Neurodevelopmental functioning in probands and non-proband carriers of 22q11.2 microduplication.

Microduplication of the LCR22-A to LCR22-D region on chromosome 22q11.2 is a recurrent copy number variant found in clinical populations undergoing chromosomal microarray, and at lower frequency in controls. Often inherited, there is limited data on intellectual (IQ) and psychological functioning, particularly in those individuals ascertained through a family member rather than because of neurodevelopmental disorders. To investigate the range of cognitive-behavioral phenotypes associated with 22q11.2 duplication, we studied both probands and their non-proband carrier relatives. Twenty-two individuals with 22q11.2 duplication (10 probands, 12 non-proband carriers) were prospectively assessed with a battery of neuropsychological tests, physical examination, and medical record review. Assessment measures with standardized norms included IQ, academic, adaptive, psychiatric, behavioral, and social functioning. IQ and academic skills were within the average range, with a trend toward lower scores in probands versus non-probands. Adaptive skills were within age expectations. Prevalence of attention deficits (probands only) and anxiety (both groups) was high compared with norms. The prevalence of autism spectrum disorder was relatively low (5% of total sample). Assessment of both probands and non-probands with 22q11.2 duplication suggests that the phenotypic spectrum with respect to neurodevelopment overlaps significantly with the general population. IQ and academic abilities are in the average range for most of the individuals with 22q11.2 duplication in our study, regardless of ascertainment as a proband or non-proband relative. Symptoms of attention deficit and anxiety were identified, which require further study. Results of this study further clarify the phenotype of individuals with 22q11.2 duplication, and provides important information for genetic counseling regarding this recurrent copy number variant.

MYmind: a Concurrent Group-Based Mindfulness Intervention for Youth with Autism and Their Parents.

OBJECTIVES: The current study evaluated the use of MYmind, a concurrent mindfulness program in which youth with autism and their parents simultaneously receive group specific mindfulness training. Youth with autism can experience emotional and behavioral challenges, which are associated with parental stress. Mindfulness-based programs are emerging as a promising support for these challenges, for both children and parents. While two studies have documented the use of concurrent parent-child programs, neither involve control conditions. METHODS: Using a within-subject repeated measures design with a baseline component, 23 parent-child dyads were assessed on mindfulness, mental health, and youth emotion regulation and autism symptoms. Participants also rated their perceived improvement on a social validity questionnaire. RESULTS: There was improvement in youth autism symptoms, emotion regulation, and adaptive skills, and in parent reports of their own mindfulness following the program. There was also some indication of a waitlist effect for parent mental health, but not for other outcome variables. Participant feedback was mainly positive. CONCLUSIONS: MYmind has the potential to contribute to emotion regulation and adaptability in youth with autism, and mindfulness in parents, though more rigorous controlled trials are needed.

Atypical autism in a boy with double duplication of 22q11.2: implications of increasing dosage.

Duplication of chromosome 22q11.2 (LCR A-D) has been reported at higher frequencies in clinical samples than the general population, but phenotypes vary widely. Triplication (4 copies) is rare, but studying the associated phenotype may provide insight into dosage-sensitivity of the genes in this chromosomal interval. We describe a proband with a triplication, specifically a "double duplication" (two copies per chromosome) of the 22q11.2 region, while his parents and two siblings each have a single duplication (3 copies). The proband had a heart malformation, dysmorphic features, and learning and socialization deficits, whereas the other family members did not. This family illustrates that while duplication of the 22q11.2 may not be sufficient to cause clinically significant neurodevelopmental or health-related phenotypes, triplication of the same region may result in a phenotype characterized by a mild neurodevelopmental disorder, facial dysmorphism, and possibly cardiac anomalies.

Feasibility, Acceptability and Preliminary Treatment Outcomes in a School-Based CBT Intervention Program for Adolescents with ASD and Anxiety in Singapore.

Adolescents with autism spectrum disorder (ASD) are at high risk for anxiety difficulties and disorders. Clinic-based cognitive behavioral therapy (CBT) is effective; however, few published school-based CBT programs for youth with ASD exist. In this study, the Facing Your Fears CBT protocol was adapted for delivery and piloted within a school setting by non-clinicians, with culturally appropriate adaptations. 44 13-15 aged youth with ASD from 22 mainstream schools in Singapore participated. Feasibility, acceptability and preliminary treatment outcomes were examined. Decreases in youth and parent reported anxiety symptoms were reported. Staff and parents found the program useful. Stakeholder support was important for implementation. Initial findings reflect the importance of carefully bridging research-to-practice for youth with ASD and anxiety.

Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

SHANK1 Deletions in Males with Autism Spectrum Disorder.

Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers--but not female carriers--have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.

Regional EEG alpha power, coherence, and behavioral symptomatology in autism spectrum disorder.

OBJECTIVE: Although distinct patterns of resting brain electrical activity (EEG) and functional connectivity are believed to distinguish individuals with autism spectrum disorders (ASD) from their unimpaired peers, researchers have only recently begun to link patterns of brain activity and connectivity to behavior in ASD. METHOD: We examined regional eyes-closed and eyes-open EEG alpha power and coherence at rest in relation to self-reported perceptual and social behavior in 15 adults diagnosed with ASD and a matched comparison group of 16 unimpaired adults. RESULTS: The groups did not differ on eyes-closed EEG alpha power or coherence, but adults with ASD showed less alpha suppression for the eyes-open condition than did controls. In the ASD group, preferential attention to detail (perceptual domain) was associated with lower levels of alpha activity and reduced coherence in posterior regions. No relations between social interaction difficulties (social domain) and alpha measures were found for either group alone. CONCLUSIONS: These relations suggest that the processing of perceptual details may be carried out by relatively less synchronized neuronal units in adults with ASD, and may be relatively automatic. SIGNIFICANCE: Findings are discussed in relation to recent models of narrow minicolumnar brain structure and reduced functional neural connectivity in ASD.

Behavioral and cardiac responses to emotional stroop in adults with autism spectrum disorders: influence of medication.

Researchers have recently hypothesized that autism spectrum disorders (ASD) may be partly characterized by physiological over-arousal. One way to assess physiological arousal is through autonomic measures. Here heart period (HP) and parasympathetic activity measured by respiratory sinus arrhythmia (RSA) were examined in adults with ASD and matched controls at rest and during performance of an emotional Stroop task. Resting HP and RSA were lower in adults with ASD than in matched controls, consistent with hypothesized over-arousal in ASD. However, dividing the ASD group on the basis of antipsychotic medication usage revealed that group differences in autonomic arousal may be related to the effects of these medications or their correlates. Autonomic adjustments for Stroop performance were comparable across groups, but in the control group, larger RSA reductions were correlated with faster responding (i.e., better performance). This relation was reversed in the unmedicated ASD group and absent in the medicated ASD group. Findings highlight the importance of considering medication status in the recently burgeoning area of psychophysiological studies of autism.

An event-related source localization study of response monitoring and social impairments in autism spectrum disorder.

A number of studies suggest anterior cingulate cortex (ACC) abnormalities in autism spectrum disorder (ASD), which might underlie response monitoring and social impairments exhibited by children and adolescents with ASD. The goal of the present study was to extend this work by examining error and correct response monitoring using event-related potentials (ERN, Pe, CRN) and LORETA source localization in high functioning adults with ASD and controls. Adults with ASD showed reduced ERN and Pe amplitudes and reduced rostral ACC activation compared with controls. Adults with ASD also showed less differentiation between error and correct ERP components. Social impairments and higher overall autism symptoms were related to reduced rostral ACC activity at the time of the ERN, particularly in adults with ASD. These findings suggest that reduced ACC activity may reflect a putative brain mechanism involved in the origins and maintenance of social impairments and raise the possibility of the presence of stable brain-behavior relation impairment across development in some individuals with ASD.

Autonomic predictors of Stroop performance in young and middle-aged adults.

Although changes in autonomic activity have been extensively examined as responses to cognitive challenges, relatively few studies have used individual differences in autonomic parameters to predict executive performance in healthy adults. Here we examined baseline and task-related changes in heart rate and heart rate variability (measured by respiratory sinus arrhythmia (RSA)) to predict performance of a pictorial Stroop task in a group of 81 healthy adults aged 17-55. Greater autonomic reactivity (increased heart rate and reduced RSA for task performance) was associated with faster colour naming of faces in the Stroop task. Dividing the group by median age revealed that middle-aged adults reduced RSA to a greater degree than their younger counterparts in the context of equivalent performance across groups. Findings suggest that performance of executive function tasks that evoke attentional control may depend in part on the responsiveness of autonomic control parameters via age-dependent mechanisms.

Children with autism: effect of iron supplementation on sleep and ferritin.

To determine if there is a relationship between low serum ferritin and sleep disturbance in children with autism spectrum disorder, an 8-week open-label treatment trial with oral iron supplementation was conducted as a pilot study. At baseline and posttreatment visits, parents completed a Sleep Disturbance Scale for Children and a Food Record. Blood samples were obtained. Thirty-three children completed the study. Seventy-seven percent had restless sleep at baseline, which improved significantly with iron therapy, suggesting a relationship between sleep disturbance and iron deficiency in children with autism spectrum disorder. Sixty-nine percent of preschoolers and 35% of school-aged children had insufficient dietary iron intake. Mean ferritin increased significantly (16 microg/L to 29 microg/L), as did mean corpuscular volume and hemoglobin, suggesting that low ferritin in this patient group resulted from insufficient iron intake. Similar prevalence of low ferritin at school age as preschool age indicates that children with autism spectrum disorder require ongoing screening for iron deficiency.