1. Ash RT, Buffington SA, Park J, Suter B, Costa-Mattioli M, Zoghbi HY, Smirnakis SM. Inhibition of Elevated Ras-MAPK Signaling Normalizes Enhanced Motor Learning and Excessive Clustered Dendritic Spine Stabilization in the MECP2-Duplication Syndrome Mouse Model of Autism. eNeuro. 2021; 8(4).

The inflexible repetitive behaviors and « insistence on sameness » seen in autism imply a defect in neural processes controlling the balance between stability and plasticity of synaptic connections in the brain. It has been proposed that abnormalities in the Ras-ERK/MAPK pathway, a key plasticity-related cell signaling pathway known to drive consolidation of clustered synaptic connections, underlie altered learning phenotypes in autism. However, a link between altered Ras-ERK signaling and clustered dendritic spine plasticity has yet to be explored in an autism animal model in vivo The formation and stabilization of dendritic spine clusters is abnormally increased in the MECP2-duplication syndrome mouse model of syndromic autism, suggesting that ERK signaling may be increased. Here, we show that the Ras-ERK pathway is indeed hyperactive following motor training in MECP2-duplication mouse motor cortex. Pharmacological inhibition of ERK signaling normalizes the excessive clustered spine stabilization and enhanced motor learning behavior in MECP2-duplication mice. We conclude that hyperactive ERK signaling may contribute to abnormal clustered dendritic spine consolidation and motor learning in this model of syndromic autism.

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2. Burrows CA, Bodfish JW, Wolff JJ, Vollman EP, Altschuler MR, Botteron KN, Dager SR, Estes AM, Hazlett HC, Pruett JR, Jr., Schultz RT, Zwaigenbaum L, Piven J, Elison JT. Cataloguing and characterizing interests in typically developing toddlers and toddlers who develop ASD. Autism research : official journal of the International Society for Autism Research. 2021; 14(8): 1710-23.

Intense interests are common in children with and without autism spectrum disorder (ASD), and little research has characterized aspects of interests that are unique to or shared among children with and without ASD. We aimed to characterize interests in a sample of infants at high-familial-risk (HR) and low-familial-risk (LR) for ASD using a novel interview. Participants included HR siblings who were diagnosed with ASD at 24 months (HR-ASD, n = 56), HR siblings who did not receive an ASD diagnosis at 24 months (HR-Neg, n = 187), and a LR comparison group (n = 109). We developed and collected data with the Intense Interests Inventory at 18- and 24-months of age, a semi-structured interview that measures intensity and peculiarity of interests in toddlers and preschool-aged children. Intensity of interests differed by familial risk at 24 months, with HR-ASD and HR-Neg groups demonstrating equivalent intensity of interests that were higher than the LR group. By contrast, peculiarity of interest differed by ASD diagnosis, with the HR-ASD group showing more peculiar interests than the HR-Neg and LR groups at 24 months. At 18 months the HR-ASD group had more peculiar interests than the LR group, though no differences emerged in intensity of interests. This measure may be useful in identifying clinically-relevant features of interests in young children with ASD. We also replicated previous findings of males showing more intense interests at 18 months in our non-ASD sample. These results reveal new information about the nature of interests and preoccupations in the early autism phenotype. LAY SUMMARY: Intense interests are common in young children with autism and their family members. Intense interests are also prevalent among typically-developing children, and especially boys. Here we catalog interests and features of these interests in a large sample of toddlers enriched for autism risk. Children who had family members with autism had more intense interests, and those who developed autism themselves had more unusual interests at 24 months. These results highlight the importance of different aspects of interest in autism.

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3. De Clercq LE, Prinzie P, Warreyn P, Soenens B, Dieleman LM, De Pauw SSW. Expressed Emotion in Families of Children With and Without Autism Spectrum Disorder, Cerebral Palsy and Down Syndrome: Relations with Parenting Stress and Parenting Behaviors. Journal of autism and developmental disorders. 2022; 52(4): 1789-806.

This study examined the family emotional climate as assessed by Five Minute Speech Samples and the relation with parenting stress and parenting behaviors among parents of children (6-17 years, 64.7% boys) with autism spectrum disorder, cerebral palsy, Down syndrome, and without any known disability (n = 447). The large majority of parents (79%) showed low levels of Expressed Emotion, an indicator of a positive family climate. In all groups, more Emotional Over-involvement, more Criticism and fewer expressions of Warmth were associated with higher levels of parenting stress. Across groups, Emotional Over-involvement was related to more autonomy-supportive parenting, Criticism to more psychologically controlling and overreactive parenting, and Warmth was associated with more responsive and less psychologically controlling and overreactive parenting.

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4. Eltokhi A, Gonzalez-Lozano MA, Oettl LL, Rozov A, Pitzer C, Röth R, Berkel S, Hüser M, Harten A, Kelsch W, Smit AB, Rappold GA, Sprengel R. Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders. Molecular psychiatry. 2021; 26(11): 6482-504.

Mutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca(2+)-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused by SHANK2 mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.

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5. Erbs E, Fenger-Grøn J, Jacobsen CM, Lildballe DL, Rasmussen M. Spontaneous rescue of a FMR1 repeat expansion and review of deletions in the FMR1 non-coding region. European journal of medical genetics. 2021; 64(8): 104244.

Fragile X syndrome (FXS) is caused by CGG-repeat expansion in the 5′ UTR of FMR1 of >200 repeats. Rarely, FXS is caused by deletions; however, it is not clear whether deletions including only the non-coding region of FMR1 are pathogenic. We report a deletion in the 5′ UTR of FMR1 in an unaffected male infant and review 12 reported deletions involving only the non-coding region of FMR1. Genetic testing was requested in a male infant born to a mother harbouring a FMR1 full mutation. The maternal grandmother carried a FMR1 premutation. FMR1 CGG repeats were analysed using repeat-primed PCR. Only a short PCR fragment was amplified and subsequent Sanger sequencing detected an 88 bp deletion in hemizygous form. The deletion included all CGG repeats and flanking sequences but no FMR1 exons. Linkage analysis using STR markers revealed that the deletion had occurred on the allele, which was expanded in the mother and the maternal grandmother. Reverse transcription and quantitative PCR showed normal FMR1 mRNA levels. Grønskov et al. reported a 157 bp deletion of all CGG repeats and flanking sequences in a female without FXS hemizygous for the FMR1 gene due to a deletion on the other X chromosome. Protein expression was unaffected by the deletion. The reported deletion comprises the deletion detected in the male infant. At almost 2 years of age he is unaffected. Based on these observations and the normal FMR1 mRNA level, we conclude that a spontaneous rescue of an FMR1 repeat expansion has occurred.

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6. Licari MK, Varcin K, Hudry K, Leonard HC, Alvares GA, Pillar SV, Stevenson PG, Cooper MN, Whitehouse AJO. The course and prognostic capability of motor difficulties in infants showing early signs of autism. Autism research : official journal of the International Society for Autism Research. 2021; 14(8): 1759-68.

Delays within the motor domain are often overlooked as an early surveillance marker for autism. The present study evaluated motor difficulties and its potential as an early predictive marker for later autism likelihood in a cohort of infants (N = 96) showing early behavioral signs of autism aged 9-14 months. The motor domain was evaluated using the motor subscales of the Mullen Scales of Early Learning at baseline, and at a 6-month follow-up. The Autism Diagnostic Observation Schedule – Toddler Module (ADOS-T) was completed at follow-up as a measure of autism likelihood. Motor difficulties were common at baseline, with 63/96 (65.6%) infants scoring very low or below average in the gross motor domain and 29/96 (30.2%) in the fine motor domain. At follow-up, gross motor difficulties had resolved for many, with 23/63 (36.5%) infants maintaining these difficulties. Fine motor difficulties resolved in fewer infants, with 20/29 (69.0%) continuing to present with fine motor delays at follow-up. Adjusted linear regression models suggested that fine motor scores at baseline (β = -0.12, SE = 0.04) and follow-up (β = -0.17, SE = 0.05) were associated with higher ADOS-T scores; with difficulties across both timepoints (β = 5.60, SE = 1.35) the strongest (largest in magnitude) association with ADOS-T scores of the predictors examined. Motor difficulties are prominent in children displaying emerging signs of autism, with persistent fine motor difficulties predictive of the developing autism phenotype. The findings indicate the potential clinical value of including evaluation of motor skills within early autism surveillance measures. LAY SUMMARY: This prospective study evaluated motor development over a 6-month period in infants showing early behavioral signs of autism. Atypical motor development was a common feature of infants showing early signs of autism and persistent fine motor difficulties were predictive of the emerging autism phenotype.

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7. Loomba N, Beckerson ME, Ammons CJ, Maximo JO, Kana RK. Corpus callosum size and homotopic connectivity in Autism spectrum disorder. Psychiatry research Neuroimaging. 2021; 313: 111301.

By examining how morphology of the corpus callosum (CC) in autism spectrum disorder (ASD) may affect functional communication across hemispheres, we hope to provide new insights into the structure-function relationship in the brain. We used a sample of 94 participants from the Autism Brain Imaging Data Exchange (ABIDE) database (55 typically-developing (TD) and 39 with ASD). The CC was segmented into five sub-regions (anterior, mid-anterior, central, mid-posterior, posterior) using FreeSurfer software, which were further examined for group differences. The total volume and specific sub-region volumes of the CC, and interhemispheric (homotopic) functional connectivity were calculated, along with the relationship between volume and connectivity. These measures were correlated with social ability assessed by the Social Responsiveness Scale (SRS). The central sub-region of CC was significantly smaller in ASD, although there was no group difference in total CC volume. ASD participants also showed stronger homotopic connectivity in the superior frontal gyrus. SRS scores were negatively correlated with the CC central sub-region volumes in ASD. The findings of this study add to the body of research showing morphological differences in the CC in ASD as well as connectivity differences. The absence of a significant relationship between structure and homotopic functional connectivity aligns with previous findings.

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8. Rashaid AHB, Nusair SD, Alqhazo MT, Adams JB, Abu-Dalo MA, Bashtawi MA. Heavy metals and trace elements in scalp hair samples of children with severe autism spectrum disorder: A case-control study on Jordanian children. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2021; 67: 126790.

BACKGROUND: Elemental analysis has been increasingly used for biomonitoring heavy metals and trace elements. METHODS: This study monitored the levels of two heavy metals (Al and Pb), and seven trace elements (Macroelements Mg, K, P and Ca; Microelements Zn, Cu, Fe) in scalp hair of 57 children with severe autism spectrum disorder (ASD) and 50 age-matched controls, using Inductively Coupled Plasma Atomic Emission Spectrophotometry (ICP-AES). RESULTS: Compared to controls, significantly higher levels of Al (p =  0.001), Pb (p =  0.001) and K (p =  0.021), with lower levels of Mg and Zn (p = 0.038) were observed for the ASD group. ASD boys had higher levels of Al (p =  0.001), Pb (p =  0.001) and K (p =  0.017) than control boys, while ASD girls had higher Pb levels (p =  0.005) than control girls. The ASD subgroup exposed to passive smokers had higher levels of Al (p =  0.033) and Pb (p =  0.001, and the ASD subgroup not exposed to passive smoke had higher levels of Al (p =  0.011), Pb (p =  0.001), K (p =  0.003); and lower levels of Mg (p =  0.011) than their controls. Other confounding factors and the correlation between these elements were also investigated. CONCLUSION: This data suggests that exposure to Al and Pb, increase intake of K, and decreased intake of magnesium and zinc, may contribute to ASD etiology.

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9. Vanpaemel W, Bayer J. Prototype-based category learning in autism: A review. Neuroscience and biobehavioral reviews. 2021; 127: 607-18.

Similarity-based categorization, as an important cognitive skill, can be performed by abstracting a categories’ central tendency, the so-called prototype, or by memorizing individual exemplars of a category. The flexible selection of an appropriate strategy is crucial for effective cognitive functioning. The detail-focused cognitive style in individuals with autism spectrum disorders (ASD) has been hypothesized to specifically impair prototype-based categorization but to leave exemplar-based categorization unimpaired. We first give an overview of approaches to investigate prototype-based abstraction in the prototype-distortion task, with an emphasis on model-based approaches suitable to discern the two strategies on the individual level. The second part summarizes literature speaking to prototype-based categorization in ASD using that task. Despite considerable inconsistencies, most studies appear to confirm that autistic individuals have more difficulties to perform prototype-distortion tasks than non-autistic individuals. We highlight how inconsistencies in literature can be resolved by taking the differences in task designs into account. The current review illustrates the need for sensitive computational approaches, suitable to detect hidden individual differences and potential compensatory strategies.

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10. Wieckowski AT, de Marchena A, Algur Y, Nichols L, Fernandes S, Thomas RP, McClure LA, Dufek S, Fein D, Adamson LB, Stahmer A, Robins DL. The first five minutes: Initial impressions during autism spectrum disorder diagnostic evaluations in young children. Autism research : official journal of the International Society for Autism Research. 2021; 14(9): 1923-34.

Diagnosticians report that autism spectrum disorder (ASD) is immediately apparent in some, but not all, children ultimately diagnosed. Clinicians’ initial diagnostic impressions have implications for ASD early detection, yet the literature raises questions about their accuracy. This study explores diagnostic impressions of ASD specialists made within the first 5 minutes of meeting a young child and investigates factors associated with the match between initial impressions and final diagnoses. Participants were children (n = 294, aged 12-53 months) referred for an ASD evaluation as part of multi-site ASD screening studies. After 5 minutes observing each child, clinicians with expertise diagnosing ASD recorded if they thought the child would meet criteria for ASD following a complete evaluation, and recorded their confidence in this impression. Clinicians’ initial impressions matched the final diagnosis in 81% of cases. Ninety-two percent of cases initially thought to have ASD met criteria following a full evaluation; however, 24% of cases initially thought not to have ASD also met criteria, suggesting a high miss rate. Clinicians were generally confident in their initial impressions, reporting highest confidence for children initially thought correctly not to have ASD. ASD behavioral presentation, but not demographic characteristics or developmental level, were associated with matching initial impression and final diagnosis, and confidence. Brief observations indicating ASD should trigger referral to intervention services, but are likely to under-detect positive cases and should not be used to rule out ASD, highlighting the need to incorporate information beyond initial clinical impression. LAY SUMMARY: When children come in for an autism evaluation, clinicians often form early impressions-before doing any formal testing-about whether the child has autism. We studied how often these early impressions match the final diagnosis, and found that clinicians could not easily rule out autism (many children who initially appeared not to have autism were ultimately diagnosed), but were generally accurate ruling in autism (when a child appeared to have autism within 5 minutes, they were almost always so diagnosed).

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11. Wright CF, Quaife NM, Ramos-Hernández L, Danecek P, Ferla MP, Samocha KE, Kaplanis J, Gardner EJ, Eberhardt RY, Chao KR, Karczewski KJ, Morales J, Gallone G, Balasubramanian M, Banka S, Gompertz L, Kerr B, Kirby A, Lynch SA, Morton JEV, Pinz H, Sansbury FH, Stewart H, Zuccarelli BD, Cook SA, Taylor JC, Juusola J, Retterer K, Firth HV, Hurles ME, Lara-Pezzi E, Barton PJR, Whiffin N. Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms. American journal of human genetics. 2021; 108(6): 1083-94.

Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5′ untranslated regions (5′ UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5′ UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5′ UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.

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12. Zhang XH, Yang T, Chen J, Chen L, Dai Y, Jia FY, Wu LJ, Hao Y, Li L, Zhang J, Ke XY, Yi MJ, Hong Q, Chen JJ, Fang SF, Wang YC, Wang Q, Jin CH, Li TY. [Association between serum trace elements and core symptoms in children with autism spectrum disorder: a national multicenter survey]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2021; 23(5): 445-50.

OBJECTIVE: To study the association of serum levels of trace elements with core symptoms in children with autism spectrum disorder (ASD). METHODS: From September 2018 to September 2019, an investigation was performed for 1 020 children with ASD and 1 038 healthy children matched for age and sex in the outpatient service of grade A tertiary hospitals and special education institutions in 13 cities of China. Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Childhood Autism Rating Scale (CARS) were used to assess the core symptoms of the children with ASD. The inductively coupled plasma mass spectrometry was used to measure serum levels of trace elements magnesium, iron, copper, and zinc. RESULTS: The children with ASD had significantly lower serum levels of magnesium, copper, and zinc than the healthy children (P < 0.05). The children with severe ASD had significantly lower serum levels of magnesium and zinc than those with mild-to-moderate ASD (P < 0.05). The results of partial correlation analysis showed that serum magnesium level was negatively correlated with the total score of ABC and the score of communication (r=-0.318 and -0.282 respectively; P 0.001), and serum zinc level was negatively correlated with the total score of ABC and the scores of communication and somatic movement (r=-0.221, -0.270, and -0.207 respectively; P < 0.001). CONCLUSIONS: The serum levels of magnesium and zinc may be associated with core symptoms in children with ASD, which requires further studies. The nutritional status of trace elements should be monitored for children with ASD in clinical practice. Publisher: Abstract available from the publisher. chi.

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