Evon Batey Lee

Can Autism Be Diagnosed Accurately in Children Under 3 Years

This study investigated the reliability and stability of an autism diagnosis in children under 3 years of age who received independent diagnostic evaluations from two clinicians during two consecutive yearly evaluations. Strong evidence for the reliability and stability of the diagnosis was obtained. Diagnostic agreement between clinicians was higher for the broader discrimination of autism spectrum vs. no autism spectrum than for the more specific discrimination of autism vs. PDD-NOS. The diagnosis of autism at age 2 was more stable than the diagnosis of PDD-NOS at the same age. Social deficits and delays in spoken language were the most prominent DSM-IV characteristics evidenced by very young children with autism.

Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder

Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.

Gastrointestinal Dysfunction in Autism: Parental Report, Clinical Evaluation, and Associated Factors

The objectives of this study were to characterize gastrointestinal dysfunction (GID) in autism spectrum disorder (ASD), to examine parental reports of GID relative to evaluations by pediatric gastroenterologists, and to explore factors associated with GID in ASD. One hundred twenty‐one children were recruited into three groups: co‐occurring ASD and GID, ASD without GID, and GID without ASD. A pediatric gastroenterologist evaluated both GID groups. Parents in all three groups completed questionnaires about their childs behavior and GI symptoms, and a dietary journal. Functional constipation was the most common type of GID in children with ASD (85.0%). Parental report of any GID was highly concordant with a clinical diagnosis of any GID (92.1%). Presence of GID in children with ASD was not associated with distinct dietary habits or medication status. Odds of constipation were associated with younger age, increased social impairment, and lack of expressive language (adjusted odds ratio in nonverbal children: 11.98, 95% confidence interval 2.54–56.57). This study validates parental concerns for GID in children with ASD, as parents were sensitive to the existence, although not necessarily the nature, of GID. The strong association between constipation and language impairment highlights the need for vigilance by health‐care providers to detect and treat GID in children with ASD. Medications and diet, commonly thought to contribute to GID in ASD, were not associated with GID status. These findings are consistent with a hypothesis that GID in ASD represents pleiotropic expression of genetic risk factors.

Prader-Willi syndrome and autism spectrum disorders: an evolving story

Prader–Willi syndrome (PWS) is well-known for its genetic and phenotypic complexities. Caused by a lack of paternally derived imprinted material on chromosome 15q11–q13, individuals with PWS have mild to moderate intellectual disabilities, repetitive and compulsive behaviors, skin picking, tantrums, irritability, hyperphagia, and increased risks of obesity. Many individuals also have co-occurring autism spectrum disorders (ASDs), psychosis, and mood disorders. Although the PWS 15q11–q13 region confers risks for autism, relatively few studies have assessed autism symptoms in PWS or directly compared social, behavioral, and cognitive functioning across groups with autism or PWS. This article identifies areas of phenotypic overlap and difference between PWS and ASD in core autism symptoms and in such comorbidities as psychiatric disorders, and dysregulated sleep and eating. Though future studies are needed, PWS provides a promising alternative lens into specific symptoms and comorbidities of autism.

Association of MET with social and communication phenotypes in individuals with autism spectrum disorder.

Autism is a complex neurodevelopmental disorder diagnosed by impairments in social interaction, communication, and behavioral flexibility. Autism is highly heritable, but it is not known whether a genetic risk factor contributes to all three core domains of the disorder or autism results from the confluence of multiple genetic risk factors for each domain. We and others reported previously association of variants in the gene encoding the MET receptor tyrosine kinase in five independent samples. We further described enriched association of the MET promoter variant rs1858830 C allele in families with co‐occurring autism and gastrointestinal conditions. To test the contribution of this functional MET promoter variant to the domains of autism, we analyzed its association with quantitative scores derived from three instruments used to diagnose and describe autism phenotypes: the Autism Diagnostic Interview—Revised (ADI‐R), the Autism Diagnostic Observation Schedule (ADOS), and both the parent and the teacher report forms of the Social Responsiveness Scale (SRS). In 748 individuals from 367 families, the transmission of the MET C allele from parent to child was consistently associated with both social and communication phenotypes of autism. Stratification by gastrointestinal conditions revealed a similar pattern of association with both social and communication phenotypes in 242 individuals with autism from 118 families with co‐occurring gastrointestinal conditions, but a lack of association with any domain in 181 individuals from 96 families with ASD and no co‐occurring gastrointestinal condition. These data indicate that the MET C allele influences at least two of the three domains of the autism triad.

Rigid–Compulsive Behaviors are Associated with Mixed Bowel Symptoms in Autism Spectrum Disorder

Based on clinical experience, we hypothesized that rigid–compulsive behaviors are associated with severe constipation and co-occurring diarrhea or underwear staining in children with autism spectrum disorder. Using data from the Autism Treatment Network, we evaluated the association between these gastrointestinal symptoms and measures of rigid compulsive behavior in children ages 2–17. Following statistical correction, four of five primary measures were significantly associated with constipation and diarrhea or underwear staining, including parental report of repetitive behavior, parental report of compulsive behavior, clinician diagnosis of obsessive–compulsive disorder, and report of rituals observed on the autism diagnostic observation schedule. This association could point to a causal connection between these symptoms or to a common biological pathway that impacts both gut and brain.

Neurocognitive and Behavioral Outcomes of Younger Siblings of Children with Autism Spectrum Disorder at Age Five

Later-born siblings of children with Autism Spectrum Disorders (ASD) are at increased risk for ASD as well as qualitatively similar traits not meeting clinical cutoffs for the disorder. This study examined age five neurocognitive and behavioral outcomes of 39 younger siblings of children with ASD (Sibs-ASD) and 22 younger siblings of typically developing children (Sibs-TD) previously assessed in a longitudinal investigation starting in the second year of life. There were few group differences between Sibs-TD and Sibs-ASD on global measures of IQ, language, or behavior problems. Sibs-ASD did show vulnerabilities on measures of executive functioning, social cognition, and repetitive behaviors. These results highlight the importance of following sibling risk groups over an extended time period and employing measures targeting broader aspects of development.

Enrichment of elevated plasma F2t-isoprostane levels in individuals with autism who are stratified by presence of gastrointestinal dysfunction.

Etiology is unknown in the majority of individuals with autism spectrum disorder (ASD). One strategy to investigate pathogenesis is to stratify this heterogeneous disorder based on a prominent phenotypic feature that enriches for homogeneity within population strata. Co-occurring gastrointestinal dysfunction (GID) characterizes a subset of children with ASD. Our current objective was to investigate a potential pathophysiological measure to test the hypothesis that children with both ASD and GID have a more severe metabolic dysfunction than children with ASD-only, given that the highly metabolically active brain and gastrointestinal system may additively contribute measurable impairment. Plasma levels of F2t-Isoprostanes (F2-IsoPs), a gold standard biomarker of oxidative stress, were measured in 87 children in four groups: ASD-GID, ASD-only, GID-only and Unaffected. F2-IsoP levels were elevated in all 3 clinical groups compared to the Unaffected group, with the ASD-GID group significantly elevated above the ASD-only group (mean, SD in pg/mg: ASD-GID 53.6, 24.4; ASD-only 36.5, 13.3; p = 0.007). Adjusting for age, sex, and triglyceride levels, F2-IsoP levels remained significantly different between study groups, with a moderate effect size of ηp 2 = 0.187 (p = 0.001). Elevation in peripheral oxidative stress is consistent with, and may contribute to, the more severe functional impairments in the ASD-GID group. With unique medical, metabolic, and behavioral features in children with ASD-GID, the present findings serve as a compelling rationale for both individualized approaches to clinical care and integrated studies of biomarker enrichment in ASD subgroups that may better address the complex etiology of ASD.

Psychophysiological Associations with Gastrointestinal Symptomatology in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is often accompanied by gastrointestinal disturbances, which also may impact behavior. Alterations in autonomic nervous system functioning are also frequently observed in ASD. The relationship between these findings in ASD is not known. We examined the relationship between gastrointestinal symptomatology, examining upper and lower gastrointestinal tract symptomatology separately, and autonomic nervous system functioning, as assessed by heart rate variability and skin conductance level, in a sample of 120 individuals with ASD. Relationships with co‐occurring medical and psychiatric symptoms were also examined. While the number of participants with significant upper gastrointestinal tract problems was small in this sample, 42.5% of participants met criteria for functional constipation, a disorder of the lower gastrointestinal tract. Heart rate variability, a measure of parasympathetic modulation of cardiac activity, was found to be positively associated with lower gastrointestinal tract symptomatology at baseline. This relationship was particularly strong for participants with co‐occurring diagnoses of anxiety disorder and for those with a history of regressive ASD or loss of previously acquired skills. These findings suggest that autonomic function and gastrointestinal problems are intertwined in children with ASD; although it is not possible to assess causality in this data set. Future work should examine the impact of treatment of gastrointestinal problems on autonomic function and anxiety, as well as the impact of anxiety treatment on gastrointestinal problems. Clinicians should be aware that gastrointestinal problems, anxiety, and autonomic dysfunction may cluster in children with ASD and should be addressed in a multidisciplinary treatment plan. Autism Res 2017, 10: 276–288.

Association of Rigid-Compulsive Behavior with Functional Constipation in Autism Spectrum Disorder.

Based upon checklist data from the Autism Speaks Autism Treatment Network, we hypothesized that functional constipation (FC) would be associated with rigid-compulsive behavior in children with autism spectrum disorder (ASD). We used the Questionnaire on Pediatric Gastrointestinal Symptoms—Rome III to assess FC symptoms in 108 children with ASD. As hypothesized, FC was associated with parent ratings on the Repetitive Behavior Scales—Revised (RBS-R) Compulsive, Ritualistic, and Sameness subscales in the overall population. Of note, FC was less common in children who were not taking medications that target behavior or treat FC. In the medication-free children, rigid-compulsive behavior was not significantly associated with FC. More research is needed to understand the mechanisms underlying these associations.