1. Aglinskas A, Anzellotti S. Precision psychiatry requires disentangling disorder-specific variation: The case of ASD. Clinical and translational medicine. 2022; 12(10): e1079.

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2. Bin Eid W, Lim M, Gabrieli G, Kölbel M, Halstead E, Esposito G, Dimitriou D. Habilitation of sleep problems among mothers and their children with autism spectrum disorder: Insights from multi-level exploratory dyadic analyses. Frontiers in rehabilitation sciences. 2022; 3: 915060.

Few habilitation strategies for children with autism spectrum disorder (ASD) consider their sleep-related problems. Together with the fact that caregivers of children with ASD also face issues with sleep, there may be yet-to-be uncovered relationships between caregiver-child sleep patterns and sleep quality, offering a key opportunity for clinicians to consider the needs of both child and caregiver in terms of sleep. 29 dyads of mothers and their children with ASD were recruited for this cohort study and both subjective (self-report questionnaires and sleep diaries) and objective (cortisol samples and actigraphy) measures of sleep were collected to investigate significant predictors of sleep quality. Comparative, correlational, and hierarchical analyses were conducted. Findings indicated that both mother and child experience sleep deprivation in terms of shorter sleep duration and poor sleep quality in terms of longer sleep onset latencies and a higher frequency of wake bouts. Exploratory hierarchical analyses also found that child-related sleep difficulties such as sleep disordered breathing and night waking significantly predict mothers’ sleep quality, which may point to the bi-directional influence of mother-child sleep. Based on these findings, it is recommended that clinicians adopt a family systems perspective and consider the sleep environment of the household, particularly that of the caregiver and child, when designing interventions for sleep-related problems in ASD. Finally, there is a need for additional support to promote good quality sleep among caregivers of children with ASD to bolster out-of-clinic care.

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3. Brewer N, Lucas CA, Lim A, Young RL. Detecting dodgy behaviour: The role of autism, autistic traits and theory of mind. Autism : the international journal of research and practice. 2022: 13623613221125564.

Difficulties in reading others’ minds make it difficult to anticipate their future behaviour. It has often been argued that such difficulties contribute to autistic individuals becoming enmeshed in criminal activity. However, supportive scientific evidence is virtually non-existent. We compared the ability of groups of autistic and non-autistic adults of similar intellectual ability to detect dodgy or suspicious behaviour across a wide range of scenarios. Although the autistic group performed more poorly than the non-autistic group on an established measure of mindreading, there were no group differences in the ability to detect dodginess. Nor did we find any evidence that detecting dodgy behaviour was associated with the degree of autistic traits reported by individual participants. However, when we combined the two groups, difficulty reading the minds of others was indeed associated with poorer detection of dodginess, thus highlighting a characteristic of individuals that may well increase the likelihood of becoming involved in crime or exploited for autistic and non-autistic individuals alike.

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4. Bupp CP, English BK, Rajasekaran S, Prokop JW. Introduction to Personalized Medicine in Pediatrics. Pediatric annals. 2022; 51(10): e381-e6.

Exciting new developments in biomedical and computational sciences provide an extraordinary and unparalleled opportunity to compile, connect, and analyze multiple types of « big data, » driving the development of personalized medicine. These insights must begin in early life (ie, pregnancy, neonatal, and infancy) and focus on early prevention, diagnosis, and intervention-areas of medicine where pediatricians are poised to lead the way to a personalized medicine future. The rapid growth of genomics (including pharmacogenomics), transcriptomics, and related « omics » has revolutionized the diagnosis of rare monogenic disorders. It is now clarifying the pathogenesis of complex conditions ranging from autism spectrum disorder to asthma. Collaborations between clinicians and basic scientists integrating multiomics approaches in evaluating children with severe illness are transforming the fields of perinatal, neonatal, and pediatric critical care medicine. Improvements in rapid diagnostic and prognostic information suggest that pediatric personalized medicine is under way and has an exciting future. [Pediatr Ann. 2022;51(10):e381-e386.].

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5. Güneş H, Tanıdır C, Doktur H, Yılmaz S, Yıldız D, Özbek F, Bozbey S, Özşirin G. Prenatal, Perinatal, Postnatal risk factors, and excess screen time in autism spectrum disorder. Pediatrics international : official journal of the Japan Pediatric Society. 2022: e15383.

BACKGROUND: The aim of this study is to investigate prenatal, perinatal, and postnatal factors, screen time in a group of patients with ASD and age and sex-matched clinical controls to evaluate risk factors specific to ASD. METHODS: The study included 211 ASD patients (177 boys, 34 girls; mean age 44.3±13.0 months) and 241 (190 boys, 51 girls; mean age 44.6±14.1 months) age and sex group matched clinical controls. Non-ASD diagnoses were expressive language disorder (n=135, 56.0 %), intellectual disability (n=15, 6.2%), attention deficit-hyperactivity disorder (n=6, 2.4%), oppositional disorder (n=6, 2.4%), and other behavioral or emotional problems (no diagnosis) (n=79, 32.8%). A sociodemographic data form was used to collect data regarding pre-, peri-, and postnatal factors and total daily screen exposure. RESULTS: According to our findings, maternal severe psychological stress and depression during pregnancy, and maternal postpartum depression were more frequent in the ASD group (p=0.005, p=0.035, and p=0.001 respectively). There was a statistically significant difference between groups with regards to maternal any medication use during pregnancy (p=0.004). The mean duration of daily screen exposure was higher in the ASD group (9.90±5.10 hours) compared to non-ASD children (4.46±3.40 hours) (p<0.001). A ROC curve showed that 8.5 hours and above total daily screen exposure (AUC = 0.808 [95%CI, 0.769-0.848], p<000; 55% sensitivity, 90.5% specificity) is likely to be associated with increased risk for ASD. CONCLUSION: Our study suggests that prenatal maternal psychological stress, prenatal and postpartum depression, and excess exposure to screen might be related to an increased risk for ASD.

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6. He AX, Luyster RJ, Arunachalam S. Parental tuning of language input to autistic and nonspectrum children. Frontiers in psychology. 2022; 13: 954983.

Caregivers’ language input supports children’s language development, and it is often tuned to the child’s current level of skill. Evidence suggests that parental input is tuned to accommodate children’s expressive language levels, but accommodation to receptive language abilities is less understood. In particular, little is known about parental sensitivity to children’s abilities to process language in real time. Compared to nonspectrum children, children on the spectrum are slower to process language. In this study, we ask: Do parents of autistic children and those of nonspectrum children tune their language input to accommodate children’s different language processing abilities? Children with and without a diagnosis of autism (ages 2-6 years, N = 35) and their parents viewed a display of six images, one of which was the target. The parent labeled the target to direct the child’s attention to it. We first examined children’s language processing abilities by assessing their latencies to shift gaze to the labeled referent; from this, we found slower latencies in the autistic group than in the nonspectrum group, in line with previous findings. We then examined features of parents’ language and found that parents in both groups produced similar language, suggesting that parents may not adjust their language input according to children’s speed of language processing. This finding suggests that (1) capturing parental sensitivity to children’s receptive language, and specifically language processing, may enrich our models of individual differences in language input, and (2) future work should investigate if supporting caregivers in tuning their language use according to children’s language processing can improve children’s language outcomes.

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7. Hendrix NM, Pickard KE, Binion GE, Kushner E. A systematic review of emotion regulation in parent-mediated interventions for autism spectrum disorder. Frontiers in psychiatry. 2022; 13: 846286.

Autistic individuals are at elevated risk for difficulties with emotion regulation (ER) that emerge early in life and are associated with a range of internalizing and externalizing disorders. Existing interventions that support ER have focused on school-age autistic children and adolescents as well as adults. Proactive approaches to improving ER in early childhood are thus needed, as is understanding the approaches by which ER skills can be feasibly supported in this young population. This review summarizes how ER has been measured within parent-mediated interventions for children at or under the age of 6 years and the extent to which ER is measured concurrently with or distinctly from observable behaviors that have been referenced in existing literature as externalizing or challenging behavior. Using PsycInfo, EBSCOhost, and PubMed databases, we searched for peer-reviewed journal articles published through August 2021, that focused on the use of parent-mediated interventions targeting ER and/or challenging behavior. The systematic search resulted in 4,738 publications; following multi-stage screening, the search yielded 20 studies. Eighteen of 20 studies were designed to target challenging behavior using manualized curricula or behavior analytic methodologies and assessed child outcomes through validated caregiver rating scales and/or direct behavioral observation. One study measured changes in ER as secondary to the social communication skills that were targeted in the intervention. Only one study specifically supported ER skill development and measured changes in ER as the primary intervention outcome. Findings highlight the need for better assessment of ER outcomes within the context of parent-mediated interventions for toddlers and young autistic children.

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8. Hogan AL, Winston M, Barstein J, Losh M. Slower Peak Pupillary Response to Emotional Faces in Parents of Autistic Individuals. Frontiers in psychology. 2022; 13: 836719.

BACKGROUND: Atypical autonomic arousal has been consistently documented in autism spectrum disorder (ASD) and is thought to contribute to the social-communication phenotype of ASD. Some evidence suggests that clinically unaffected first-degree relatives of autistic individuals may also show subtle differences in indices of autonomic arousal, potentially implicating heritable pathophysiological mechanisms in ASD. This study examined pupillary responses in parents of autistic individuals to investigate evidence that atypical autonomic arousal might constitute a subclinical physiological marker of ASD heritability within families of autistic individuals. METHODS: Pupillary responses to emotional faces were measured in 47 ASD parents and 20 age-matched parent controls. Macro-level pupillary responses (e.g., mean, peak, latency to peak) and dynamic pupillary responses over the course of the stimulus presentation were compared between groups, and in relationship to subclinical ASD-related features in ASD parents. A small ASD group (n = 20) and controls (n = 17) were also included for exploratory analyses of parent-child correlations in pupillary response. RESULTS: Parents of autistic individuals differed in the time course of pupillary response, exhibiting a later primary peak response than controls. In ASD parents, slower peak response was associated with poorer pragmatic language and larger peak response was associated with poorer social cognition. Exploratory analyses revealed correlations between peak pupillary responses in ASD parents and mean and peak pupillary responses in their autistic children. CONCLUSION: Differences in pupillary responses in clinically unaffected parents, together with significant correlations with ASD-related features and significant parent-child associations, suggest that pupillary responses to emotional faces may constitute an objective physiological marker of ASD genetic liability, with potential to inform the mechanistic underpinnings of ASD symptomatology.

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9. Karal MA, Riccomini PJ, Hughes EM. Effects of video modeling on addition word-problem performance of students with autism spectrum disorder. International journal of developmental disabilities. 2022; 68(5): 756-65.

Many students with autism spectrum disorder (ASD) experience academic challenges and difficulties. These struggles are especially pronounced in mathematics with students with ASD performing significantly below than their peers without disabilities on measures of mathematical performance. The current study used a single case experimental design with concurrent multiple probe across students to investigate the effects of a point-of-view video modeling (POVM) intervention on accuracy of addition with regrouping word problems. The participants were three secondary grade level students with ASD. Findings showed that each student demonstrated considerable improvement during intervention over baseline levels, and subsequently sustaining their performance through the maintenance phase. Limitations, implications for practitioners and future research directions are presented.

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10. Kim JI, Kim BN, Lee YA, Shin CH, Hong YC, Lim YH. The mediating role of the gut microbiome in the association between ambient air pollution and autistic traits. International journal of hygiene and environmental health. 2022; 246: 114047.

Air pollution has been reported to be an environmental risk factor for autism spectrum disorder. However, the gut microbiome’s role as a potential mediator has not been investigated. We aimed to clarify whether particulate matter with an aerodynamic diameter ≤10 μm (PM₁₀) and nitrogen dioxide (NO₂) exposure impact autistic traits through the gut microbiome. Using 170 mother-child pairs, PM₁₀ and NO₂ exposure levels during pregnancy (1st, 2nd, and 3rd trimesters) and annual residential PM₁₀ levels at age 2, 4, and 6 years were estimated. Autistic traits and gut microbiome were assessed at age 6 years. The associations of PM₁₀ or NO₂ exposure, gut microbiome composition, and autistic traits were explored, and mediation analyses of statistically significant findings were also conducted. Exposure to PM₁₀ during the 1st trimester of pregnancy was associated with increased autistic traits (10.6% change per interquartile range (IQR) increase, 95% confidence interval [CI]: 1.1, 21.0) and with Proteobacteria relative abundance at age 6 years (66.9% change per IQR increase, 95% CI: 21.3, 129.8). First trimester NO₂ exposure was associated with autistic traits (12.1% change, 95% CI: 0.1, 25.5) and Proteobacteria relative abundance at age 6 years (48.1% change, 95% CI: -0.1, 119.6). Proteobacteria relative abundance was related to autistic traits (4.4% change per 2-fold increase, 95% CI: 1.3, 7.5). Relations between PM₁₀ or NO₂ exposure during the 1st trimester and autistic traits at age 6 years were partially mediated by Proteobacteria (proportion mediated 23.2%, p = 0.01 and 16.7%, p = 0.06; respectively). PM₁₀ and possibly NO₂ exposure during early pregnancy may affect autistic traits at age 6 years through the alteration of Proteobacteria abundance.

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11. Leppanen J, Sedgewick F, Halls D, Tchanturia K. Autism and anorexia nervosa: Longitudinal prediction of eating disorder outcomes. Frontiers in psychiatry. 2022; 13: 985867.

BACKGROUND: Recently, elevated levels of autistic features and autism diagnoses have been reported among people with anorexia nervosa (AN). In clinical settings high levels of autistic features have been linked to more complex, highly comorbid illness presentation and poorer treatment outcome. This study aimed to examine whether autistic features predict AN symptom profile in long term. METHODS: Altogether 118 women with lived experience of AN completed two autism assessments at time 1, the Autism Diagnostic Observation Schedule (ADOS) and the short version of the Autism Quotient (AQ10). Measures assessing AN symptom profile, including eating disorders symptoms, anxiety, depression, OCD symptoms, and Body Mass Index (BMI), were also recorded. The symptom profile measures were administered again 6 months and 2 years later. We conducted two analyses to examine the extent to which the ADOS and AQ10 scores predicted broad AN symptom profile at each three time points. RESULTS: Overall, high levels of autistic features were consistently associated with worse psychological symptoms, but not BMI, across all time points. Both the analysis using baseline ADOS scores and self-reported AQ10 scores showed similar pattern. CONCLUSION: The present findings consolidate previously reported associations between autistic features and worse psychological outcome among people with AN. The findings also suggest that self-report measures may be sufficient for assessing the impact of autistic features on illness outcome among people with AN. Importantly, the study highlights the need for development and further investigation of neurodiversity accommodations in the treatment of AN.

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12. Lightbody AA, Bartholomay KL, Jordan TL, Lee CH, Miller JG, Reiss AL. Anxiety, Depression, and Social Skills in Girls with Fragile X Syndrome: Understanding the Cycle to Improve Outcomes. Journal of developmental and behavioral pediatrics : JDBP. 2022; 43(9): e565-e72.

OBJECTIVE: Female patients with fragile X syndrome (FXS), a genetic condition associated with a mutation in the FMR1 gene, are at significantly elevated risk for developing anxiety and depression. This study is designed to better understand these symptoms in school-age girls, particularly as they relate to age, social skills, and functional outcomes. METHODS: We compared 58 girls aged 6 to 16 years with FXS with 46 age-matched, sex-matched, and developmentally matched peers without FXS on measures of anxiety, depression, social skills, adaptive behavior, and quality of life. RESULTS: Girls with FXS 10.5 years and older demonstrated significantly higher levels of depression, withdrawal, and social avoidance than girls younger than 10.5 years with FXS ( p -values < 0.01). Girls in the comparison group did not show any age-related differences on these measures. The older FXS cohort also showed associations between social communication and interaction skills, adaptive behavior, and measures of anxiety and depression ( p -values < 0.05) not seen in the comparison group, regardless of age. CONCLUSION: We found that age seems to play an important role in the development of mood symptoms and that such symptoms are uniquely correlated with social communication and reciprocal social interaction behaviors and adaptive functioning in girls with FXS after puberty. These data suggest a critical window of intervention for girls with FXS in the improvement of social interaction skills and the prevention of social avoidance and symptoms of anxiety and depression, with the ultimate goal of improving quality of life and promoting greater independence.

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13. Luo Y, Zhao Y, Wang Y, Liang R, Hong C, Yang Y, Zheng X. Characteristics and treatment patterns of autism spectrum disorder in China, 2020. Psychiatry research. 2022; 317: 114879.

This study aimed to investigate the characteristics of children diagnosed with ASD in China and to estimate ASD treatment patterns in 2020. This study used data from the 2020 Survey on Family Circumstance and Demand Support and Resources among Autistic Children in China. The study sample included 4,557 children diagnosed with ASD aged 2-16 years old. Data were collected through questionnaires completed by parents. Of the 4,557 children with ASD, there was a male-to-female ratio of 5.75:1, and the average age when ASD risk symptoms were first reported was 27.97(SD=10.83) months. Higher proportions of families with highly educated parents (college and above; around 58%) and advanced parental age at childbirth (≥35 years; over 50%) were found among autistic children. Additionally, about 41.05% of autistic children had an immediate family member diagnosed with mental/intellectual disorders. In terms of the treatment patterns for autistic children, 84.82% had received behavioral and developmental treatments and 77.74% had received therapy-based treatments, whereas 3% children had not received any treatment. Higher odds of non-treatment were found among children who were male (OR=1.69, 95% CI: 1.01,3.03) and had ASD diagnosed later on (OR= 1.02, 95% CI:1.01,1.03), as compared to their counterparts. Future studies will need to explore the etiology of the disparities of ASD, and policy efforts are critically needed to understand and address the barriers for children with ASD to receive appropriate treatments.

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14. Moussa AJ, Wester JC. Cell-type specific transcriptomic signatures of neocortical circuit organization and their relevance to autism. Frontiers in neural circuits. 2022; 16: 982721.

A prevailing challenge in neuroscience is understanding how diverse neuronal cell types select their synaptic partners to form circuits. In the neocortex, major classes of excitatory projection neurons and inhibitory interneurons are conserved across functionally distinct regions. There is evidence these classes form canonical circuit motifs that depend primarily on their identity; however, regional cues likely also influence their choice of synaptic partners. We mined the Allen Institute’s single-cell RNA-sequencing database of mouse cortical neurons to study the expression of genes necessary for synaptic connectivity and physiology in two regions: the anterior lateral motor cortex (ALM) and the primary visual cortex (VISp). We used the Allen’s metadata to parse cells by clusters representing major excitatory and inhibitory classes that are common to both ALM and VISp. We then performed two types of pairwise differential gene expression analysis: (1) between different neuronal classes within the same brain region (ALM or VISp), and (2) between the same neuronal class in ALM and VISp. We filtered our results for differentially expressed genes related to circuit connectivity and developed a novel bioinformatic approach to determine the sets uniquely enriched in each neuronal class in ALM, VISp, or both. This analysis provides an organized set of genes that may regulate synaptic connectivity and physiology in a cell-type-specific manner. Furthermore, it identifies candidate mechanisms for circuit organization that are conserved across functionally distinct cortical regions or that are region dependent. Finally, we used the SFARI Human Gene Module to identify genes from this analysis that are related to risk for autism spectrum disorder (ASD). Our analysis provides clear molecular targets for future studies to understand neocortical circuit organization and abnormalities that underlie autistic phenotypes.

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15. Raspa M, Wheeler A, Okoniewski KC, Edwards A, Scott S. Research Gaps in Fragile X Syndrome: An Updated Literature Review to Inform Clinical and Public Health Practice. Journal of developmental and behavioral pediatrics : JDBP. 2022.

OBJECTIVE: The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the fragile X messenger ribonucleoprotein 1 gene 30 years ago. However, gaps remain in clinical and public health research. The purpose of this literature review was to determine the extent to which these gaps have been addressed and identify targeted areas of future research. METHODS: We conducted an electronic search of several scientific databases using a variety of key words. The search focused on 5 areas identified as research gaps by an earlier review: (1) diagnosis, (2) phenotypic presentation, (3) familial impact, (4) interventions and treatments, and (5) life span perspectives. Inclusion criteria included publication between 2014 and 2020, focus on human subjects, and publication in English. A total of 480 articles were identified, 365 were reviewed, and 112 are summarized in this review. RESULTS: Results are organized into the following categories: (1) FXS phenotype and subtypes (FXS subtypes, medical profile, cognitive/developmental profile, social and behavioral profile); (2) needs of adults; (3) public health needs (clinical diagnosis and newborn screening, health care needs, and access); (4) treatment (treatment priorities, pharmacological treatments, and behavioral and educational interventions); and (5) families (economic burden and mother-child relationship). CONCLUSION: Despite the progress in many areas of FXS research, work remains to address gaps in clinical and public health knowledge. We pose 3 main areas of focused research, including early detection and diagnosis, determinants of health, and development and implementation of targeted interventions.

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16. Riccioni A, Siracusano M, Vasta M, Ribolsi M, Nastro FF, Gialloreti LE, Di Lorenzo G, Mazzone L. Clinical profile and conversion rate to full psychosis in a prospective cohort study of youth affected by autism spectrum disorder and attenuated psychosis syndrome: A preliminary report. Frontiers in psychiatry. 2022; 13: 950888.

Psychosis can occur at high rates in individuals with autism spectrum disorder (ASD). However, the detection of prodromal psychotic symptoms, including attenuated psychosis syndrome (APS), conditions at high risk of converting to full psychosis, has not been extensively investigated in ASD. We longitudinally evaluate a sample of young ASD individuals (age, mean ± SD: 13 ± 2.9) with (n = 13) or without (n = 18) concomitant APS through a standardized assessment of autistic (Autism Diagnostic Observation Schedule-Second Edition; ADOS-2) and psychotic (Structured Interview for Psychosis-Risk Syndromes, SIPS) symptoms and cognitive and adaptive skills. Individuals with other neuropsychiatric disorders were excluded. We estimated the conversion rate to full psychosis (according to SIPS criteria) over time (39.6 ± 11.5 months) and explored the role of clinical variables at baseline in the transition to full psychosis. A conversion rate to full psychosis of 30.7% was found in ASD/APS. Conversion to full psychosis was not affected by the severity of the autistic and psychotic symptoms. At baseline, young individuals with ASD/APS who later converted to full psychosis showed lower cognitive performance (d = 2.05) and greater impairment of adaptive social functioning profile (d = 1.2) than those with ASD. The results of this preliminary report revealed that nearly a third of young individuals with ASD/APS convert to full psychosis over time. Conversion to full psychosis is affected by decreased cognitive and adaptive skills. Further investigations are needed to confirm the utility of APS detection and to better characterize the psychotic developmental trajectory in ASD, with consequent important implications on prognosis and therapeutic strategies.

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17. Rinaldi A, Martins MCM, Maioli M, Rinaldi S, Fontani V. REAC Noninvasive Neurobiological Stimulation in Autism Spectrum Disorder for Alleviating Stress Impact. Advances in neurodevelopmental disorders. 2022: 1-8.

OBJECTIVES: Autism spectrum disorder (ASD) symptoms can become more evident because of different factors. Among these, depression, anxiety, and stress play an important role. Additionally, several studies have revealed the impact of the COVID-19 pandemic on participants with ASD. In previous studies, two noninvasive neurobiological stimulation treatments with radio electric asymmetric conveyer (REAC) technology, called neuropostural optimization (NPO) and neuropsychophysical optimization (NPPO), were shown to be effective in improving the subjective response to environmental stressors in the general population and in ASD population. Based on the proven efficacy of REAC NPO and NPPOs treatments in alleviating anxiety, stress, and depression, the purpose of this study is to verify how these treatments can reduce the severity of ASD symptoms expression, which is aggravated by depression, anxiety, and stress. The treatments’ effects were perceived by caregivers and assessed by the Autism Treatment Evaluation Checklist (ATEC). METHODS: This study involved 46 children with a previous diagnosis of ASD made using the Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised. The participants received one session of NPO treatment and one NPPOs treatment cycle of 18 sessions, administered within approximately 3 weeks. The Autism Treatment Evaluation Checklist (ATEC) was used to evaluate the efficacy of the REAC treatments. ATEC allows to evaluate four clusters (speech or language communication; sociability; sensory or cognitive awareness; and health/physical/behavior) through a numerical scale that measures increasing levels of ASD severity. RESULTS: The comparison between the scores of the ATEC administered pre- and post-REAC treatments highlighted an improvement of ASD symptoms in each of the four clusters of ATEC. CONCLUSIONS: The results confirm the usefulness of REAC treatments to optimize the individual response to environmental stressors and reduce the symptomatic expression and deficits present in ASD.

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18. Sleyp Y, Valenzuela I, Accogli A, Ballon K, Ben-Zeev B, Berkovic SF, Broly M, Callaerts P, Caylor RC, Charles P, Chatron N, Cohen L, Coppola A, Cordeiro D, Cuccurullo C, Cuscó I, Janette d, Duran-Romaña R, Ekhilevitch N, Fernández-Alvarez P, Gordon CT, Isidor B, Keren B, Lesca G, Maljaars J, Mercimek-Andrews S, Morrow MM, Muir AM, Rousseau F, Salpietro V, Scheffer IE, Schnur RE, Schymkowitz J, Souche E, Steyaert J, Stolerman ES, Vengoechea J, Ville D, Washington C, Weiss K, Zaid R, Sadleir LG, Mefford HC, Peeters H. De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder. Genetics in medicine : official journal of the American College of Medical Genetics. 2022.

PURPOSE: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. METHODS: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. RESULTS: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. CONCLUSION: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.

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19. Song C, Jiang ZQ, Hu LF, Li WH, Liu XL, Wang YY, Jin WY, Zhu ZW. A machine learning-based diagnostic model for children with autism spectrum disorders complicated with intellectual disability. Frontiers in psychiatry. 2022; 13: 993077.

BACKGROUND: Early detection of children with autism spectrum disorder (ASD) and comorbid intellectual disability (ID) can help in individualized intervention. Appropriate assessment and diagnostic tools are lacking in primary care. This study aims to explore the applicability of machine learning (ML) methods in diagnosing ASD comorbid ID compared with traditional regression models. METHOD: From January 2017 to December 2021, 241 children with ASD, with an average age of 6.41 ± 1.96, diagnosed in the Developmental Behavior Department of the Children’s Hospital Affiliated with the Medical College of Zhejiang University were included in the analysis. This study trained the traditional diagnostic models of Logistic regression (LR), Support Vector Machine (SVM), and two ensemble learning algorithms [Random Forest (RF) and XGBoost]. Socio-demographic and behavioral observation data were used to distinguish whether autistic children had combined ID. The hyperparameters adjustment uses grid search and 10-fold validation. The Boruta method is used to select variables. The model’s performance was evaluated using discrimination, calibration, and decision curve analysis (DCA). RESULT: Among 241 autistic children, 98 (40.66%) were ASD comorbid ID. The four diagnostic models can better distinguish whether autistic children are complicated with ID, and the accuracy of SVM is the highest (0.836); SVM and XGBoost have better accuracy (0.800, 0.838); LR has the best sensitivity (0.939), followed by SVM (0.952). Regarding specificity, SVM, RF, and XGBoost performed significantly higher than LR (0.355). The AUC of ML (SVM, 0.835 [95% CI: 0.747-0.944]; RF, 0.829 [95% CI: 0.738-0.920]; XGBoost, 0.845 [95% CI: 0.734-0.937]) is not different from traditional LR (0.858 [95% CI: 0.770-0.944]). Only SVM observed a good calibration degree. Regarding DCA, LR, and SVM have higher benefits in a wider threshold range. CONCLUSION: Compared to the traditional regression model, ML model based on socio-demographic and behavioral observation data, especially SVM, has a better ability to distinguish whether autistic children are combined with ID.

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20. West KA, Yin X, Rutherford EM, Wee B, Choi J, Chrisman BS, Dunlap KL, Hannibal RL, Hartono W, Lin M, Raack E, Sabino K, Wu Y, Wall DP, David MM, Dabbagh K, DeSantis TZ, Iwai S. Multi-angle meta-analysis of the gut microbiome in Autism Spectrum Disorder: a step toward understanding patient subgroups. Scientific reports. 2022; 12(1): 17034.

Observational studies have shown that the composition of the human gut microbiome in children diagnosed with Autism Spectrum Disorder (ASD) differs significantly from that of their neurotypical (NT) counterparts. Thus far, reported ASD-specific microbiome signatures have been inconsistent. To uncover reproducible signatures, we compiled 10 publicly available raw amplicon and metagenomic sequencing datasets alongside new data generated from an internal cohort (the largest ASD cohort to date), unified them with standardized pre-processing methods, and conducted a comprehensive meta-analysis of all taxa and variables detected across multiple studies. By screening metadata to test associations between the microbiome and 52 variables in multiple patient subsets and across multiple datasets, we determined that differentially abundant taxa in ASD versus NT children were dependent upon age, sex, and bowel function, thus marking these variables as potential confounders in case-control ASD studies. Several taxa, including the strains Bacteroides stercoris t__190463 and Clostridium M bolteae t__180407, and the species Granulicatella elegans and Massilioclostridium coli, exhibited differential abundance in ASD compared to NT children only after subjects with bowel dysfunction were removed. Adjusting for age, sex and bowel function resulted in adding or removing significantly differentially abundant taxa in ASD-diagnosed individuals, emphasizing the importance of collecting and controlling for these metadata. We have performed the largest (n = 690) and most comprehensive systematic analysis of ASD gut microbiome data to date. Our study demonstrated the importance of accounting for confounding variables when designing statistical comparative analyses of ASD- and NT-associated gut bacterial profiles. Mitigating these confounders identified robust microbial signatures across cohorts, signifying the importance of accounting for these factors in comparative analyses of ASD and NT-associated gut profiles. Such studies will advance the understanding of different patient groups to deliver appropriate therapeutics by identifying microbiome traits germane to the specific ASD phenotype.

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21. Wu H, Chen X, Zhang S, Li J. Gut Microbiota, the Potential Biological Medicine for Prevention, Intervention and Drug Sensitization to Fight Diseases. Nutrients. 2022; 14(20).

As the largest « immune organ » of human beings, the gut microbiota is symbiotic and mutually beneficial with the human host, playing multiple physiological functions. Studies have long shown that dysbiosis of gut microbiota is associated with almost all human diseases, mainly including type II diabetes, cancers, neurodegenerative diseases, autism spectrum disorder, and kidney diseases. As a novel and potential biological medicine for disease prevention, intervention and drug sensitization, the gut microbiota has attracted more and more attention recently. Although the gut microbiota is a comprehensive microbial community, several star bacteria have emerged as possible tools to fight against various diseases. This review aims to elucidate the relevance of gut microbiota dysbiosis with disease occurrence and progression, and mainly summarizes four well-known genera with therapeutic and sensitizing potential, Akkermansia, Bifidobacterium, Lactobacillus and Parabacteroides, thoroughly elucidate their potential value as biological drugs to treat diverse disease.

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22. Xu D, Meng Y, An S, Meng W, Li H, Zhang W, Xue Y, Lan X, Wang X, Li M, Zhang X, Zhihao Z, Zhao Y, Yang H, Zhang C, Zhang R, Zhen Z. Swimming exercise is a promising early intervention for autism-like behavior in Shank3 deletion rats. CNS neuroscience & therapeutics. 2022.

INTRODUCTION: SHANK3 is an important excitatory postsynaptic scaffold protein, and its mutations lead to genetic cause of neurodevelopmental diseases including autism spectrum disorders (ASD), Philan McDermid syndrome (PMS), and intellectual disability (ID). Early prevention and treatment are important for Shank3 gene mutation disease. Swimming has been proven to have a positive effect on neurodegenerative diseases. METHODS: Shank3 gene exon 11-21 knockout rats were intervened by a 40 min/day, 5 day/week for 8-week protocol. After the intervention, the rats were tested to behavioral measures such as learning and memory, and the volume and H-spectrum of the brain were measured using MRI; hippocampal dendritic spines were measured using Golgi staining and laser confocal. RESULTS: The results showed that Shank3-deficient rats had significant deficits in social memory, object recognition, and water maze learning decreased hippocampal volume and number of neurons, and lower levels of related scaffold proteins and receptor proteins were found in Shank3-deficient rats. CONCLUSION: It is suggested that early swimming exercise has a positive effect on Shank3 gene-deficient rats, which provides a new therapeutic strategy for the prevention and recovery of neurodevelopmental disorders.

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