Autism spectrum disorder symptoms from ages 2 to 19 years: Implications for diagnosing adolescents and young adults

This study explored change in social-communicative symptoms in 140 individuals with childhood autism spectrum disorder (ASD) diagnoses. Trajectories of caregiver-reported social-communicative symptoms were examined for three groups (verbal, delayed speech, minimally verbal) from ages 2 to 19 years. Groups showed comparable levels of social-communicative impairment at 2 years and significant decreases in overall symptom levels across the 17-year period (P < .001). Across three subdomains, main effects of time and language (P < .001) reflected patterns of overall improvement, although children with more impaired language tended to have more caregiver-reported symptoms relative to verbal peers. A significant time-by-language interaction (P < .001) reflected that trajectories of socioemotional reciprocity symptoms differed according to patterns of language development. In contrast, improvements in the nonverbal communication domain were seen across language groups, whereas deficits in the development and maintenance of relationships improved for only verbal children. Verbal adults showed significant reductions in the prevalence of kseveral symptoms exhibited during childhood. Improvements suggest that symptoms indicative of ASD in young children may no longer be diagnostic markers in adolescents and adults. Relative stability of several items suggests that impaired facial expression may be a core ASD symptom that warrants more systematic study across the lifespan. Research investigating the manifestation of ASD in older individuals is needed to foster development of appropriate assessment tools and interventions. Differential relationships to developmental factors within the broader social-communication domain underscores a need to focus on more narrowly defined symptom constructs when exploring links between pathophysiology and observable phenotypes. Autism Research 2019, 12: 89-99. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.

LAY SUMMARY: In a sample of 140 participants with autism spectrum disorder (ASD) followed from 2 to 19 years old, this study found that overall social-communicative symptoms improve across childhood and adolescence. However, timing and amount of change varied for different symptom categories and participants with different language abilities. Findings suggest that some older adolescents and adults with ASD may not exhibit the same difficulties observed in young children with ASD. More research is needed to better understand the strengths and needs of young adults with ASD.

Preschoolers with severe autism and minimal speech were assigned either a discrete trial or a naturalistic language treatment, and parents of all participants also received parent responsiveness training. After 12 weeks, both groups showed comparable improvement in number of spoken words produced, on average. Approximately half the children in each group achieved benchmarks for the first stage of functional spoken language development, as defined by Tager-Flusberg et al. (J Speech Lang Hear Res, 52: 643-652, 2009). Analyses of moderators of treatment suggest that joint attention moderates response to both treatments, and children with better receptive language pre-treatment do better with the naturalistic method, while those with lower receptive language show better response to the discrete trial treatment. The implications of these findings are discussed.

Background: Previous studies of the frequency of cerebral palsy in the United States have found excess prevalence in black children relative to other groups. Whether the severity of cerebral palsy differs between black and white children has not previously been investigated.

Methods: A population-based surveillance system in 4 regions of the United States identified 476 children with cerebral palsy among 142,338 8-year-old children in 2006. Motor function was rated by the Gross Motor Function Classification System and grouped into 3 categories of severity. We used multiple imputation to account for missing information on motor function and calculated the race-specific prevalence of each cerebral palsy severity level.

Results: The prevalence of cerebral palsy was 3.7 per 1000 black children and 3.2 per 1000 white children (prevalence odds ratio [OR] = 1.2 [95% confidence interval = 1.0-1.4]). When stratified by severity of functional limitation, the racial disparity was present only for severe cerebral palsy (black vs. white prevalence OR=1.7 [1.1-2.4]). The excess prevalence of severe cerebral palsy in black children was evident in term and very preterm birth strata.

Conclusion: Black children in the United States appear to have a higher prevalence of cerebral palsy overall than white children, although the excess prevalence of cerebral palsy in black children is seen only among those with the most severe limitations. Further research is needed to explore reasons for this disparity in functional limitations; potential mechanisms include racial differences in risk factors, access to interventions, and under-identification of mild cerebral palsy in black children.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% ± 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients.

The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer’s, Parkinson’s, Huntington’s, and prion disease. The utility of this system lies in the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer’s disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background and recurred on reintroduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds, indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.

Autism spectrum disorders (ASDs) are estimated to occur among about one percent of children in the United States. This estimate is in line with estimates from other industrialized countries. However, the identified prevalence of ASDs has increased significantly in a short time period based on data from multiple studies including the U.S. Centers for Disease Control and Prevention’s (CDC) Autism and Developmental Disabilities Monitoring (ADDM) Network. Whether increases in ASD prevalence are partly attributable to a true increase in the risk of developing ASD or solely to changes in community awareness and identification patterns is not known. It is clear that more children are identified with an ASD now than in the past and the impact on individuals, families, and communities is significant. However, disentangling the many potential reasons for ASD prevalence increases has been challenging. Understanding the relative contribution of multiple factors such as variation in study methods, changes in diagnostic and community identification, and potential changes in risk factors is an important priority for the ADDM Network and for CDC. This article summarizes the discussion from a workshop that was co-sponsored by CDC and Autism Speaks as a forum for sharing knowledge and opinions of a diverse range of stakeholders about changes in ASD prevalence. Panelists discussed recommendations for building on existing infrastructure and developing new initiatives to better understand ASD trends. The information, research, and opinions shared during this workshop add to the knowledge base about ASD prevalence in an effort to stimulate further work to understand the multiple reasons behind increasing ASD prevalence.

Keywords: ASD; Autism; autism spectrum disorders; occurrence; prevalence.

Objectives: Anecdotal reports suggest that elopement behavior in children with autism spectrum disorders (ASDs) increases risk of injury or death and places a major burden on families. This study assessed parent-reported elopement occurrence and associated factors among children with ASDs.

Methods: Information on elopement frequency, associated characteristics, and consequences was collected via an online questionnaire. The study sample included 1218 children with ASD and 1076 of their siblings without ASD. The association among family sociodemographic and child clinical characteristics and time to first elopement was estimated by using a Cox proportional hazards model.

Results: Forty-nine percent (n = 598) of survey respondents reported their child with an ASD had attempted to elope at least once after age 4 years; 26% (n = 316) were missing long enough to cause concern. Of those who went missing, 24% were in danger of drowning and 65% were in danger of traffic injury. Elopement risk was associated with autism severity, increasing, on average, 9% for every 10-point increase in Social Responsiveness Scale T score (relative risk 1.09, 95% confidence interval: 1.02, 1.16). Unaffected siblings had significantly lower rates of elopement across all ages compared with children with ASD.

Conclusions: Nearly half of children with ASD were reported to engage in elopement behavior, with a substantial number at risk for bodily harm. These results highlight the urgent need to develop interventions to reduce the risk of elopement, to support families coping with this issue, and to train child care professionals, educators, and first responders who are often involved when elopements occur.

While much research has examined the development of facial recognition abilities, less is known about the ability of individuals with and without autism to categorize facial gender. The current study tested gender categorization abilities in high-functioning children (5-7 and 8-12 years), adolescents (13-17 years), and adults (18-53 years) with autism and matched controls. Naturalistic videos depicted faces that were either typical or less typical of each gender. Both groups improved in their performance across development. However, control children reached expertise that was similar to control adults by 8-12 years; whereas, adults with autism never reached this level of expertise, particularly with less typical gender faces. Results suggest that individuals with autism employ different face processing mechanisms than typically developing individuals.

Recent reports suggest certain behaviors among children with autism spectrum disorders (ASD) may indicate underlying gastro-intestinal (GI) problems, and that the presence of these behaviors may help alert primary care providers to the need to evaluate a child with ASD for GI problems. The purpose of this population-based study of 487 children with ASD, including 35 (7.2%) with a medically documented history of GI problems, was to compare behavioral features of children with and without a history of GI problems. Unusual sleeping or eating habits and oppositional behavior were significantly associated with GI problems. These behaviors, however, were frequent in both children with and without GI problems, suggesting they may have limited utility in a screening capacity for GI problems.

Recent findings suggest impaired motor skill development during infancy in children later diagnosed with autism spectrum disorders (ASD). However, it remains unclear whether infants at high familial risk for ASD would benefit from early interventions targeting the motor domain. The current study investigated this issue by providing 3-month-old infants at high familial risk for ASD with training experiences aimed at facilitating independent reaching. A group of 17 high-risk (HR) infants received 2 weeks of scaffolded reaching experiences using “sticky mittens,” and was compared to 72 low-risk (LR) infants experiencing the same or alternative training procedures. Results indicate that HR infants – just like LR infants – show an increase in grasping activity following “sticky mittens” training. In contrast to LR infants, evidence that motor training encouraged a preference for faces in HR infants was inconclusive.

Keywords: autism spectrum disorders; grasping; infancy; motor development; sticky mittens.

Mouse models recapitulate many symptoms of Rett Syndrome, an X-linked disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2). The study of Mecp2-null male mice has provided insight into pathogenesis of the disorder; most recently, dysregulation of cholesterol and lipid metabolism. Perisymptomatic treatment with statin drugs successfully mitigates the effects of this metabolic syndrome, increases longevity and improves motor function. Described here is a metabolic drug screening protocol and timeline for symptom evaluation in Mecp2-mutant mice. Specifically, mice are treated twice weekly with a compound of interest alongside subjective health assessments, bi-weekly body composition measurements and blood chemistries. Throughout treatment, behavioral phenotyping tests are carried out at specific time points. This protocol is highly adaptable to other neurological diseases; however, the time for completion depends on the specific mutant model under study. The protocol highlights the use of several different CPMo protocols to carry out testing in a preclinical model.

Keywords: Behavioral Assessment; Cholesterol; Drug Treatment; Lipid; Metabolism; Neurodevelopmental Disorders; Rett Syndrome.

Mutations in MECP2, encoding methyl CpG-binding protein 2, cause Rett syndrome, the most severe autism spectrum disorder. Re-expressing Mecp2 in symptomatic Mecp2-null mice markedly improves function and longevity, providing hope that therapeutic intervention is possible in humans. To identify pathways in disease pathology for therapeutic intervention, we carried out a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis suppressor screen in Mecp2-null mice and isolated five suppressors that ameliorate the symptoms of Mecp2 loss. We show that a stop codon mutation in Sqle, encoding squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis, underlies suppression in one line. Subsequently, we also show that lipid metabolism is perturbed in the brains and livers of Mecp2-null male mice. Consistently, statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice. Our genetic screen therefore points to cholesterol homeostasis as a potential target for the treatment of patients with Rett syndrome.