1. Alampi JD, Lanphear BP, Braun JM, Chen A, Takaro TK, Muckle G, Arbuckle TE, McCandless LC. Association Between Gestational Exposure to Toxicants and Autistic Behaviors Using Bayesian Quantile Regression. American journal of epidemiology. 2021; 190(9): 1803-13.

Autism spectrum disorder, which is characterized by impaired social communication and stereotypic behaviors, affects 1%-2% of children. Although prenatal exposure to toxicants has been associated with autistic behaviors, most studies have been focused on shifts in mean behavior scores. We used Bayesian quantile regression to assess the associations between log2-transformed toxicant concentrations and autistic behaviors across the distribution of behaviors. We used data from the Maternal-Infant Research on Environmental Chemicals study, a pan-Canadian cohort (2008-2011). We measured metal, pesticide, polychlorinated biphenyl, phthalate, bisphenol-A, and triclosan concentrations in blood or urine samples collected during the first trimester of pregnancy. Using the Social Responsiveness Scale (SRS), in which higher scores denote more autistic-like behaviors, autistic behaviors were assessed in 478 children aged 3-4 years old. Lead, cadmium, and most phthalate metabolites were associated with mild increases in SRS scores at the 90th percentile of the SRS distribution. Manganese and some pesticides were associated with mild decreases in SRS scores at the 90th percentile of the SRS distribution. We identified several monotonic trends in which associations increased in magnitude from the bottom to the top of the SRS distribution. These results suggest that quantile regression can reveal nuanced relationships and, thus, should be more widely used by epidemiologists.

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2. Brandsma AE, van der Doelen RHA, Ester WA. [Hyperprolactinemia and antipsychotics: it’s not always what it seems to be]. Tijdschrift voor psychiatrie. 2021; 63(3): 209-14.

Hyperprolactinemia is a relatively frequent laboratory abnormality (30-80%) as a result of antipsychotics and a reason to reduce or stop them. We describe two youngsters with autism spectrum disorder whose hyperprolactinemia was based on a false-positive laboratory finding due to macroprolactin. The consequences were: unnecessary endocrinological evaluation including a brain MRI, and undesirable antipsychotic dose reduction. Thus, hyperprolactinemia can be due to a falsely elevated prolactin concentration. There should be an addition to the current guidelines in which a work-up for macroprolactin screening is included.

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3. Coulter KL, Barton ML, Robins DL, Stone WL, Fein DA. DSM-5 symptom expression in toddlers. Autism : the international journal of research and practice. 2021; 25(6): 1653-65.

Children with autism show more social-communication symptoms and repetitive behaviors than children with typical development or those diagnosed with other developmental disorders; however, non-autistic children often show some behaviors that are associated with autism. We compared the behavioral reports from caregivers of children in these three groups to identify the behaviors that were specific to autism. Children with autism were found to show more of these behaviors, and behaviors that are particularly indicative of autism were identified. These behaviors included social symptoms (approaching others to interact, showing things, looking back while showing, responding to an approaching child, spontaneous imitation) and repetitive behavior symptoms (specific, inflexible play, unusual body movements, strong specific interest, carrying around an unusual object, sensory seeking, and sensory hyper-reactivity).These findings may aid professionals in determining the most appropriate diagnosis for a child between the ages of 12 and 36 months.

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4. De Ridder J, Verhelle B, Vervisch J, Lemmens K, Kotulska K, Moavero R, Curatolo P, Weschke B, Riney K, Feucht M, Krsek P, Nabbout R, Jansen AC, Wojdan K, Domanska-Pakieła D, Kaczorowska-Frontczak M, Hertzberg C, Ferrier CH, Samueli S, Benova B, Aronica E, Kwiatkowski DJ, Jansen FE, Jóźwiak S, Lagae L. Early epileptiform EEG activity in infants with tuberous sclerosis complex predicts epilepsy and neurodevelopmental outcomes. Epilepsia. 2021; 62(5): 1208-19.

OBJECTIVE: To study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED-EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC). METHODS: Patients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy – Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24 months. The timing and characteristics of the first ED-EEG were studied in relation to clinical outcome. Epilepsy-related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]). RESULTS: Eighty-three infants with TSC were enrolled at a median age of 28 days (interquartile range [IQR] 14-54). Seventy-nine of 83 patients (95%) developed epileptiform discharges at a median age of 77 days (IQR 23-111). Patients with a pathogenic TSC2 variant were significantly younger (P-value .009) at first ED-EEG and more frequently had multifocal IED (P-value .042) than patients with a pathogenic TSC1 variant. A younger age at first ED-EEG was significantly associated with lower cognitive (P-value .010), language (P-value .001), and motor (P-value .013) developmental quotients at 24 months. In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED-EEG was predictive of earlier seizure onset (P-value .030). Earlier recording of epileptiform discharges (P-value .019), especially when multifocal (P-value .026) was associated with higher risk of drug-resistant epilepsy. In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED-EEG, preventive treatment delayed the onset of seizures significantly (P-value <.001). SIGNIFICANCE: Early EEG findings help to identify TSC infants at risk of severe epilepsy and neurodevelopmental delay and those who may benefit from preventive treatment with vigabatrin.

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5. Derguy C, Aubé B, Rohmer O, Marotta F, Loyal D. Another step to school inclusion: Development and validation of the Children’s Attitudes Toward Autism Questionnaire. Autism : the international journal of research and practice. 2021; 25(6): 1666-81.

Research has shown that negative attitudes toward a different child can appear very early in development. Unfortunately, these negative attitudes are one of the most important barriers to the school inclusion of children with autism. Despite the increasing amount of research, no tool reliably measures these attitudes among young students. The objective of this study was to develop and validate a questionnaire (Children’s Attitudes Toward Autism Questionnaire) to evaluate attitudes of students in elementary school toward their peers with autism. Elementary school students (N = 204) completed the Children’s Attitudes Toward Autism Questionnaire and two other scales assessing behavioral intentions toward peers with a mental disability (Shared Activities Questionnaire-B) and familiarity with disability and autism. Results first showed that the Children’s Attitudes Toward Autism Questionnaire reliably measured the concept of attitude through three sub-dimensions (namely, the cognitive, affective, and behavioral dimensions). Second, analyses confirmed that the Children’s Attitudes Toward Autism Questionnaire corresponds with previous knowledge on this topic, namely, that attitudes were more positive in girls, older children, and children familiar with disability. In conclusion, the Children’s Attitudes Toward Autism Questionnaire is the first scale (1) to assess all the dimensions of attitudes toward autism among elementary school children (from the age of 6 years old) and (2) to show theoretical and statistical relevance. From now on, the Children’s Attitudes Toward Autism Questionnaire can be used to assess attitudes of young children toward their peers with autism. This is an important step forward, in particular for evaluating the effects of anti-stigma programs that are increasingly implemented in schools.

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6. Di Marco B, Dell’Albani P, D’Antoni S, Spatuzza M, Bonaccorso CM, Musumeci SA, Drago F, Bardoni B, Catania MV. Fragile X mental retardation protein (FMRP) and metabotropic glutamate receptor subtype 5 (mGlu5) control stress granule formation in astrocytes. Neurobiology of disease. 2021; 154: 105338.

Fragile X syndrome (FXS) is a common form of intellectual disability and autism caused by the lack of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA transport and protein synthesis. Upon cellular stress, global protein synthesis is blocked and mRNAs are recruited into stress granules (SGs), together with RNA-binding proteins including FMRP. Activation of group-I metabotropic glutamate (mGlu) receptors stimulates FMRP-mediated mRNA transport and protein synthesis, but their role in SGs formation is unexplored. To this aim, we pre-treated wild type (WT) and Fmr1 knockout (KO) cultured astrocytes with the group-I-mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) and exposed them to sodium arsenite (NaAsO(2)), a widely used inducer of SGs formation. In WT cultures the activation of group-I mGlu receptors reduced SGs formation and recruitment of FMRP into SGs, and also attenuated phosphorylation of eIF2α, a key event crucially involved in SGs formation and inhibition of protein synthesis. In contrast, Fmr1 KO astrocytes, which exhibited a lower number of SGs than WT astrocytes, did not respond to agonist stimulation. Interestingly, the mGlu5 receptor negative allosteric modulator (NAM) 2-methyl-6-(phenylethynyl)pyridine (MPEP) antagonized DHPG-mediated SGs reduction in WT and reversed SGs formation in Fmr1 KO cultures. Our findings reveal a novel function of mGlu5 receptor as modulator of SGs formation and open new perspectives for understanding cellular response to stress in FXS pathophysiology.

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7. Doucette LP, Noel NCL, Zhai Y, Xu M, Caluseriu O, Hoang SC, Radziwon AJ, MacDonald IM. Whole exome sequencing reveals putatively novel associations in retinopathies and drusen formation. European journal of human genetics : EJHG. 2021; 29(8): 1171-85.

Inherited retinal dystrophies (IRDs) affect 1 in 3000 individuals worldwide and are genetically heterogeneous, with over 270 identified genes and loci; however, there are still many identified disorders with no current genetic etiology. Whole exome sequencing (WES) provides a hypothesis-free first examination of IRD patients in either a clinical or research setting to identify the genetic cause of disease. We present a study of IRD in ten families from Alberta, Canada, through the lens of novel gene discovery. We identify the genetic etiology of IRDs in three of the families to be variants in known disease-associated genes, previously missed by clinical investigations. In addition, we identify two potentially novel associations: LRP1 in early-onset drusen formation and UBE2U in a multi-system condition presenting with retinoschisis, cataracts, learning disabilities, and developmental delay. We also describe interesting results in our unsolved cases to provide further information to other investigators of these blinding conditions.

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8. Hashimoto T, Yokota S, Matsuzaki Y, Kawashima R. Intrinsic hippocampal functional connectivity underlying rigid memory in children and adolescents with autism spectrum disorder: A case-control study. Autism : the international journal of research and practice. 2021; 25(7): 1901-12.

Atypical learning and memory in early life can promote atypical behaviors in later life. Specifically, less relational learning and inflexible retrieval in childhood may enhance restricted and repeated behaviors in patients with autism spectrum disorder. The purpose of this study was to elucidate the mechanisms of atypical memory in children with autism spectrum disorder. We conducted picture-name pair learning and delayed-recognition tests with two groups of youths: one group with high-functioning autism spectrum disorder children (aged 7-16, n = 41) and one group with typically developing children (n = 82) that matched the first group’s age, sex, and full-scale IQ. We examined correlations between successful recognition scores and neural connectivity during resting in the magnetic resonance imaging scanner without thinking about anything. Although both learning and retrieval performances were comparable between the two groups, we observed significantly fewer memory gains in the autism spectrum disorder group than in the typically developing group. The memory network was involved in successful memory retrieval in youths with typically developing, while the other memory systems that do not depend to a great degree on networks may be involved in successful memory in youths with autism spectrum disorder. Context-independent and less relational memory processing may be associated with fewer memory gains in autism spectrum disorder. In other words, autism spectrum disorder youths might benefit from non-relational memory. These atypical memory characteristics in autism spectrum disorder may exaggerate their inflexible behaviors in some situations, or-vice versa-their atypical behaviors may result in rigid and less connected memories.

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9. Hollocks MJ, Simonoff E. Inspecting the Glass Half-Full Identifies Strengths in the Development of Children With Autism Spectrum Disorder. JAMA network open. 2021; 4(3): e213155.

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10. Hurwich-Reiss E, Chlebowski C, Lind T, Martinez K, Best KM, Brookman-Frazee L. Characterizing therapist delivery of evidence-based intervention strategies in publicly funded mental health services for children with autism spectrum disorder: Differentiating practice patterns in usual care and AIM HI delivery. Autism : the international journal of research and practice. 2021; 25(6): 1709-20.

This study was conducted to identify patterns of therapist delivery of evidence-based intervention strategies with children with autism spectrum disorder receiving publicly funded mental health services and compare strategy use for therapists delivering usual care to those trained to deliver AIM HI (« An Individualized Mental Health Intervention for ASD »), an intervention designed to reduce challenging behaviors in children with autism spectrum disorder. For therapists trained in AIM HI, intervention strategies grouped onto two factors, Autism Engagement Strategies and Active Teaching Strategies, while strategies used by usual care therapists grouped onto a broader single factor, General Strategies. Among usual care therapists, General Strategies were related to an increase in child behavior problems, whereas for AIM HI therapists, Active Teaching Strategies were related with reductions in child behavior problems over 18 months. Findings support the use of active teaching strategies in reducing challenging behaviors in children with autism spectrum disorder and provide support for the effectiveness of training therapists in evidence-based interventions to promote the delivery of targeted, specific intervention strategies to children with autism spectrum disorder in mental health services.

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11. Laister D, Stammler M, Vivanti G, Holzinger D. Social-communicative gestures at baseline predict verbal and nonverbal gains for children with autism receiving the Early Start Denver Model. Autism : the international journal of research and practice. 2021; 25(6): 1640-52.

Although there is growing evidence of the effectiveness and importance of certain early intervention programs for children with autism spectrum disorders, little is known about predictive information before intervention to search for the most accurate therapeutic approach for the individual child and his family. In children with autism spectrum disorder, atypical gesture use is one core deficit with consequences for the development of social interaction and language, but there is little knowledge about the relevance of early gesture use in predicting developmental outcomes of children receiving early interventions targeting social-communicative behaviors such as the Early Start Denver Model. In this study, we found that the parent-rated « Gestural Approach Behavior » subscale of the Pervasive Developmental Disorder Behavior Inventory was predictively associated with clinically assessed developmental changes after 1 year of intervention. This subscale was as strong a predictor as nonverbal development before intervention. Our findings suggest that children who use more gestures in daily life might be better equipped to respond to learning opportunities offered by early interventions targeting social communication strategies such as the Early Start Denver Model. Furthermore, we conclude that the parent-rated questionnaire might be a valuable and economic set of questions with high relevance for clinical assessments.

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12. Li CX, Liu YG, Che YP, Ou JL, Ruan WC, Yu YL, Li HF. Association Between MTHFR C677T Polymorphism and Susceptibility to Autism Spectrum Disorders: A Meta-Analysis in Chinese Han Population. Frontiers in pediatrics. 2021; 9: 598805.

Prior studies have examined the influence of MTHFR C677T on autism susceptibility, however, there are no consensus conclusions and specific analyses of a Chinese population. This meta-analysis included a false-positive report probability (FPRP) test to comprehensively evaluate the association of MTHFR C677T polymorphism with autism susceptibility among a Chinese Han population. A large-scale literature retrieval was conducted using various databases including PubMed, Embase, Wan Fang, and the Chinese National Knowledge Infrastructure (CNKI) up to July 31, 2020, with a total of 2,258 cases and 2,073 controls included. The strength of correlation was assessed by odds ratios (ORs) and 95% confidence intervals (95% CIs). MTHFR C677T showed a significant correlation with increased ASD susceptibility under all genetic models (T vs. C, OR = 1.89, 95% CI 1.28 to 2.79; TT vs. CC: OR = 2.44, 95% CI 1.43 to 4.15; CT vs. CC, OR = 1.73; 95% CI 1.19 to 2.51; CT + TT vs. CC: OR = 2.03, 95% CI 1.31 to 3.15; TT vs. CT + CC, OR = 1.95, 95% CI 1.21 to 3.13). Stratification analysis by region also revealed a consistent association in the Northern Han subgroup, but not in the Southern Han subgroup. Pooled minor allele frequency (MAF) of 30 studies were 45% in Northern Han and 39% in Southern Han. To avoid a possible « false positive report, » we further investigated the significant associations observed in the present meta-analysis using the FPRP test, which consolidated the results. In conclusion, MTHFR C677T polymorphism is associated with the increased risk of autism in China, especially in Northern Han. For those mothers and children who are generally susceptible to autism, prenatal folate and vitamin B12 may reduce the risk that children suffer from autism, especially in Northern Han populations. In the future, more well-designed studies with a larger sample size are expected.

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13. Li X, Zhang K, He X, Zhou J, Jin C, Shen L, Gao Y, Tian M, Zhang H. Structural, Functional, and Molecular Imaging of Autism Spectrum Disorder. Neuroscience bulletin. 2021; 37(7): 1051-71.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder associated with both genetic and environmental risks. Neuroimaging approaches have been widely employed to parse the neurophysiological mechanisms underlying ASD, and provide critical insights into the anatomical, functional, and neurochemical changes. We reviewed recent advances in neuroimaging studies that focused on ASD by using magnetic resonance imaging (MRI), positron emission tomography (PET), or single-positron emission tomography (SPECT). Longitudinal structural MRI has delineated an abnormal developmental trajectory of ASD that is associated with cascading neurobiological processes, and functional MRI has pointed to disrupted functional neural networks. Meanwhile, PET and SPECT imaging have revealed that metabolic and neurotransmitter abnormalities may contribute to shaping the aberrant neural circuits of ASD. Future large-scale, multi-center, multimodal investigations are essential to elucidate the neurophysiological underpinnings of ASD, and facilitate the development of novel diagnostic biomarkers and better-targeted therapy.

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14. Lorsung E, Karthikeyan R, Cao R. Biological Timing and Neurodevelopmental Disorders: A Role for Circadian Dysfunction in Autism Spectrum Disorders. Frontiers in neuroscience. 2021; 15: 642745.

Autism spectrum disorders (ASDs) are a spectrum of neurodevelopmental disorders characterized by impaired social interaction and communication, as well as stereotyped and repetitive behaviors. ASDs affect nearly 2% of the United States child population and the worldwide prevalence has dramatically increased in recent years. The etiology is not clear but ASD is thought to be caused by a combination of intrinsic and extrinsic factors. Circadian rhythms are the ∼24 h rhythms driven by the endogenous biological clock, and they are found in a variety of physiological processes. Growing evidence from basic and clinical studies suggest that the dysfunction of the circadian timing system may be associated with ASD and its pathogenesis. Here we review the findings that link circadian dysfunctions to ASD in both experimental and clinical studies. We first introduce the organization of the circadian system and ASD. Next, we review physiological indicators of circadian rhythms that are found disrupted in ASD individuals, including sleep-wake cycles, melatonin, cortisol, and serotonin. Finally, we review evidence in epidemiology, human genetics, and biochemistry that indicates underlying associations between circadian regulation and the pathogenesis of ASD. In conclusion, we propose that understanding the functional importance of the circadian clock in normal and aberrant neurodevelopmental processes may provide a novel perspective to tackle ASD, and clinical treatments for ASD individuals should comprise an integrative approach considering the dynamics of daily rhythms in physical, mental, and social processes.

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15. Qi Z, Lyu M, Yang L, Yuan H, Cao Y, Zhai L, Dang W, Liu J, Yang F, Li Y. A Novel and Reliable Rat Model of Autism. Frontiers in psychiatry. 2021; 12: 549810.

Background: Autism spectrum disorders (ASD) is a complex neurodevelopmental disorder that lacks an ideal animal model to recapitulate the disease state of ASD. Previous studies have reported that transplanting gut microbiota of ASD patients into pregnant mice is sufficient to promote the changes of autism-like behavior in offspring. This study aims to explore whether fecal microbiota transplantation (FMT) can be used as a new method to establish the ASD animal model. Methods: We transplanted the fecal sample extract of ASD children into pregnant rats (rFMT) repeatedly to establish an ASD rat model (oFMT) and compare it with the classical valproic acid (VPA) model (oVPA). Results: First, we reveal that oFMT shows hypoevolutism and typical behavioral characteristics of ASD, consistent with the previous study. Second, the gut microbiota of oFMT mainly consists of Firmicutes and Bacteroidetes, recapitulating the abnormal gut microbiota of ASD. In oFMT, the abundance of Lactobacillus and Collinsella increased (Lactobacillus: oFMT 60.16%, oVPA 64.13%, oCON 40.11%; Collinsella: oFMT 3.73%, oVPA 1.39%, oCON 1.28%), compared with oVPA, gut microbiota also showed high consistency. Third, the expression of 5-hydroxytryptamine (5-HT) in oFMT serum increased, γ-aminobutyric acid (GABA) and norepinephrine (NE) in oFMT serum decreased. Fourth, the gut microbiota of oFMT also has some ASD characteristic gut microbiota not found in oVPA. Fifth, pregnant rat with VPA showed significant immune activation, while those with FMT showed relatively minor immune activation. Limitations: Although the mechanism of establishing FMT autism rat model (oFMT) has not clearly defined, the data show that the model has high structural validity, and FMT model is likely to be a new and reliable potential animal model of ASD, and will have potential value in studying gut microbiota of ASD. Conclusions: The FMT autism rat model has high structural validity, and the FMT model is likely to be a new and reliable potential animal model of ASD.

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16. Racine E, Taylor BP, Ferretti CJ, Doernberg E, Noone R, Nezgovorova V, Vats T, Hollander E. Challenges in assessing change in autistic adults: scale limitations and discrepancies in reporting in clinical trials. International journal of psychiatry in clinical practice. 2022; 26(1): 3-7.

Autism Spectrum Disorder (ASD) is a developmental disorder marked by deficits in social communication and social interaction, together with restricted and/or repetitive patterns of behaviours, activities or interests. As more adults are being diagnosed with ASD, and more diagnosed children are aging into adulthood, the need for effective treatments and support services for autistic adults is quickly growing. As such, clinical research targeting autistic adults has emerged in recent years. Currently, caregiver ratings are commonly used as outcome measures in child treatment studies, but these scales present challenges when utilised to assess the autistic adult population. In this commentary, we seek to unveil the difficulties and obstacles in assessing change in clinical treatment trials for autistic adults. Specifically, this article uses case examples to explore the limitations of rating scales. Steps for improving the accuracy of ratings, and for developing novel self-rating scales for autistic adults are discussed. It is hoped that in exploring these difficulties in more depth, clinical research with adult ASD populations will continue to improve and that reliable, valid and sensitive outcome measures will be developed to ensure the highest quality treatments emerge.

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17. Roman-Urrestarazu A, van Kessel R, Allison C, Matthews FE, Brayne C, Baron-Cohen S. Association of Race/Ethnicity and Social Disadvantage With Autism Prevalence in 7 Million School Children in England. JAMA pediatrics. 2021; 175(6): e210054.

IMPORTANCE: The global prevalence of autism spectrum disorder (ASD) has been reported to be between 1% and 2% of the population, with little research in Black, Asian, and other racial/ethnic minority groups. Accurate estimates of ASD prevalence are vital to planning diagnostic, educational, health, and social care services and may detect possible access barriers to diagnostic pathways and services and inequalities based on social determinants of health. OBJECTIVE: To evaluate whether socioeconomic disadvantage is associated with ASD prevalence and the likelihood of accessing ASD services in racial/ethnic minority and disadvantaged groups in England. DESIGN, SETTING, AND PARTICIPANTS: This case-control prevalence cohort study used the Spring School Census 2017 from the Pupil Level Annual Schools Census of the National Pupil Database, which is a total population sample that includes all English children, adolescents, and young adults aged 2 to 21 years in state-funded education. Data were collected on January 17, 2017, and analyzed from August 2, 2018, to January 28, 2020. EXPOSURES: Age and sex were treated as a priori confounders while assessing correlates of ASD status according to (1) race/ethnicity, (2) social disadvantage, (3) first language spoken, (4) Education, Health and Care Plan or ASD Special Educational Needs and Disability support status, and (5) mediation analysis to assess how social disadvantage and language might affect ASD status. MAIN OUTCOMES AND MEASURES: Sex- and age-standardized ASD prevalence by race/ethnicity and 326 English local authority districts in pupils aged 5 to 19 years. RESULTS: The final population sample consisted of 7 047 238 pupils (50.99% male; mean [SD] age, 10.18 [3.47] years) and included 119 821 pupils with ASD, of whom 21 660 also had learning difficulties (18.08%). The standardized prevalence of ASD was 1.76% (95% CI, 1.75%-1.77%), with male pupils showing a prevalence of 2.81% (95% CI, 2.79%-2.83%) and female pupils a prevalence of 0.65% (95% CI, 0.64%-0.66%), for a male-to-female ratio (MFR) of 4.32:1. Standardized prevalence was highest in Black pupils (2.11% [95% CI, 2.06%-2.16%]; MFR, 4.68:1) and lowest in Roma/Irish Travelers (0.85% [95% CI, 0.67%-1.03%]; MFR, 2.84:1). Pupils with ASD were more likely to face social disadvantage (adjusted prevalence ratio, 1.61; 95% CI, 1.59-1.63) and to speak English as an additional language (adjusted prevalence ratio, 0.64; 95% CI, 0.63-0.65). The effect of race/ethnicity on ASD status was mediated mostly through social disadvantage, with Black pupils having the largest effect (standardized mediation coefficient, 0.018; P < .001) and 12.41% of indirect effects through this way. CONCLUSIONS AND RELEVANCE: These findings suggest that significant differences in ASD prevalence exist across racial/ethnic groups and geographic areas and local authority districts, indicating possible differential phenotypic prevalence or differences in detection or referral for racial/ethnic minority groups.

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18. Song CG, Kang X, Yang F, Du WQ, Zhang JJ, Liu L, Kang JJ, Jia N, Yue H, Fan LY, Wu SX, Jiang W, Gao F. Endocannabinoid system in the neurodevelopment of GABAergic interneurons: implications for neurological and psychiatric disorders. Reviews in the neurosciences. 2021; 32(8): 803-31.

In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.

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19. Szatmari P, Cost KT, Duku E, Bennett T, Elsabbagh M, Georgiades S, Kerns M, Mirenda P, Smith IM, Ungar WJ, Vaillancourt T, Waddell C, Zaidman-Zait A, Zwaigenbaum L. Association of Child and Family Attributes With Outcomes in Children With Autism. JAMA network open. 2021; 4(3): e212530.

IMPORTANCE: The prevalence and attributes of positive outcomes (or doing well) among children with autism spectrum disorder (ASD) in midchildhood are not well known. OBJECTIVE: To estimate the prevalence of doing well according to metrics of proficiency and growth and to investigate the extent to which significant associations exist between child- and family-level variables and doing well. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study included children with ASD from regional clinics across Canada. Participants were sampled 3 times between ages 2 and 4.9 years (T1) and twice in follow-up into middle childhood (T2). Data were analyzed March 2018 through January 2020. EXPOSURES: Language and IQ assessments at first sample; household income, parent coping, and family functioning. MAIN OUTCOMES AND MEASURES: Key outcome domains of developmental health included measures of socialization, communication, independent living skills, and measures of internalizing and externalizing behaviors. Thresholds for doing well in these domains by either proficiency or growth were established. The extent to which language, IQ, household income, parent coping, and family functioning were associated with assessed outcomes was determined by logistic regression. The association between outcomes and concurrent Autism Diagnostic Observation Schedule (ADOS) classification scores was also estimated. RESULTS: In a total cohort of 272 children (234 [86.0%] boys; mean [SD] age, 10.76 [0.26] years), approximately 78.8% (95% CI, 73.2%-84.4%) of the sample were estimated to be doing well by either metric on at least 1 domain, and 23.6% (95% CI, 17.7%-29.4%) were doing well in 4 or 5 domains. It was possible to be doing well by either proficiency or growth and still meet ADOS criteria for ASD. For the growth metric, between 61.5% (95% CI, 40.7%-79.1%) and 79.6% (95% CI, 66.0%-88.9%) of participants had ADOS scores of 4 or greater; for the proficiency metric, between 63.8% (95% CI, 48.4%-76.9%) and 75.8% (95% CI, 63.0%-85.4%) had scores of 4 or greater. Doing well by either metric for all domains was associated with T1 scores on that outcome domain (eg, T1 daily living skills associated with doing well at T2 daily living by the proficiency metric as measured by the Vineland Adaptive Behavior Scales-Second Edition daily living skills scale [202 participants]: β = 0.07; OR, 1.07; 95% CI, 1.03-1.11; P < .001). Doing well in socialization by the growth metric was also associated with better T1 language skills scores (202 participants) (β = 0.04; OR, 1.04; 95% CI, 1.00-1.07, P = .04). Doing well in externalizing by the growth metric was also associated with higher household income at T1 (178 participants) (β = 0.10; OR, 1.10; 95% CI, 1.06-1.15; P < .001). Better family functioning at T1 was associated with doing well on both socialization and externalizing by proficiency metric and on internalizing by growth metric (socialization by proficiency [202 participants]: β = -1.01; OR, 0.36; 95% CI, 0.14-0.93; P = .04; externalizing by proficiency [178 participants]: β = 1.00; OR, 0.37; 95% CI, 0.16-0.82; P = .02; internalizing by growth [178 participants]: β = -1.03; OR, 0.36; 95% CI, 0.16-0.79; P = .01). CONCLUSIONS AND RELEVANCE: This cohort study found that a substantial proportion of children with ASD were doing well by middle childhood in at least 1 key domain of developmental health, and that doing well was possible even in the context of continuing to meet criteria for ASD. These results support a strengths-based approach to treatment planning that should include robust support for families to increase the potential likelihood of doing well later in life.

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20. Ünsel Bolat G, Bolat H. The Role of Copy Number Variations and FHIT Gene on Phenotypic Characteristics of Cases Diagnosed with Autism Spectrum Disorder. Molecular syndromology. 2021; 12(1): 12-9.

Copy number variations (CNVs) have been implied in the etiology of autism spectrum disorder (ASD), and microarray-based techniques are performed as a first-step genetic test. Our aim was to present clinical features and CNV profiles of patients with ASD and their parents. Array-CGH was applied to detect CNVs. Previously as likely pathogenic reported duplications were detected at 16p13.11 and 11p15.2p15.1. Other variants were found in 16p11.2p11.1, 3p14.2, 15q11.2, 10q11.22, 3p26.3, 4q13.3, 22q13.32q13.33, and 1q44 and were classified as variants of unknown significance. Deletion of the FHIT gene was associated with the regression of language and social skills without mental impairment. Paternal inheritance of difficulty in social skills and the FHIT gene was documented. In addition, varying olfactory receptor family genes were implicated in de novo and hereditary CNVs. In this study, we aimed to present the clinical characteristics of the cases and parents in more detail, especially in pathogenic CNV cases, which enables us to increase our knowledge on inherited CNVs and genotype-phenotype correlation. We suggest that both genetic and psychiatric evaluation of the parents of the cases is important for better understanding the clinical relevance of the CNV results.

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