1. Abdel Ghafar MA, Abdelraouf OR, Abdelgalil AA, Seyam MK, Radwan RE, El-Bagalaty AE. Quantitative Assessment of Sensory Integration and Balance in Children with Autism Spectrum Disorders: Cross-Sectional Study. Children (Basel, Switzerland). 2022; 9(3).

Postural stability is dependent on the interpretation of external inputs acquired by sensory information processes, such as visual, vestibular, and proprioceptive systems, in order to accomplish neuromuscular control, balance maintenance, and appropriate motor response. A defect in any of these systems, or in the integration of information given by these systems, might threaten their capacity to maintain balance. Therefore, the purpose of this study was to investigate the sensory integration and balance using the Biodex balance system (BBS) in children with autism spectrum disorder (ASD) during the static posture. Seventy-four children from both sexes, 38 with ASD matched with 36 typically developed (TD) children as a control group, were included in the study. Using the Biodex balance system, the postural sway was evaluated through the modified Clinical Test of Sensory Integration and Balance (m-CTSIB) during quiet standing. In this test, four different situations were considered from standing position: eyes open/firm surface, eyes closed/firm surface, eyes open/foam surface, and eyes closed/foam surface. ASD children showed a significant increase in postural sway under all tested conditions when compared to the TD children group, especially for the conditions in which visual and somatosensory inputs were disrupted (p-value < 0.05). These results provide evidence that postural stability decreased in ASD children. Under static postural challenges, the current study’s findings imply that children diagnosed with ASD have postural control deficiencies, especially for the conditions in which visual and somatosensory input was disrupted. Further research must be conducted to find the best balance training program for ASD cases using the Biodex balance system and considering its impact on motor skills.

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2. Abualhommos AK, Aldoukhi AH, Alyaseen AAA, AlQanbar FA, Alshawarib N, Almuhanna ZA. Community Knowledge about Autism Spectrum Disorder in the Kingdom of Saudi Arabia. International journal of environmental research and public health. 2022; 19(6).

OBJECTIVES: To explore the knowledge of the general community in Saudi Arabia about autism spectrum disorder. METHOD: A cross-sectional study was conducted for the period between June and September 2021 in Saudi Arabia using an online questionnaire tool. The questionnaire tool was developed based on a literature review. The questionnaire tool consists of 34 items that assess knowledge about autism spectrum disorder in terms of its etiology, autistic patient features, autistic children’s abilities and needs, and autistic adults’ abilities and needs. The total score for each subscale was used to define the level of knowledge of it. Correct answers were given a score of one, and the total score for each subscale was used to describe the level of knowledge of it. Logistic regression was used to identify predictors of good knowledge about autism spectrum disorder (defined as a total score equal or above the mean score of the study participants). RESULTS: This study enlisted the participation of 500 people. The participants’ overall understanding of autism spectrum disorder was moderate, with a mean score of 20.6 (SD: 5.6) out of 34, or 60.6%. The participants’ knowledge levels ranged from 32.2% to 77.5%. The items about the abilities and needs of adolescents and young people with autism had the highest degree of knowledge (77.5%). The items about autism’s causes had the lowest level of expertise (32.2%). When compared to others, females, those with a master’s degree, and those working in the healthcare field had a higher likelihood of knowing more about the autism spectrum condition. (p ≤ 0.05). CONCLUSION: Knowledge about autism spectrum disorder in Saudi Arabia is moderate. Social media channels and healthcare centers should be used to conduct educational campaigns for parents. The goal of this educational campaign should be to improve parents’ ability to recognize the causes of autism.

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3. Alyami HS, Naser AY, Alyami MH, Alharethi SH, Alyami AM. Knowledge and Attitudes toward Autism Spectrum Disorder in Saudi Arabia. International journal of environmental research and public health. 2022; 19(6).

AIMS: The diagnosis of autism spectrum disorder (ASD) is not easy as there is no direct test that exists to establish such a diagnosis. Increasing community and healthcare professional knowledge of the ASD spectrum is crucial because it will encourage parents of ASD children to seek screening and diagnosis from a specialist, allowing for better early detection and treatment. This study explored the knowledge of the general population in Saudi Arabia regarding ASD and assessed variables associated with an accurate understanding of ASD. METHODS: A total of 769 participants were involved in this cross-sectional study, which was conducted in Saudi Arabia between November 2021 and February 2022 using an online survey tool to explore the knowledge of the general population in Saudi Arabia regarding typical child development and ASD. A binary logistic regression analysis was used to determine factors affecting participants’ knowledge of autism. RESULTS: Overall, the study participants showed a weak level of knowledge about autism with a mean score of 5.9 (SD: 3.1), comprising 34.7% of the total maximum obtainable score. Participants with a middle income category of 5000-7500 SR are less likely to be knowledgeable about autism compared to others (OR: 0.60 (95% CI: 0.39-0.92)) (p-value = 0.020). CONCLUSION: The participants in our study showed limited knowledge about autism. Government funds should be made available to facilitate educational services for ASD children. More funding and resources should be allocated by the government to provide assistance for children with special needs, and changes in public facilities are required to meet the demands of ASD patients. Through an informed educational effort, various media platforms should assist in improving the community’s understanding of ASD and their attitude toward ASD patients. Educational campaigns should focus on enhancing the public’s knowledge about ASD treatment and etiology.

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4. Awadu JE, Sikorskii A, Zalwango S, Coventry A, Giordani B, Ezeamama AE. Developmental Disorder Probability Scores at 6-18 Years Old in Relation to In-Utero/Peripartum Antiretroviral Drug Exposure among Ugandan Children. International journal of environmental research and public health. 2022; 19(6).

(1) We examined the hypothesis that in utero/peripartum antiretroviral (IPA) exposure may affect the likelihood of developmental disorders-i.e., attention deficit and hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and functional impairment (FI). (2) Children and their primary caregivers were enrolled and followed for 12 months. The sample included 250 children perinatally HIV-infected (CPHIV), 250 children HIV-exposed and uninfected (CHEU) of women living with HIV, and 250 children HIV unexposed and uninfected (CHUU) at 6-18 years of age. CHEU’s IPA exposure -type was established via medical records and categorized as no IPA, single-dose nevirapine with/without zidovudine (SdNVP ± AZT), SdNVP + AZT + Lamivudine (3TC), or combination ART (cART). Developmental disorders were assessed at months 0, 6, and 12 per caregiver response to standardized questions from the third edition of Behavioral Assessment System for Children. Multivariable repeated measures linear regression models estimated standardized mean differences (SMDs) with 95% confidence intervals (95% CI) according to the IPA exposure type relative to CHUU with adjustment for the dyad’s sociodemographic and psychosocial factors. (3) Relative to the CHUU, outcomes were similar for CPHIV/CHEU with cART, SdNVP ± AZT, and no anti-retroviral drug exposure in the peripartum period. For CHEU relative to CHUU, SdNVP + AZT + 3TC exposure was associated with lower resiliency (SMD = -0.26, 95% CI: -0.49, -0.51), and elevated scores on ADHD (SMD = 0.41, 95% CI: 0.12, 0.70), ASD (SMD = 0.40, 95% CI: 0.19, 0.61), and EBD (SMD = 0.32, 95% CI: 0.08, 0.56) probability and functional impairment (SMD = 0.39, 95% CI: 0.18, 0.61) index scores. With the exception of ADHD, the adverse association between SdNVP + AZT + 3TC and outcomes were replicated for CPHIV vs. CHUU. (4) The results provided reassuring evidence that cART exposure in the peripartum period is unlikely to be adversely associated with developmental disorder probability scores in late childhood and adolescent years. However, the peripartum SdNVP + AZT + 3TC exposure associated elevation in developmental disorder probability and functional limitation at 6-18 years of life is a concern.

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5. Barrios-Fernández S, Carlos-Vivas J, Muñoz-Bermejo L, Mendoza-Muñoz M, Apolo-Arenas MD, García-Gómez A, Gozalo M, Adsuar JC. Effects of Square-Stepping Exercise on Motor and Cognitive Skills in Autism Spectrum Disorder Children and Adolescents: A Study Protocol. Healthcare (Basel, Switzerland). 2022; 10(3).

Individuals with autism spectrum disorder (ASD) diagnoses present not only cognitive, emotional, communicative, and social challenges but also movement issues that affect their everyday activities, learning, and leisure. The use of the square-stepping exercise (SSE), a motor program initially created to strengthen the lower limbs of older adults, is spreading because of its advantages (e.g., balance and lower limb strength improvements). A study protocol to assess the SSE effects on motor, sensory, and cognitive skills in Spanish children and adolescents between 6 and 12 years old with ASD diagnoses is presented. A randomised clinical will be performed, recruiting 52 children and adolescents with ASD who will be distributed into two groups: an experimental (n = 26) and a control (n = 26) group. The SSE sessions will be held for 9 weeks (two times per week). The main variable will be balance, which will be measured with the Movement Assessment Battery for Children 2 (MABC2), and secondary outcomes will include sensory processing, attention, and executive functions. Assessments will be carried out before and at the end of the program implementation, including an additional follow up one month later. If this program obtains positive results, it should be implemented in different settings (schools, clinics, associations, etc.) to improve the quality of movement and development in children and adolescents with ASD, as it is an easy-to-use and structured tool.

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6. Brašić JR, Goodman JA, Nandi A, Russell DS, Jennings D, Barret O, Martin SD, Slifer K, Sedlak T, Mathur AK, Seibyl JP, Berry-Kravis EM, Wong DF, Budimirovic DB. Fragile X Mental Retardation Protein and Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome: A Pilot Study. Brain sciences. 2022; 12(3).

Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR(5)) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR(5) expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR(5) expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR(5) expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR(5) expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR(5) expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR(5) expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR(5) expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([(18)F]FPEB), a specific mGluR(5) radioligand for quantitative measurements of the density and the distribution of mGluR(5)s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR(5) expression and FMRP showed that mGluR(5) expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR(5) expression measured by PET with [(18)F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR(5) expression by combining both FMRP levels and mGluR(5) expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR(5) expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions.

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7. Cammarata-Scalisi F, Callea M, Martinelli D, Willoughby CE, Tadich AC, Araya Castillo M, Lacruz-Rengel MA, Medina M, Grimaldi P, Bertini E, Nevado J. Clinical and Genetic Aspects of Phelan-McDermid Syndrome: An Interdisciplinary Approach to Management. Genes. 2022; 13(3).

Phelan-McDermid syndrome (PMS) is a rare, heterogeneous, and complex neurodevelopmental disorder. It is generally caused by a heterozygous microdeletion of contiguous genes located in the distal portion of the long arm of chromosome 22, including the SHANK3 gene. Sequence variants of SHANK3, including frameshift, nonsense mutations, small indels and splice site mutations also result in PMS. Furthermore, haploinsufficiency in SHANK3 has been suggested as the main cause of PMS. SHANK3 is also associated with intellectual disability, autism spectrum disorder and schizophrenia. The phenotype of PMS is variable, and lacks a distinctive phenotypic characteristic, so the clinical diagnosis should be confirmed by genetic analysis. PMS is a multi-system disorder, and clinical care must encompass various specialties and therapists. The role of risperidone, intranasal insulin, insulin growth factor 1, and oxytocin as potential therapeutic options in PMS will be discussed in this review. The diagnosis of PMS is important to provide an appropriate clinical evaluation, treatment, and genetic counseling.

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8. Cassim N, Mylopoulos M, Campbell K, Dempster L. Dental student’s perceptions and experience treating adults with developmental disabilities. Journal of dental education. 2022.

OBJECTIVES: The objective of this study was to investigate the perceptions and experiences of dental students with regards to treating adults with developmental disabilities (AWDDs). METHODS: Semi-structured interviews were conducted with three groups of participants: experts who extensively work with AWDDs (n = 3), students who had no clinical training to treat AWDDs (n = 3), and students who had completed their clinical training to treat AWDDs (n = 8). One-on-one interviews were conducted in-person or via video call with each participant. Interviews were transcribed, coded, and analyzed for themes. RESULTS: Experts described their motivations for working with AWDDs. Students in both groups identified the challenges of working with AWDDs and highlighted the impact of the informal curriculum as well as the increased importance of clinical training. Students who had received clinical training described the clinical rotation as a transformative learning experience that instilled a sense of health advocacy. There was alignment of themes between all three groups in terms of skills desired, acquired, and required to work with AWDDs; however, the students who had received clinical training and the experts differed on their opinion of the relative importance of the skills they developed. CONCLUSIONS: The alignment of perceptions between students and experts is promising and demonstrates the successes of the existing curriculum. The misalignment between students and experts highlights areas in the curriculum that can be improved through adjustments and augmentation.

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9. Davidson J, Gauthier-Signore C, Bishop KP, Wicks C, Monteiro MA, Roy PN, Auzanneau FI. ROESY and (13)C NMR to distinguish between D- and L-rhamnose in the α-D-Manp-(1 → 4)-β-Rhap-(1 → 3) repeating motif. Organic & biomolecular chemistry. 2022; 20(14): 2964-80.

Many children suffering from autism spectrum disorder (ASD) experience gastrointestinal (GI) conditions. Enterocloster bolteae has been regularly detected in the stool of individuals suffering from GI symptoms and autism. Literature has suggested that E. bolteae strains WAL 16351 and WAL 14578 produce an immunogenic capsular polysaccharide (CPS) comprised of disaccharide repeating units: α-D-Man-(1 → 4)-β-Rha-(1 → 3) that could be used for the development of an immunotherapeutic vaccine. Ambiguity in the configuration of rhamnose led to the synthesis of tri- and disaccharide analogues containing D-rhamnose and L-rhamnose, respectively. ROESY-NMR spectra showed that CH(3)-6 of rhamnose and H-2 of mannose in the L-Rha containing disaccharide gave correlation. No such correlation was seen between the CH(3)-6 of rhamnose and the H-2 of mannose in the D-Rha containing trisaccharide. Molecular dynamics studies on hexasaccharide containing L-Rha or D-Rha confirmed that these structures adopt conformations resulting in different distances between the C6-rhamnose and the H-2 mannose of the preceding residue. We also demonstrate that assignment of the absolute configuration of the rhamnosyl residue in the β-Rhap-(1 → 3)-D-Man linkage can be determined using the (13)C chemical shift of C-2 in of D-Mannose. While β-D-Rha will lead to an upfield shift of C-2 due to γ-gauche interaction between H-1 Rha and H-2 Man, β-L-Rha will not. Our results provide insights to distinguish between D- and L-rhamnose in the α-D-Manp-(1 → 4)-β-Rhap-(1 → 3) repeating motif.

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10. Diez-Itza E, Viejo A, Fernández-Urquiza M. Pragmatic Profiles of Adults with Fragile X Syndrome and Williams Syndrome. Brain sciences. 2022; 12(3).

Linguistic phenotypes of individuals with Fragile X (FXS) and Williams (WS) syndromes exhibit various degrees of pragmatic impairment, involving difficulties in social communication and in adapting to conversational principles. The goal of the present study was to explore syndrome-specific pragmatic profiles of adults with FXS and WS based on the assessment of the observance of Gricean maxims of conversation. The participants were 12 Spanish-speaking adults (6 FXS/6 WS), without a diagnosis of ASD, whose extensive naturalistic conversations (71,859 words) were transcribed and coded with the CHILDES/TALKBANK tools and the PREP-CORP pragmatic protocol. Violations of the maxims of conversation were analyzed, and indexes of cooperation and conversational response were obtained. Both groups showed reduced verbal production and repetitive dysfluencies; prominent features in the FXS profile were higher proportion of non-contingent language, perseverations of topic and form, and impulsive conversational responses; in the WS profile, salient characteristics were higher proportion of tangential utterances, reformulations, and conversational responses reflecting overly literal interpretation. Pragmatic profiles of violation of conversational maxims reflect specific communication skills impaired in adults with FXS and WS and raise the need for assessment and intervention methods that specifically address their social communication abilities.

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11. Evans DR, Qiao Y, Trost B, Calli K, Martell S, Jones SJM, Scherer SW, Lewis MES. Complex Autism Spectrum Disorder with Epilepsy, Strabismus and Self-Injurious Behaviors in a Patient with a De Novo Heterozygous POLR2A Variant. Genes. 2022; 13(3).

Autism spectrum disorder (ASD) describes a complex and heterogenous group of neurodevelopmental disorders. Whole genome sequencing continues to shed light on the multifactorial etiology of ASD. Dysregulated transcriptional pathways have been implicated in neurodevelopmental disorders. Emerging evidence suggests that de novo POLR2A variants cause a newly described phenotype called ‘Neurodevelopmental Disorder with Hypotonia and Variable Intellectual and Behavioral Abnormalities’ (NEDHIB). The variable phenotype manifests with a spectrum of features; primarily early onset hypotonia and delay in developmental milestones. In this study, we investigate a patient with complex ASD involving epilepsy and strabismus. Whole genome sequencing of the proband-parent trio uncovered a novel de novo POLR2A variant (c.1367T>C, p. Val456Ala) in the proband. The variant appears deleterious according to in silico tools. We describe the phenotype in our patient, who is now 31 years old, draw connections between the previously reported phenotypes and further delineate this emerging neurodevelopmental phenotype. This study sheds new insights into this neurodevelopmental disorder, and more broadly, the genetic etiology of ASD.

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12. Fallea A, Zuccarello R, Roccella M, Quatrosi G, Donadio S, Vetri L, Calì F. Sensory-Adapted Dental Environment for the Treatment of Patients with Autism Spectrum Disorder. Children (Basel, Switzerland). 2022; 9(3).

PURPOSE: The importance of dental care and oral hygiene is often underestimated in people with autism spectrum disorder (ASD). Comorbidity with dental anxiety is greater in ASD subjects who also show unusual reactions to sensory stimuli. The aim of our study was to assess the efficacy for a sensory-adapted environment and targeted methods in reducing anxiety and positively influencing cooperation in children with ASD during a dental examination or specific treatments. MATERIAL AND METHODS: The sample consisted of 50 Italian children with a diagnosis of ASD (36 males and 14 females; aged 9-10 years) presenting with mild intellectual disability (ID) and verbal language skills. The subjects enrolled in the study had at least two decayed teeth and all were treated in two different dental environments: regular dental environment (RDE) and sensory-adapted dental environment (SADE). RESULTS: 20% of the sample was successfully treated in RDE, while 68% of subjects were successfully treated in SADE. CONCLUSIONS: Results suggest that a sensory-adapted environment positively affects the therapeutic dental treatment in patients with ASD and reaffirm that sensory dysregulation in children with ASD is a crucial factor influencing the successful outcome of oral care.

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13. Frye RE. A Personalized Multidisciplinary Approach to Evaluating and Treating Autism Spectrum Disorder. Journal of personalized medicine. 2022; 12(3).

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder without a known cure. Current standard-of-care treatments focus on addressing core symptoms directly but have provided limited benefits. In many cases, individuals with ASD have abnormalities in multiple organs, including the brain, immune and gastrointestinal system, and multiple physiological systems including redox and metabolic systems. Additionally, multiple aspects of the environment can adversely affect children with ASD including the sensory environment, psychosocial stress, dietary limitations and exposures to allergens and toxicants. Although it is not clear whether these medical abnormalities and environmental factors are related to the etiology of ASD, there is evidence that many of these factors can modulate ASD symptoms, making them a potential treatment target for improving core and associated ASD-related symptoms and improving functional limitation. Additionally, addressing underlying biological disturbances that drive pathophysiology has the potential to be disease modifying. This article describes a systematic approach using clinical history and biomarkers to personalize medical treatment for children with ASD. This approach is medically comprehensive, making it attractive for a multidisciplinary approach. By concentrating on treatable conditions in ASD, it is possible to improve functional ability and quality of life, thus providing optimal outcomes.

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14. Herring J, Johnson K, Richstein J. The Use of « Retardation » in FRAXA, FMRP, FMR1 and Other Designations. Cells. 2022; 11(6).

The European Fragile X Network met in Wroclaw, Poland, November 2021, and agreed to work towards the eradication of the word « retardation » in regard to the naming of the fragile X gene (FRAXA) and protein (FMRP). There are further genes which have « retardation » or abbreviations for « retardation » in their names or full designations, including FMR1, FMR2, FXR1, FXR2, NUFIP1, AFF1, CYFIP1, etc. « Retardation » was commonly used as a term in years past, but now any reference, even in an abbreviation, is offensive. This article discusses the stigmatisation associated with « retardation », which leads to discrimination; the inaccuracy of using « retardation » in these designations; and the breadth of fragile X syndrome being beyond that of neurodiversity. A more inclusive terminology is called for, one which ceases to use any reference to « retardation ». Precedents for offensive gene names being altered is set out. The proposal is to approach the HGNC (HUGO [Human Genome Organisation] Gene Nomenclature Committee) for new terminology to be enacted. Ideas from other researchers in the field are welcomed.

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15. Kuo HY, Liu FC. Pathophysiological Studies of Monoaminergic Neurotransmission Systems in Valproic Acid-Induced Model of Autism Spectrum Disorder. Biomedicines. 2022; 10(3).

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. The core syndromes of ASD are deficits in social communication and self-restricted interests and repetitive behaviors. Social communication relies on the proper integration of sensory and motor functions, which is tightly interwoven with the limbic function of reward, motivation, and emotion in the brain. Monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine, are key players in the modulation of neuronal activity. Owing to their broad distribution, the monoamine neurotransmitter systems are well suited to modulate social communication by coordinating sensory, motor, and limbic systems in different brain regions. The complex and diverse functions of monoamine neurotransmission thus render themselves as primary targets of pathophysiological investigation of the etiology of ASD. Clinical studies have reported that children with maternal exposure to valproic acid (VPA) have an increased risk of developing ASD. Extensive animal studies have confirmed that maternal treatments of VPA include ASD-like phenotypes, including impaired social communication and repetitive behavior. Here, given that ASD is a neurodevelopmental disorder, we begin with an overview of the neural development of monoaminergic systems with their neurochemical properties in the brain. We then review and discuss the evidence of human clinical and animal model studies of ASD with a focus on the VPA-induced pathophysiology of monoamine neurotransmitter systems. We also review the potential interactions of microbiota and monoamine neurotransmitter systems in ASD pathophysiology. Widespread and complex changes in monoamine neurotransmitters are detected in the brains of human patients with ASD and validated in animal models. ASD animal models are not only essential to the characterization of pathogenic mechanisms, but also provide a preclinical platform for developing therapeutic approaches to ASD.

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16. Marques AR, Santos JX, Martiniano H, Vilela J, Rasga C, Romão L, Vicente AM. Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder. Biomedicines. 2022; 10(3).

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with unclear etiology. Many genes have been associated with ASD risk, but the underlying mechanisms are still poorly understood. An important post-transcriptional regulatory mechanism that plays an essential role during neurodevelopment, the Nonsense-Mediated mRNA Decay (NMD) pathway, may contribute to ASD risk. In this study, we gathered a list of 46 NMD factors and regulators and investigated the role of genetic variants in these genes in ASD. By conducting a comprehensive search for Single Nucleotide Variants (SNVs) in NMD genes using Whole Exome Sequencing data from 1828 ASD patients, we identified 270 SNVs predicted to be damaging in 28.7% of the population. We also analyzed Copy Number Variants (CNVs) from two cohorts of ASD patients (N = 3570) and discovered 38 CNVs in 1% of cases. Importantly, we discovered 136 genetic variants (125 SNVs and 11 CNVs) in 258 ASD patients that were located within protein domains required for NMD. These gene variants are classified as damaging using in silico prediction tools, and therefore may interfere with proper NMD function in ASD. The discovery of NMD genes as candidates for ASD in large patient genomic datasets provides evidence supporting the involvement of the NMD pathway in ASD pathophysiology.

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17. Mohammad FK, Palukuri MV, Shivakumar S, Rengaswamy R, Sahoo S. A Computational Framework for Studying Gut-Brain Axis in Autism Spectrum Disorder. Frontiers in physiology. 2022; 13: 760753.

INTRODUCTION: The integrity of the intestinal epithelium is crucial for human health and is harmed in autism spectrum disorder (ASD). An aberrant gut microbial composition resulting in gut-derived metabolic toxins was found to damage the intestinal epithelium, jeopardizing tissue integrity. These toxins further reach the brain via the gut-brain axis, disrupting the normal function of the brain. A mechanistic understanding of metabolic disturbances in the brain and gut is essential to design effective therapeutics and early intervention to block disease progression. Herein, we present a novel computational framework integrating constraint based tissue specific metabolic (CBM) model and whole-body physiological pharmacokinetics (PBPK) modeling for ASD. Furthermore, the role of gut microbiota, diet, and oxidative stress is analyzed in ASD. METHODS: A representative gut model capturing host-bacteria and bacteria-bacteria interaction was developed using CBM techniques and patient data. Simultaneously, a PBPK model of toxin metabolism was assembled, incorporating multi-scale metabolic information. Furthermore, dynamic flux balance analysis was performed to integrate CBM and PBPK. The effectiveness of a probiotic and dietary intervention to improve autism symptoms was tested on the integrated model. RESULTS: The model accurately highlighted critical metabolic pathways of the gut and brain that are associated with ASD. These include central carbon, nucleotide, and vitamin metabolism in the host gut, and mitochondrial energy and amino acid metabolisms in the brain. The proposed dietary intervention revealed that a high-fiber diet is more effective than a western diet in reducing toxins produced inside the gut. The addition of probiotic bacteria Lactobacillus acidophilus, Bifidobacterium longum longum, Akkermansia muciniphila, and Prevotella ruminicola to the diet restores gut microbiota balance, thereby lowering oxidative stress in the gut and brain. CONCLUSION: The proposed computational framework is novel in its applicability, as demonstrated by the determination of the whole-body distribution of ROS toxins and metabolic association in ASD. In addition, it emphasized the potential for developing novel therapeutic strategies to alleviate autism symptoms. Notably, the presented integrated model validates the importance of combining PBPK modeling with COBRA -specific tissue details for understanding disease pathogenesis.

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18. Narzisi A, Alonso-Esteban Y, Masi G, Alcantud-Marín F. Research-Based Intervention (RBI) for Autism Spectrum Disorder: Looking beyond Traditional Models and Outcome Measures for Clinical Trials. Children (Basel, Switzerland). 2022; 9(3).

The rising prevalence of Autism Spectrum Disorders (ASD) has led to a quickly increasing need for effective interventions. Several criteria and measures have been developed to critically assess these interventions with particular focus on the evaluation of the efficacy. Given the huge diversity of ASD symptoms and the different levels of severity across individuals, identifying a one size fits all intervention approach is challenging, and the question What works and for whom? Remains still unanswered. Why do we seem to be dragging our feet on this fundamental issue? The main aim of this paper is to answer this question through four non-alternative points. First, there are a scarce number of studies with a solid methodology. Secondly, most trials on intervention efficacy for ASD are designed exclusively in terms of behavioral outcomes. Thirdly, there is a reduced use of biologically oriented outcome measures. Fourthly, in most clinical trials, appropriate practices emerging from research evidence are not systematically applied. A strong effort to improve the methodology of clinical trials is mandatory for the future of autism research. The development of a research-based intervention (RBI) perspective aimed at better integrating: (a) evidence-based approaches; (b) more sensitive behavioral outcome measures; and (c) biomarkers, with the aim of increasing a more detailed clustering of phenotypes, may strongly improve our approach to a precision medicine.

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19. Narzisi A, Fabbri-Destro M, Crifaci G, Scatigna S, Maugeri F, Berloffa S, Fantozzi P, Prato A, Muccio R, Valente E, Viglione V, Pecchini E, Pelagatti S, Rizzo R, Milone A, Barone R, Masi G. Sensory Profiles in School-Aged Children with Autism Spectrum Disorder: A Descriptive Study Using the Sensory Processing Measure-2 (SPM-2). Journal of clinical medicine. 2022; 11(6).

BACKGROUND: Sensory reactivity is considered one of the diagnostic criteria for Autism Spectrum Disorders (ASD) and has been associated with poorer functional outcomes, behavioral difficulties, and autism severity across the lifespan. The characterization of the sensory processing in ASD has thus become crucial to identify the sensory and motor features influencing the development of personal autonomy. OBJECTIVES: The present study has two aims: (1) to compare the sensory processing between school-aged children with ASD and typically developing peers (TD); (2) to evaluate whether, within the ASD sample, the cognitive level and reported sensory symptoms explain the scores exhibited at the Sensory Processing Measure (SPM-2). METHODS: The SPM-2 test was administered to the parents of 105 children with ASD and 70 TD. The ASD group was further subdivided into two groups, namely high and low functioning based on their cognitive level (High Functioning (HF), IQ > 80; Low Functioning (LF), IQ < 80). RESULTS: ASD children exhibited higher scores throughout the SPM-2 total score and its multiple subscales. Within ASD, while HF and LF children did not differ in terms of the SPM-2 total score, a significant difference was found for the hearing, social participation, and balance and motion subscales. CONCLUSIONS: Aside from classical knowledge that the ASD population suffers from sensory processing disorders, we revealed that different sensory patterns are associated with high or low cognitive functioning. Beyond its neurobiological interest, such knowledge may be of fundamental importance for individualizing psychoeducational interventions in preschool- and school-aged children and later developmental stages.

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20. Nguyen XP, Vilkaite A, Messmer B, Dietrich JE, Hinderhofer K, Schäkel K, Strowitzki T, Rehnitz J. Expression of FMRpolyG in Peripheral Blood Mononuclear Cells of Women with Fragile X Mental Retardation 1 Gene Premutation. Genes. 2022; 13(3).

Fragile X-associated primary ovarian insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergonadotropic hypogonadism and is caused by the expansion of the CGG repeat in the 5’UTR of Fragile X Mental Retardation 1 (FMR1). Approximately 20% of women carrying an FMR1 premutation (PM) allele (55-200 CGG repeat) develop FXPOI. Repeat Associated Non-AUG (RAN)-translation dependent on the variable CGG-repeat length is thought to cause FXPOI, due to the production of a polyglycine-containing FMR1 protein, FMRpolyG. Peripheral blood monocyte cells (PBMCs) and granulosa cells (GCs) were collected to detect FMRpolyG and its cell type-specific expression in FMR1 PM carriers by immunofluorescence staining (IF), Western blotting (WB), and flow cytometric analysis (FACS). For the first time, FMRpolyG aggregates were detected as ubiquitin-positive inclusions in PBMCs from PM carriers, whereas only a weak signal without inclusions was detected in the controls. The expression pattern of FMRpolyG in GCs was comparable to that in the lymphocytes. We detected FMRpolyG as a 15- to 25-kDa protein in the PBMCs from two FMR1 PM carriers, with 124 and 81 CGG repeats. Flow cytometric analysis revealed that FMRpolyG was significantly higher in the T cells from PM carriers than in those from non-PM carriers. The detection of FMRpolyG aggregates in the peripheral blood and granulosa cells of PM carriers suggests that it may have a toxic potential and an immunological role in ovarian damage in the development of FXPOI.

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21. Parente M, Tonini C, Buzzelli V, Carbone E, Trezza V, Pallottini V. Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome. International journal of molecular sciences. 2022; 23(6).

Fragile X Syndrome (FXS) is the most frequent form of inherited X-linked pathology, associated with an intellectual and developmental disability, and currently considered the first monogenic cause of autism spectrum disorder (ASD). Low levels of total cholesterol reported in the serum of FXS patients, and evidence that FMRP targets a subset of mRNAs encoding proteins of lipid synthesis and transport suggests that the cholesterol metabolism impairments could be involved in FXS. Thus, the aim of the presented work was to investigate the modulations of the cholesterol biosynthetic pathway and its end-products in a recently developed Fmr1-Δexon 8 rat model of FXS. Here, we show that this experimental model mimics what is found in FXS patients, exhibiting a lower serum cholesterol content, accompanied by a reduction in food intake and body weight compared to WT animals. Moreover, alterations of proteins committed to cholesterol synthesis and uptake have been observed in the amygdala, prefrontal cortex and nucleus accumbens. Interestingly, the end-products show a brain region-dependent modulation in Fmr1-Δexon 8 rats. Overall, our results demonstrate that the cholesterol biosynthetic pathway is altered in some brain regions of this preclinical model of FXS. This finding has relevance for future studies to delve deeper into the involvement of this metabolic process in FXS, and thus its possible role as a therapeutic target.

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22. Pastore SF, Ko SY, Frankland PW, Hamel PA, Vincent JB. PTCHD1: Identification and Neurodevelopmental Contributions of an Autism Spectrum Disorder and Intellectual Disability Susceptibility Gene. Genes. 2022; 13(3).

Over the last one and a half decades, copy number variation and whole-genome sequencing studies have illuminated the considerable genetic heterogeneity that underlies the etiologies of autism spectrum disorder (ASD) and intellectual disability (ID). These investigations support the idea that ASD may result from complex interactions between susceptibility-related genetic variants (single nucleotide variants or copy number variants) and the environment. This review outlines the identification and neurobiological characterization of two such genes located in Xp22.11, Patched domain-containing 1 (PTCHD1), and its antisense lncRNA PTCHD1-AS. Animal models of Ptchd1 disruption have recapitulated a subset of clinical symptoms related to ASD as well as to ID. Furthermore, these Ptchd1 mouse knockout studies implicate the expression of Ptchd1 in both the thalamic and the hippocampal brain regions as being crucial for proper neurodevelopment and cognitive function. Altered kynurenine metabolic signalling has been postulated as a disease mechanism in one of these animal studies. Additionally, ASD patient-derived induced pluripotent stem cells (iPSCs) carrying a copy number loss impacting the antisense non-coding RNA PTCHD1-AS have been used to generate 2D neuronal cultures. While copy number loss of PTCHD1-AS does not affect the transcription of PTCHD1, the neurons exhibit diminished miniature excitatory postsynaptic current frequency, supporting its role in ASD etiology. A more thorough understanding of risk factor genes, such as PTCHD1 and PTCHD1-AS, will help to clarify the intricate genetic and biological mechanisms that underlie ASD and ID, providing a foundation for meaningful therapeutic interventions to enhance the quality of life of individuals who experience these conditions.

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23. Pretzsch CM, Schäfer T, Lombardo MV, Warrier V, Mann C, Bletsch A, Chatham CH, Floris DL, Tillmann J, Yousaf A, Jones E, Charman T, Ambrosino S, Bourgeron T, Dumas G, Loth E, Oakley B, Buitelaar JK, Cliquet F, Leblond CS, Baron-Cohen S, Beckmann CF, Banaschewski T, Durston S, Freitag CM, Murphy DGM, Ecker C. Neurobiological Correlates of Change in Adaptive Behavior in Autism. The American journal of psychiatry. 2022; 179(5): 336-49.

OBJECTIVE: Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is associated with significant difficulties in adaptive behavior and variation in clinical outcomes across the life span. Some individuals with ASD improve, whereas others may not change significantly, or regress. Hence, the development of « personalized medicine » approaches is essential. However, this requires an understanding of the biological processes underpinning differences in clinical outcome, at both the individual and subgroup levels, across the lifespan. METHODS: The authors conducted a longitudinal follow-up study of 483 individuals (204 with ASD and 279 neurotypical individuals, ages 6-30 years), with assessment time points separated by ∼12-24 months. Data collected included behavioral data (Vineland Adaptive Behavior Scale-II), neuroanatomical data (structural MRI), and genetic data (DNA). Individuals with ASD were grouped into clinically meaningful « increasers, » « no-changers, » and « decreasers » in adaptive behavior. First, the authors compared neuroanatomy between outcome groups. Next, they examined whether deviations from the neurotypical neuroanatomical profile were associated with outcome at the individual level. Finally, they explored the observed neuroanatomical differences’ potential genetic underpinnings. RESULTS: Outcome groups differed in neuroanatomical features (cortical volume and thickness, surface area), including in « social brain » regions previously implicated in ASD. Also, deviations of neuroanatomical features from the neurotypical profile predicted outcome at the individual level. Moreover, neuroanatomical differences were associated with genetic processes relevant to neuroanatomical phenotypes (e.g., synaptic development). CONCLUSIONS: This study demonstrates, for the first time, that variation in clinical (adaptive) outcome is associated with both group- and individual-level variation in anatomy of brain regions enriched for genes relevant to ASD. This may facilitate the move toward better targeted/precision medicine approaches.

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24. Purpura G, Cerroni F, Carotenuto M, Nacinovich R, Tagliabue L. Behavioural Differences in Sensorimotor Profiles: A Comparison of Preschool-Aged Children with Sensory Processing Disorder and Autism Spectrum Disorders. Children (Basel, Switzerland). 2022; 9(3).

Sensory Processing Disorders (SPDs) define dysfunctions in modulating, organising, and using information from several sensory channels for regulating motor, behavioural, emotional and attention responses. Although SPD can be identified also as an isolated condition in young children, its presence in Autism Spectrum Disorder (ASD) population is really frequent. The study purpose is to explore the SPD clinical expression and the putative correlation with several behavioural aspects both in children with ASD and in those with isolated SPD. Therefore, 43 preschool-aged children (25 ASD vs. 18 SPD) were recruited, and their parents completed three questionnaires (Developmental Profile-3, Sensory Processing Measure-Preschool, Repetitive Behaviour Scale-Revised) to evaluate behavioural alterations and developmental levels. The main result is that both ASD and SPD groups had significantly sensory-related behavioural symptoms, although ASD children seem to be more impaired in all areas. Several significant correlations were found between sensory processing difficulties and repetitive behaviours, but in the SPD group a specific relationship between Body Awareness and Ritualistic/Sameness Behaviour was found. Conversely, in the ASD group, more diffuse interlinks between sensory processing difficulties and motor behaviours were significant. In conclusion, the present study confirms the key role of sensory-motor skills in early diagnosis and intervention among children at risk for neurodevelopmental disorders.

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25. Rincón-Rufo D, Vera-Pérez V, Cuesta-Gómez A, Carratalá-Tejada M. Prediction of Communicative Disorders Linked to Autistic Spectrum Disorder Based on Early Psychomotor Analysis. Children (Basel, Switzerland). 2022; 9(3).

This systematic review evaluated psychomotor differences between children with and without siblings who have autism spectrum disorder (ASD), as well as the most reliable psychomotor skills that can help predict ASD and its associated language disorders. Literature from 2005 to 2020 was searched using the following databases: PubMed, Trip Medical Database, Cochrane, Web of Science, Science Direct, and Brain. A total 11 papers were included. Fine motor skills and joint attention displayed reliable results in order to predict ASD and its associated language disorders. The period between the first and the second year of life was considered the most appropriate one for the assessment of psychomotor skills. The best period to predict language disorders and ASD diagnosis is around 36 months old.

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26. Robinson-Agramonte MLA, Noris García E, Fraga Guerra J, Vega Hurtado Y, Antonucci N, Semprún-Hernández N, Schultz S, Siniscalco D. Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?. International journal of molecular sciences. 2022; 23(6).

Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental disorders characterized by a wide and variable set of neuropsychiatric symptoms, including deficits in social communication, narrow and restricted interests, and repetitive behavior. The immune hypothesis is considered to be a major factor contributing to autism pathogenesis, as well as a way to explain the differences of the clinical phenotypes and comorbidities influencing disease course and severity. Evidence highlights a link between immune dysfunction and behavioral traits in autism from several types of evidence found in both cerebrospinal fluid and peripheral blood and their utility to identify autistic subgroups with specific immunophenotypes; underlying behavioral symptoms are also shown. This review summarizes current insights into immune dysfunction in ASD, with particular reference to the impact of immunological factors related to the maternal influence of autism development; comorbidities influencing autism disease course and severity; and others factors with particular relevance, including obesity. Finally, we described main elements of similarities between immunopathology overlapping neurodevelopmental and neurodegenerative disorders, taking as examples autism and Parkinson Disease, respectively.

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27. Salgado-Cacho JM, Moreno-Jiménez MDP, Ríos-Rodríguez ML. Intensive Family Intervention as Support for Professional Treatment: Evolution of Symptoms in a Diagnosed Case of Autism Spectrum Disorder. Children (Basel, Switzerland). 2022; 9(3).

This article shows the progress achieved in a child who has received professional treatment combined with a family intervention at home. It discusses a 22-month-old patient identified as showing warning signs of autism spectrum disorder (ASD), a diagnosis that was subsequently confirmed through a standardized ADOS-2 test at 31 months of age. To establish the initial working objectives, a functional diagnosis was carried out at 23 months of age using the Battelle Developmental Inventory; a maturational delay was detected, situating the child at an age equivalent to 16 months. A professional intervention was designed in an early childhood care center, complemented by family intervention, so that the hours in which the child participated in learning experiences were increased. Notable advances were made in the areas of cognitive and motor skills, with more standard scores than when initially evaluated. Progress was also observed (though to a lesser extent) in other developmental areas such as language total, adaptive behavior, and self-help, while slight delays in the areas of socio-emotional development and reasoning and academic skills were found.

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28. Samadi SA, Noori H, Abdullah A, Ahmed L, Abdalla B, Biçak CA, McConkey R. The Psychometric Properties of the Gilliam Autism Rating Scale (GARS-3) with Kurdish Samples of Children with Developmental Disabilities. Children (Basel, Switzerland). 2022; 9(3).

There is marked variation internationally in the prevalence of children identified as having autism spectrum disorders (ASD). In part, this may reflect a shortage of screening tools for the early identification of children with ASD in many countries. This study aimed to evaluate the Kurdish translation of the Gilliam autism rating scale-third edition (GARS-3), a scale commonly used in Western countries that evaluates six domains related to the ASD definition from the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5, notably Restricted/Repetitive Behavior, deficits in Social interaction and Social Communication, as well as differences in Cognitive Style, Maladaptive Speech, and Emotional Response. GARS-3 assessments were completed through interviews with parents of 735 children, 442 (53%) of whom were diagnosed with ASD. 165 (22%) with an intellectual disability, 49 (7%) with communication disorders, and 133 (18%) typically developing children. The reliability, construct, and the predictive validity of the scale was assessed, and the scores suggestive of a child having ASD were identified. The factor structure was broadly replicated, especially on items relating to social interaction and social communication. The cutoffs for the total scores that were indicative of possible ASD had a high degree of specificity and sensitivity in distinguishing children with ASD from typically developing peers. Some children with I.D. and communication disorders may also score above the threshold, and further assessments should be sought to confirm the presence of autistic traits. Although GARS-3 could be recommended for use in Kurdistan and possibly similar cultures, further prospective research is needed to confirm a diagnosis of assessment with children who score above and below the cutoff scores identified in this study. Moreover, the development of normative data drawn from Kurdish samples of children would be advantageous, although ambitious, given the lack of diagnostic services in many low- and middle-income countries.

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29. Shen MD, Swanson MR, Wolff JJ, Elison JT, Girault JB, Kim SH, Smith RG, Graves MM, Weisenfeld LAH, Flake L, MacIntyre L, Gross JL, Burrows CA, Fonov VS, Collins DL, Evans AC, Gerig G, McKinstry RC, Pandey J, St John T, Zwaigenbaum L, Estes AM, Dager SR, Schultz RT, Styner MA, Botteron KN, Hazlett HC, Piven J. Subcortical Brain Development in Autism and Fragile X Syndrome: Evidence for Dynamic, Age- and Disorder-Specific Trajectories in Infancy. The American journal of psychiatry. 2022: appiajp21090896.

OBJECTIVE: Previous research has demonstrated that the amygdala is enlarged in children with autism spectrum disorder (ASD). However, the precise onset of this enlargement during infancy, how it relates to later diagnostic behaviors, whether the timing of enlargement in infancy is specific to the amygdala, and whether it is specific to ASD (or present in other neurodevelopmental disorders, such as fragile X syndrome) are all unknown. METHODS: Longitudinal MRIs were acquired at 6-24 months of age in 29 infants with fragile X syndrome, 58 infants at high likelihood for ASD who were later diagnosed with ASD, 212 high-likelihood infants not diagnosed with ASD, and 109 control infants (1,099 total scans). RESULTS: Infants who developed ASD had typically sized amygdala volumes at 6 months, but exhibited significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen’s d=0.56) compared with all other groups. Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the infants were diagnosed with ASD. Infants with fragile X syndrome had a persistent and significantly enlarged caudate volume at all ages between 6 and 24 months (d=2.12), compared with all other groups, which was significantly associated with greater repetitive behaviors. CONCLUSIONS: This is the first MRI study comparing fragile X syndrome and ASD in infancy, demonstrating strikingly different patterns of brain and behavior development. Fragile X syndrome-related changes were present from 6 months of age, whereas ASD-related changes unfolded over the first 2 years of life, starting with no detectable group differences at 6 months. Increased amygdala growth rate between 6 and 12 months occurs prior to social deficits and well before diagnosis. This gradual onset of brain and behavior changes in ASD, but not fragile X syndrome, suggests an age- and disorder-specific pattern of cascading brain changes preceding autism diagnosis.

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30. Sohl K, Rynkiewicz A, Nanclares-Nogués V, Brewer Curran A, Scorah J, Steiman M, Lord C, Vasa RA, Słopień A, Janas-Kozik M, Łucka I, Mazur A. Project Extension for Community Health Outcomes (ECHO) Autism: A Successful Model to Increase Capacity in Community-Based Care. Brain sciences. 2022; 12(3).

Individuals with autism spectrum disorder (ASD) struggle to access high-quality health care due to the shortage of trained providers. ECHO (Extension for Community Healthcare Outcomes) Autism is a unique educational program that allows ASD experts to provide knowledge and skills to professionals in local communities to deliver evidence-based care to children with ASD and their families. The model teaches clinicians how to screen and diagnose ASD, as well as manage common co-occurring medical and mental health issues. ECHO Autism is particularly useful for addressing the complex needs of children with ASD and reducing disparities often present in rural and underserved communities. The model can be disseminated globally due to its flexibility in accommodating local and regional differences in social norms and constructs. This article provides an overview of the format of the ECHO Autism model, data supporting the model’s efficacy, and discusses future research directions.

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31. Stefaniak U, Malak R, Mojs E, Samborski W. Autistic-like Behaviors Associated with a Novel Non-Canonical Splice-Site DDX3X Variant: A Case Report of a Rare Clinical Syndrome. Brain sciences. 2022; 12(3).

BACKGROUND: Heterozygous pathogenic variants in the DDX3X gene account for 1-3% of females with intellectual and developmental disabilities (IDD). The clinical presentation is variable, including a wide range of neurological and behavioral deficits and structural defects of the brain. Approximately 52% of affected females remain nonverbal after five years of age. CASE PRESENTATION: We report a 7 year old nonverbal female with a likely novel de novo pathogenic heterozygous variant in the DDX3X gene affecting the non-canonical splice-site in the intron 1 (NM_001356:c.45+12G>A). The patient presents with features typical for the DDX3X phenotype, such as: movement disorders, behavioral problems, a diagnosis of autism spectrum disorder (ASD), and some other features uncommon for DDX3X such as: muscle hypertonia and spinal asymmetry evaluated through the scoliometer. CONCLUSIONS: Due to its rare occurrence, the clinical picture of DDX3X syndrome is yet to be fully determined. So far, behavioral disorders, including those from ASD, and neurological abnormalities seem to be the dominant features of this disorder.

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32. Sun L, Lukkarinen L, Noppari T, Nazari-Farsani S, Putkinen V, Seppälä K, Hudson M, Tani P, Lindberg N, Karlsson HK, Hirvonen J, Salomaa M, Venetjoki N, Lauerma H, Tiihonen J, Nummenmaa L. Aberrant motor contagion of emotions in psychopathy and high-functioning autism. Cerebral cortex (New York, NY : 1991). 2022.

Psychopathy and autism are both associated with aberrant social skills and empathy, yet only psychopaths are markedly antisocial and violent. Here, we compared the functional neural alterations underlying these two groups that both have aberrant empathetic abilities but distinct behavioral phenotypes. We studied 19 incarcerated male offenders with high psychopathic traits, 20 males with high-functioning autism, and 19 age-matched healthy controls. All groups underwent functional magnetic resonance imaging while they viewed dynamic happy, angry, and disgusted faces or listened to laughter and crying sounds. Psychopathy was associated with reduced somatomotor responses to almost all expressions, while participants with autism demonstrated less marked and emotion-specific alterations in the somatomotor area. These data suggest that psychopathy and autism involve both common and distinct functional alterations in the brain networks involved in the socioemotional processing. The alterations are more profound in psychopathy, possibly reflecting the more severely disturbed socioemotional brain networks in this population.

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33. Tei S, Tanicha M, Itahashi T, Aoki YY, Ohta H, Qian C, Hashimoto RI, Nakamura M, Takahashi H, Kato N, Fujino J. Decision Flexibilities in Autism Spectrum Disorder: An fMRI Study of Moral Dilemmas. Social cognitive and affective neuroscience. 2022.

People make flexible decisions across a wide range of contexts to resolve social or moral conflicts. Individuals with autism spectrum disorder (ASD) frequently report difficulties in such behaviors, which hinders the flexibility in changing strategies during daily activities or adjustment of perspective during communication. However, the underlying mechanisms of this issue are insufficiently understood. This study aimed to investigate decision flexibility in ASD using a functional magnetic resonance imaging task that involved recognizing and resolving two types of moral dilemma (MD): cost-benefit analysis (CBA) and mitigating inevitable misconducts (MIM). The CBA session assessed the participants’ pitting of result-oriented outcomes against distressful harmful actions, whereas the MIM session assessed their pitting of the extenuation of a criminal sentence against a sympathetic situation of defendants suffering from violence or disease. The behavioral outcome in CBA-related flexibility was significantly lower in the ASD group compared to that of the typical development (TD) group. In the corresponding CBA contrast, activation in the left inferior frontal gyrus was lower in the ASD group. Meanwhile, in the MIM-related flexibility, there were no significant group differences in behavioral outcome or brain activity. Our findings add to our understanding of flexible decision-making in ASD.

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34. Tian H, Qiao S, Zhao Y, Jin X, Wang C, Wang R, Wang Y, Jiao Y, Liu Y, Zhang B, Jin J, Chen Y, Jiang Q, Tian W. Krüppel-like Transcription Factor 7 Is a Causal Gene in Autism Development. International journal of molecular sciences. 2022; 23(6).

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental disease. To date, more than 1000 genes have been shown to be associated with ASD, and only a few of these genes account for more than 1% of autism cases. Klf7 is an important transcription factor of cell proliferation and differentiation in the nervous system, but whether klf7 is involved in autism is unclear. METHODS: We first performed ChIP-seq analysis of klf7 in N2A cells, then performed behavioral tests and RNA-seq in klf7(+/-) mice, and finally restored mice with adeno-associated virus (AAV)-mediated overexpression of klf7 in klf7(+/-) mice. RESULTS: Klf7 targeted genes are enriched with ASD genes, and 631 ASD risk genes are also differentially expressed in klf7(+/-) mice which exhibited the core symptoms of ASD. When klf7 levels were increased in the central nervous system (CNS) in klf7(+/-) adult mice, deficits in social interaction, repetitive behavior and majority of dysregulated ASD genes were rescued in the adults, suggesting transcriptional regulation. Moreover, knockdown of klf7 in human brain organoids caused dysregulation of 517 ASD risk genes, 344 of which were shared with klf7(+/-) mice, including some high-confidence ASD genes. CONCLUSIONS: Our findings highlight a klf7 regulation of ASD genes and provide new insights into the pathogenesis of ASD and promising targets for further research on mechanisms and treatments.

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35. Trembath D, Stainer M, Caithness T, Dissanayake C, Eapen V, Fordyce K, Frewer V, Frost G, Hudry K, Iacono T, Mahler N, Masi A, Paynter J, Pye K, Quan S, Shellshear L, Sutherland R, Sievers S, Thirumanickam A, Westerveld MF, Tucker M. Spoken Language Change in Children on the Autism Spectrum Receiving Community-Based Interventions. Journal of autism and developmental disorders. 2022.

We assessed the spoken language of 73 preschool aged children on the autism spectrum receiving community-based early intervention at two time points, approximately 7 months apart. Using the Spoken Language Benchmarks, there was a small non-significant change in the proportion of children transitioning from below, to at or above, Phase 3 (word combinations). Using binomial regression, a model comprising seven of nine clinician-proposed child-related predictors explained 64% of the variance. None of the predictors were individually significant, although a large effect size (OR = 16.71) was observed for children’s baseline rate of communicative acts. The findings point to substantial unmet clinical need in children with minimal verbal language, but also the relevance of clinician-proposed predictors of their spoken language outcomes.

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36. Vens N, Dewitte G, Van Waelvelde H, Bar-On L, De Roubaix A. Developmental Coordination Disorder before the Age of Three: A Longitudinal Retrospective Study in a Belgian Center for Developmental Disabilities. Children (Basel, Switzerland). 2022; 9(3).

This study aimed to explore the association between developmental coordination disorder (DCD) diagnosed after the age of three and both a standardized motor test-the Alberta Infant Motor Scale (AIMS)-and non-standardized observation of movement quality carried out before the age of three. Children at risk or with developmental concerns were studied retrospectively. Children were excluded in case of a diagnosis, excluding DCD, e.g., cerebral palsy, or IQ < 70. Of the 503 included children, 246 were diagnosed with (at-risk) DCD. Multivariate binary logistic regression revealed a significant association between DCD diagnosis after the age of three and male gender and with different aspects of poor movement quality in different age groups before the age three. Univariate analyses revealed an association between DCD diagnosis and the number of poor movement-quality descriptions at 0-6 months, 6-12 months, and 18 months-3 years but not with the AIMS scores. The MABC-2 scores after the age of three were significantly correlated with the number of poor movement-quality descriptions in age groups 0-6 months and 18 months-3 years and with the AIMS scores in age groups 6-12 months and 12-18 months. The results suggest that DCD can be associated with poor movement quality before the age of three.

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37. Walker AR, Trollor JN, Florio T, Srasuebkul P. Predictors and outcomes of recognition of intellectual disability for adults during hospital admissions: A retrospective data linkage study in NSW, Australia. PloS one. 2022; 17(3): e0266051.

Adults with intellectual disability have high health care needs. Despite frequent contact with health services, they often receive inadequate health care. One method to improve health care delivery is reasonable adjustments, that is, the adaptation of health care delivery such that barriers to participation are removed for the person with disability. A starting point for the provision of reasonable adjustments is recognition of intellectual disability during the health care contact. To determine rates and predictors of the recognition of intellectual disability during hospital admissions, and its impact on admission metrics, we examined a population of adults with intellectual disability identified from disability services datasets from New South Wales, Australia between 2005 and 2014. Recognition of intellectual disability was determined by the recording of an International Classification of Diseases 10th revision (ICD-10) diagnostic code for intellectual disability during a given hospital admission. We examined how recognition of intellectual disability related to length of hospital episodes. We found an overall low rate of recognition of intellectual disability (23.79%) across all hospital episodes, with the proportion of hospital episodes recognising intellectual disability decreasing from 2005-2015. Admissions for adults with complex health profiles (e.g., those with many comorbidities, those with Autism Spectrum Disorder, and those admitted for urgent treatment) were more likely to recognise intellectual disability, but admissions for adults with complexity in other domains (i.e., for those in custody, or those with drug and alcohol disorders) were less likely to recognise intellectual disability. Recognition of intellectual disability was associated with longer episodes of care, possibly indicating the greater provision of reasonable adjustments. To improve the recognition of intellectual disability for adults during health service contacts, we advocate for the implementation of targeted initiatives (such as a nationwide disability flag to be included in health service records) to improve the provision of reasonable adjustments.

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38. Yang R, Zhang G, Shen Y, Ou J, Liu Y, Huang L, Zeng Y, Lin J, Liu R, Wu R, Xia K, Zhang F, Zhao J. Odor identification impairment in autism spectrum disorder might be associated with mitochondrial dysfunction. Asian journal of psychiatry. 2022; 72: 103072.

Deficits in olfactory function in autism spectrum disorder (ASD) have already been reported. However, the results of previous studies are not consistent, and the pathophysiological mechanisms of olfactory dysfunction in ASD are not clear. Fifty-three male ASD children or teenagers aged 9-16 years were recruited for the study. The identification and discrimination portion of the Sniffin’ Sticks test (SST) was used to assess the olfactory function of the enrolled subjects. The severity of ASD core symptoms and the intelligence quotient (IQ) of participants were assessed. In addition, to explore the potential mechanism underlying olfactory dysfunction, a series of plasma biochemical indicators of oxidative stress, mitochondrial function and inflammation were measured. The mean raw scores on the SST identification and discrimination test of the study subjects were significantly lower than those of typically developing subjects reported in normative data studies. After adjusting for IQ, the odor identification score was not significantly associated with any ASD symptoms. Odor identification was found to be significantly associated with the ratio of L-lactate (L)/pyruvate (P) but not with other measured indicators. The current study validates the impairment of odor identification and discrimination in Chinese ASD children. Odor identification dysfunction may be an independent clinical symptom of ASD. The plasma L/P ratio was found to be significantly associated with odor identification performance, which suggests that mitochondrial dysfunction may be a potential mechanism underlying odor identification impairment in ASD.

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39. Zakharevich NV, Nikitin MS, Kovtun AS, Malov VO, Averina OV, Danilenko VN, Artamonova, II. CRISPR-Cas Systems in Gut Microbiome of Children with Autism Spectrum Disorders. Life (Basel, Switzerland). 2022; 12(3).

The human gut microbiome is associated with various diseases, including autism spectrum disorders (ASD). Variations of the taxonomical composition in the gut microbiome of children with ASD have been observed repeatedly. However, features and parameters of the microbiome CRISPR-Cas systems in ASD have not been investigated yet. Here, we demonstrate such an analysis in order to describe the overall changes in the microbiome CRISPR-Cas systems during ASD as well as to reveal their potential to be used in diagnostics and therapy. For the systems identification, we used a combination of the publicly available tools suited for completed genomes with subsequent filtrations. In the considered data, the microbiomes of children with ASD contained fewer arrays per Gb of assembly than the control group, but the arrays included more spacers on average. CRISPR arrays from the microbiomes of children with ASD differed from the control group neither in the fractions of spacers with protospacers from known genomes, nor in the sets of known bacteriophages providing protospacers. Almost all bacterial protospacers of the gut microbiome systems for both children with ASD and the healthy ones were located in prophage islands, leaving no room for the systems to participate in the interspecies competition.

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40. Zhang S, Hao Y, Feng Y, Lee NY. COVID-19 Pandemic Impacts on Children with Developmental Disabilities: Service Disruption, Transition to Telehealth, and Child Wellbeing. International journal of environmental research and public health. 2022; 19(6).

The COVID-19 pandemic has resulted in substantial service disruption and transition from in-person services to telehealth for children with developmental disabilities. However, there is limited knowledge about the specific dimensions and consequences of the disruption and transition. This study aims to examine the extent of service disruption and transition, the experiences of client children and their caregivers with telehealth vis-à-vis in-person services, and the impacts of the disruption and transition on child wellbeing. The cross-sectional study collected data from parents of children with developmental disabilities using an online survey. McNemar’s tests were used to compare service changes before and after the pandemic outbreak, and multivariate analyses were used to examine how service changes were associated with child wellbeing. Results show that more than two-thirds of the children experienced reduction in service amount, and one-third lost services for more than two months in about five months into the pandemic. While telehealth had comparable features relative to in-person services, it had lower ratings with respect to diagnostic accuracy, treatment effectiveness, and rapport building. Service disruption/transition and social isolation were associated with behavioral and emotional deterioration in children. However, child and family stress may have confounded these adverse effects. We concluded that the magnitude of service disruption and transition was large in the first half year after the pandemic outbreak, and the amount and duration of service loss varied substantially across clients. Diagnostic accuracy, treatment efficacy, and rapport building were areas in which parents had major concerns toward telehealth relative to in-person services. However, such drawbacks may partially be due to the limited logistics in telehealth implementation during the pandemic. Service disruption and transition seemed to contribute to family stress, which played a direct role in eroding child wellbeing. Implications of these findings for future research and practices are discussed.

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41. Zhang XY, Spruyt K. Literature Cases Summarized Based on Their Polysomnographic Findings in Rett Syndrome. International journal of environmental research and public health. 2022; 19(6).

Rett syndrome (RTT) is a severe and rare neurodevelopmental disorder affecting mostly girls. In RTT, an impaired sleep pattern is a supportive criterion for the diagnosis, yet little is known regarding the sleep structure and sleep respiratory events. Aiming to delineate sleep by aggregating RTT case (series) data from published polysomnographic studies, seventy-four RTT cases were collected from eleven studies up until 6 February 2022 (PROSPERO: CRD 42020198099). We compared the polysomnographic data within RTT stratifications and to a typically developing population. MECP2 cases demonstrated shortened total sleep time (TST) with increased stage N3 and decreased REM sleep. In cases with CDKL5 mutations, TST was longer and they spent more time in stage N1 but less in stage N3 than those cases affected by MECP2 mutations and a typically developing population. Sleep-disordered breathing was confirmed by the abnormal apnea/hypopnea index of 11.92 ± 23.67/h TST in these aggregated cases. No association of sleep structure with chronological age was found. In RTT, the sleep macrostructure of MECP2 versus CDKL5 cases showed differences, particularly regarding sleep stage N3. A severe REM sleep propensity reduction was found. Aberrant sleep cycling, possibly characterized by a poor REM ‘on switch’ and preponderance in slow and high-voltage sleep, is proposed.

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