Transdiagnostic Case Conceptualization of Emotional Problems in Youth with ASD: An Emotion Regulation Approach

Youth with autism spectrum disorder often struggle to cope with co‐occurring anxiety, depression, or anger, and having both internalizing and externalizing symptoms is a common clinical presentation. A number of authors have designed cognitive‐behavioral interventions to address transdiagnostic factors related to multiple emotional problems, although none have applied this focus to youth with ASD. The current review article describes how a transdiagnostic emotion regulation framework may inform cognitive‐behavioral interventions for youth with ASD, which until now have focused almost exclusively on anxiety. Research is needed to empirically test how a transdiagnostic intervention can address the processes of emotion regulation and assist youth with ASD to cope with their emotional disorders.     

Assessment of Social Anxiety in Children and Adolescents With Autism Spectrum Disorder

Despite the high prevalence of social anxiety in individuals with autism spectrum disorder (ASD), there is little agreement on how to best assess such problems in this population. To inform evidence‐based assessment, we conducted a comprehensive review of research that has assessed social anxiety in children and adolescents with ASD without co‐occurring intellectual disability. Although some evidence in support of the reliability of existing measures exists, there are concerns about inflated estimates of the co‐occurrence of social anxiety because of symptom overlap with ASD diagnostic criteria, and the diagnostic sensitivity of existing measures is questionable. Recommendations for clinical assessment of social anxiety in this population and future directions for research on this topic, including the development of new measures, are provided.     

Association of IMMP2L deletions with autism spectrum disorder: A trio family study and meta‐analysis

IMMP2L, the gene encoding the inner mitochondrial membrane peptidase subunit 2‐like protein, has been reported as a candidate gene for Tourette syndrome, autism spectrum disorder (ASD) and additional neurodevelopmental disorders. Here we genotyped 100 trio families with an index proband with autism spectrum disorder in Han Chinese population and found three cases with rare exonic IMMP2L deletions. We have conducted a comprehensive meta‐analysis to quantify the association of IMMP2L deletions with ASD using 5,568 cases and 10,279 controls. While the IMMP2L deletions carried non‐recurrent breakpoints, in contrast to previous reports, our meta‐analysis found no evidence of association (P > 0.05) between IMMP2L deletions and ASD. We also observed common exonic deletions impacting IMMP2L in a separate control (5,971 samples) cohort where subjects were screened for psychiatric conditions. This is the first systematic review and meta‐analysis regarding the effect of IMMP2L deletions on ASD, but further investigations in different populations, especially Chinese population may be still needed to confirm our results.     

Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study

Introduction  

There exists a small subset of children with autism spectrum disorders (ASD) characterized by fluctuating behavioral symptoms and cognitive skills following immune insults. Some of these children also exhibit specific polysaccharide antibody deficiency (SPAD), resulting in frequent infection caused by encapsulated organisms, and they often require supplemental intravenous immunoglobulin (IVIG) (ASD/SPAD). This study assessed whether these ASD/SPAD children have distinct immunological findings in comparison with ASD/non-SPAD or non-ASD/SPAD children.     

Anxiety Disorders Interview Schedule–Autism Addendum: Reliability and Validity in Children With Autism Spectrum Disorder

Assessing anxiety in autism spectrum disorder (ASD) is inherently challenging due to overlapping (e.g., social avoidance) and ambiguous symptoms (e.g., fears of change). An ASD addendum to the Anxiety Disorders Interview Schedule–Child/Parent, Parent Version (ADIS/ASA) was developed to provide a systematic approach for differentiating traditional anxiety disorders from symptoms of ASD and more ambiguous, ASD-related anxiety symptoms. Interrater reliability and convergent and discriminant validity were examined in a sample of 69 youth with ASD (8–13 years, 75% male, IQ = 68–143) seeking treatment for anxiety. The parents of participants completed the ADIS/ASA and a battery of behavioral measures. A second rater independently observed and scored recordings of the original interviews. Findings suggest reliable measurement of comorbid (intraclass correlation = 0.85–0.98, κ = 0.67–0.91) as well as ambiguous anxiety-like symptoms (intraclass correlation = 0.87–95, κ = 0.77–0.90) in children with ASD. Convergent and discriminant validity were supported for the traditional anxiety symptoms on the ADIS/ASA, whereas convergent and discriminant validity were partially supported for the ambiguous anxiety-like symptoms. Results provide evidence for the reliability and validity of the ADIS/ASA as a measure of traditional anxiety categories in youth with ASD, with partial support for the validity of the ambiguous anxiety-like categories. Unlike other measures, the ADIS/ASA differentiates comorbid anxiety disorders from overlapping and ambiguous anxiety-like symptoms in ASD, allowing for more precise measurement and clinical conceptualization. Ambiguous anxiety-like symptoms appear phenomenologically distinct from comorbid anxiety disorders and may reflect either symptoms of ASD or a novel variant of anxiety in ASD.     

The Presentation and Classification of Anxiety in Autism Spectrum Disorder

Research on the expression and prevalence of co‐occurring anxiety disorders and autism spectrum disorders (ASDs) has produced variable results, in part due to the diversity in sample ascertainment and composition, methodology, and the operationalization of anxiety across studies. The present review organizes these findings to consider whether anxiety symptoms reported in ASD are better categorized as (a) a part of ASD or (b) a comorbid disorder. Although there is some support for the presence of co‐occurring, potentially comorbid anxiety disorders in ASD, a shift toward measurement validation and dimensional approaches in future research is needed to determine the role of anxiety in ASD, particularly regarding its “typical” and “atypical” presentation in this population.     

Exploring the Nature and Function of Anxiety in Youth with Autism Spectrum Disorders

[Clin Psychol Sci Prac 17: 281–292, 2010] This article considers the nosology and pathogenesis of anxiety disorders in youth with autism. The comparability of anxiety in the autism spectrum disorder (ASD) population in relation to the typically developing population has been suggested by some recent findings, but conceptual and empirical ambiguities remain. It is suggested that anxiety may play at least three roles: (a) a downstream consequence of ASD symptoms (e.g., via stress generation through social rejection); (b) a moderator of ASD symptom severity, such that certain core autism symptoms like social skill deficits and repetitive behaviors may be exacerbated by anxiety; and (c) as a proxy of core ASD symptoms. Suggestions for clarifying the nature and function of anxiety in autism are made.     

Future Directions for Research on Early Intervention for Young Children at Risk for Social Anxiety

Anxiety disorders are common among young children, with earlier onset typically associated with greater severity and persistence. A stable behaviorally inhibited (BI) temperament and subsequent shyness and social withdrawal (SW) place children at increased risk of developing anxiety disorders, particularly social anxiety. In this Future Directions article, we briefly review developmental and clinical research and theory that point to parenting and peer interactions as key moderators of both the stability of BI/SW and risk for later anxiety, and we describe existing interventions that address early BI/SW and/or anxiety disorders in young children. We recommend that future research on early intervention to disrupt the trajectory of anxiety in children at risk (a) be informed by both developmental science and clinical research, (b) incorporate multiple levels of analysis (including both individual and contextual factors), (c) examine mediators that move us closer to understanding how and why treatments work, (d) be developed with the end goal of dissemination, (e) examine moderators of outcome toward the goal of treatment efficiency, (f) consider transdiagnostic or modular approaches, (g) integrate technology, and (h) consider cultural norms regarding BI/SW/anxiety and parenting.     

Impact of innate immunity in a subset of children with autism spectrum disorders: a case control study

Background  

Among patients with autism spectrum disorders (ASD) evaluated in our clinic, there appears to be a subset that can be clinically distinguished from other ASD children because of frequent infections (usually viral) accompanied by worsening behavioural symptoms and/or loss/decrease in acquired skills. This study assessed whether these clinical features of this ASD subset are associated with atopy, asthma, food allergy (FA), primary immunodeficiency (PID), or innate immune responses important in viral infections.     

Mutation pattern and genotype-phenotype correlations of SETD2 in neurodevelopmental disorders

SETD2 encodes an important protein for epigenetic modification of histones which plays an essential role in early development. Variants in SETD2 have been reported in neurodevelopmental disorders including autism spectrum disorder (ASD). However, most de novo SETD2 variants were reported in different large-cohort sequencing studies, mutation pattern and comprehensive genotype-phenotype correlations for SETD2 are still lacking. We have applied target sequencing to identify rare, clinical-relevant SETD2 variants and detected two novel de novo SETD2 variants, including a de novo splicing variant (NM_014159: c.4715+1G>A) and a de novo missense variant (c.3185C>T: p.P1062L) in two individuals with a diagnosis of ASD. To analyze the correlations between SETD2 mutations and corresponding phenotypes, we systematically review the reported individuals with de novo SETD2 variants, classify the pathogenicity, and analyze the detailed phenotypes. We subsequently manually curate 17 SETD2 de novo variants in 17 individuals from published literature. Individuals with de novo SETD2 variants present common phenotypes including speech and motor delay, intellectual disability, macrocephaly, ASD, overgrowth and recurrent otitis media. Our study reveals new SETD2 mutations and provided a relatively homozygous phenotype spectrum of SETD2-related neurodevelopmental disorders which will be beneficial for disease classification and diagnosis in clinical practice.     

CNTN6 copy number variations: Uncertain clinical significance in individuals with neurodevelopmental disorders

Copy number variations (CNVs) of the CNTN6 gene - a member of the contactin gene superfamily - have been previously proposed to have an association with neurodevelopmental and autism spectrum disorders. However, no functional evidence has been provided to date and phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. In view of conflicting reports on the pathogenicity of CNVs involving CNTN6 and association with different phenotypes, we, independently, evaluated clinical features of nineteen patients with detected CNV of CNTN6 as part of their clinical microarray analysis at Children's Mercy and Nationwide Children's Hospitals for the period of 2008–2015. The clinical presentations of these patients were variable making it difficult to establish genotype-phenotype correlations. CNVs were inherited in six patients. For thirteen patients, inheritance pattern was not established due to unavailability of parental samples for testing. In three cases CNV was inherited from a healthy parent and in three cases from a parent with neurodevelopmental symptoms. Of the nineteen patients, four had a separate genetic abberation in addition to CNV of the CNTN6 that could independently explain their respective phenotypes. Separately, CNTN6 sequencing was performed on an autism spectrum disorder (ASD) research cohort of 94 children from 80 unrelated families. We found no difference in frequency of rare coding variants between the cohort of patients and controls. We conclude that CNVs involving CNTN6 alone seem to be most likely a neutral variant or a possible modifier rather than a disease-causing variant. Patients with CNVs encompassing CNTN6 could benefit from additional genetic testing since a clinical diagnosis due to a CNV of CNTN6 alone is still questionable.     

Cortisol profiles differentiated in adolescents and young adult males with fragile X syndrome versus autism spectrum disorder

Background

Fragile X syndrome (FXS) and non‐syndromic autism spectrum disorder (ASD) are distinct disorders with overlapping behavioral features. Both disorders are also highly associated with anxiety with abnormal physiological regulation implied mechanistically. Some reports suggest atypical hypothalamus‐pituitary‐adrenal (HPA) axis function, indexed via aberrant cortisol reactivity, in both FXS and non‐syndromic ASD. However, no study has compared cortisol reactivity across these two disorders, or its relationship to ASD symptom severity.

Methods

Cortisol reactivity (prior to and following a day of assessments) was measured in 54 adolescent/young adult males with FXS contrasted to 15 males with non‐syndromic ASD who had low cognitive abilities.

Results

Greater ASD symptom severity was related to increased cortisol reactivity and higher levels at the end of the day, but only in the non‐syndromic ASD group. Elevated anxiety was associated with increased HPA activation in the group with FXS alone.

Conclusions

Taken together, findings suggest a unique neuroendocrine profile that distinguishes adolescent/young adult males with FXS from those with non‐syndromic ASD. Severity of ASD symptoms appears to be related to cortisol reactivity in the non‐syndromic ASD sample, but not in FXS; while anxiety symptoms are associated with HPA activation in the FXS sample, but not in ASD despite a high prevalence of ASD, anxiety and physiological dysregulation characteristic in both populations.     

Chromosomal microarray testing influences medical management

PurposeChromosomal microarray (CMA) testing provides the highest diagnostic yield for clinical testing of patients with developmental delay (DD), intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorders (ASD). Despite improved diagnostic yield and studies to support cost-effectiveness, concerns regarding the cost and reimbursement for CMA have been raised because it is perceived that CMA results do not influence medical management.MethodsWe conducted a retrospective chart review of CMA testing performed during a 12-month period on patients with DD/ID, ASD, and congenital anomalies to determine the proportion of cases where abnormal CMA results impacted recommendations for clinical action.ResultsAmong 1792 patients, 13.1% had clinically relevant results, either abnormal (n = 131; 7.3%) or variants of possible significance (VPS; n = 104; 5.8%). Abnormal variants generated a higher rate of recommendation for clinical action (54%) compared with VPS (34%; Fisher exact test, P = 0.01). CMA results influenced medical care by precipitating medical referrals, diagnostic imaging, or specific laboratory testing.ConclusionsFor all test indications, CMA results influenced medical management in a majority of patients with abnormal variants and a substantial proportion of those with VPS. These results support the use of CMA as a clinical diagnostic test that influences medical management for this patient population.     

Autism and chromosome abnormalities—A review

The neuro‐behavioral disorder of autism was first described in the 1940s and was predicted to have a biological basis. Since that time, with the growth of genetic investigations particularly in the area of pediatric development, an increasing number of children with autism and related disorders (autistic spectrum disorders, ASD) have been the subject of genetic studies both in the clinical setting and in the wider research environment. However, a full understanding of the biological basis of ASDs has yet to be achieved. Early observations of children with chromosomal abnormalities detected by G‐banded chromosome analysis (karyotyping) and in situ hybridization revealed, in some cases, ASD associated with other features arising from such an abnormality. The introduction of higher resolution techniques for whole genome screening, such as array comparative genome hybridization (aCGH), allowed smaller imbalances to be detected, some of which are now considered to represent autism susceptibility loci. In this review, we describe some of the work underpinning the conclusion that ASDs have a genetic basis; a brief history of the developments in genetic analysis tools over the last 50 years; and the most common chromosome abnormalities found in association with ASDs. Introduction of next generation sequencing (NGS) into the clinical diagnostic setting is likely to provide further insights into this complex field but will not be covered in this review. Clin. Anat. 29:620–627, 2016. © 2016 Wiley Periodicals, Inc.     

Nonrandom occurrence of multiple de novo coding variants in a proband indicates the existence of an oligogenic model in autism

PurposeElucidating the genetic architecture underlying autism spectrum disorder (ASD) will aid in the understanding of its genetic etiology and clinical diagnosis.MethodsA comprehensive set of coding de novo variants (DNVs) from 4504 trios with ASD and 3012 control/sibling trios from several large-scale sequencing studies were collected and combined. Multiple in-depth analyses including DNVs burden, clinical phenotypes, and functional networks underlying the combined data set were used to evaluate the nonrandom occurrence of multiple extreme DNVs (loss-of-function and damaging missense variants) in the same patients.ResultsWe observed a significant excess of multiple extreme DNVs among patients with ASD compared with controls. Meanwhile, patients with ASD carrying 2+ extreme DNVs had significantly lower IQs than patients carrying 0 or 1 DNV. Moreover, much closer functional connectivity than expected was observed among 2 or more genes with extreme DNVs from the same individuals. In particular, we identified 56 key genes as more confident ASD genes compared with other known ASD genes. In addition, we detected 23 new ASD candidate genes with recurrent DNVs, including VIP, ZWILCH, MSL2, LRRC4, and CAPRIN1.ConclusionsOur findings present compelling statistical evidence supporting an oligogenic model and provide new insights into the genetic architecture of ASD.     

Maternal immune activation in neurodevelopmental disorders

Converging lines of evidence from basic science and clinical studies suggest a relationship between maternal immune activation (MIA) and neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. The mechanisms through which MIA increases the risk of neurodevelopmental disorders have become a subject of intensive research. This review aims to describe how dysregulation of microglial function and immune mechanisms may link MIA and neurodevelopmental pathologies. We also summarize the current evidence in animal models of MIA. Developmental Dynamics 247:588–619, 2018. © 2017 Wiley Periodicals, Inc.     

Childhood anxiety: An early predictor of mood disorders in offspring of bipolar parents

Background

Anxiety disorders are common among the offspring of parents with bipolar disorder (BD). This study investigated the nature of the association between anxiety disorders and mood disorders in a prospectively studied high-risk cohort.

Methods

High-risk offspring were identified from families in which one parent had confirmed BD based on SADS-L interviews and best estimate diagnostic procedures. All agreeable offspring aged 8–25 years were enrolled in a longitudinal study involving repeated KSADS-PL format clinical assessments. Control (C) offspring from families in which neither parent met lifetime criteria for a psychiatric disorder were similarly assessed. All DSM-IV diagnoses in the offspring were confirmed on blind consensus review. Cumulative incidence and adjusted Cox Proportional Hazards models were used to calculate the risk of anxiety disorders and the predictive association with mood disorders.

Results

The cumulative incidence of anxiety disorders was higher (23.40% vs. 10.42%; HR=2.136; p=.0382) and occurred earlier (9.79 vs. 14.84 years; p=.0125) in high-risk compared to C offspring. In high-risk offspring generalized anxiety disorders (GAD) followed by social phobia were the most incident anxiety subtypes; while high emotionality (HR 1.111; p=.0096) and shyness (HR 1.144; p=.0053) increased the risk of anxiety disorders. Anxiety disorders increased the adjusted risk of mood disorders (HR 2.166; p=.0004), on average 8.49 years later (SD 5.97).

Limitations

The cumulative incidence of BD is relatively low, as the cohort is still in the period of risk.

Conclusions

Findings highlight the need for longitudinal surveillance of symptomatic high-risk children and suggest anxiety disorders are an important early intervention target.     

Genetic testing in autism: how much is enough?

PurposeTo evaluate the yield of genetic testing in children with autism spectrum disorders.MethodsWe performed a retrospective chart review of 71 unrelated patients with a diagnosis of an isolated autism spectrum disorder seen in a genetics clinic over a period of 14 months. For most, referrals occurred after evaluation by a developmental pediatrician and/or psychologist to establish the diagnosis. Tiered laboratory testing for the majority of the patients followed a guideline that was developed in collaboration with clinicians at The Autism Center at Children's Hospital, Columbus, OH.ResultsThe patients included 57 males and 14 females; 57 met DSM-IV criteria for autism, with the rest being Asperger or pervasive developmental disorder not otherwise specified. Macrocephaly [head circumference (HC) ≥95%] was present in 19 (27%). Two children had visible chromosome abnormalities (47,XYY; 48,XY + 2mar/49,XY + 3mar). Two patients with autism and macrocephaly had heterozygous mutations in the PTEN tumor suppressor gene. Three females had Rett syndrome, each confirmed by DNA sequencing of the MECP2 gene. Extensive metabolic testing produced no positive results, nor did fragile X DNA testing.ConclusionThe overall diagnostic yield was 10% (7/71). PTEN gene sequencing should be considered in any child with macrocephaly and autism or developmental delay. Metabolic screening may not be warranted in autism spectrum disorders without more specific indications or additional findings.