Beyond IQ: executive function deficits and their relation to functional, clinical, and neuroimaging outcomes in 3q29 deletion syndrome.

BACKGROUND: 3q29 deletion syndrome (3q29del) is a rare (~1:30 000) genomic disorder associated with a wide array of neurodevelopmental and psychiatric phenotypes. Prior work by our team identified clinically significant executive function (EF) deficits in 47% of individuals with 3q29del; however, the nuances of EF in this population have not been described. METHODS: We used the Behavior Rating Inventory of Executive Function (BRIEF) to perform the first in-depth assessment of real-world EF in a cohort of 32 individuals with 3q29del (62.5% male, mean age = 14.5 ± 8.3 years). All participants were also evaluated with gold-standard neuropsychiatric and cognitive assessments. High-resolution structural magnetic resonance imaging was performed on a subset of participants (n = 24). RESULTS: We found global deficits in EF; individuals with 3q29del scored higher than the population mean on the BRIEF global executive composite (GEC) and all subscales. In total, 81.3% of study subjects (n = 26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were higher among 3q29del participants with a diagnosis of attention deficit/hyperactivity disorder (ADHD), and BRIEF GEC T scores were associated with schizophrenia spectrum symptoms as measured by the Structured Interview for Psychosis-Risk Syndromes. BRIEF GEC T scores were not associated with cognitive ability. The BRIEF-2 ADHD form accurately (sensitivity = 86.7%) classified individuals with 3q29del based on ADHD diagnosis status. BRIEF GEC T scores were correlated with cerebellar white matter and subregional cerebellar cortex volumes. CONCLUSIONS: Together, these data expand our understanding of the phenotypic spectrum of 3q29del and identify EF as a core feature linked to both psychiatric and neuroanatomical features of the syndrome.

Deep phenotyping in 3q29 deletion syndrome: recommendations for clinical care.

PURPOSE: To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care. METHODS: Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments. RESULTS: Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit-hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities. CONCLUSION: By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.

Comprehensive phenotyping of neuropsychiatric traits in a multiplex 3q29 deletion family: a case report.

BACKGROUND: 3q29 deletion syndrome is associated with a range of medical, neurodevelopmental, and psychiatric phenotypes. The deletion is usually de novo but cases have been reported where the deletion is inherited from apparently unaffected parents. The presence of these unaffected or mildly affected individuals suggests there may be an ascertainment bias for severely affected cases of 3q29 deletion syndrome, thus the more deleterious consequence of the 3q29 deletion may be overestimated. However, a substantial fraction of 3q29 deletion syndrome morbidity is due to psychiatric illness. In many case reports, probands and transmitting parents are not systematically evaluated for psychiatric traits. Here we report results from a systematic phenotyping protocol for neurodevelopmental and neuropsychiatric traits applied to all 3q29 deletion carriers in a multiplex family. CASE PRESENTATION: Through the 3q29 registry at Emory University, a multiplex family was identified where three offspring had a paternally inherited 3q29 deletion. We evaluated all 4 3q29 deletion family members using our previously described standardized, systematic phenotyping protocol. The transmitting parent reported no psychiatric history, however upon evaluation he was discovered to meet criteria for multiple psychiatric diagnoses including previously undiagnosed schizoaffective disorder. All four 3q29 deletion individuals in the pedigree had multiple psychiatric diagnoses that interfered with quality of life and prohibited successful academic and occupational functioning. Cognitive ability for all individuals was average or below average, but within the normal range. CONCLUSIONS: This is the first case report of inherited 3q29 deletion syndrome where all affected individuals in the pedigree have been comprehensively and systematically evaluated for neurodevelopmental and psychiatric symptoms, using a standard battery of normed instruments administered by expert clinicians. Our investigation reveals that individuals with 3q29 deletion syndrome may have psychiatric morbidity that is debilitating, but only apparent through specialized evaluation by an expert. In the absence of appropriate evaluation, individuals with 3q29 deletion syndrome may suffer from psychiatric illness but lack avenues for access to care. The individuals evaluated here all have cognition in the normal range alongside multiple psychiatric diagnoses each, suggesting that cognitive ability alone is not a representative proxy for 3q29 deletion-associated disability. These results require replication in a larger cohort of individuals with 3q29 deletion syndrome.

The Autism Managing Eating Aversions and Limited Variety Plan vs Parent Education: A Randomized Clinical Trial.

OBJECTIVE: To assess the feasibility and initial efficacy of a structured parent training program for children with autism spectrum disorder and moderate food selectivity. STUDY DESIGN: This 16-week randomized trial compared the Managing Eating Aversions and Limited variety (MEAL) Plan with parent education. MEAL Plan (10 core and 3 booster sessions) provided parents with nutrition education and strategies to structure meals and expand the child's diet. Parent education (10 sessions) provided information about autism without guidance on nutrition, meal structure, or diet. In addition to feasibility outcomes, primary efficacy outcomes included the Clinical Global Impression - Improvement scale and the Brief Autism Mealtime Behaviors Inventory. Grams consumed during a meal observation served as a secondary outcome. RESULTS: There were 38 eligible children (19 per group, 32 males). For MEAL Plan, attrition was <10% and attendance >80%. Therapists achieved >90% fidelity. At week 16, positive response rates on the Clinical Global Impression - Improvement scale were 47.4% for the MEAL Plan and 5.3% for parent education (P < .05). The adjusted mean difference (SE) on Brief Autism Mealtime Behaviors Inventory at week 16 was 7.04 (2.71) points (P = .01) in favor of MEAL Plan. For grams consumed, the adjusted standard mean difference (SE) was 30.76 (6.75), also in favor of MEAL Plan (P = .001). CONCLUSIONS: The MEAL Plan seems to be feasible, and preliminary efficacy results are encouraging. If further study replicates these results, the MEAL Plan could expand treatment options for children with autism spectrum disorder and moderate food selectivity. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02712281.

Exploration of Treatment Response in Parent Training for Children with Autism Spectrum Disorder and Moderate Food Selectivity.

Managing Eating Aversions and Limited Variety (MEAL) Plan is a structured parent-mediated intervention for children with autism spectrum disorder and moderate food selectivity. Our previously reported group-based clinical trial revealed a positive treatment response rate of 47.3%. Although encouraging, this response rate raises questions about factors that may affect treatment outcomes. Here, we examine the impact of child and parent characteristics and feeding behaviors on treatment response. Higher maternal education and higher child communication abilities at baseline were associated with positive treatment response. Improvement in sitting at the table and reductions in disruptive mealtime behavior promoted treatment success. Results also suggest that individually delivered MEAL Plan may offer more flexibility than group-based intervention for some parents.

Examining adaptations necessary to support the implementation of a parent-mediated intervention for children with autism spectrum disorder and moderate feeding problems.

LAY ABSTRACT: Moderate feeding problems and disruptive mealtime behaviors are common in children with autism spectrum disorder. Although parent-mediated interventions are able to support feeding problems in autistic children, most research has occurred within specialty clinics when delivered by highly trained clinicians. Thus, the fit of these interventions within community settings is not clear. To address this limitation, this study explored adaptations to a parent-mediated intervention, Managing Eating Aversions and Limited Variety (i.e. MEAL Plan), to improve its fit and use within community settings. Participants were 14 multidisciplinary providers who attended one of the three intensive workgroups that included focus groups about the fit of MEAL Plan in their practice setting. Qualitative analysis was used to determine the main themes that came up within the focus groups. Specific themes included the appropriateness MEAL Plan for autistic and non-autistic children, how providers might adapt their delivery of MEAL Plan, billing and insurance considerations, administrator support for MEAL Plan, and the content and format of ongoing training and consultation. By proactively considering and responding to these factors, it may be possible to enhance MEAL Plan so that it is better able to be delivered and sustained within community practices that support autistic children.

Adaptive behavior deficits in individuals with 3q29 deletion syndrome.

Background: 3q29 deletion syndrome (3q29del) is associated with a significantly increased risk for neurodevelopmental and neuropsychiatric phenotypes. Mild to moderate intellectual disability (ID) is common in this population, and previous work by our team identified substantial deficits in adaptive behavior. However, the full profile of adaptive function in 3q29del has not been described, nor has it been compared to other genomic syndromes associated with elevated risk for neurodevelopmental and neuropsychiatric phenotypes. Methods: Individuals with 3q29del (n=32, 62.5% male) were evaluated using the Vineland Adaptive Behavior Scales, Third Edition, Comprehensive Parent/Caregiver Form (Vineland-3). We explored the relationship between adaptive behavior and cognitive function, executive function, and neurodevelopmental and neuropsychiatric comorbidities in our 3q29del study sample, and we compared subjects with 3q29del to published data on Fragile X syndrome, 22q11.2 deletion syndrome, and 16p11.2 deletion and duplication syndromes. Results: Individuals with 3q29del had global deficits in adaptive behavior that were not driven by specific weaknesses in any given domain. Individual neurodevelopmental and neuropsychiatric diagnoses had a small effect on adaptive behavior, and the cumulative number of comorbid diagnoses was significantly negatively associated with Vineland-3 performance. Both cognitive ability and executive function were significantly associated with adaptive behavior, and executive function was a better predictor of Vineland-3 performance than cognitive ability. Finally, the severity of adaptive behavior deficits in 3q29del was distinct from previously published data on comparable genomic disorders. Conclusions: Individuals with 3q29del have significant deficits in adaptive behavior, affecting all domains assessed by the Vineland-3. Executive function is a better predictor of adaptive behavior than cognitive ability in this population and suggests that interventions targeting executive function may be an effective therapeutic strategy.

Visual-Motor Integration Deficits in 3q29 Deletion Syndrome.

3q29 deletion syndrome (3q29del) is associated with neuropsychiatric and neurodevelopmental phenotypes. We previously reported that graphomotor weakness is present in up to 78% of individuals with 3q29del. We have now explored nuances of the graphomotor phenotype and its association with other comorbidities in this population. Participants were recruited from the online 3q29 registry (3q29deletion.org) for two days of deep phenotyping. 32 individuals with 3q29del (62.5% male) were evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) to assess visual-motor integration. Participants were also evaluated with measures of cognitive ability, executive function, adaptive behavior, and school function. Males with 3q29del performed significantly worse than females on the VMI and Motor Coordination subtest. VMI performance was significantly associated with ADHD diagnosis and cognitive ability. Compared to published data from individuals with 22q11.2 deletion syndrome, individuals with 3q29del showed significantly more impairment. The 3q29 deletion is associated with substantial deficits in visual-motor integration, Visual Perception, and Motor Coordination. Our data suggests that 3q29del may qualify as a nonverbal learning disability. Future studies should assess whether individuals with 3q29del would benefit from early interventions, including occupational therapy.

Autism spectrum disorder symptom expression in individuals with 3q29 deletion syndrome.

BACKGROUND: The 1.6 Mb 3q29 deletion is associated with neurodevelopmental and neuropsychiatric phenotypes, including a 19-fold increased risk for autism spectrum disorder (ASD). Previous work by our team identified elevated social disability in this population via parent-report questionnaires. However, clinical features of ASD in this population have not been explored in detail. METHODS: Thirty-one individuals with 3q29 deletion syndrome (3q29del, 61.3% male) were evaluated using two gold-standard clinical ASD evaluations: the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the Autism Diagnostic Interview, Revised (ADI-R). Four matched comparators for each subject were ascertained from the National Database for Autism Research. Item-level scores on the ADOS-2 and ADI-R were compared between subjects with 3q29del and matched comparators. RESULTS: Subjects with 3q29del and no ASD (3q29del-ASD) had greater evidence of social disability compared to typically developing (TD) comparison subjects across the ADOS-2. Subjects with 3q29del and ASD (3q29del + ASD) were largely indistinguishable from non-syndromic ASD (nsASD) subjects on the ADOS-2. 3q29del + ASD performed significantly better on social communication on the ADI-R than nsASD (3q29 + ASD mean = 11.36; nsASD mean = 15.70; p = 0.01), and this was driven by reduced deficits in nonverbal communication (3q29 + ASD mean = 1.73; nsASD mean = 3.63; p = 0.03). 3q29del + ASD reported significantly later age at the first two-word phrase compared to nsASD (3q29del + ASD mean = 43.89 months; nsASD mean = 37.86 months; p = 0.01). However, speech delay was not related to improved nonverbal communication in 3q29del + ASD. LIMITATIONS: There were not enough TD comparators with ADI-R data in NDAR to include in the present analysis. Additionally, our relatively small sample size made it difficult to assess race and ethnicity effects. CONCLUSIONS: 3q29del is associated with significant social disability, irrespective of ASD diagnosis. 3q29del + ASD have similar levels of social disability to nsASD, while 3q29del-ASD have significantly increased social disability compared to TD individuals. However, social communication is reasonably well preserved in 3q29del + ASD relative to nsASD. It is critical that verbal ability and social disability be examined separately in this population to ensure equal access to ASD and social skills evaluations and services.

Feasibility of a Structured, Multidisciplinary Intervention for Weight Management in Children With Autism Spectrum Disorder.

Children with autism spectrum disorder (ASD) are at an increased risk for obesity. Although treatments for obesity exist, they do not address unique ASD related characteristics. The current study evaluates a structured multidisciplinary treatment program, the Changing Health in Autism through Nutrition, Getting fit and Expanding (food) variety (CHANGE) program. Ten children (ages 5-12) with ASD who were overweight or obese participated in either CHANGE or parent education program for 16 weeks. CHANGE provided nutrition and behavior management strategies, while the parent education program provided ASD education. BMI-for-age percentile at screening was 92.8% ± 5.2. Ten eligible participants enrolled in the study and 2 (20%) dropped out prior to study completion. Attendance of sessions was moderate (57%); however, parental adherence (eg, homework completion, session participation) was high. All participants indicated that they would recommend the interventions to others. Preliminary evidence supports the feasibility of the CHANGE program in children with ASD.

Feasibility of Group Parent Training for Children with Autism Spectrum Disorder and Disruptive Behavior: A Demonstration Pilot.

Delivery of interventions in a group format is a potential solution to limited access to specialized services for children with autism spectrum disorder (ASD). We conducted an open feasibility trial of group-based RUBI parent training in 18 children (mean age 6.12 ± 1.95 years) with ASD and disruptive behaviors. Parents participated in one of five groups (3 to 4 parents per group). Eighty-three percent of participants completed the 24-week trial. Session attendance was moderate (74.2%). All parents indicated that they would recommend the treatment. Therapists demonstrated 98.8% fidelity to the manual. Eleven of 18 (64.7%) participants were rated as much/very much improved by an independent evaluator at Week 24. Preliminary efficacy findings justify further study.

Dietary Intake, Nutrient Status, and Growth Parameters in Children with Autism Spectrum Disorder and Severe Food Selectivity: An Electronic Medical Record Review.

BACKGROUND: Food selectivity is common in children with autism spectrum disorder (ASD). The clinical characteristics, however, of severe food selectivity in children with ASD is not well documented. OBJECTIVE: This study examined the demographic characteristics, anthropometric parameters, risk of nutritional inadequacy, dietary variety, and problematic mealtime behaviors in a sample of children with ASD with severe food selectivity. DESIGN: The study involved a cross-sectional electronic medical record review. Data extraction followed a systematic protocol for data extraction. PARTICIPANTS/SETTING: Children (age 2 to 17 years) with ASD, severe food selectivity, and complete nutritional data who received a multidisciplinary evaluation at a specialty feeding clinic in the southeastern United States between January 2014 and January 2016. Criteria for severe food selectivity used in this clinical practice required complete omission of one or more food groups (eg, fruit, vegetable, protein, grain, dairy) or consuming a narrow range of items on a weekly basis (eg, five or fewer total food items). MAIN OUTCOME MEASURES: Analyses examined demographic characteristics, dietary preferences, risk for nutritional inadequacies, anthropometric parameters, and problematic mealtime behaviors. RESULTS: Of the 279 patients evaluated during the 24-month period, 70 children with ASD and severe food selectivity met inclusion criteria. Caregivers reported 67% of the sample (n=47) omitted vegetables and 27% omitted fruits (n=19). Seventy-eight percent consumed a diet at risk for five or more inadequacies. Risk for specific inadequacies included vitamin D (97% of the sample), fiber (91%) vitamin E (83%), and calcium (71%). Children with five or more nutritional inadequacies (n=55) were more likely to make negative statements during meals (P<0.05). Severe food selectivity was not associated with compromised growth or obesity. CONCLUSION: Children with ASD and severe food selectivity may be at increased risk for nutritional inadequacies. Future research should examine causes, consequences, and remediation of severe food selectivity in this population.

Feasibility of Parent Training via Telehealth for Children with Autism Spectrum Disorder and Disruptive Behavior: A Demonstration Pilot.

Telehealth is a potential solution to limited access to specialized services for children with autism spectrum disorder (ASD) in rural areas. We conducted a feasibility trial of parent training with children ages 3-8 with ASD and disruptive behavior from rural communities. Fourteen children (mean age 5.8 ± 1.7) from four telehealth sites enrolled. Thirteen families (92.9%) completed treatment, with 91.6% of core sessions attended. Therapists attained 98% fidelity to the manual and 93% of expected outcome measures were collected at week 24. Eleven of 14 (78.6%) participants were rated as much/very much improved. Parent training via telehealth was acceptable to parents and treatment could be delivered reliably by therapists. Preliminary efficacy findings suggests further study is justified.

A Systematic Review and Meta-analysis of Parent Training for Disruptive Behavior in Children with Autism Spectrum Disorder.

Parent training (PT) has emerged as a promising treatment for disruptive behavior in children with autism spectrum disorder (ASD). This review summarizes the essential elements of PT for disruptive behavior in children with ASD and evaluates the available evidence for PT using both descriptive and meta-analytic procedures. We searched Medline, PsycINFO, and PubMed databases (1980-2016) in peer-reviewed journals for randomized controlled trials (RCTs) of PT for disruptive behavior in children with ASD. The systematic search of 2023 publications yielded eight RCTs involving a total of 653 participants. We calculated effect sizes using either raw post-treatment means and standard deviations for each treatment group (PT and control) or group mean differences with associated 95% confidence intervals (CIs). Differences in post-treatment means were converted to a standardized difference in means (SMD) for each primary outcome. Results support the efficacy of PT for disruptive behavior in children with ASD, with a SMD of -0.59 [95% CI (-0.88, -0.30); p < 0.001]. Across these eight studies, there was significant heterogeneity in the effect of PT on disruptive behavior. This variability is likely due to differences in sample size, number of treatment sessions, study duration, and control condition employed. Current findings provide solid support for the efficacy of PT for disruptive behavior in children with ASD. Future studies should focus on effectiveness trials to promote wider implementation of PT in clinical settings.

Parent Training in Autism Spectrum Disorder: What's in a Name?

Parent training (PT) is well understood as an evidence-based treatment for typically developing children with disruptive behavior. Within the field of autism spectrum disorder (ASD), the term parent training has been used to describe a wide range of interventions including care coordination, psychoeducation, treatments for language or social development, as well as programs designed to address maladaptive behaviors. As a result, the meaning of "parent training" in ASD is profoundly uncertain. This paper describes the need to delineate the variants of PT in ASD and offers a coherent taxonomy. Uniform characterization of PT programs can facilitate communication with families, professionals, administrators, and third-party payers. Moreover, it may also serve as a framework for comparing and contrasting PT programs. In support of the taxonomy, a purposive sampling of the literature is presented to illustrate the range of parent training interventions in ASD.

The Autism MEAL Plan: a parent-training curriculum to manage eating aversions and low intake among children with autism.

Feeding problems represent a frequent concern reported by caregivers of children with autism spectrum disorders, and growing evidence suggests atypical patterns of intake may place this population at risk of nutritional and/or related medical issues, including chronic vitamin and mineral deficiencies, poor bone growth, and obesity. This combination of factors emphasizes a clear need to identify and disseminate evidence-based treatment of feeding problems associated with autism spectrum disorders. Behavioral intervention represents an effective treatment for chronic feeding concerns in this population; however, evidence has largely been established with trained therapists working in highly structured settings. This pilot study seeks to fill this gap in the literature by describing and evaluating the Autism MEAL Plan, a behaviorally based parent-training curriculum to address feeding problems associated with autism spectrum disorders. We assessed the feasibility of the intervention in terms of program content and study protocol (e.g. recruitment and retention of participants, assessment procedures), as well as efficacy in terms of changes in feeding behaviors. A total of 10 families participated in the treatment condition, and the program was evaluated using a waitlist control design (n = 9), representing the first randomized-control study of a feeding intervention in autism spectrum disorders. Results provide provisional support regarding the utility of the program, including high social validity, parent perception of effectiveness, and reduced levels of caregiver stress following intervention. Implications, limitations, and future directions for this line of research are discussed.