1. Adirim Z, Sockalingam S, Thakur A. Post-graduate Medical Training in Intellectual and Developmental Disabilities : a Systematic Review. Acad Psychiatry ;2021 (Jan 12)

OBJECTIVE : Despite the increasing number of people with autism-spectrum disorder (ASD), intellectual disabilities (ID), and developmental disabilities (DDs), individuals with these conditions continue to have high levels of unmet physical and mental health needs. Robust training of health professionals can help bridge this gap. A systematic review was conducted to describe the features and educational outcomes of existing postgraduate medical education curricula to inform the development of future training to address the growing unmet care needs of people with intellectual and developmental disabilities (IDD) such as ASD and ID. METHODS : Four major databases were searched for peer-reviewed, English-language research focusing on post-graduate training in IDD education. Educational curricula and outcomes were summarized including Best Evidence in Medical Education (BEME) Quality of Evidence and Kirkpatrick training evaluation model. RESULTS : Sixteen studies were identified with a majority published after 2000 (69%). Pediatric departments were involved in 69%, Psychiatry 19%, Medicine-Pediatrics 19%, and Family Medicine 6.3%. Analysis of Kirkpatrick outcomes showed 31% were level 1 (satisfaction or comfort) ; 38% level 2 (change in objective knowledge or skills) ; 13% level 3 (change in behavior) ; and none at level 4. BEME analysis showed 19% of studies were grade 1 (no clear conclusions), 31% grade 2 (ambiguous results), and half (50%) grade 3 (conclusions can probably be based on findings), with none scoring four or higher. CONCLUSIONS : There is a paucity of objectively evaluated research in the area. Studies reviewed show clear promise for specialized, interdisciplinary, competency-based education which may be foundational for future curriculum development.

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2. Alonso-Gonzalez A, Calaza M, Amigo J, González-Peñas J, Martínez-Regueiro R, Fernández-Prieto M, Parellada M, Arango C, Rodriguez-Fontenla C, Carracedo A. Exploring the biological role of postzygotic and germinal de novo mutations in ASD. Sci Rep ;2021 (Jan 11) ;11(1):319.

De novo mutations (DNMs), including germinal and postzygotic mutations (PZMs), are a strong source of causality for Autism Spectrum Disorder (ASD). However, the biological processes involved behind them remain unexplored. Our aim was to detect DNMs (germinal and PZMs) in a Spanish ASD cohort (360 trios) and to explore their role across different biological hierarchies (gene, biological pathway, cell and brain areas) using bioinformatic approaches. For the majority of the analysis, a combined ASD cohort (N = 2171 trios) was created using previously published data by the Autism Sequencing Consortium (ASC). New plausible candidate genes for ASD such as FMR1 and NFIA were found. In addition, genes harboring PZMs were significantly enriched for miR-137 targets in comparison with germinal DNMs that were enriched in GO terms related to synaptic transmission. The expression pattern of genes with PZMs was restricted to early mid-fetal cortex. In contrast, the analysis of genes with germinal DNMs revealed a spatio-temporal window from early to mid-fetal development stages, with expression in the amygdala, cerebellum, cortex and striatum. These results provide evidence of the pathogenic role of PZMs and suggest the existence of distinct mechanisms between PZMs and germinal DNMs that are influencing ASD risk.

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3. Ayaydın H, Kılıçaslan F, Koyuncu İ, Çelik H, Çalık M, Güzelçiçek A, Kirmit A. Impaired Thiol/Disulfide Homeostasis in Children Diagnosed with Autism : A Case-Control Study. J Mol Neurosci ;2021 (Jan 12)

Although genetic factors occupy an important place in the development of autism spectrum disorder (ASD), oxidative stress and exposure to environmental toxicants have also been linked to the condition. The aim of this study was to examine dynamic thiol/disulfide homeostasis in children diagnosed with ASD. Forty-eight children aged 3-12 years diagnosed with ASD and 40 age- and sex-matched healthy children were included in the study. A sociodemographic data form was completed for all the cases, and the Childhood Autism Rating Scale (CARS) was applied to the patients. Thiol/disulfide parameters in serum were measured in all cases and compared between the two groups. Mean native thiol, total thiol concentrations (μmol/L), and median reduced thiol ratios were significantly lower in the ASD group than in the control group (p = 0.001 for all). Median disulfide concentrations (μmol/L), redox potential, and median oxidized thiol ratios were significantly higher in the ASD group than in the control group (p = 0.001, p = 0.001, and p = 0.001, respectively). ROC analysis revealed that area under the curve (AUC) values with « excellent discriminatory potential, » for native thiol, total thiol, the reduced thiol ration, the oxidized thiol ratio, and redox potential and with « acceptable discriminatory potential » for disulfide were significantly capable of differentiating individuals with ASD from healthy individuals. No correlation was determined between the severity of autism and laboratory parameters. Impaired dynamic thiol/disulfide homeostasis was observed in children with ASD, suggesting that dynamic thiol/disulfide homeostasis in serum may be of diagnostic value in autism.

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4. Bonsall A, Thullen M, Stevenson BL, Sohl K. Parental Feeding Concerns for Children With Autism Spectrum Disorder : A Family-Centered Analysis. OTJR (Thorofare N J) ;2021 (Jan 12):1539449220985906.

This study identifies and describes feeding concerns of parents of children with autism spectrum disorder (ASD) and examines the extent to which parents relate those concerns as having been addressed by therapists. Survey data were collected from 113 parents of children with ASD. Of the parents surveyed, 68% described a past or present concern with feeding ; 60% of those parents with concerns said a therapist had not addressed those concerns. Feeding concerns were more likely addressed when therapists shared parent’s concerns. Specific types of concerns, such as those around food selectivity and food refusal, were more likely addressed than difficulties around mealtime. A gap is identified between parental report of feeding difficulties and parental report of professional services addressing feeding needs. This analysis presents an opportunity for occupational therapists in the area of feeding, particularly around identifying and addressing parental concerns.

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5. Carmona-Serrano N, Moreno-Guerrero AJ, Marín-Marín JA, López-Belmonte J. Evolution of the Autism Literature and the Influence of Parents : A Scientific Mapping in Web of Science. Brain Sci ;2021 (Jan 8) ;11(1)

Parents interventions are relevant to address autism spectrum disorder (ASD). The objective of this study is to analyze the importance and evolution of ASD and its relationship with the parents (ASD-PAR) in the publications indexed in Web of Science. For this, a bibliometric methodology has been used, based on a scientific mapping of the reported documents. We have worked with an analysis unit of 1381 documents. The results show that the beginnings of scientific production date back to 1971. There are two clearly differentiated moments in scientific production. A first moment (1971-2004), where the production volume is low. A second moment (2005-2019), where the volume of production increases considerably. Therefore, it can be said that the subject began to be relevant for the scientific community from 2005 to the present. The keyword match rate between set periods marks a high level of match between periods. It is concluded that the main focus of the research on ASD-PAR is on the stress that is generated in families with children with ASD, in addition to the family problems that the fact that these children also have behavior problems can cause.

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6. Conrad C, Linnea K, Augustyn M. Congenital Blindness and Autism Spectrum Disorder. J Dev Behav Pediatr ;2021 (Jan 7) ;Publish Ahead of Print

Emily is a 10-year-old girl who is in fifth grade. She has known congenital blindness secondary to septo-optic dysplasia with bilateral optic nerve hypoplasia and precocious puberty. Emily was referred to a Developmental-Behavioral Pediatrics clinic for concerns of academic, social, and language challenges.Emily was born at term gestation after an uncomplicated pregnancy. At 4 months of age, she underwent ophthalmologic evaluation because of nystagmus, reduced visual tracking and response to light, and increased startle response to touch. An magnetic resonance imaging of the brain and orbits demonstrated bilateral hypoplastic optic nerves and the absence of posterior pituitary. Subsequent endocrinological evaluation for pituitary function was reassuring. Emily’s early developmental milestones were delayed across all domains. She participated in early intervention programming including speech/language, physical, and occupational therapy with interval improvement in skills. She also received supports for low vision. In the elementary school, she received supports and services for low vision in a general education classroom. It was observed that Emily had reduced interest in her peers, a strong preference for routine, and distinctive play interests. As elementary school progressed, Emily had increasing challenges with academic achievement, despite performing well on formal testing in second grade.At a recent ophthalmology visit, Emily’s best-corrected visual acuity was noted to be 20/800 in each eye.Neuropsychological testing was completed with visual accommodation and administration of measures with minimal visual requirements. Cognitive testing revealed variable verbal intellect and language skills. Academic testing revealed strong reading abilities and a relative weakness in math. Adaptive measures were notable for reduced function and highlighted social vulnerabilities. Parent measures regarding mood and behavior were not concerning.Emily’s speech was noted to have a very distinctive prosody with notable response latency. Echolalia and scripting were appreciated, and Emily often asked about names and used made-up words. When excited, Emily flapped her arms and hands, jumped up and down, or clapped her hands quickly. Socially, Emily was engaged and seemed eager to please. She was able to participate in back-and-forth conversation. Although she often responded to social bids, she frequently directed the conversation to her own areas of interest. Emily looked in the direction of the examiner when talking to the examiner and when the examiner spoke. Although a diagnosis of autism spectrum disorder is under consideration, what special considerations are necessary in the context of congenital blindness ?

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7. Day DB, Collett BR, Barrett ES, Bush NR, Swan SH, Nguyen RHN, Szpiro AA, Sathyanarayana S. Phthalate mixtures in pregnancy, autistic traits, and adverse childhood behavioral outcomes. Environ Int ;2021 (Feb) ;147:106330.

BACKGROUND : Prenatal exposure to multiple phthalates is ubiquitous, and yet few studies have evaluated these exposures as a mixture in relation to child autistic traits and behavioral problems. OBJECTIVES : To assess cumulative associations between prenatal phthalate mixtures and child behaviors, including effect modification by exposure timing and child sex. METHODS : Analyses included 501 mother/child pairs from the multicenter pregnancy cohort The Infant Development and Environment Study (TIDES). Nine maternal urinary phthalate metabolites were measured in early and late pregnancy, and behavior was assessed at ages 4-5 years using composite T scores for the Behavioral Assessment System for Children (BASC-2), which measures several dimensions of child behavior, and the Social Responsiveness Scale (SRS-2), which measures social impairment consistent with autistic traits. We utilized weighted quantile sum (WQS) regressions to examine pregnancy period-specific associations between phthalate mixtures and behavioral outcomes. Full-sample 95% WQS confidence intervals are known to be anti-conservative, so we calculated a confirmatory p-value using a permutation test. Effect modification by sex was examined with stratified analyses. RESULTS : A one-quintile increase in the early pregnancy phthalate mixture was associated with increased SRS-2 total score (coefficient = 1.0, confirmatory p = 0.01) and worse adaptive skills (coefficient = -1.0, confirmatory p = 0.06) in both sexes. In sex-stratified analyses, the early pregnancy phthalate mixture was associated with increased SRS-2 total score in boys (coefficient = 1.2, confirmatory p = 0.04) and girls (coefficient = 1.0, confirmatory p = 0.10) and worse BASC-2 adaptive skills score in girls (coefficient = -1.5, confirmatory p = 0.06), while the late pregnancy phthalate mixture was associated with increased BASC-2 externalizing score in boys (coefficient = 1.3, confirmatory p = 0.03). CONCLUSION : Our results suggest cumulative adverse associations between prenatal phthalate mixtures and multiple facets of childhood behavior.

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8. Eleftheriadou M, Medici-van den Herik E, Stuurman K, van Bever Y, Hellebrekers D, van Slegtenhorst M, Ruijter G, Barakat TS. Isobutyryl-CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing : A case report. Mol Genet Genomic Med ;2021 (Jan 11):e1595.

BACKGROUND : Isobutyryl-CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched-chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl-CoA dehydrogenase deficiency (IBDD), which is identified by increased C4-acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. METHODS : Here, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature. RESULTS : To assess whether a phenotype-genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4-acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these parameters did not establish significant differences amongst both groups. CONCLUSION : As in our proband, trio whole exome sequencing did not establish an alternative secondary genetic diagnosis for autism, and reported long-term follow-up of IBDD patients is limited, it is possible that autism spectrum disorders could be one of the disease-associated features. Further long-term follow-up is suggested in order to delineate the full clinical spectrum associated with IBDD.

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9. Greene SM, Sanchez YR, Pathapati N, Davis GN, Gould GG. Assessment of autism-relevant behaviors in C57BKS/J leptin receptor deficient mice. Horm Behav ;2021 (Jan 20) ;129:104919.

Gestational diabetes mellitus (GDM) was associated with greater autism risk in epidemiological studies. Disrupted leptin signaling may contribute to their coincidence, as it is found in both disorders. Given this we examined leptin receptor (Lepr) deficient (BKS.Cg-Dock7(m) +/+ Lepr(db)/J diabetic (db)) heterozygous (db/+) mice for autism-relevant behaviors. BKS db/+ females are lean with normal blood glucose, but they develop GDM while pregnant. We hypothesized BKS db/+ offspring might exhibit physiological and behavior traits consistent with autism. Adolescent body weight, fasting blood glucose, serum corticosterone, social preferences, self-grooming, marble burying, social dominance and cognitive flexibility of BKS db/+ mice was compared to C57BLKS/J (BKS) and C57BL/6J (BL6) mice. Male db/+ weighed more and had higher blood glucose and corticosterone relative to BL6, but not BKS mice. Also, male db/+ lacked social interaction preference, explored arenas less, and buried more marbles than BL6, but not BKS males. Male and female db/+ were more dominant and made more mistakes in water T-mazes locating a sunken platform after its position was reversed than BL6, but not BKS mice. Overall BKS db/+, particularly males, exhibited some autism-like social deficits and restrictive-repetitive behaviors relative to BL6, but BKS strain contributions to BKS db/+ behaviors were evident. Since BKS db/+ and BKS behavioral and physiological phenotypes are already so similar, it will be difficult to use these models in studies designed to detect contributions of fetal GDM exposures to offspring behaviors.

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10. Hashimoto K, Hammock BD. Reply to Reeves and Dunn : Risk for autism in offspring after maternal glyphosate exposure. Proc Natl Acad Sci U S A ;2021 (Jan 12) ;118(2)

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11. Jan TY, Wong LC, Yang MT, Huang CJ, Hsu CJ, Peng SS, Tseng WI, Lee WT. Correlation of dystonia severity and iron accumulation in Rett syndrome. Sci Rep ;2021 (Jan 12) ;11(1):838.

Individuals with Rett syndrome (RTT) commonly demonstrate Parkinsonian features and dystonia at teen age ; however, the pathological reason remains unclear. Abnormal iron accumulation in deep gray matter were reported in some Parkinsonian-related disorders. In this study, we investigated the iron accumulation in deep gray matter of RTT and its correlation with dystonia severity. We recruited 18 RTT-diagnosed participants with MECP2 mutations, from age 4 to 28, and 28 age-gender matched controls and investigated the iron accumulation by susceptibility weighted image (SWI) in substantia nigra (SN), globus pallidus (GP), putamen, caudate nucleus, and thalamus. Pearson’s correlation was applied for the relation between iron accumulation and dystonia severity. In RTT, the severity of dystonia scales showed significant increase in subjects older than 10 years, and the contrast ratios of SWI also showed significant differences in putamen, caudate nucleus and the average values of SN, putamen, and GP between RTT and controls. The age demonstrated moderate to high negative correlations with contrast ratios. The dystonia scales were correlated with the average contrast ratio of SN, putamen and GP, indicating iron accumulation in dopaminergic system and related grey matter. As the first SWI study for RTT individuals, we found increased iron deposition in dopaminergic system and related grey matter, which may partly explain the gradually increased dystonia.

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12. Kõlves K, Fitzgerald C, Nordentoft M, Wood SJ, Erlangsen A. Assessment of Suicidal Behaviors Among Individuals With Autism Spectrum Disorder in Denmark. JAMA Netw Open ;2021 (Jan 4) ;4(1):e2033565.

IMPORTANCE : There is limited evidence supporting an association of autism spectrum disorder (ASD) with suicidality and the risk factors for suicide attempt and suicide among people with ASD. Existing research highlights the need for national cohort studies. OBJECTIVES : To analyze whether people with ASD have higher rates of suicide attempt and suicide compared with people without ASD using national register data, identify potential risk factors for suicide attempt and suicide among those with ASD, and examine associations with comorbid disorders. DESIGN, SETTING, AND PARTICIPANTS : In this cohort study, nationwide register data from January 1, 1995, to December 31, 2016, were gathered on 6 559 266 individuals in Denmark aged 10 years or older. Statistical analysis was performed from November 20, 2018, to November 21, 2020. MAIN OUTCOMES AND MEASURES : Rates of suicide attempt and suicide among persons with ASD were compared with rates among persons without ASD, using Poisson regression models to calculate incidence rate ratios adjusted for sex, age, and time period. RESULTS : Of the total study population of 6 559 266 individuals, 35 020 individuals (25 718 male [73.4%] ; mean [SD] age at diagnosis, 13.4 [9.3] years) received a diagnosis of ASD. A total of 64 109 incidents of suicide attempts (587 [0.9%] among individuals with ASD) and 14 197 suicides (53 [0.4%] among individuals with ASD) were recorded. Persons with ASD had a more than 3-fold higher rate of suicide attempt (adjusted incidence rate ratio [aIRR], 3.19 ; 95% CI, 2.93-3.46) and suicide (aIRR, 3.75 ; 95% CI, 2.85-4.92) than those without ASD. For individuals with ASD, the aIRR for suicide attempt among female individuals was 4.41-fold (95% CI, 3.74-5.19) higher compared with male individuals ; for individuals without ASD, the aIRR for female individuals was 1.41-fold (95% CI, 1.39-1.43) higher compared with male individuals. Higher rates of suicide attempt were noted across all age groups for those with ASD. Persons with a diagnosis of ASD only had an aIRR of 1.33 (95% CI, 0.99-1.78) for suicide attempt, whereas those with other comorbid disorders had an aIRR of 9.27 (95% CI, 8.51-10.10) for suicide attempt compared with those without any psychiatric disorders. A total of 542 of 587 individuals with ASD (92.3%) who attempted suicide had at least 1 other comorbid condition and 48 of 53 individuals with ASD (90.6%) who died by suicide had at least 1 other comorbid condition. CONCLUSIONS AND RELEVANCE : This nationwide retrospective cohort study found a higher rate of suicide attempt and suicide among persons with ASD. Psychiatric comorbidity was found to be a major risk factor, with more than 90% of those with ASD who attempted or died by suicide having another comorbid condition. Several risk factors are different from the risk factors in the general population, which suggests the need for tailored suicide prevention strategies.

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13. Lin IF, Itahashi T, Kashino M, Kato N, Hashimoto RI. Brain activations while processing degraded speech in adults with autism spectrum disorder. Neuropsychologia ;2021 (Jan 5) ;152:107750.

Individuals with autism spectrum disorder (ASD) are found to have difficulties in understanding speech in adverse conditions. In this study, we used noise-vocoded speech (VS) to investigate neural processing of degraded speech in individuals with ASD. We ran fMRI experiments in the ASD group and a typically developed control (TDC) group while they listened to clear speech (CS), VS, and spectrally rotated VS (SRVS), and they were requested to pay attention to the heard sentence and answer whether it was intelligible or not. The VS used in this experiment was spectrally degraded but still intelligible, but the SRVS was unintelligible. We recruited 21 right-handed adult males with ASD and 24 age-matched and right-handed male TDC participants for this experiment. Compared with the TDC group, we observed reduced functional connectivity (FC) between the left dorsal premotor cortex and left temporoparietal junction in the ASD group for the effect of task difficulty in speech processing, computed as VS-(CS + SRVS)/2. Furthermore, the observed reduced FC was negatively correlated with their Autism-Spectrum Quotient scores. This observation supports our hypothesis that the disrupted dorsal stream for attentive process of degraded speech in individuals with ASD might be related to their difficulty in understanding speech in adverse conditions.

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14. Mitchell RA, Barton SM, Harvey AS, Ure AM, Williams K. Factors associated with autism spectrum disorder in children with tuberous sclerosis complex : a systematic review and meta-analysis. Dev Med Child Neurol ;2021 (Jan 11)

AIM : To investigate associations between clinical factors and the development of autism spectrum disorder (ASD) in children with tuberous sclerosis complex (TSC), specifically seizures, electroencephalogram abnormalities, tubers and other neurostructural abnormalities, and genetic factors. METHOD : MEDLINE, Embase, PubMed, the Cochrane Library, and Web of Science were searched until January 2019. Studies that considered the predefined factors for development of ASD in children with TSC were included, following PRISMA-P guidelines. Two authors independently reviewed titles, abstracts, and full texts, extracted data, and assessed risk of bias. RESULTS : Forty-two studies with 3542 children with TSC were included. ASD was associated with a history of seizures (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.77-8.14), infantile spasms compared with other seizure types (OR 3.04, 95% CI 2.17-4.27), onset of any seizure type during infancy (OR 2.65, 95% CI 1.08-6.54), and male sex (OR 1.62, 95% CI 1.23-2.14). There was no association with tuber number, tuber location, or genotype. INTERPRETATION : While a causal link between seizures and ASD in children with TSC cannot be inferred, a strong association between seizures and ASD in children with TSC, particularly with seizure onset during infancy and specifically infantile spasms, is present. Children with TSC and infant-onset seizures should be monitored for emerging features of ASD.

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15. Mumbardó-Adam C, Barnet-López S, Balboni G. How have youth with Autism Spectrum Disorder managed quarantine derived from COVID-19 pandemic ? An approach to families perspectives. Res Dev Disabil ;2021 (Jan 12) ;110:103860.

Quarantine derived from COVID-19 pandemic has challenged children and adolescents with Autism Spectrum Disorder (ASD) and their families daily life and routines. Because of these children unique needs related to manage uncertainty and overcoming situations, an in-depth approach to how they navigated through quarantine urged to better comprehend their current support needs. Forty-seven families with a child with ASD ranging in age between 2 and 17 years old (M = 7.3, SD = 3.4) from the north of Spain responded to an online developed questionnaire on different aspects of their daily life management of quarantine. Most of the families stressed that their offspring better drove quarantine than expected. Some families reported that youth participated more often in families’ routines and were more communicative with their parents. Families, beyond some difficulties aroused, had more time to qualitatively spend with their children to teach new skills as autonomy or house care related skills. Families also developed new strategies to manage quarantine, such as structuring their days, using visual supports or new technologies for learning or leisure, and found more useful in this effort their family cohesion, online contact with relatives, and having online psychological supports.

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16. Pejhan S, Rastegar M. Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease. Biomolecules ;2021 (Jan 8) ;11(1)

Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry de novo mutation(s) in the Methyl-CpG-Binding Protein 2 (MECP2) gene. While the majority of RTT patients have MECP2 mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (miR132) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the MECP2 gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and miR132.

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17. Pekkoc Uyanik KC, Kalayci Yigin A, Dogangun B, Seven M. Evaluation of IL1B rs1143634 and IL6 rs1800796 Polymorphisms with Autism Spectrum Disorder in the Turkish Children. Immunol Invest ;2021 (Jan 12):1-12.

Background : Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder caused by genetic, environmental and immunological factors. It is known that neural development processes are affected by immune functions. The aim of this study is to evaluate the relationship between cytokines IL6 and IL1B gene polymorphisms in ASD. Methods : DNA isolations were performed in 95 children diagnosed with ASD and 84 unrelated healthy children, single-nucleotide changes in IL6 (rs1800796) and IL1B (rs1143634) genes were determined by using Real-Time PCR (Real-Time Polymerase Chain Reaction) method. Results : IL6 rs1800796 polymorphism presented an elevated risk for the development of ASD with CG genotype and dominant model (CG+GG vs. CC), CG+GG carriers (OR = 1.867, p = 0.057 ; OR = 1.847, p = 0.055, respectively). CT genotype in IL1B rs1143634 polymorphism associated with 2.33 times elevated risk of autism and showed a significant association compared to wild-type CC genotype (p = 0.02). IL1B rs1143634 polymorphism presented a significantly elevated risk for the development of ASD with recessive model (CC+CT vs.TT), TT genotype (OR = 8.145, p = 0.02). Conclusion : This study concludes that rs1143634 is associated with the risk of ASD in Turkish children. Determining these polymorphisms in a larger sample group may contribute to understanding the etiology of ASD and developing new treatment protocols. Abbreviations : ASD : Autism spectrum disorder ; DNA : Deoxyribonucleic acid ; IL6 : Interleukin 6 ; IL1B : Interleukin 1 beta ; Real-time PCR : Real-time polymerase chain reaction ; JAK-STAT : The Janus kinase/signal transducers and activators of transcription ; MAPK : The mitogen-activated protein kinase ; 5’UTR : The 5′ untranslated region ; IL1α : Interleukin 1 alpha ; IL-1Ra : Interleukin 1 receptor antagonist ; NF-κB : Nuclear factor-kappa B ; DSM-V : The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ; M-CHAT : Modified Checklist for Autism in Toddlers ; EDTA : Ethylenediaminetetraacetic acid ; gDNA : Genomic DNA ; HWE : Hardy-Weinberg equilibrium ; ANK2 : Ankyrin 2 ; NL3 : Neuroligin-3 ; XRCC4 : X-ray repair cross complementing 4.

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18. Rodin RE, Dou Y, Kwon M, Sherman MA, D’Gama AM, Doan RN, Rento LM, Girskis KM, Bohrson CL, Kim SN, Nadig A, Luquette LJ, Gulhan DC, Park PJ, Walsh CA. The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing. Nat Neurosci ;2021 (Jan 11)

We characterize the landscape of somatic mutations-mutations occurring after fertilization-in the human brain using ultra-deep ( 250×) whole-genome sequencing of prefrontal cortex from 59 donors with autism spectrum disorder (ASD) and 15 control donors. We observe a mean of 26 somatic single-nucleotide variants per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces 3.4 mutations, followed by 2-3 mutations in subsequent generations. This suggests that a typical individual possesses 80 somatic single-nucleotide variants present in ≥2% of cells-comparable to the number of de novo germline mutations per generation-with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. ASD brains show an excess of somatic mutations in neural enhancer sequences compared with controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.

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19. Sherman MA, Rodin RE, Genovese G, Dias C, Barton AR, Mukamel RE, Berger B, Park PJ, Walsh CA, Loh PR. Large mosaic copy number variations confer autism risk. Nat Neurosci ;2021 (Jan 11)

Although germline de novo copy number variants (CNVs) are known causes of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. In this study, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 probands with ASD and 5,500 unaffected siblings. We detected 46 mCNVs in probands and 19 mCNVs in siblings, affecting 2.8-73.8% of cells. Probands carried a significant burden of large (>4-Mb) mCNVs, which were detected in 25 probands but only one sibling (odds ratio = 11.4, 95% confidence interval = 1.5-84.2, P = 7.4 × 10(-4)). Event size positively correlated with severity of ASD symptoms (P = 0.016). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD (eg, 16p11.2). We further experimentally validated two mCNVs in postmortem brain tissue from 59 additional probands. These results indicate that mCNVs contribute a previously unexplained component of ASD risk.

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20. South M, Costa AP, McMorris C. Death by Suicide Among People With Autism : Beyond Zebrafish. JAMA Netw Open ;2021 (Jan 4) ;4(1):e2034018.

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21. Tateno Y, Kumagai K, Monden R, Nanba K, Yano A, Shiraishi E, Teo AR, Tateno M. The Efficacy of Early Start Denver Model Intervention in Young Children with Autism Spectrum Disorder Within Japan : A Preliminary Study. Soa Chongsonyon Chongsin Uihak ;2021 (Jan 1) ;32(1):35-40.

OBJECTIVES : Among the many intervention programs for children with autism spectrum disorder (ASD), the Early Start Denver Model (ESDM) is one of the few approaches that has succeeded in demonstrating clinical efficacy in randomized control trials. Here, we inves-tigate the clinical efficacy of ESDM intervention in young children with ASD in a community setting within Japan. METHODS : All subjects were children with ASD who received ESDM intervention during the study period. Each ESDM session lasted 75 min and occurred once per week for at least 12 weeks. The outcome measures consisted of the Kyoto Scale of Psychological Develop-ment (K-test), Aberrant Behavior Checklist-Japanese version (ABC-J), and the Clinical Global Impression-Severity scale (CGI-S). RESULTS : Twenty-seven subjects (29.4±6.4 months old) received ESDM intervention that lasted for 8.0±2.6 months on average. The score on Language and Social developmental quotient on the K-test increased significantly after the intervention. The total scores on the ABC-J and CGI-S significantly decreased after completion of the ESDM intervention. CONCLUSION : Our results suggest that ESDM intervention could reduce the severity of distinct clinical features of ASD, such as impair-ments in social interaction and communication assessed by the K-test, and maladaptive behavior rated by the ABC-J and CGI-S. We be-lieve that the ESDM adapted to each institution might become one of the standard options for children with ASD in Japan.

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22. Tokatly Latzer I, Leitner Y, Karnieli-Miller O. Core experiences of parents of children with autism during the COVID-19 pandemic lockdown. Autism ;2021 (Jan 12):1362361320984317.

The lockdown and home isolation due to the COVID-19 pandemic led to significant transformation in lifestyles. Being a parent in this situation was not easy for anyone, much less for parents of children with special needs. The shutting down of special education systems meant that parents lost a vital support network and had to be the sole full-time caregivers despite often lacking the skills to cope with this new and daunting situation. We interviewed parents and learned that the main difficulties faced by homebound autistic children stemmed from the change in routine, lack of special education services, limited physical space, and food- and sleep-related issues. Some children experienced worsening in behavioral, social, and developmental domains, yet others seemed to not only overcome the challenges of changing conditions but even benefit from them. The children’s success or failure was directly related to how their parents coped. The key factors that enabled successful coping were the parents’ ability to accommodate to the child’s needs, their own creativeness and resourcefulness, and a generally positive outlook. The results of this analysis revealed that the best way to benefit autistic children caught up in drastic changes in their routine lifestyle is to invest in a strong support system for their parents.

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23. Win-Shwe TT, Kyi-Tha-Thu C, Fujitani Y, Tsukahara S, Hirano S. Perinatal Exposure to Diesel Exhaust-Origin Secondary Organic Aerosol Induces Autism-Like Behavior in Rats. Int J Mol Sci ;2021 (Jan 7) ;22(2)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication, poor social interactions, and repetitive behaviors. We aimed to examine autism-like behaviors and related gene expressions in rats exposed to diesel exhaust (DE)-origin secondary organic aerosol (DE-SOA) perinatally. Sprague-Dawley pregnant rats were exposed to clean air (control), DE, and DE-SOA in the exposure chamber from gestational day 14 to postnatal day 21. Behavioral phenotypes of ASD were investigated in 10 13-week-old offspring using a three-chambered social behavior test, social dominance tube test, and marble burying test. Prefrontal cortex was collected to examine molecular analyses including neurological and immunological markers and glutamate concentration, using RT-PCR and ELISA methods. DE-SOA-exposed male and female rats showed poor sociability and social novelty preference, socially dominant behavior, and increased repetitive behavior. Serotonin receptor (5-HT(5B)) and brain-derived neurotrophic factor (BDNF) mRNAs were downregulated whereas interleukin 1 β (IL-β) and heme oxygenase 1 (HO-1) mRNAs were upregulated in the prefrontal cortex of male and female rats exposed to DE-SOA. Glutamate concentration was also increased significantly in DE-SOA-exposed male and female rats. Our results indicate that perinatal exposure to DE-SOA may induce autism-like behavior by modulating molecules such as neurological and immunological markers in rats.

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24. Yue F, Deng S, Xi Q, Jiang Y, He J, Zhang H, Liu R. Prenatal detection of a 3q29 microdeletion in a fetus with ventricular septum defect : A case report and literature review. Medicine (Baltimore) ;2021 (Jan 8) ;100(1):e24224.

RATIONALE : Chromosomal 3q deletion is a recurrent genomic alternation, which is rarely reported in clinic. PATIENT CONCERNS : A 27-year-old woman underwent amniocentesis for cytogenetic analysis and single nucleotide polymorphism (SNP) array analysis at 27 weeks of gestation, due to ventricular septum defect in prenatal ultrasound findings. DIAGNOSES : G-banding analysis showed the karyotype of the fetus was normal and the couple also had normal karyotypes. However, SNP array detected a 1.71 Mb microdelection in 3q29, which was described as arr[hg19]3q29(194184392-195887205) × 1. There are 12 genes located in this locus. INTERVENTIONS : The couple refused SNP array to testify the 3q29 microdeletion was inherited or de novo and they chose termination of pregnancy. OUTCOMES : The deleted region in the fetus overlapped with part 3q29 microdeletion syndrome, which was characterized by learning disability, speech delay, mental deficiency, ocular abnormalities and craniofacial features. In addition, no similar/overlapping 3q29 microdeletion cases were reported according to the published literature and database. LESSONS : For the chromosomal microscopic imbalances partially overlapping with the defined pathogenic syndrome, deleted/duplicated size, genetic materials and phenotypic diversity should be taken into consideration when genetic counseling is offered by the clinicians.

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25. Zhang Y, Tian Y, Wu P, Chen D. Application of Skeleton Data and Long Short-Term Memory in Action Recognition of Children with Autism Spectrum Disorder. Sensors (Basel) ;2021 (Jan 8) ;21(2)

The recognition of stereotyped action is one of the core diagnostic criteria of Autism Spectrum Disorder (ASD). However, it mainly relies on parent interviews and clinical observations, which lead to a long diagnosis cycle and prevents the ASD children from timely treatment. To speed up the recognition process of stereotyped actions, a method based on skeleton data and Long Short-Term Memory (LSTM) is proposed in this paper. In the first stage of our method, the OpenPose algorithm is used to obtain the initial skeleton data from the video of ASD children. Furthermore, four denoising methods are proposed to eliminate the noise of the initial skeleton data. In the second stage, we track multiple ASD children in the same scene by matching distance between current skeletons and previous skeletons. In the last stage, the neural network based on LSTM is proposed to classify the ASD children’s actions. The performed experiments show that our proposed method is effective for ASD children’s action recognition. Compared to the previous traditional schemes, our scheme has higher accuracy and is almost non-invasive for ASD children.

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26. Zheng ZK, Staubitz JE, Weitlauf AS, Staubitz J, Pollack M, Shibley L, Hopton M, Martin W, Swanson A, Juárez P, Warren ZE, Sarkar N. A Predictive Multimodal Framework to Alert Caregivers of Problem Behaviors for Children with ASD (PreMAC). Sensors (Basel) ;2021 (Jan 7) ;21(2)

Autism Spectrum Disorder (ASD) impacts 1 in 54 children in the US. Two-thirds of children with ASD display problem behavior. If a caregiver can predict that a child is likely to engage in problem behavior, they may be able to take action to minimize that risk. Although experts in Applied Behavior Analysis can offer caregivers recognition and remediation strategies, there are limitations to the extent to which human prediction of problem behavior is possible without the assistance of technology. In this paper, we propose a machine learning-based predictive framework, PreMAC, that uses multimodal signals from precursors of problem behaviors to alert caregivers of impending problem behavior for children with ASD. A multimodal data capture platform, M2P3, was designed to collect multimodal training data for PreMAC. The development of PreMAC integrated a rapid functional analysis, the interview-informed synthesized contingency analysis (IISCA), for collection of training data. A feasibility study with seven 4 to 15-year-old children with ASD was conducted to investigate the tolerability and feasibility of the M2P3 platform and the accuracy of PreMAC. Results indicate that the M2P3 platform was well tolerated by the children and PreMAC could predict precursors of problem behaviors with high prediction accuracies.

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27. Zürcher NR, Walsh EC, Phillips RD, Cernasov PM, Tseng CJ, Dharanikota A, Smith E, Li Z, Kinard JL, Bizzell JC, Greene RK, Dillon D, Pizzagalli DA, Izquierdo-Garcia D, Truong K, Lalush D, Hooker JM, Dichter GS. A simultaneous [(11)C]raclopride positron emission tomography and functional magnetic resonance imaging investigation of striatal dopamine binding in autism. Transl Psychiatry ;2021 (Jan 11) ;11(1):33.

The social motivation hypothesis of autism posits that autism spectrum disorder (ASD) is characterized by impaired motivation to seek out social experience early in life that interferes with the development of social functioning. This framework suggests that impaired mesolimbic dopamine function underlies compromised responses to social rewards in ASD. Although this hypothesis is supported by functional magnetic resonance imaging (fMRI) studies, no molecular imaging study has evaluated striatal dopamine functioning in response to rewards in ASD. Here, we examined striatal functioning during monetary incentive processing in ASD and controls using simultaneous positron emission tomography (PET) and fMRI. Using a bolus + infusion protocol with the D2/D3 dopamine receptor antagonist [(11)C]raclopride, voxel-wise binding potential (BP(ND)) was compared between groups (controls = 12, ASD = 10) in the striatum. Striatal clusters showing significant between-group BP(ND) differences were used as seeds in whole-brain fMRI general functional connectivity analyses. Relative to controls, the ASD group demonstrated decreased phasic dopamine release to incentives in the bilateral putamen and left caudate, as well as increased functional connectivity between a PET-derived right putamen seed and the precuneus and insula. Within the ASD group, decreased phasic dopamine release in the putamen was related to poorer theory-of-mind skills. Our findings that ASD is characterized by impaired striatal phasic dopamine release to incentives provide support for the social motivation hypothesis of autism. PET-fMRI may be a suitable tool to evaluate novel ASD therapeutics targeting the striatal dopamine system.

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