1. Amano Y, Mizutani K, Kato Y, Fujii T, Yagami A, Tamura T. Causative agent for perioperative anaphylaxis in a child with autism successfully identified using the intradermal test under general anesthesia. JA Clin Rep;2024 (Aug 8);10(1):48.

BACKGROUND: The skin-prick and intradermal tests are the main diagnostic methods used to identify the causative agent in patients with suspected perioperative anaphylaxis. Although the intradermal test is more sensitive than the skin-prick test, multiple intradermal injections can be painful for children. Here, we present the case of a child with autism and suspected perioperative anaphylaxis. The causative agent was successfully identified using the intradermal test under general anesthesia. CASE PRESENTATION: An 8-year-old boy with autism developed anaphylaxis during general anesthesia for the fourth cleft lip and palate surgery. An allergic workout was performed, but both the skin-prick and basophil activation tests for suspected causative agents yielded negative results. The patient was afraid of multiple injections, and an intradermal test was performed under general anesthesia by anesthesiologists and allergists. Piperacillin was confirmed as the causative agent, and subsequent surgery using the same anesthetic agents without piperacillin was uneventful. CONCLUSIONS: Concerted efforts should be made to identify the causative agent for diagnosing perioperative anaphylaxis.

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2. Brett JD, Preece DA, Becerra R, Whitehouse A, Maybery MT. Empathy and Autism: Establishing the Structure and Different Manifestations of Empathy in Autistic Individuals Using the Perth Empathy Scale. J Autism Dev Disord;2024 (Aug 8)

PURPOSE: There is a common mischaracterisation that autistic individuals have reduced or absent empathy. Measurement issues may have influenced existing findings on the relationships between autism and empathy, and the structure of the empathy construct in autism remains unclear. METHODS: The present study sought to address these gaps by examining the structure and psychometric properties of the Perth Empathy Scale (PES) in autistic individuals (N = 239) compared to non-autistic individuals (N = 690). RESULTS: Our moderated non-linear factor analysis revealed that the multidimensional empathy construct manifested similarly in autistic and non-autistic individuals, with the PES displaying good validity and reliability. Moreover, the results revealed that autistic individuals reported reduced cognitive empathy and reduced affective empathy for positive and negative emotions. However, there was greater heterogeneity of empathic tendencies in the autistic sample, indicating that these mean differences may not be generalisable for all autistic individuals. CONCLUSION: The present study highlights that the PES is suitable for assessing empathy across autistic and non-autistic individuals. This work with the PES also provides greater nuance to our understanding of empathy and autism, and based on these findings, we propose the empathy heterogeneity hypothesis of autism as a new way of describing empathy in autism.

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3. Chi MH, Bourgeois JA, Santos E, Kim K, Ponzini MD, Mendoza G, Schneider A, Hessl D, Tassone F, Hagerman RJ. Psychiatric Manifestations in Early to Middle Stages of Fragile X-Associated Tremor-Ataxia Syndrome (FXTAS). J Neuropsychiatry Clin Neurosci;2024 (Aug 8):appineuropsych20230215.

OBJECTIVE: The purpose of the present study was to assess the psychiatric manifestations of early to middle stages of fragile X-associated tremor-ataxia syndrome (FXTAS) and their relationship with executive function and FMR1 cytosine-guanine-guanine (CGG) repeat numbers across genders. METHODS: Cross-sectional data from 100 participants (62 men, 38 women; mean±SD age=67.11±7.90 years) with FXTAS stage 1, 2, or 3 were analyzed, including demographic information, cognitive measures, psychiatric assessments (Symptom Checklist-90-Revised and Behavioral Dyscontrol Scale-II [BDS-II]), and CGG repeat number. RESULTS: Participants with FXTAS stage 3 exhibited significantly worse psychiatric outcomes compared with participants with either stage 1 or 2, with distinct gender-related differences. Men showed differences in anxiety and hostility between stage 3 and combined stages 1 and 2, whereas women exhibited differences in anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, and somatization, as well as in the Global Severity Index, the Positive Symptom Distress Index, and the Positive Symptom Total. Among male participants, negative correlations were observed between BDS-II total scores and obsessive-compulsive symptoms, as well as between anxiety and CGG repeat number. CONCLUSIONS: These findings suggest that even at early FXTAS stages, patients have significant cognitive and other psychiatric symptoms, with notable gender-specific differences. This study underscores the clinical and prognostic relevance of comorbid psychiatric conditions in FXTAS, highlighting the need for early intervention and targeted support for individuals with relatively mild motor deficits.

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4. Croom K, Rumschlag JA, Molinaro G, Erickson MA, Binder DK, Huber KM, Razak KA. Developmental trajectory and sex differences in auditory processing in a PTEN-deletion model of autism spectrum disorders. Neurobiol Dis;2024 (Aug 5);200:106628.

Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a Pten-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which Pten is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.

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5. Dias C, Mo A, Cai C, Sun L, Cabral K, Brownstein CA, Rockowitz S, Walsh CA. Cell-type-specific effects of autism-associated 15q duplication syndrome in the human brain. Am J Hum Genet;2024 (Aug 8);111(8):1544-1558.

Recurrent copy-number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder. Duplication of 15q11-q13 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of autism more than 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex, we conducted single-nucleus RNA sequencing and multi-omic sequencing on dup15q-affected individuals (n = 6) as well as individuals with non-dup15q autism (n = 7) and neurotypical control individuals (n = 7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene-expression changes. As compared to other cell types, neuronal subtypes showed greater upregulation of gene expression across a critical region within the duplication. Genes that fell within the duplicated region and had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and autism had largely distinct signatures of chromatin accessibility but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding-factor motifs implicated in each condition implicated distinct biological mechanisms: neuronal JUN and FOS networks in autism vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain, and it finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects of copy-number variants more broadly in neurodevelopmental disorders.

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6. Du B, Zhang W, Chen L, Deng X, Li K, Lin F, Jia F, Su S, Tang W. Higher or lower? Interpersonal behavioral and neural synchronization of movement imitation in autistic children. Autism Res;2024 (Aug 8)

How well autistic children can imitate movements and how their brain activity synchronizes with the person they are imitating have been understudied. The current study adopted functional near-infrared spectroscopy (fNIRS) hyperscanning and employed a task involving real interactions involving meaningful and meaningless movement imitation to explore the fundamental nature of imitation as a dynamic and interactive process. Experiment 1 explored meaningful and meaningless gesture imitation. The results revealed that autistic children exhibited lower imitation accuracy and behavioral synchrony than non-autistic children when imitating both meaningful and meaningless gestures. Specifically, compared to non-autistic children, autistic children displayed significantly higher interpersonal neural synchronization (INS) in the right inferior parietal lobule (r-IPL) (channel 12) when imitating meaningful gestures but lower INS when imitating meaningless gestures. Experiment 2 further investigated the imitation of four types of meaningless movements (orofacial movements, transitive movements, limb movements, and gestures). The results revealed that across all four movement types, autistic children exhibited significantly lower imitation accuracy, behavioral synchrony, and INS in the r-IPL (channel 12) than non-autistic children. This study is the first to identify INS as a biomarker of movement imitation difficulties in autistic individuals. Furthermore, an intra- and interindividual imitation mechanism model was proposed to explain the underlying causes of movement imitation difficulties in autistic individuals.

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7. Duffy F, Gillespie-Smith K, Sharpe H, Buchan K, Nimbley E, Maloney E, Sader M, Kettley S, Kerr-Gaffney J, Waiter G, Tchanturia K. Eating Disorder and Autism Collaborative project outline: promoting eating disorder research embedded in a neurodiversity-affirming culture. BJPsych Bull;2024 (Aug 8):1-6.

EDAC (Eating Disorders and Autism Collaborative) is an innovative project aiming to increase research capacity by supporting collaboration in the fields of eating disorders and autism. EDAC comprises four integrated workstreams to co-produce interdisciplinary research, directed by Autistic individuals with lived experience of eating disorders. Workstream 1 will outline best collaborative practices, informing the research network. Workstream 2 will use arts-based methodologies to set research priorities, with emphasis on the perspectives of underrepresented groups. Workstream 3 will support interdisciplinary collaborations to develop innovative research. Finally, workstream 4 will maximise knowledge mobilisation with the aim of reducing barriers to rapid incorporation of research into policy and clinical practice. A core aim of EDAC is to embed a neurodiversity-affirming culture within eating disorder research and to support the development of a new generation of researchers conducting innovative and meaningful research with the potential to improve clinical outcomes.

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8. El-Ansary A, Alfawaz HA, Ben Bacha A, Al-Ayadhi L. Assessing the COX-2/PGE2 Ratio and Anti-Nucleosome Autoantibodies as Biomarkers of Autism Spectrum Disorders: Using Combined ROC Curves to Improve Diagnostic Values. Curr Issues Mol Biol;2024 (Aug 8);46(8):8699-8709.

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by restricted and repetitive behaviors as well as difficulties with social interaction. Numerous studies have revealed aberrant lipid mediators and autoimmunity as a recognized etiological cause of ASD that is amenable to therapeutic intervention. In this study, the relationship between the relative cyclooxygenase-2/prostaglandin E2 ratio (COX-2/PGE2) as a lipid mediator marker and anti-nucleosome autoantibodies as an autoimmunity marker of ASD was investigated using multiple regression and combined receiver operating characteristic (ROC) curve analyses. The study also sought to identify the linear combination of these variables that optimizes the partial area under the ROC curves. There were forty ASD children and forty-two age- and gender-matched controls included in the current study. Using combined ROC curve analysis, a notable increase in the area under the curve was seen in the patient group, using the control group as a reference group. Additionally, it was reported that the combined markers had improved specificity and sensitivity. This study demonstrates how the predictive value of particular biomarkers associated with lipid metabolism and autoimmunity in children with ASD can be measured using a ROC curve analysis. This technique should help us better understand the etiological mechanism of ASD and how it may adversely affect cellular homeostasis, which is essential to maintaining healthy metabolic pathways. Early diagnosis and intervention may be facilitated by this knowledge.

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9. Elbedour L, Balaum R, Alhozyel E, Meiri G, Zigdon D, Michaelovski A, Kerub O, Menashe I. Breastfeeding patterns in infants are associated with a later diagnosis of autism Spectrum disorder. Autism Res;2024 (Aug);17(8):1696-1704.

Breastfeeding is associated with medical and developmental benefits. This study aimed to assess associations between nutritional patterns in the first year of life and the likelihood of autism spectrum disorder (ASD). 270 children diagnosed with ASD (cases) and 500 neurotypical children (controls) matched to cases by sex, ethnicity, and birth date (± 3 months) were included in this retrospective case-control study. Both groups were ascertained from children born between 2014 and 2017 whose development/nutrition were monitored at mother-child health clinics in southern Israel. Conditional logistic regression was used to determine the independent association of nutritional patterns with ASD while adjusting for socio-demographic and clinical characteristics. Both exclusive and partial breastfeeding modes were associated with decreased odds of ASD diagnosis (aOR = 0.221, 95%CI = 0.136-0.360; aOR = 0.494, 95%CI = 0.328-0.743, respectively). A breastfeeding duration of >12 months was associated with lower ASD odds (aOR = 0.418, 95%CI = 0.204-0.855), while the introduction of solids after 6 months of age was associated with higher ASD odds than the introduction of solids at 6 months (aOR = 2.455, 95%CI = 1.116-4.201). These findings suggest that a longer period of exclusive breastfeeding is associated with a subsequent reduced likelihood of ASD diagnosis, thus reiterating the importance of proper post-natal nutrition for infant neurodevelopment.

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10. Galazka MA, Thorsson M, Lundin Kleberg J, Hadjikhani N, Åsberg Johnels J. Pupil contagion variation with gaze, arousal, and autistic traits. Sci Rep;2024 (Aug 7);14(1):18282.

Pupillary contagion occurs when one’s pupil size unconsciously adapts to the pupil size of an observed individual and is presumed to reflect the transfer of arousal. Importantly, when estimating pupil contagion, low level stimuli properties need to be controlled for, to ensure that observations of pupillary changes are due to internal change in arousal rather than the external differences between stimuli. Here, naturalistic images of children’s faces depicting either small or large pupils were presented to a group of children and adolescents with a wide range of autistic traits, a third of whom had been diagnosed with autism. We examined the extent to which pupillary contagion reflects autonomic nervous system reaction through pupil size change, heart rate and skin conductance response. Our second aim was to determine the association between arousal reaction to stimuli and degree of autistic traits. Results show that pupil contagion and concomitant heart rate change, but not skin conductance change, was evident when gaze was restricted to the eye region of face stimuli. A positive association was also observed between pupillary contagion and autistic traits when participants’ gaze was constrained to the eye region. Findings add to a broader understanding of the mechanisms underlying pupillary contagion and its association with autism.

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11. Goryunov AV. [Controversial issues of diagnosis and theoretical concepts of schizophrenia in childhood]. Zh Nevrol Psikhiatr Im S S Korsakova;2024;124(7):17-24.

The article presents modern approaches to classification, presents debatable diagnostic issues, including the differences between domestic approaches to the diagnosis of schizophrenia in childhood from foreign taxonomies. The modern hypothesis of the etiological continuum of schizophrenic and autistic spectrum disorders is discussed, as well as clinical models of manifest stages of schizophrenia in childhood, with an emphasis on the influence of the age factor on the clinic, dynamics and prognosis of diseases.

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12. Gulle BT, Yassibas U, Sarigedik E. Vaccine Hesitancy in the Autism Spectrum Disorder Context: Parental Vaccine Decision-Making and Coping with Stress Strategies. J Autism Dev Disord;2024 (Aug 8)

BACKGROUND: Despite no scientific evidence linking vaccines to Autism Spectrum Disorder (ASD), vaccine hesitancy persists among parents of children with ASD. This study aims to compare vaccine hesitancy and behaviors among parents of children with ASD, other Neurodevelopmental Disorders (NDD), and without NDD, and to examine the relationship between stress coping mechanisms and vaccine hesitancy, including comparing coping mechanisms between diagnostic groups as well as their association with hesitancy. METHODS: In this cross-sectional study, one parent of each child with ASD, non-ASD NDD, or without NDD was included. Data were collected using a researcher-created form, the Vaccine Hesitancy Scale in Turkish, and the Coping Style Scale Brief Form. Vaccine hesitancy, parents’ COVID-19 vaccination status, and vaccination status of children’s younger siblings were analyzed through univariate and multivariate analyses, with a focus on correlations between vaccine hesitancy and coping styles. RESULTS: The study included one parent from each of 299 children. Parents of children with ASD showed an adjusted odds ratio of 2.66 (95% CI 1.35-5.06) for high vaccine hesitancy, 2.57 (95% CI 1.17-5.65) for not receiving the COVID-19 vaccine, and 1.40 (95% CI 0.45-4.40) for younger siblings not receiving routine vaccines. A weak but significant correlation was observed between vaccine hesitancy and the use of restraint coping style among these parents (r = 0.280; p = 0.010). CONCLUSIONS: The study underscores the importance of targeted educational efforts and personalized communication to address vaccine hesitancy among parents of children with ASD. Enhancing vaccination coverage in this community requires further research to develop interventions tailored to their specific needs.

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13. Hamdan SZ, Bennett A. Autism-Friendly Healthcare: A Narrative Review of the Literature. Cureus;2024 (Jul);16(7):e64108.

Disparities in healthcare access, delivery, and outcomes exist between autistic and non-autistic individuals. Autism-friendly healthcare initiatives aim to facilitate and improve the healthcare experience of autistic individuals by addressing commonly encountered challenges. While there is no consensus regarding the definition of autism-friendly healthcare, in this narrative review, we examine previously published research to determine the most important components of autism-friendly healthcare. Patient-related factors, provider-related factors, and system-related factors should be addressed. Proactivity, flexibility, and collaboration should guide the process of transforming the healthcare system. Finally, multiple strategies can be utilized as appropriate to the setting and individuals.

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14. Helton JJ, Koetting C, Kronk R, Kong V, Kim YS. Autism Severity, Adverse Childhood Experiences, and Oral Health: A Comparative Study of Adolescents in the United States. J Autism Dev Disord;2024 (Aug 8)

Dental health significantly influences overall child physical well-being, academic success, and psychosocial development. This paper explores the intersection of a range of Autism Spectrum Disorder (ASD) functionality, multiple types of Adverse Childhood Experiences (ACEs), and dental health in adolescents. The purpose is to investigate the independent and interactive effects of ASD severity and ACEs on dental outcomes. Data from the 2018 and 2019 National Surveys of Children’s Health were analyzed, focusing on 28,263 adolescents (ages 11-17). Logistic regressions assessed associations between ASD severity (mild, moderate, severe), cumulative number of ACEs, and dental outcomes (teeth condition, cavities or bleeding gums, check-ups, cleanings). Covariates included demographic and socioeconomic factors. Controlling for covariates, severe autism independently increased the odds of poor teeth (odds ratio = 6.17), cavities or bleeding gums (OR = 3.76), no previous year check-up(OR = 2.94), and no previous year cleaning (OR = 4.20). Higher ACE scores also independently increased the odds of all dental outcomes. Interactions revealed a cumulative effect of multiple ACEs on poor dental outcomes only for adolescents with severe levels of autism. This study illuminates the heightened vulnerability of adolescents with severe autism and a history of ACEs, emphasizing the need for targeted interventions. Multidisciplinary strategies integrating dental care and mental health support within tailored interventions are crucial for improving dental health and access for older youth with low functioning autism. While these findings provide valuable insights, the cross-sectional design and reliance on parental reports necessitate cautious interpretation.

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15. Inoue M, Yamaguchi H, Nakatani K, Nishimoto A, Namiki K, Kuroda S, Tran TVH, Dinh NTT. Effectiveness of Online Parent Training for Vietnamese Parents of Children with Autism Spectrum Disorders. Yonago Acta Med;2024 (Aug);67(3):213-224.

BACKGROUND: Parent training (PT) programs have been implemented for neurodevelopmental disorders such as autism spectrum disorder (ASD) in recent years. However, in Southeast Asia, the diffusion of rehabilitation programs for children with ASD and that of PT as a parental support measure has been slow. METHODS: This study assessed the effectiveness of an online PT program that was developed in Japan and remotely delivered to Vietnamese parents of children with ASD residing in Vietnam. Sixteen parents of Vietnamese children with ASD participated in seven online Tottori University-style PT sessions. The online PT was conducted in real-time from Japan, considering the two-hour time difference between countries. Lectures and exercises were presented in Vietnamese with PowerPoint materials. Japanese staff provided explanations in Japanese, which were then simultaneously translated by a Vietnamese interpreter. Attendance, completion of homework assignments, and the number of statements on Zoom and social media were tallied. A pre-post-test design was employed to measure changes in parents’ mental health factors and children’s behavior. A post-intervention questionnaire was administered to assess participant’s acceptance of PT. RESULTS: The findings showed that attendance and task completion rates were considerably high. The study found that the mental health scores of parents significantly improved after participating in online parenting training compared to before. However, there were no statistically significant improvements found in children’s behavior. The study also confirmed high satisfaction with the cross-country online parenting training. CONCLUSION: This study confirmed that TUPT, developed in Japan and implemented as an online PT for parents of children with ASD living in Vietnam, was effective in improving parental mental health. The program acceptability questionnaire also showed positive results. This study is the first step in the evaluation and dissemination of Internet-based, cross-country parent training for parental support in Asia.

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16. Mazur LE, Even KM, Krawiec C. Retrospective Analysis of Dog Bite Injuries in Children with Autism Spectrum Disorder. J Autism Dev Disord;2024 (Aug 8)

PURPOSE: Children with autism spectrum disorder (ASD) may suffer a dog bite injury, but the frequency and its clinical impact is unknown. We sought to evaluate the (1) subject characteristics; (2) injury type; (3) clinical care provided; and (4) mortality in children with ASD who suffer a dog bite injury. We hypothesized that children with ASD have higher mortality and require more clinical care than children without ASD. METHODS: This is a retrospective observational cohort study utilizing the TriNetX (®) EHR database of subjects aged 0 to 18 years with dog bite diagnostic codes. Data were analyzed for demographics, diagnostic, medication, procedural codes, and mortality. RESULTS: We analyzed 38,337 subjects (n, %) coded for a dog bite injury [619 (1.6%) with ASD and 37718 (98.4%) without ASD]. Children with ASD had a higher odds of a traumatic injury to the head [1.34 (1.15, 1.57), p < 0.0001] compared to those without. There was no difference in critical care services, hospitalization, mechanical ventilation, and rabies vaccine administration. All-cause mortality at 1 year was low with no deaths reported within the ASD cohort and 37 (0.1%) deaths reported within the no ASD cohort. CONCLUSIONS: Children with ASD that suffer dog bite injuries have similar clinical needs to children without ASD but are more likely to suffer a traumatic injury to the head. Future studies are needed to better understand inciting factors for injuries in this population.

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17. Miao C, Shen Y, Lang Y, Li H, Gong Y, Liu Y, Li H, Jones BC, Chen F, Feng S. Biomimetic nanoparticles with enhanced rapamycin delivery for autism spectrum disorder treatment via autophagy activation and oxidative stress modulation. Theranostics;2024;14(11):4375-4392.

Rationale: Autism spectrum disorder (ASD) represents a complex neurodevelopmental condition lacking specific pharmacological interventions. Given the multifaced etiology of ASD, there exist no effective treatment for ASD. Rapamycin (RAPA) can activate autophagy by inhibiting the mTOR pathway and has exhibited promising effects in treating central nervous system disorders; however, its limited ability to cross the blood-brain barrier (BBB) has hindered its clinical efficacy, leading to substantial side effects. Methods: To address this challenge, we designed a drug delivery system utilizing red blood cell membrane (CM) vesicles modified with SS31 peptides to enhance the brain penetration of RAPA for the treatment of autism. Results: The fabricated SCM@RAPA nanoparticles, with an average diameter of 110 nm, exhibit rapid release of RAPA in a pathological environment characterized by oxidative stress. In vitro results demonstrate that SCM@RAPA effectively activate cellular autophagy, reduce intracellular ROS levels, improve mitochondrial function, thereby ameliorating neuronal damage. SS31 peptide modification significantly enhances the BBB penetration and rapid brain accumulation of SCM@RAPA. Notably, SCM@RAPA nanoparticles demonstrate the potential to ameliorate social deficits, improve cognitive function, and reverse neuronal impairments in valproic acid (VPA)-induced ASD models. Conclusions: The therapeutic potential of SCM@RAPA in managing ASD signifies a paradigm shift in autism drug treatment, holding promise for clinical interventions in diverse neurological conditions.

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18. Mohammad S, Gentreau M, Dubol M, Rukh G, Mwinyi J, Schiöth HB. Association of polygenic scores for autism with volumetric MRI phenotypes in cerebellum and brainstem in adults. Mol Autism;2024 (Aug 7);15(1):34.

Previous research on autism spectrum disorders (ASD) have showed important volumetric alterations in the cerebellum and brainstem. Most of these studies are however limited to case-control studies with small clinical samples and including mainly children or adolescents. Herein, we aimed to explore the association between the cumulative genetic load (polygenic risk score, PRS) for ASD and volumetric alterations in the cerebellum and brainstem, as well as global brain tissue volumes of the brain among adults at the population level. We utilized the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and constructed the ASD PRS in an independent cohort, the UK Biobank. Regression analyses controlled for multiple comparisons with the false-discovery rate (FDR) at 5% were performed to investigate the association between ASD PRS and forty-four brain magnetic resonance imaging (MRI) phenotypes among ~ 31,000 participants. Primary analyses included sixteen MRI phenotypes: total volumes of the brain, cerebrospinal fluid (CSF), grey matter (GM), white matter (WM), GM of whole cerebellum, brainstem, and ten regions of the cerebellum (I_IV, V, VI, VIIb, VIIIa, VIIIb, IX, X, CrusI and CrusII). Secondary analyses included twenty-eight MRI phenotypes: the sub-regional volumes of cerebellum including the GM of the vermis and both left and right lobules of each cerebellar region. ASD PRS were significantly associated with the volumes of seven brain areas, whereby higher PRS were associated to reduced volumes of the whole brain, WM, brainstem, and cerebellar regions I-IV, IX, and X, and an increased volume of the CSF. Three sub-regional volumes including the left cerebellar lobule I-IV, cerebellar vermes VIIIb, and X were significantly and negatively associated with ASD PRS. The study highlights a substantial connection between susceptibility to ASD, its underlying genetic etiology, and neuroanatomical alterations of the adult brain.

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19. Nissenkorn A, Bar L, Ben-Bassat A, Rothstein L, Abdelrahim H, Sokol R, Gabis LV, Attali B. Donepezil as a new therapeutic potential in KCNQ2- and KCNQ3-related autism. Front Cell Neurosci;2024;18:1380442.

INTRODUCTION: The KCNQ2/KCNQ3 genes encode the voltage-gated K channel underlying the neuronal M-current, regulating neuronal excitability. Loss-of-function (LoF) variants cause neonatal epilepsy, treatable with the M-current-opener retigabine, which is no longer marketed due to side effects. Gain-of-function (GoF) variants cause developmental encephalopathy and autism that could be amenable to M-current, but such therapies are not clinically available. In this translational project, we investigated whether donepezil, a cholinergic drug used in Alzheimer’s, suppresses M currents in vitro and improves cognitive symptoms in patients with GoF variants. METHODS: (1) The effect of 1 μM donepezil on the amplitude of the M-current was measured in excitatory and inhibitory neurons of mouse primary cultured hippocampal cells. M-current was measured using the standard deactivation protocol (holding at 0 mV and deactivation at -60 mV) in the voltage-clamp configuration of the whole-cell patch clamp technique. The impact of donepezil was also examined on the spontaneous firing activity of hippocampal neurons in the current-clamp configuration. (2) Four children with autism, aged 2.5-8 years, with the following GoF variants were enrolled: KCNQ2 (p. Arg144Gln) and KCNQ 3 (p.Arg227Gln, p.Arg230Cys). Patients were treated off-label with donepezil 2.5-5 mg/d for 12 months and assessed with: clinical Global Impression of Change (CGI-c), Childhood Autism Rating Scale 2 (CARS-2), Adaptive Behavior Assessment System-II (ABAS-II), and Child Development Inventory (CDI). RESULTS: (1) Application of donepezil for at least 6 min produced a significant inhibition of the M-current with an IC50 of 0.4 μM. At 1 μM, donepezil reduced by 67% the M-current density of excitatory neurons (2.4 ± 0.46 vs. 0.89 ± 0.15 pA/pF, p < 0.05(*)). In inhibitory neurons, application of 1 μM donepezil produced a lesser inhibition of 59% of the M-current density (1.39 ± 0.43 vs. 0.57 ± 0.21, p > 0.05). Donepezil (1 μM) potently increased by 2.6-fold the spontaneous firing frequency, which was prevented by the muscarinic receptor antagonist atropine (10 μM). (2) The CARS-2 decreased by 3.8 ± 4.9 points (p > 0.05), but in two patients with KCNQ3 variants, the improvement was over the 4.5 clinically relevant threshold. The global clinical change was also clinically significant in these patients (CGI-c = 1). The CDI increased by 65% (p < 0.05(*)), while the ABAS-II remained unchanged. DISCUSSION: Donepezil should be repurposed as a novel alternative treatment for GoF variants in KCNQ2/KCNQ3 encephalopathy.

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20. Qiu L, Liang C, Kochunov P, Hutchison KE, Sui J, Jiang R, Zhi D, Vergara VM, Yang X, Zhang D, Fu Z, Bustillo JR, Qi S, Calhoun VD. Associations of alcohol and tobacco use with psychotic, depressive and developmental disorders revealed via multimodal neuroimaging. Transl Psychiatry;2024 (Aug 7);14(1):326.

People affected by psychotic, depressive and developmental disorders are at a higher risk for alcohol and tobacco use. However, the further associations between alcohol/tobacco use and symptoms/cognition in these disorders remain unexplored. We identified multimodal brain networks involving alcohol use (n = 707) and tobacco use (n = 281) via supervised multimodal fusion and evaluated if these networks affected symptoms and cognition in people with psychotic (schizophrenia/schizoaffective disorder/bipolar, n = 178/134/143), depressive (major depressive disorder, n = 260) and developmental (autism spectrum disorder/attention deficit hyperactivity disorder, n = 421/346) disorders. Alcohol and tobacco use scores were used as references to guide functional and structural imaging fusion to identify alcohol/tobacco use associated multimodal patterns. Correlation analyses between the extracted brain features and symptoms or cognition were performed to evaluate the relationships between alcohol/tobacco use with symptoms/cognition in 6 psychiatric disorders. Results showed that (1) the default mode network (DMN) and salience network (SN) were associated with alcohol use, whereas the DMN and fronto-limbic network (FLN) were associated with tobacco use; (2) the DMN and fronto-basal ganglia (FBG) related to alcohol/tobacco use were correlated with symptom and cognition in psychosis; (3) the middle temporal cortex related to alcohol/tobacco use was associated with cognition in depression; (4) the DMN related to alcohol/tobacco use was related to symptom, whereas the SN and limbic system (LB) were related to cognition in developmental disorders. In summary, alcohol and tobacco use were associated with structural and functional abnormalities in DMN, SN and FLN and had significant associations with cognition and symptoms in psychotic, depressive and developmental disorders likely via different brain networks. Further understanding of these relationships may assist clinicians in the development of future approaches to improve symptoms and cognition among psychotic, depressive and developmental disorders.

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21. Reilly AM, Bak MYS, Johnson LD. Researcher-Reported Variables Needed for Translation of Social Communication Evidence-Based Practices for Elementary-Aged Students with Autism. J Autism Dev Disord;2024 (Aug 8)

Organizations such as the National Clearinghouse on Autism Evidence and Practice have disseminated reports on evidence-based practices (EBPs) for individuals with autism to inform practice. However, some practitioners routinely employ unvalidated interventions more frequently than EBPs, signaling the presence of a research-to-practice gap. The current review investigated the degree to which single-case research studies with social communication outcomes for elementary-aged students with autism included details on variables that may impact the adoption and implementation of EBPs in practice. The results suggest limited reporting of variables that aid decision-making in the adoption and implementation of EBPs. Limited reporting can negatively impact uptake and fidelity and, therefore, student outcomes. Suggestions are made to improve researchers’ reporting of the critical components of EBPs that will facilitate adoption and implementation by practitioners.

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22. Scarpelli S, Menghini D, Alfonsi V, Giumello F, Annarumma L, Gorgoni M, Valeri G, Pazzaglia M, De Gennaro L, Vicari S. Sleep Disturbances and Co-sleeping in Italian Children and Adolescents with Autism Spectrum Disorder. J Autism Dev Disord;2024 (Aug 8)

The current study aimed (1) to provide an analysis of the frequency and prevalence of sleep disturbances in a large Italian sample of children and adolescents with ASD, detecting specific predictors of the presence/absence of sleep disorders, (2) to examine the phenomenon of co-sleeping within a subgroup of participants with ASD. A total of 242 children and adolescents with ASD (194 males, mean age 5.03 ± 3.15 years) were included. After the diagnostic procedure, caregivers were requested to complete the Sleep Disturbance Scale for Children (SDSC) to assess sleep disorders among participants. The presence of co-sleeping was investigated in a subgroup of 146 children and adolescents with ASD. An elevated or clinically relevant global score for sleep disorders (≥ 60) was found in 33% of participants. The most prevalent sleep disorder in our group was related to difficulties with sleep onset and sleep maintenance (~ 41% of cases). Sleep disturbances were predicted by higher intelligence quotient (IQ)/developmental quotient (DQ), increased internalizing problems, and elevated parental stress. The subgroup of participants engaged in co-sleeping (N = 87) were younger and had lower IQ/DQ scores, reduced adaptive functioning, and diminished psychological wellbeing than the non-co-sleeping group. Our findings are consistent with the current literature highlighting that insomnia is the most widespread sleep problem associated with ASD. The relationship between IQ/DQ and sleep alterations is a crucial topic that deserves additional research. Future studies should assess sleep by objective measures such as EEG topography to better understand the mechanisms underlying sleep alterations in this neurodevelopmental disorder.

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23. Shaw W. Hypothesis: 2 Major Environmental and Pharmaceutical Factors-Acetaminophen Exposure and Gastrointestinal Overgrowth of Clostridia Bacteria Induced By Ingestion of Glyphosate-Contaminated Foods-Dysregulate the Developmental Protein Sonic Hedgehog and Are Major Causes of Autism. Integr Med (Encinitas);2024 (Jul);23(3):12-23.

Epidemiological studies have found 2 significant factors associated with the increased incidence of autism spectrum disorder (ASD): the increased use of acetaminophen in the 1970s when this drug largely replaced the use of aspirin for many patients because of a fear of Reye syndrome, and the agricultural use in the 1990s of the herbicide glyphosate on crops that were genetically modified (GM) to tolerate glyphosate. The incidence of autism in the United States, where acetaminophen is widely available, is more than 1000 times greater than in Cuba, where acetaminophen is available only by prescription. Metabolites of both glyphosate and acetaminophen likely alter the function of the developmental protein sonic hedgehog (SHH). Glyphosate likely affects SHH indirectly by decreasing the beneficial flora of the gastrointestinal tract and increasing pathogenic Clostridia bacteria, which are resistant to glyphosate. The marked increase of certain Clostridia species caused by glyphosate results in Clostridia production of large amounts of 3-(3-hydroxyphenyl)-3-hydroxypropionate (HPHPA) and 4-cresol (p-cresol). The 4-cresol metabolite 4-methyl-o-hydroquinone and the acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) likely react with the sulfhydryl group of the N-terminal cysteine of SHH, blocking the function of this critical amino acid required for the activation of SHH. HPHPA and 4-cresol also inhibit dopamine β-hydroxylase, resulting in overproduction of dopamine and its toxic metabolites, such as aminochrome, that cause biochemical damage to mitochondria and structural proteins in brain cells. Elevated amounts of these Clostridia products in body fluids in people with autism and in animals with autistic signs have been documented in laboratories throughout the world. The synthesis of the HPHPA molecule in extremely large quantities depletes the body of free coenzyme A, which is needed for the palmitoylation of SHH. SHH covalently coupled to palmitic acid is 30 times more active than SHH without palmitic acid. These possible modifications of SHH help to explain the significantly altered quantities of SHH in the blood serum of patients with autism. The severity of autism is related to the degree of SHH abnormality. The spread of pathogenic Clostridia worldwide from soil to food animals to humans, which may be promoted by glyphosate use, is a great public health concern, not only for autism but perhaps for all the neuropsychiatric diseases that appear to be related to gastrointestinal Clostridia overgrowth These diseases include seizures, tremors, tic disorders, Parkinson disease, chronic fatigue syndrome, obsessive compulsive disorder, schizophrenia, bipolar and unipolar depression, ADHD, and anorexia nervosa.

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24. Sokolov PL, Chebanenko NV, Mednaya DM, Fedotova YA. [Epilepsy with PCDH19 mutation: polypharmacy as a consequence of the complexity and diversity of pathogenesis mechanisms]. Zh Nevrol Psikhiatr Im S S Korsakova;2024;124(7):51-55.

Mutations in the human PCDH19 gene lead to epileptic encephalopathy of early childhood. It is characterized by the early onset of serial seizures, cognitive impairment and behavioral disorders (including autistic personality traits). In most cases, difficulties arise in selecting therapy due to pharmacoresistance. The pathogenesis of the disease is complex. The data available to us at the moment from numerous studies present the pathogenesis of «PCDH19 syndrome» as multi-level, affecting both the epigenetic support of cell life, and development of stem cells and progenitor cells in the process of neuroontogenesis, and the influence on the neurotransmitter mechanisms of the brain, and disruption of the formation of neural networks with an inevitable increase in the excitability of the cerebral cortex as a whole, and local changes in the highly labile regulatory structures of the hippocampal region. And it is not surprising that all these changes entail not only (and perhaps not so much) epileptization, but a profound disruption of the regulation of brain activity, accompanied by autism spectrum disorders, more profound disorders in the form of schizophrenia or cyclothymia, and the formation of delayed psychomotor development. A «side branch» of these pathogenetic processes can also be considered the participation of PCDH19 dysfunctions in certain variants of oncogenesis. The need for polypharmacy (in most cases) confirms the diversity of mechanisms involved in the pathogenesis of the disease and makes the prospects for the development of effective and rational treatment regimens very vague. Cautious optimism is caused only by attempts at relatively specific treatment with ganaxolone.

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25. Symeonides C, Vacy K, Thomson S, Tanner S, Chua HK, Dixit S, Mansell T, O’Hely M, Novakovic B, Herbstman JB, Wang S, Guo J, Chia J, Tran NT, Hwang SE, Britt K, Chen F, Kim TH, Reid CA, El-Bitar A, Bernasochi GB, Delbridge LMD, Harley VR, Yap YW, Dewey D, Love CJ, Burgner D, Tang MLK, Sly PD, Saffery R, Mueller JF, Rinehart N, Tonge B, Vuillermin P, Ponsonby AL, Boon WC. Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype. Nat Commun;2024 (Aug 7);15(1):6367.

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

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26. Westby C, Chen KM, Cheng L, Jithavech P, Maroonroge S. Autism in Taiwan and Thailand: Influences of Culture. Neuropsychiatr Dis Treat;2024;20:1523-1538.

The prevalence of autism is increasing worldwide. The majority of autism research and development of autism assessments and interventions has been conducted in Western cultures. The prevalence of autism is reportedly lower in Asian versus Western cultures, but this is likely due to lack of personnel and uniform criteria for diagnosing autism. This article describes how two Asian cultures, Taiwan and Thailand, are dealing with the increasing identification of autistic children. National universal healthcare in both Taiwan and Thailand provides a mechanism for assessment and diagnosis of young children, but a lack of a sufficient number of trained professionals limits the availability of intervention services. A focus of research in these cultures has been on parents’ experiences and coping with the stigma and stress of having an autistic child. Cultural values associated with Confucianism and Buddhism influence attitudes toward persons with disability and how parents of autistic children experience and cope with stigma and stress. Both areas have national laws that provide a range of educational opportunities for autistic children, including inclusion into general education classrooms. Special education and general education teachers, however, have little specific training in autism. Speech and language services are rarely offered in public school programs. Available speech and language services are limited to consultation with teachers a few times a year. In general, parents of autistic children are supportive of inclusion programs, but teachers and parents of both autistic and typically developing children express concerns about the ability to implement such programs in ways that are beneficial to all children.

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27. Yoon JG, Lim SK, Seo H, Lee S, Cho J, Kim SY, Koh HY, Poduri AH, Ramakumaran V, Vasudevan P, de Groot MJ, Ko JM, Han D, Chae JH, Lee CH. De novo missense variants in HDAC3 leading to epigenetic machinery dysfunction are associated with a variable neurodevelopmental disorder. Am J Hum Genet;2024 (Aug 8);111(8):1588-1604.

Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for various developmental and physiological functions. Although its dysfunction is increasingly recognized in abnormal phenotypes, to our knowledge, there have been no established reports of human diseases directly linked to HDAC3 dysfunction. Using trio exome sequencing and extensive phenotypic analysis, we correlated heterozygous de novo variants in HDAC3 with a neurodevelopmental disorder having variable clinical presentations, frequently associated with intellectual disability, developmental delay, epilepsy, and musculoskeletal abnormalities. In a cohort of six individuals, we identified missense variants in HDAC3 (c.277G>A [p.Asp93Asn], c.328G>A [p.Ala110Thr], c.601C>T [p.Pro201Ser], c. 797T>C [p.Leu266Ser], c.799G>A [p.Gly267Ser], and c.1075C>T [p.Arg359Cys]), all located in evolutionarily conserved sites and confirmed as de novo. Experimental studies identified defective deacetylation activity in the p.Asp93Asn, p.Pro201Ser, p.Leu266Ser, and p.Gly267Ser variants, positioned near the enzymatic pocket. In addition, proteomic analysis employing co-immunoprecipitation revealed that the disrupted interactions with molecules involved in the CoREST and NCoR complexes, particularly in the p.Ala110Thr variant, consist of a central pathogenic mechanism. Moreover, immunofluorescence analysis showed diminished nuclear to cytoplasmic fluorescence ratio in the p.Ala110Thr, p.Gly267Ser, and p.Arg359Cys variants, indicating impaired nuclear localization. Taken together, our study highlights that de novo missense variants in HDAC3 are associated with a broad spectrum of neurodevelopmental disorders, which emphasizes the complex role of HDAC3 in histone deacetylase activity, multi-protein complex interactions, and nuclear localization for proper physiological functions. These insights open new avenues for understanding the molecular mechanisms of HDAC3-related disorders and may inform future therapeutic strategies.

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28. Zavadenko NN, Nesterovskiy YE, Zavadenko AN, Shypilova EM. [Anxiety disorders as comorbid conditions in neuropsychiatric diseases in children]. Zh Nevrol Psikhiatr Im S S Korsakova;2024;124(7):56-64.

The variants of heterotypic comorbidity of anxiety disorders (AD) with attention deficit hyperactivity disorder, autism spectrum disorders, speech and language development disorders, specific learning disabilities (dyslexia, dysgraphia, dyscalculia), migraine, tension type headache in children and adolescents are discussed. In cases of heterotypic comorbidity the patients with AD referrals to specialists may be primarily associated with their emotional problems. Meanwhile, the comorbidity of AD with these diseases leads to a deterioration of their clinical manifestations and a worsening of the prognosis, and anxiety symptoms often not only persist, but also increase with age. It should be borne in mind that AD in children with neurodevelopmental disorders contribute to a decrease in the quality of life, academic failure, have a negative impact on peer relationships and the family environment, and in young adulthood, patients have an increased risk of depression and substance abuse. Therefore, early intervention and a comprehensive therapeutic approach with a dynamic assessment of the patient’s condition are becoming important. When choosing pharmacotherapy, it is advisable to choose medictions that have a complex effect on the pathogenetic mechanisms of the underlying disease and concomitant AD, which include Tenoten for children.

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29. Zhou F, Zhong H, Wu B, Cui Y, Li J, Jia X, Yu C, Li D, Shu J, Cai C. Identification of the synonymous variant c.3141G > A in TNRC6B gene that altered RNA splicing by minigene assay. Mol Biol Rep;2024 (Aug 8);51(1):899.

BACKGROUND: Global developmental delay with speech and behavioral abnormalities (OMIM: 619243) is an autosomal dominant disease caused by variants in TNRC6B gene. METHOD: We reviewed and summarized clinical manifestations and genotypes in patients previously reported with TNRC6B gene variants. We used several prediction tools to predict pathogenicity and performed minigene assays to verify the function of the synonymous variant affecting RNA splicing. RESULT: The patient presented with convulsive seizures and developmental delay. WES combined with functional studies diagnosed a child with a synonymous variant in TNRC6B gene. Through minigene assay and Sanger sequencing, we demonstrated that c.3141G > A variant induced exon 7 skipping and the synonymous variant was pathogenic. CONCLUSION: Synonymous variants do not change the amino acids encoded by the codon, so we usually consider synonymous variants to be benign and ignore their pathogenicity. Minigene assay is a valuable tool to identify the effect of variation on RNA splicing and identify synonymous variants’ benign or pathogenic. We showed that the synonymous variant was pathogenic by minigene assay. WES combined with minigene assay establishes a robust basis for genetic counseling and diagnosing diseases.

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