of the deletion on individual skills and attributes, such as cognition, but lacks information on the impact of the environment. Future 22q11DS research should consider specific aspects of social functioning, including interactions with parenting styles and family communication, as well as high demands in educational settings, as possible risk factors for psychosis.

Developmental-behavioral profiles in children with autism spectrum disorder and co-occurring gastrointestinal symptoms.

Gastrointestinal (GI) symptoms are frequently reported in children with autism spectrum disorder (ASD). We evaluated the frequency and severity of GI symptoms in preschool-aged children with ASD compared to participants with typical development (TD). Our goal was to ascertain whether GI symptoms are associated with differences in sex or developmental and behavioral measures. Participants were between 2 and 3.5 years of age and included 255 children with ASD (184 males/71 females) and 129 age-matched TD controls (75 males/54 females). A parent interview was used to assess GI symptoms (abdominal pain, gaseousness/bloating, diarrhea, constipation, pain on stooling, vomiting, difficulty swallowing, blood in stool or in vomit). Children with GI symptoms in each diagnostic group were compared to children without GI symptoms on measures of developmental, behavioral, and adaptive functioning. GI symptoms were reported more frequently in children with ASD compared to the TD group (47.8% vs. 17.8%, respectively). Children with ASD were also more likely to experience multiple GI symptoms (30.6% vs. 5.4%). GI symptoms were equally common in males and females across both diagnostic groups. There were no statistically significant differences in developmental or adaptive measures based on presence of GI symptoms in either ASD or TD children. Co-occurring GI symptoms were, however, associated with increased self-injurious behaviors, restricted stereotyped behaviors, aggressive behaviors, sleep problems and attention problems in both ASD and TD children. In children with ASD, a higher number of GI symptoms was associated with an increase in self-injurious behaviors, somatic complaints, reduced sleep duration, and increased parasomnias. LAY SUMMARY: ASD is characterized by challenges in social communication and repetitive behaviors. But, people with autism have many other difficulties including gastrointestinal problems. Children with ASD were three times more likely to experience GI symptoms than typically developing peers. Increased GI symptoms are associated with increased problem behaviors such as sleep problems, self-injury, and body aches. Since GI symptoms are often treatable, it is important to recognize them as soon as possible. Both clinicians and parents should become more aware of the high occurrence of GI problems in autistic people. Autism Res 2020, 13: 1778-1789. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

Adaptive functioning in children and adolescents with Trisomy X: An exploratory analysis.

Identifying the factors related to adaptive functioning will improve the information available to families and providers of females with Trisomy X. Cognitive and behavioral features were assessed in 50 females ages 12.2 ± 3.6 years using the Behavior Assessment System for Children Second Edition (BASC-2) and Wechsler Scales of Intelligence. Executive functioning, social skills, and autistic traits were evaluated in a subset. Adaptive functioning was assessed using the BASC-2 adaptive skills composite score (ASC). Participants were classified as average adaptive skills (ASC T-score > 40) or deficits (ASC T-score < 40). Group comparisons were conducted. Multiple linear regression examined which factors contributed to ASC score. Twenty-eight females (55.6%) had adaptive skills deficits with functional communication being the most commonly affected adaptive domain. The group with ASC in the average range had higher verbal IQ (VIQ) and lower rates of numerous behavioral concerns. Internalizing behavior composite, DSM-IV inattentive symptoms score, and VIQ were significant predictors of ASC. Prenatally diagnosed females comprised over 70% of those with average adaptive skills. In this study, internalizing behaviors, inattentive ADHD symptoms, and VIQ were associated with poorer adaptive functioning. Early interventions targeting internalizing behaviors, attention/executive functioning, and communication skills may improve adaptive skills and deserve further study.

Seeing Eye to Eye With Threat: Atypical Threat Bias in Children With 22q11.2 Deletion Syndrome.

Individuals with 22q11.2 deletion syndrome (22q11DS) show high rates of anxiety associated with their increased risk of developing schizophrenia. Biased attention is associated with anxiety and is important to investigate in those with 22q11DS given this association. We analyzed attention bias to emotional faces in 7- to 17-year olds with 22q11DS and typically developing controls (TD) using a dot probe threat bias paradigm. We measured response time, eye tracking, and pupilometry. Those with 22q11DS showed no significant changes in early versus late trials, whereas those who were TD showed differing patterns in both gaze and pupilometry over time. The patterns in those who are TD may indicate adaptation that is lacking or slower in individuals with 22q11DS.

Interrelationship Between Cognitive Control, Anxiety, and Restricted and Repetitive Behaviors in Children with 22q11.2 Deletion Syndrome.

Restricted and repetitive behaviors (RRB) are common in individuals with 22q11.2 microdeletion syndrome (22q11.2DS), yet the underlying mechanisms of these behaviors remain poorly characterized. In the present pilot investigation, we aimed to further our understanding of RRB in 22q11.2DS by exploring their relationship with cognitive control and anxiety as well as with sex, chronological age, and full-scale IQ. Parents of 38 children with 22q11.2DS (17 females; Mage = 11.15 years, SD = 2.46) completed the Social Communication Questionnaire as a measure of RRB and social and communication (SC) problems and the Behavioral Assessment System for Children-2 as a measure of anxiety and cognitive control. Higher RRB scores were significantly associated with higher anxiety levels (r = 0.44, P = 0.006), more impairments in cognitive control (r = 0.56, P < 0.001), and higher SC scores (r = 0.43, P = 0.011). In the first step of the hierarchical regression model, anxiety accounted for 24.5% of variance (F = 10.05, P = 0.003); cognitive control accounted for an additional 18.1% of variance (Fchange = 11.15, P < 0.001) in the second step; SC score accounted for only 0.8% of additional variance in the third step (Fchange = 0.40, P = 0.53). The final model explained 43.4% of variance (F = 7.42, P = 0.001), with cognitive control as a unique independent predictor of RRB score (t = 2.52, P = 0.01). The current study provides the first exploration of the cognitive control-anxiety-RRB link in individuals with 22q11.2DS and points to cognitive control as a potentially viable target for treatments aimed at reducing RRB. Autism Res 2019, 12: 1737-1744. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with 22q11.2 deletion syndrome show high levels of repetitive behaviors, however, the previous research has not explored why people with this syndrome exhibit high rates of repetitive behaviors. Understanding the reasons for the high levels of repetitive behaviors is important given that these behaviors can be highly impairing. Our study found that repetitive behaviors were associated with impaired ability to self-regulate and high levels of anxiety. These findings need to be further replicated; however, they are important as they suggest potentially promising ways of reducing these behaviors.

Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms.

Over half of all children with autism spectrum disorders (ASD) have gastrointestinal (GI) co-morbidities including chronic constipation, diarrhea, and irritable bowel syndrome. The severity of these symptoms has been correlated with the degree of GI microbial dysbiosis. The study objective was to assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities. This pilot study is a randomized, double blind, controlled trial of combination treatment (BCP + B. infantis) vs. BCP alone in a cross-over study in children ages 2-11 with ASD and GI co-morbidities (n = 8). This 12-week study included 5 weeks of probiotic-prebiotic supplementation, followed by a two-week washout period, and 5 weeks of prebiotic only supplementation. The primary outcome of tolerability was assessed using validated questionnaires of GI function and atypical behaviors, along with side effects. Results suggest that the combination treatment is well-tolerated in this cohort. The most common side effect was mild gassiness. Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors. Improvement may be explained by a reduction in IL-13 and TNF-α production in some participants. Although limited conclusions can be drawn from this small pilot study, the results support the need for further research into the efficacy of these treatments.

Extra-axial cerebrospinal fluid in high-risk and normal-risk children with autism aged 2-4 years: a case-control study.

BACKGROUND: We previously showed, in two separate cohorts, that high-risk infants who were later diagnosed with autism spectrum disorder had abnormally high extra-axial cerebrospinal fluid (CSF) volume from age 6-24 months. The presence of increased extra-axial CSF volume preceded the onset of behavioural symptoms of autism and was predictive of a later diagnosis of autism spectrum disorder. In this study, we aimed to establish whether increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder, whether extra-axial CSF remains abnormally increased beyond infancy, and whether it is present in both normal-risk and high-risk children with autism. METHODS: In this case-control MRI study, children with autism spectrum disorder or with typical development aged 2-4 years were recruited from the community to the UC Davis MIND Institute Autism Phenome Project, based in Sacramento, CA, USA. The autism spectrum disorder group comprised children with autism spectrum disorder who were either normal risk (ie, from simplex families) or high risk (ie, from multiplex families). Measurements of extra-axial CSF volume, brain volume, head circumference, sleep problems, and familial risk status were derived from MRI and behavioural assessments. We applied a previously validated machine learning algorithm based on extra-axial CSF volume, brain volume, age, and sex to the current dataset. FINDINGS: Between July 20, 2007, and Dec 13, 2012, 159 children with autism spectrum disorder (132 male, 27 female) and 77 with typical development (49 male, 28 female) underwent MRI scans. The autism spectrum disorder group had an average of 15·1% more extra-axial CSF than controls after accounting for differences in brain volume, weight, age, and sex (least-squares mean 116·74 cm3 [SE 3·33] in autism group vs 101·40 cm3 [3·93] in typical development group; p=0·007; Cohen's d = 0·39). Subgroups of normal-risk (n=132) and high-risk (n=27) children with autism spectrum disorder had nearly identical extra-axial CSF volumes (p=0·78), and both subgroups had significantly greater volumes than controls. Both extra-axial CSF volume (p=0·004) and brain volume (p<0·0001) uniquely contributed to enlarged head circumference in the autism spectrum disorder group (p=0·04). Increased extra-axial CSF volume was associated with greater sleep disturbances (p=0·03) and lower non-verbal ability (p=0·04). The machine learning algorithm correctly predicted autism spectrum disorder diagnosis with a positive predictive value of 83% (95% CI 76·2-88·3). INTERPRETATION: Increased extra-axial CSF volume is a reliable brain anomaly that has now been found in three independent cohorts, comprising both high-risk and normal-risk children with autism spectrum disorder. Increased extra-axial CSF volume is detectable using conventional structural MRI scans from infancy through to age 3 years. These results suggest that increased extra-axial CSF volume could be an early stratification biomarker of a biologically based subtype of autism that might share a common underlying pathophysiology. FUNDING: US National Institutes of Health.

Comparison of maternal beliefs about causes of autism spectrum disorder and association with utilization of services and treatments.

BACKGROUND: This study aimed to describe parental perceptions of the causes of autism spectrum disorder (ASD) in an ethnically diverse sample and explore whether these perceptions relate to treatment choices. METHODS: The sample consisted of White (n = 224), Hispanic (n = 85), and Asian (n = 21) mothers of a child with ASD. A mixed methods approach was used in this secondary analysis focusing on parental perceptions about the causes of ASD and the relationship of these to utilization of services and treatment. RESULTS: Environmental and genetic factors were most often believed to be the cause or one of the causes of ASD by mothers across all ethnic groups studied. Asian mothers were more likely to cite multiple causes. Environmental causes were associated with receiving 20 or more hours of autism-related services per week, whereas belief in environmental exposures and vaccines and medications as causes were associated with complementary-alternative medicine (CAM) use. CONCLUSION: Our findings suggest that ethnic differences in autism causal beliefs and treatment choices may exist. Future research should be conducted to specifically confirm the findings, to understand parental motivation behind their service and treatment choices, and to gain more insight into the types, usage, and sources of CAM treatments. Clinicians can use parental autism causal beliefs in discussions about treatment recommendations.

Dietary Considerations in Autism Spectrum Disorders: The Potential Role of Protein Digestion and Microbial Putrefaction in the Gut-Brain Axis.

Children with autism spectrum disorders (ASD), characterized by a range of behavioral abnormalities and social deficits, display high incidence of gastrointestinal (GI) co-morbidities including chronic constipation and diarrhea. Research is now increasingly able to characterize the "fragile gut" in these children and understand the role that impairment of specific GI functions plays in the GI symptoms associated with ASD. This mechanistic understanding is extending to the interactions between diet and ASD, including food structure and protein digestive capacity in exacerbating autistic symptoms. Children with ASD and gut co-morbidities exhibit low digestive enzyme activity, impaired gut barrier integrity and the presence of antibodies specific for dietary proteins in the peripheral circulation. These findings support the hypothesis that entry of dietary peptides from the gut lumen into the vasculature are associated with an aberrant immune response. Furthermore, a subset of children with ASD exhibit high concentrations of metabolites originating from microbial activity on proteinaceous substrates. Taken together, the combination of specific protein intakes poor digestion, gut barrier integrity, microbiota composition and function all on a background of ASD represents a phenotypic pattern. A potential consequence of this pattern of conditions is that the fragile gut of some children with ASD is at risk for GI symptoms that may be amenable to improvement with specific dietary changes. There is growing evidence that shows an association between gut dysfunction and dysbiosis and ASD symptoms. It is therefore urgent to perform more experimental and clinical research on the "fragile gut" in children with ASD in order to move toward advancements in clinical practice. Identifying those factors that are of clinical value will provide an evidence-based path to individual management and targeted solutions; from real time sensing to the design of diets with personalized protein source/processing, all to improve GI function in children with ASD.

Effects of Yoga on Attention, Impulsivity, and Hyperactivity in Preschool-Aged Children with Attention-Deficit Hyperactivity Disorder Symptoms.

OBJECTIVE: Behavioral therapies are first-line for preschoolers with attention-deficit hyperactivity disorder (ADHD). Studies support yoga for school-aged children with ADHD; this study evaluated yoga in preschoolers on parent- and teacher-rated attention/challenging behaviors, attentional control (Kinder Test of Attentional Performance [KiTAP]), and heart rate variability (HRV). METHODS: This randomized waitlist-controlled trial tested a 6-week yoga intervention in preschoolers with ≥4 ADHD symptoms on the ADHD Rating Scale-IV Preschool Version. Group 1 (n = 12) practiced yoga first; Group 2 (n = 11) practiced yoga second. We collected data at 4 time points: baseline, T1 (6 weeks), T2 (12 weeks), and follow-up (3 months after T2). RESULTS: At baseline, there were no significant differences between groups. At T1, Group 1 had faster reaction times on the KiTAP go/no-go task (p = 0.01, 95% confidence interval [CI], -371.1 to -59.1, d = -1.7), fewer distractibility errors of omission (p = 0.009, 95% CI, -14.2 to -2.3, d = -1.5), and more commission errors (p = 0.02, 95% CI, 1.4-14.8, d = 1.3) than Group 2. Children in Group 1 with more severe symptoms at baseline showed improvement at T1 versus control on parent-rated Strengths and Difficulties Questionnaire hyperactivity inattention (ß = -2.1, p = 0.04, 95% CI, -4.0 to -0.1) and inattention on the ADHD Rating Scale (ß = -4.4, p = 0.02, 95% CI, -7.9 to -0.9). HRV measures did not differ between groups. CONCLUSION: Yoga was associated with modest improvements on an objective measure of attention (KiTAP) and selective improvements on parent ratings.

Baseline connectome modular abnormalities in the childhood phase of a longitudinal study on individuals with chromosome 22q11.2 deletion syndrome.

Occurring in at least 1 in 3,000 live births, chromosome 22q11.2 deletion syndrome (22q11DS) produces a complex phenotype that includes a constellation of medical complications such as congenital cardiac defects, immune deficiency, velopharyngeal dysfunction, and characteristic facial dysmorphic features. There is also an increased incidence of psychiatric diagnosis, especially intellectual disability and ADHD in childhood, lifelong anxiety, and a strikingly high rate of schizophrenia spectrum disorders, which occur in around 30% of adults with 22q11DS. Using innovative computational connectomics, we studied how 22q11DS affects high-level network signatures of hierarchical modularity and its intrinsic geometry in 55 children with confirmed 22q11DS and 27 Typically Developing (TD) children. Results identified 3 subgroups within our 22q11DS sample using a K-means clustering approach based on several midline structural measures-of-interests. Each subgroup exhibited distinct patterns of connectome abnormalities. Subtype 1, containing individuals with generally healthy-looking brains, exhibited no significant differences in either modularity or intrinsic geometry when compared with TD. By contrast, the more anomalous 22q11DS Subtypes 2 and 3 brains revealed significant modular differences in the right hemisphere, while Subtype 3 (the most anomalous anatomy) further exhibited significantly abnormal connectome intrinsic geometry in the form of left-right temporal disintegration. Taken together, our findings supported an overall picture of (a) anterior-posteriorly differential interlobar frontotemporal/frontoparietal dysconnectivity in Subtypes 2 and 3 and (b) differential intralobar dysconnectivity in Subtype 3. Our ongoing studies are focusing on whether these subtypes and their connnectome signatures might be valid biomarkers for predicting the degree of psychosis-proneness risk found in 22q11DS. Hum Brain Mapp 39:232-248, 2018. © 2017 Wiley Periodicals, Inc.

A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome.

BACKGROUND: Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABAA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. METHODS: This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years. RESULTS: Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo. CONCLUSIONS: While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01725152.