1. Al-Ayadhi L, Zayed N, Bhat RS, Moubayed NMS, Al-Muammar MN, El-Ansary A. The use of biomarkers associated with leaky gut as a diagnostic tool for early intervention in autism spectrum disorder: a systematic review. Gut pathogens. 2021; 13(1): 54.

BACKGROUND: Innovative research highlighted the probable connection between autism spectrum disorder (ASD) and gut microbiota as many autistic individuals have gastrointestinal problems as co-morbidities. This review emphasizes the role of altered gut microbiota observed frequently in autistic patients, and the mechanisms through which such alterations may trigger leaky gut. MAIN BODY: Different bacterial metabolite levels in the blood and urine of autistic children, such as short-chain fatty acids, lipopolysaccharides, beta-cresol, and bacterial toxins, were reviewed. Moreover, the importance of selected proteins, among which are calprotectin, zonulin, and lysozyme, were discussed as biomarkers for the early detection of leaky gut as an etiological mechanism of ASD through the less integrative gut-blood-brain barriers. Disrupted gut-blood-brain barriers can explain the leakage of bacterial metabolites in these patients. CONCLUSION: Although the cause-to-effect relationship between ASD and altered gut microbiota is not yet well understood, this review shows that with the consumption of specific diets, definite probiotics may represent a noninvasive tool to reestablish healthy gut microbiota and stimulate gut health. The diagnostic and therapeutic value of intestinal proteins and bacterial-derived compounds as new possible biomarkers, as well as potential therapeutic targets, are discussed.

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2. Azad G, Holingue C, Pfeiffer D, Dillon E, Reetzke R, Kalb L, Menon D, Hong JS, Landa R. The influence of race on parental beliefs and concerns during an autism diagnosis: A mixed-method analysis. Autism : the international journal of research and practice. 2021: 13623613211044345.

The goal of this study was to examine if there were differences between races in parental concern and belief about autism spectrum disorder (ASD) and the perspectives of clinicians. We studied 489 children with ASD who were having their first evaluation at an ASD clinic. Parents of White children most often believed that their child had ASD. However, White children whose parents believed the child had ASD were less severe in their symptoms. Parents of Black/African American or Hispanic children were more likely to have concerns about communication than parents of White children. In Hispanic families, parental concern about social communication was related to more severe symptoms in children. We discuss the implications of our findings for diagnosis.

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3. Bennett HJ, Jones T, Valenzuela KA, Haegele JA. Coordination variability during running in adolescents with autism spectrum disorder. Autism : the international journal of research and practice. 2021: 13623613211044395.

Walking and running are popular forms of physical activity that involve the whole body (pelvis/legs and arms/torso) and are coordinated by the neuromuscular system, generally without much conscious effort. However, autistic persons tend not to engage in sufficient amounts of these activities to enjoy their health benefits. Recent reports indicate that autistic individuals tend to experience altered coordination patterns and increased variability during walking tasks when compared to non-autistic controls. Greater stride-to-stride coordination variability, when the task has not changed (i.e. walking at same speed and on same surface), is likely indicative of motor control issues and is more metabolically wasteful. To date, although, research examining running is unavailable in any form for this population. This study aimed to determine if coordination variability during running differs between autistic adolescents and age, sex, and body mass index matched non-autistic controls. This study found that increased variability exists throughout the many different areas of the body (foot-leg, left/right thighs, and opposite arm-opposite thigh) for autistic adolescents compared to controls. Along with previous research, these findings indicate autistic persons exhibit motor control issues across both forms of locomotion (walking and running) and at multiple speeds. These findings highlight issues with motor control that can be addressed by therapeutic/rehabilitative programming. Reducing coordination variability, inherently lessening metabolic inefficiency, may be an important step toward encouraging autistic youth to engage in sufficient physical activity (i.e. running) to enjoy physiological and psychological benefits.

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4. Craig DW. Examining the effectiveness of physical activity interventions for children with autism spectrum disorders – A systematic review. Journal of prevention & intervention in the community. 2022; 50(1): 104-15.

Obesity represents a significant threat to quality of life and overall health for typically and a typically developing children with those diagnosed with Autism Spectrum Disorder (ASD) having obesity prevalence at least as high as their typically developing counterparts. A systematic review was conducted on publications describing physical activity interventions with children and adolescents diagnosed with Autism Spectrum Disorder (ASD). We searched Ovid PubMed, Medline, Cochrane Library, PsycINFO, PsycNET, Academic Search Complete, and CINAHL, as well as the citations of publications included in the study. Intervention characteristics such as study design, participant age, sample size, mode, frequency, duration, and intensity of activity were abstracted for review. Sixteen studies were selected for review. Aerobic and anaerobic activities were employed across school and community-based settings. Evidence suggests that increasing physical activity in children and adolescents with ASD is likely to improve BMI and physical fitness.

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5. Farmer CA, Thurm AE, Honnekeri B, Kim P, Swedo SE, Han JC. The contribution of platelets to peripheral BDNF elevation in children with autism spectrum disorder. Scientific reports. 2021; 11(1): 18158.

Brain-derived neurotrophic factor (BDNF), a key peptide in neurocognitive development, has been reported to be elevated in the serum of children with autism spectrum disorder (ASD). In a few studies, however, no differences or the converse have been documented. As a secondary analysis of a natural history study, we examined differences in ELISA serum BDNF between a group of children aged 1 to 9 years (69% white) with ASD (n = 94) and those with typical development (n = 52) or non-ASD developmental delay (n = 21), while accounting for the potential confounding effects of platelet quantity. Platelet counts were measured within 4 h of blood draw using an automated cell counter. Taqman single nucleotide polymorphism (SNP) assays were used to genotype 11 SNPs within the BDNF locus. Unadjusted mean BDNF concentration was higher in children with ASD than in children with typical development (standardized mean difference = 0.23; 95% CI 0.07, 0.38), but not children with non-ASD developmental delay. The magnitude of this difference was reduced after adjusting for platelet count (standardized mean difference = 0.18; 95% CI 0.02, 0.33). Although some BDNF SNPs were related to BDNF concentration, the distributions of these genotypes did not differ across diagnostic groups. This study replicates previous work suggesting that average serum BDNF concentration is higher in ASD compared to typical development, and extends that work by highlighting the potentially confounding role of platelet counts. The etiology of platelet count differences warrants further elucidation. Nonetheless, our results suggest that elevation in BDNF may be partially explained by higher platelet counts in children with ASD, an association that should be considered in future analysis and interpretation.Registration: NCT00298246.

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6. Gangfuß A, Lochmüller H, Töpf A, O’Heir E, Horvath R, Kölbel H, Schweiger B, Schara-Schmidt U, Roos A. A de novo CSDE1 variant causing neurodevelopmental delay, intellectual disability, neurologic and psychiatric symptoms in a child of consanguineous parents. American journal of medical genetics Part A. 2022; 188(1): 283-91.

CSDE1 encodes the cytoplasmic cold shock domain-containing protein E1 (CSDE1), which is highly conserved across species and functions as an RNA-binding protein involved in translationally coupled mRNA turnover. CSDE1 displays a bidirectional role: promoting and repressing the translation of RNAs but also increasing and decreasing the abundance of RNAs. Preclinical studies highlighted an involvement of CSDE1 in different forms of cancer. Moreover, CSDE1 is highly expressed in human embryonic stem cells and plays a role in neuronal migration and differentiation. A genome-wide association study suggested CSDE1 as a potential autism-spectrum disorder risk gene. A multicenter next generation sequencing approach unraveled likely causative heterozygous variants in CSDE1 in 18 patients, identifying a new autism spectrum disorder-related syndrome consisting of autism, intellectual disability, and neurodevelopmental delay. Since then, no further patients with CSDE1 variants have been reported in the literature. Here, we report a 9.5-year-old girl from a consanguineous family of Turkish origin suffering from profound delayed speech and motor development, moderate intellectual disability, neurologic and psychiatric symptoms as well as hypoplasia of corpus callosum and mildly reduced brain volume on brain magnetic resonance imaging associated with a recurrent de novo mutation in CSDE1 (c.367C > T; p.R123*) expanding the phenotypical spectrum associated with pathogenic CSDE1 variants.

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7. Kwag R, Lee J, Kim D, Lee H, Yeom M, Woo J, Cho Y, Kim HJ, Kim J, Keum G, Jeon B, Choo H. Discovery of G Protein-Biased Antagonists against 5-HT(7)R. Journal of medicinal chemistry. 2021; 64(18): 13766-79.

5-HT(7)R belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of the neurotransmitter serotonin (5-HT). To develop selective and biased 5-HT(7)R ligands, we designed and synthesized a series of pyrazolyl-diazepanes 2 and pyrazolyl-piperazines 3, which were evaluated for binding affinities to 5-HTR subtypes and functional selectivity for G protein and β-arrestin signaling pathways of 5-HT(7)R. Among them, 1-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)-1,4-diazepane 2c showed the best binding affinity for 5-HT(7)R and selectivity over other 5-HTR subtypes. It was also revealed as a G protein-biased antagonist. The self-grooming behavior test was performed with 2c in vivo with Shank3(-/-) transgenic (TG) mice, wherein 2c significantly reduced self-grooming duration time to the level of wild-type mice. The results suggest that 5-HT(7)R could be a potential therapeutic target for treating autism spectrum disorder stereotypy.

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8. Neuhaus E, Lowry SJ, Santhosh M, Kresse A, Edwards LA, Keller J, Libsack EJ, Kang VY, Naples A, Jack A, Jeste S, McPartland JC, Aylward E, Bernier R, Bookheimer S, Dapretto M, Van Horn JD, Pelphrey K, Webb SJ. Resting state EEG in youth with ASD: age, sex, and relation to phenotype. Journal of neurodevelopmental disorders. 2021; 13(1): 33.

BACKGROUND: Identification of ASD biomarkers is a key priority for understanding etiology, facilitating early diagnosis, monitoring developmental trajectories, and targeting treatment efforts. Efforts have included exploration of resting state encephalography (EEG), which has a variety of relevant neurodevelopmental correlates and can be collected with minimal burden. However, EEG biomarkers may not be equally valid across the autism spectrum, as ASD is strikingly heterogeneous and individual differences may moderate EEG-behavior associations. Biological sex is a particularly important potential moderator, as females with ASD appear to differ from males with ASD in important ways that may influence biomarker accuracy. METHODS: We examined effects of biological sex, age, and ASD diagnosis on resting state EEG among a large, sex-balanced sample of youth with (N = 142, 43% female) and without (N = 138, 49% female) ASD collected across four research sites. Absolute power was extracted across five frequency bands and nine brain regions, and effects of sex, age, and diagnosis were analyzed using mixed-effects linear regression models. Exploratory partial correlations were computed to examine EEG-behavior associations in ASD, with emphasis on possible sex differences in associations. RESULTS: Decreased EEG power across multiple frequencies was associated with female sex and older age. Youth with ASD displayed decreased alpha power relative to peers without ASD, suggesting increased neural activation during rest. Associations between EEG and behavior varied by sex. Whereas power across various frequencies correlated with social skills, nonverbal IQ, and repetitive behavior for males with ASD, no such associations were observed for females with ASD. CONCLUSIONS: Research using EEG as a possible ASD biomarker must consider individual differences among participants, as these features influence baseline EEG measures and moderate associations between EEG and important behavioral outcomes. Failure to consider factors such as biological sex in such research risks defining biomarkers that misrepresent females with ASD, hindering understanding of the neurobiology, development, and intervention response of this important population.

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9. Rudling M, Nyström P, Bölte S, Falck-Ytter T. Larger pupil dilation to nonsocial sounds in infants with subsequent autism diagnosis. Journal of child psychology and psychiatry, and allied disciplines. 2021.

BACKGROUND: Studies of infants with an elevated likelihood of autism spectrum disorder can identify basic developmental processes that are associated with subsequently emerging clinical symptoms. Atypical responsiveness to sounds in infancy is such a potential early marker of autism. Here, we used pupillometry to quantify reactivity to social and nonsocial sounds in infants with a subsequent diagnosis. Previous research suggest that pupil dilation reflects attentional alerting, and link it to the locus coeruleus norepinephrine system. METHODS: We measured pupil dilation responses to child-directed speech and the sound of running water; sounds infants often hear in their everyday life. The final sample consisted of 99 ten-month-old infants (52 girls), of whom 68 had an elevated likelihood of autism and 31 were typically developing low-likelihood infants. At follow-up (36 months of age), 18 children in the elevated-likelihood group were diagnosed with autism. RESULTS: Compared to infants without diagnosis, the infants who were subsequently diagnosed with autism had larger pupil dilation when listening to nonsocial sounds, while reactivity to speech was strikingly similar between groups. In the total sample, more pupil dilation to the nonsocial sound was associated with higher levels of autistic symptoms. We also found that on a trial-by-trial basis, across all conditions and groups, more pupil dilation was associated with making fewer gaze shifts. CONCLUSIONS: This study did not find evidence of atypical pupillary reactivity to child-directed speech early in life in autism. Instead, the results suggest that certain nonsocial sounds elicit atypically strong alerting responses in infants with a subsequent autism diagnosis. These findings may have important theoretical and clinical implications.

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10. Smith J, Sulek R, Green CC, Bent CA, Chetcuti L, Bridie L, Benson PR, Barnes J, Hudry K. Relative predictive utility of the original and Autism-Specific Five-Minute Speech Samples for child behaviour problems in autistic preschoolers: A preliminary study. Autism : the international journal of research and practice. 2021: 13623613211044336.

Parental Expressed Emotion refers to the intensity and nature of emotion shown when a parent talks about their child, and has been linked to child behaviour outcomes. Parental Expressed Emotion has typically been measured using the Five-Minute Speech Sample; however, the Autism-Specific Five-Minute Speech Sample was developed to better capture Expressed Emotion for parents of children on the autism spectrum. In each case, parents are asked to talk for 5 min about their child and how they get along with their child. Parents’ statements are then coded for features such as number of positive and critical comments, or statements reflecting strong emotional involvement. While both the Five-Minute Speech Sample and Autism-Specific Five-Minute Speech Sample have been used with parents of autistic school-aged children, their relative usefulness for measuring Expressed Emotion in parents of preschool-aged children – including their links to child behaviour problems in this group – is unclear. We collected speech samples from 51 parents of newly diagnosed autistic preschoolers to investigate similarities and differences in results from the Five-Minute Speech Sample and Autism-Specific Five-Minute Speech Sample coding schemes. This included exploring the extent to which the Five-Minute Speech Sample and Autism-Specific Five-Minute Speech Sample, separately, or together, predicted current and future child behaviour problems. While the two measures were related, we found only the Autism-Specific Five-Minute Speech Sample – but not the Five-Minute Speech Sample – was related to child behavioural challenges. This adds support to the suggestion that the Autism-Specific Five-Minute Speech Sample may be a more useful measure of parental Expressed Emotion in this group, and provides a first step towards understanding how autistic children might be better supported by targeting parental Expressed Emotion.

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11. Van Nuland A, Reddy T, Quassem F, Vassalli JD, Berg AT. PACS1-Neurodevelopmental disorder: clinical features and trial readiness. Orphanet journal of rare diseases. 2021; 16(1): 386.

BACKGROUND: PACS1-Neurodevelopmental Disorder (PACS1-NDD) is an ultra-rare condition due to a recurrent mutation in the PACS1 gene. Little systematically collected data exist about the functional abilities and neurodevelopmental morbidities in children with PACS1-NDD METHODS: Parents of individuals with PACS1-NDD completed an on-line survey designed collaboratively by researchers, parents, and clinicians. Analyses focused on those with a confirmed R203W variant. RESULTS: Of 35 individuals with confirmed variants, 18 (51%) were female. The median age was 8 years (interquartile range 4.5-15). Seventeen (49%) had a diagnosis of epilepsy. Twelve (40%, of 30 responding to the question) reported autism and (N = 11/30, 37%) reported features of autism. Most children walked independently (N = 29/32, 91%), had a pincer grasp (N = 23/32, 72%), could feed themselves independently (N = 15/32, 47%), and used speech (N = 23/32, 72%). Sixteen of twenty-nine (55%) had simple pre-academic skills. Neither epilepsy nor autism was associated with functional abilities or other clinical features (all P > 0.05). CONCLUSIONS: PACS1-NDD is a moderately-severe intellectual disability syndrome in which seizures occur but are not a defining or primary feature. Successful precision medicine clinical trials for this ultra-rare disorder must target important core features of this disorder and utilize assessment tools commensurate with the level of function in this clinical population.

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12. Wang Q, Hu K, Wang M, Zhao Y, Liu Y, Fan L, Liu B. Predicting brain age during typical and atypical development based on structural and functional neuroimaging. Human brain mapping. 2021; 42(18): 5943-55.

Exploring typical and atypical brain developmental trajectories is very important for understanding the normal pace of brain development and the mechanisms by which mental disorders deviate from normal development. A precise and sex-specific brain age prediction model is desirable for investigating the systematic deviation and individual heterogeneity of disorders associated with atypical brain development, such as autism spectrum disorders. In this study, we used partial least squares regression and the stacking algorithm to establish a sex-specific brain age prediction model based on T1-weighted structural magnetic resonance imaging and resting-state functional magnetic resonance imaging. The model showed good generalization and high robustness on four independent datasets with different ethnic information and age ranges. A predictor weights analysis showed the differences and similarities in changes in structure and function during brain development. At the group level, the brain age gap estimation for autistic patients was significantly smaller than that for healthy controls in both the ABIDE dataset and the healthy brain network dataset, which suggested that autistic patients as a whole exhibited the characteristics of delayed development. However, within the ABIDE dataset, the premature development group had significantly higher Autism Diagnostic Observation Schedule (ADOS) scores than those of the delayed development group, implying that individuals with premature development had greater severity. Using these findings, we built an accurate typical brain development trajectory and developed a method of atypical trajectory analysis that considers sex differences and individual heterogeneity. This strategy may provide valuable clues for understanding the relationship between brain development and mental disorders.

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13. Weaver LA, Bingham E, Luo K, Juárez AP, Taylor JL. What do we really mean by « inclusion? »: The importance of terminology when discussing approaches to community engagement. Autism : the international journal of research and practice. 2021; 25(8): 2149-51.

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