Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder.

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

Diagnosis of Autism in School Age and Adolescence in an Ethnically Diverse Population.

Despite policy emphasis on early identification, many children with Autism are diagnosed late, with some being diagnosed as late as adolescence. The objective of this study was to examine the demographics and clinical characteristics of school-age children and adolescents initially diagnosed with Autism age 7 and older, in an urban, university-affiliated multidisciplinary center that evaluates/treats youth with developmental disabilities. A chart review of all school-age children and adolescents referred for evaluation to determine if the child has developmental disabilities from January 2019 to May 2023 was performed. Of all children evaluated in that period (n = 825), 164 (19.8%) were diagnosed with Autism, 123 (75%) had a previous diagnosis, and 41 (25%) were newly diagnosed with Autism. Patients newly diagnosed with Autism age ≥7 were more likely to be diagnosed with Language Disorder (100% vs. 82%, p = 0.001) and Anxiety Disorder (27% vs. 13%, p = 0.04), be prescribed with an antidepressant (10% vs. 1%, p = 0.03), and less likely to be diagnosed with Intellectual Disabilities (13% vs. 34%, p = 0.001) than those who had a previous diagnosis of Autism, with no other differences in demographics or developmental diagnosis between the groups. Of the 136 patients referred for evaluation with a previous diagnosis of Autism, 13 (9.5%) did not meet the criteria for Autism any longer after multidisciplinary evaluations but continued to present developmental disorders, including Language Disorder (100%), attention-deficit/hyperactivity disorder (46%), and Speech Sound Disorder (38%). Of the 87 families who were concerned about Autism (without a previous diagnosis), 32 (36.8%) confirmed the diagnosis of Autism, 9 (1.5%) patients were newly diagnosed with Autism, and there were no parental concerns. In conclusion, in this ethnically diverse group of school-age children and adolescents with developmental disabilities, 25% received an initial diagnosis of Autism after age 7. Similar to previous reports, children who received a later diagnosis were more likely to present a language impairment, anxiety, and higher cognitive skills. Longitudinal studies, in ethnically diverse populations, are necessary to understand the trajectory and clinical profile of Autism.

Effects from birth brachial plexus injury and postural control.

Of 32 children with birth brachial plexus injury, 31 had postural control deficits, including asymmetrical posture and atypical movements. Management of children with birth brachial plexus injury should address motor development of the entire body, not merely the affected extremity.

Rett syndrome: an eye-tracking study of attention and recognition memory.

AIM: The aim of this study was to examine attention and recognition memory for faces and patterns in Rett syndrome, a severely disabling neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. METHOD: Because Rett syndrome impairs speech and hand use, precluding most neuropsychological testing, the visual paired-comparison paradigm (VPC) was used, together with eye tracking. In the VPC, two identical stimuli are presented for familiarization. On test, the familiar stimulus and a new one are paired, and recognition inferred from preferential looking to the novel target. Attention is measured by looking time, gaze dispersion, and number/length of fixations. Twenty-seven female patients with Rett syndrome (mean age 10y 6mo; SD 6y 8mo, age range 2-22y) from the Rett clinic at a children's hospital were assessed in this study, along with 30 age- and sex-matched typically developing participants (outpatients from the same hospital). RESULTS: Although patients with Rett syndrome showed recognition of both faces and patterns, with novelty scores greater than chance (50%), their performance was significantly poorer than that of the typically developing comparison group. Their attention to both was less mature and marked by a more narrowly focused gaze, with fewer and longer fixations. When inspecting faces, attention to the eyes was similar in both groups; however, patients with Rett syndrome tended to ignore the nose and mouth. INTERPRETATION: This is one of the first studies to characterize attention and memory in individuals with Rett syndrome. Visually based techniques, such as the VPC, open a new avenue for quantifying the cognitive phenotype associated with this syndrome.

Comorbidities in School-Age Children and Adolescents with Autism in an Ethnically Diverse Population: Brief Report.

Objectives: (1) To examine psychiatric and developmental comorbidities in school-age children and adolescents with Autism in a university-affiliated urban developmental center that serves children with developmental disabilities, and (2) to compare comorbidities by age groups. Methods: Review of all school-age children and adolescents evaluated and diagnosed with autism from 1/2019 to 1/2022. Data included: Demographics (age, gender, race/ethnic group, bilingual English/Spanish households) and other developmental and psychiatric diagnoses besides autism, including language disorder, specific learning disorders (LD), attention-deficit/hyperactivity disorder (ADHD), intellectual disabilities (ID), anxiety disorders (i.e., generalized anxiety disorder, anxiety disorder, unspecified, social anxiety disorder), and depressive disorders (i.e., major depressive disorder, depressive disorder, unspecified). Statistics included chi-square, and nonparametric tests, comorbidities were compared between school-age children and adolescents. Results: Of all children evaluated in that period (n = 599), 119 (20%) were diagnosed with autism, 97 (81%) boys, age 11.8 ± 3 years old, 46 (39%) bilingual English/Spanish households; 65 (55%) were school-age children and 54 (45%) were adolescents (age = 12-18). Of the 119, 115 (96%) presented with one or more co-occurring conditions, including language disorder in 101 (85%), LD in 23 (19%), ADHD in 50 (42%), and ID in 30 (25%). Psychiatric co-occurring conditions included anxiety disorders in 24 (20%) and depressive disorders in 8 (6%). School-age children with autism were more likely to be diagnosed with ADHD combined type (42% vs. 22%, p = 0.04) and language disorders (91% vs. 73%, p = 0.04), whereas adolescents with autism were more likely to be diagnosed with depressive disorders (13% vs. 1%, p = 0.03), with no other differences between the groups. Conclusion: In this urban, ethnically diverse group of children with autism, the vast majority presented with one or more comorbid diagnoses. School-age children were more likely to be diagnosed with language disorder and ADHD, while adolescents were more likely to be diagnosed with depression. Early detection and treatment of co-occurring conditions in autism are necessary.

Age at diagnosis of autism spectrum disorders.

Early identification of autism has become a national priority but, despite efforts, there are children who are being identified at a later age. In this study, children of Hispanic and African American origin, foreign-born children, and children born to foreign mothers were more likely to be diagnosed later.

Remote Learning Experience for Children With Developmental Disabilities During COVID-19 Pandemic in an Ethnically Diverse Community.

Owing to the COVID-19 pandemic, K-12 education in New York City quickly transitioned to remote learning. We performed a structured interview with 50 consecutive families of children with developmental disabilities about their experience with remote learning 2 months after COVID-19 lockdown. We observed that setting up the remote learning system was challenging for families who were born outside of the United States, spoke limited English, or had a lower level of education. Though some special education supports were in place, remote learning for children with developmental disabilities led to gaps in their therapeutic services. Children with more severe developmental disabilities joined less than 2 hours of remote learning per day and had a decrease in their therapeutic services. Most children (80%) relied on their parents for education. Additionally, for low-income communities, with families who spoke languages other than English, remote learning revealed a new barrier to access: technology.

Screening for Depression in Adolescents with Developmental Disabilities: Brief Report.

Objectives: (1) To examine adherence of universal screening for adolescent depression at initial visits by using an established screening instrument (Patient Health Questionnaire 9 [PHQ-9]) in a university-affiliated urban developmental center that serves children with developmental disabilities (DDs); (2) to study the frequency of positive screening for depression in adolescents with DD. Methods: Review of all adolescents referred for multidisciplinary evaluation in a developmental center in 2019. Data included demographics, DD diagnoses, and use of and scores on the PHQ-9 at initial visit. Statistics included chi-square and non-parametrics. Results: Of all the children evaluated in 2019 (n = 240), 52 were adolescents, 35 boys (63%)/17 girls (37%), age 14 ± 2 years old, and 27 (54%) belonging to a bilingual English-Spanish household. DD: Developmental Language Disorder (88%), Learning Disabilities (54%), attention-deficit/hyperactivity disorder (44%), Autism Spectrum Disorder (25%), Intellectual Disabilities (12%), and Phonological Disorder (8%). The PHQ-9 was administered to 30 (58%) individuals. Scores varied from minimal depression for 17 (57%), mild for 10 (33%), and moderate and severe for 3 (10%); 3 patients endorsed suicidality. Females were more likely to obtain higher scores on the PHQ-9 than males. Adolescents diagnosed with Autism Spectrum Disorder, Intellectual Disabilities, and Phonological Disorder were less likely to be screened. Conclusion: More than half of the sample of urban adolescents with DD were screened for depression at initial visit, and 10% screened positive for moderate to severe depression. Efforts to follow the U.S. Preventive Services Task Force recommendation of universal screening of adolescent depression should continue. However, given challenges with reading and verbal abilities, screening modifications (reading to them) should be considered.

Social Differences Between Monolingual English and Bilingual English-Spanish Children With Autism Spectrum Disorders.

OBJECTIVE: Bilingualism is increasingly prevalent; however, research in bilingual children with autism is sparse. The purpose of this study was to compare social skills and autistic features in monolingual English and bilingual English-Spanish children with autism spectrum disorder. METHODS: We conducted a review of the multidisciplinary evaluations done in all children aged one to six years diagnosed with autism spectrum disorder in an inner city, university-affiliated clinic from 2003 to 2013. Collected information included demographics, developmental testing, and autistic characteristics. RESULTS: We identified 462 children; 165 were bilingual English-Spanish and 297 were monolingual English. Parents of bilingual children reported stereotyped or repetitive use of language more often (66% vs 48% P = 0.002) than monolinguals. Significant differences were not found in social interaction, use of nonverbal behaviors, peer relationships, sharing or social or emotional reciprocity, mannerisms, or autism severity. CONCLUSIONS: Bilingualism does not seem to confer an extra vulnerability on children with autism spectrum disorder; however, differences in qualitative use of language were observed.

When an Early Diagnosis of Autism Spectrum Disorder Resolves, What Remains?

A chart review was performed of 38 children diagnosed with autism spectrum disorder (ASD) by 3 years of age at an inner-city developmental program who subsequently experienced resolution of ASD symptomatology and no longer met diagnostic criteria for ASD at follow-up an average of 4 years later. Demographic, developmental/cognitive data, Childhood Autism Rating Scale, and Autism Diagnostic Observation Schedule data as available were reviewed from the initial diagnostic evaluation and at the time of follow-up. Services received by the children between the time of diagnosis and follow-up, educational setting at the time of follow-up, and emotional/behavioral and learning diagnoses made by the multidisciplinary team at follow-up were reviewed. The findings indicate that residual emotional/behavioral and learning problems were present at follow-up in the vast majority of children in this group and that the majority continued to require educational support.

Sleep Problems in Children With Autism and Other Developmental Disabilities: A Brief Report.

Sleep problems in children with autism and the association with child behavioral problems was studied in an ethnically diverse population, in a cross-sectional study with structured interview. Sample included 50 families of children with autism and 50 families of children with other developmental disabilities, matched by age/gender. Interview included Child Sleep Habits Questionnaire and Aberrant Behavior Checklist. In this ethnically diverse sample, at least 78% of families of children with autism reported significant sleep problems compared to 34% of families of children with other developmental disabilities. Specifically, children with autism reported more frequent bedtime resistance, sleep anxiety, and night wakings than children with other developmental disabilities. Across groups, sleep problems were related to child behavioral difficulties, including irritability and hyperactivity, although this association did not reach significance for the group with autism. Specifics in terms of the nature of sleep disorders will help our understanding and design of effective treatment options.

Gastrointestinal symptoms in children with an autism spectrum disorder and language regression.

Few studies have compared gastrointestinal problems in children with an autism spectrum disorder with and without a history of language regression. A cross-sectional study was conducted with structured interviews in 100 children with autism spectrum disorder, using a gastrointestinal questionnaire and a familial autoimmune questionnaire. By parental report, children with language regression more frequently exhibited an abnormal stool pattern (40% vs 12%, P = 0.006) and had an increased family history of celiac disease or inflammatory bowel disease (24% vs 0%, P = 0.001) and of rheumatoid arthritis (30% vs 11%, P = 0.03). Among 35 children with a family history of autoimmune disease, an abnormal stool pattern was reported more frequently in those with language regression (78% vs 15%, P = 0.001) than in those without. An association was observed between children with language regression, a family history of autoimmune disease, and gastrointestinal symptoms. Additional studies are needed to examine a possible shared autoimmune process.

Clinical effects and adverse reactions of off-label use of aripiprazole in children and adolescents with developmental disabilities.

OBJECTIVE: The aim of this study was to report on the clinical efficacy and side effects of aripiprazole in treating behavioral symptoms of children with a developmental disability (DDs). DESIGN/METHODS: A retrospective chart review of the first 32 children treated with aripiprazole at an urban clinic for children with DD was conducted. RESULTS: Ages ranged from 5 to 19 years; 9 (28%) were female. Twenty four had diagnoses within the autistic spectrum and 18 had mental retardation (MR). Other disorders included: attention-deficit/hyperactivity disorder/disruptive behavior disorders (n = 13), mood disorders (n = 7), reactive attachment (n = 2), and sleep disorders (n = 2). Target symptoms included aggression, hyperactivity, impulsivity and, self-injurious behaviors. Twenty eight of the children were switched from another antipsychotic. The mean daily aripiprazole starting dose was 7.1 +/- 0.32 mg (0.17 mg/kg/day) and the mean daily maintenance dose was 10.55 +/- 6.9 mg (0.27 mg/kg/day). Aripiprazole had been used for a period between 6 and 15 months. Improvement in target symptoms was found in 56%. When treating a child with MR, the concomitant presence of an autistic spectrum diagnosis predicted a worse outcome. Side effects were reported in 16 (50%), with the most frequent being sleepiness (n = 6). Mean body mass index (BMI) rose from 22.5 to 24.1 (p = 0.003) over the follow up period, with changes in the BMI z scores. These changes were more pronounced in children younger than 12 years. CONCLUSIONS: These results with aripiprazole in this difficult-to-treat population suggest that this medication warrants controlled studies of its effectiveness and safety.

Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease.

This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD.