1. Al-Saei A, Nour-Eldine W, Rajpoot K, Arshad N, Al-Shammari AR, Kamal M, Akil AA, Fakhro KA, Thornalley PJ, Rabbani N. Validation of plasma protein glycation and oxidation biomarkers for the diagnosis of autism. Mol Psychiatry;2023 (Dec 22)

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder in children. It is currently diagnosed by behaviour-based assessments made by observation and interview. In 2018 we reported a discovery study of a blood biomarker diagnostic test for ASD based on a combination of four plasma protein glycation and oxidation adducts. The test had 88% accuracy in children 5-12 years old. Herein, we present an international multicenter clinical validation study (N = 478) with application of similar biomarkers to a wider age range of 1.5-12 years old children. Three hundred and eleven children with ASD (247 male, 64 female; age 5.2 ± 3.0 years) and 167 children with typical development (94 male, 73 female; 4.9 ± 2.4 years) were recruited for this study at Sidra Medicine and Hamad Medical Corporation hospitals, Qatar, and Hospital Regional Universitario de Málaga, Spain. For subjects 5-12 years old, the diagnostic algorithm with features, advanced glycation endproducts (AGEs)-N(ε)-carboxymethyl-lysine (CML), N(ω)-carboxymethylarginine (CMA) and 3-deoxyglucosone-derived hydroimidazolone (3DG-H), and oxidative damage marker, o,o’-dityrosine (DT), age and gender had accuracy 83% (CI 79 – 89%), sensitivity 94% (CI 90-98%), specificity 67% (CI 57-76%) and area-under-the-curve of receiver operating characteristic plot (AUROC) 0.87 (CI 0.84-0.90). Inclusion of additional plasma protein glycation and oxidation adducts increased the specificity to 74%. An algorithm with 12 plasma protein glycation and oxidation adduct features was optimum for children of 1.5-12 years old: accuracy 74% (CI 70-79%), sensitivity 75% (CI 63-87%), specificity 74% (CI 58-90%) and AUROC 0.79 (CI 0.74-0.84). We conclude that ASD diagnosis may be supported using an algorithm with features of plasma protein CML, CMA, 3DG-H and DT in 5-12 years-old children, and an algorithm with additional features applicable for ASD screening in younger children. ASD severity, as assessed by ADOS-2 score, correlated positively with plasma protein glycation adducts derived from methylglyoxal, hydroimidazolone MG-H1 and N(ε)(1-carboxyethyl)lysine (CEL). The successful validation herein may indicate that the algorithm modifiable features are mechanistic risk markers linking ASD to increased lipid peroxidation, neuronal plasticity and proteotoxic stress.

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2. Botsas G, Koidou E, Chatzinikolaou K, Grouios G. Environmental Influences on Individuals with Autistic Spectrum Disorders with Special Emphasis on Seasonality: An Overview. Children (Basel);2023 (Nov 25);10(12)

This paper offers an in-depth exploration of the intricate relationship between environmental factors and autism spectrum disorder (ASD), with a special emphasis on seasonality. It reviews existing research, providing a comprehensive summary of findings and highlighting the multifaceted dimensions of several environmental factors influencing the etiology of ASD. The discussion encompasses various elements, including birth months, maternal health, dietary choices, and vitamin D deficiency, delving into the intricate interplay of seasonality with environmental influences such as viral infections and solar radiation. The present study raises essential questions regarding the timing of environmental influences and the factors contributing to the rising prevalence of ASD. Ultimately, it underscores the need for future epidemiological research to incorporate more extensive investigations of environmental risk factors and employ advanced statistical analyses. This comprehensive overview contributes to a deeper understanding of how environmental factors, particularly seasonality, may be linked to the occurrence of ASD and its increasing prevalence, recognizing the multifaceted and diverse nature of these interactions.

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3. Caffarelli C, Al Refaie A, Mondillo C, De Vita M, Baldassini L, Valacchi G, Gonnelli S. Bone Fracture in Rett Syndrome: Mechanisms and Prevention Strategies. Children (Basel);2023 (Nov 27);10(12)

The present study aimed to evaluate the burden and management of fragility fractures in subjects with Rett syndrome. We searched all relevant medical literature from 1 January 1986 to 30 June 2023 for studies under the search term « Rett syndrome and fracture ». The fracture frequency ranges from a minimum of 13.9% to a maximum of 36.1%. The majority of such fractures occur in lower limb bones and are associated with low bone mineral density. Anticonvulsant use, joint contractures, immobilization, low physical activity, poor nutrition, the genotype, and lower calcium and vitamin D intakes all significantly impair skeletal maturation and bone mass accrual in Rett syndrome patients, making them more susceptible to fragility fractures. This review summarizes the knowledge on risk factors for fragility fracture in patients with Rett syndrome and suggests a possible diagnostic and therapeutic care pathway for improving low bone mineral density and reducing the risk of fragility fractures. The optimization of physical activity, along with adequate nutrition and the intake of calcium and vitamin D supplements, should be recommended. In addition, subjects with Rett syndrome and a history of fracture should consider using bisphosphonates.

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4. Czech H. Herwig Czech: To assess Asperger’s knowledge on the Nazi ‘child euthanasia’ programme, his own words should matter (response to Tatzer et al.). Acta Paediatr;2023 (Dec 22)

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5. De Laet H, Nijhof AD, Wiersema JR. Adults with Autism Prefer Person-First Language in Dutch: A Cross-Country Study. J Autism Dev Disord;2023 (Dec 23)

The correct language to refer to someone with a diagnosis of autism spectrum disorder has received a lot of attention in recent years. Studies in English-speaking countries found a main identity-first language (IFL) preference (e.g. autistic person) opposed to a person-first language preference (PFL) (e.g. person with autism) among adults with autism. However, a recent study conducted in a Dutch-speaking country (the Netherlands) reported a PFL preference (Buijsman et al., 2023). The goal of the current study was to gain insights into language preferences in two Dutch-speaking countries and, in contrast to previous studies, give participants the option to indicate not having a specific language preference. In the current study, we asked 414 Dutch-speaking adults with autism, living either in Belgium or the Netherlands, to fill in an online questionnaire about their language preference. We found that over half of the participants had a PFL preference (54%), followed by having no preference (27%). Only 14% of them had an IFL preference, and 5% proposed another term. Having more years of education was identified as a predictor for having an IFL preference when compared to a PFL preference, while being older predicted having no preference compared to a PFL preference. The majority of Dutch-speaking adults with autism showed a PFL preference, which is in contrast to findings from English-speaking countries, but in accord with a recent study conducted in the Netherlands (Buijsman et al., 2023). Implications of this finding for language use are discussed.

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6. Fan G, Ma J, Ma R, Suo M, Chen Y, Zhang S, Zeng Y, Chen Y. Microglia Modulate Neurodevelopment in Autism Spectrum Disorder and Schizophrenia. Int J Mol Sci;2023 (Dec 9);24(24)

Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills. These disorders result in significant morbidity for children, thus burdening families and healthcare/educational systems. However, there is a lack of early diagnosis and effective therapies. Therefore, a more connected approach is required to explore these disorders. Microglia, the primary phagocytic cells within the central nervous system, are crucial in regulating neuronal viability, influencing synaptic dynamics, and determining neurodevelopmental outcomes. Although the neurobiological basis of autism spectrum disorder (ASD) and schizophrenia (SZ) has attracted attention in recent decades, the role of microglia in ASD and SZ remains unclear and requires further discussion. In this review, the important and frequently multifaceted roles that microglia play during neurodevelopment are meticulously emphasized and potential microglial mechanisms that might be involved in conditions such as ASD and SZ are postulated. It is of utmost importance to acquire a comprehensive understanding of the complexities of the interplay between microglia and neurons to design effective, targeted therapeutic strategies to mitigate the effects of NDDs.

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7. Hnoonual A, Plong-On O, Worachotekamjorn J, Charalsawadi C, Limprasert P. Clinical and molecular characteristics of FMR1 microdeletion in patient with fragile X syndrome and review of the literature. Clin Chim Acta;2023 (Dec 23);553:117728.

BACKGROUND: Fragile X syndrome (FXS) is mainly caused by FMR1 CGG repeat expansions. Other types of mutations, particularly deletions, are also responsible for FXS phenotypes, however these mutations are often missed by routine clinical testing. MATERIALS AND METHODS: Molecular diagnosis in cases of suspected FXS was a combination of PCR and Southern blot. Measurement of the FMRP protein level was useful for detecting potentially deleterious impact. RESULTS: PCR analysis and Southern blot revealed a case with premutation and suspected deletion alleles. Sanger sequencing showed that the deletion involved 313 bp upstream of repeats and some parts of CGG repeat tract, leaving transcription start site. FMRP was detected in 5.5 % of blood lymphocytes. CONCLUSION: According to our review of case reports, most patients carrying microdeletion and full mutation had typical features of FXS. To our knowledge, our case is the first to describe mosaicism of a premutation and microdeletion in the FMR1 gene. The patient was probably protected from the effects of the deletion by mosaicism with premutation allele, leading to milder phenotype. It is thus important to consider appropriate techniques for detecting FMR1 variants other than repeat expansions which cannot be detected by routine FXS diagnosis.

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8. Jasenovec T, Radosinska D, Jansakova K, Kopcikova M, Tomova A, Snurikova D, Vrbjar N, Radosinska J. Alterations in Antioxidant Status and Erythrocyte Properties in Children with Autism Spectrum Disorder. Antioxidants (Basel);2023 (Nov 28);12(12)

Erythrocytes are responsible for the transport of oxygen within the organism, which is particularly important for nerve tissues. Erythrocyte quality has been shown to be deteriorated in oxidative stress conditions. In this study, we measured the same series of oxidative stress markers in plasma and erythrocytes to compare the differences between neurotypical children (controls) and children with autism spectrum disorder (ASD). We also focused on erythrocyte properties including their deformability, osmotic resistance, Na,K-ATPase activity, nitric oxide levels and free radical levels in children with ASD and controls. Greater oxidative damage to proteins and lipids was observed in the erythrocytes than in the plasma of ASD subjects. Additionally, antioxidant enzymes were more active in plasma samples from ASD children than in their erythrocytes. Significantly higher nitric oxide level and Na,K-ATPase enzyme activity were detected in erythrocytes of ASD individuals in comparison with the controls. Changes in oxidative status could at least partially contribute to the deterioration of erythrocyte morphology, as more frequent echinocyte formation was detected in ASD individuals. These alterations are most probably responsible for worsening the erythrocyte deformability observed in children with ASD. We can conclude that abnormalities in antioxidant status and erythrocyte properties could be involved in the pathomechanisms of ASD and eventually contribute to its clinical manifestations.

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9. Kargar M, Hagerman RJ, Martínez-Cerdeño V. Neurodegeneration of White and Gray Matter in the Hippocampus with FXTAS. Int J Mol Sci;2023 (Dec 8);24(24)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects older premutation carriers (55-200 CGG repeats) of the fragile X gene. Despite the high prevalence of the FXTAS disorder, neuropathology studies of individuals affected by FXTAS are limited. We performed hematoxylin and eosin (H&E) staining in the hippocampus of 26 FXTAS cases and analyzed the tissue microscopically. The major neuropathological characteristics were white matter disease, intranuclear inclusions in neurons and astrocytes, and neuron loss. Astrocytes contained more and larger inclusions than neurons. There was a negative correlation between age of death and CGG repeat length in cases over the age of 60. The number of astroglial inclusions (CA3 and dentate gyrus) and the number of CA3 neuronal inclusions increased with elevated CGG repeat length. In the two cases with a CGG repeat size less than 65, FXTAS intranuclear inclusions were not present in the hippocampus, while in the two cases with less than 70 (65-70) CGG repeat expansion, neurons and astrocytes with inclusions were occasionally identified in the CA1 sub-region. These findings add hippocampus neuropathology to the previously reported changes in other areas of the brain in FXTAS patients, with implications for understanding FXTAS pathogenesis.

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10. Lagod PP, Naser SA. The Role of Short-Chain Fatty Acids and Altered Microbiota Composition in Autism Spectrum Disorder: A Comprehensive Literature Review. Int J Mol Sci;2023 (Dec 13);24(24)

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in communication and social interactions, restrictive and repetitive behavior, and a wide range of cognitive impediments. The prevalence of ASD tripled in the last 20 years and now affects 1 in 44 children. Although ASD’s etiology is not yet elucidated, a growing body of evidence shows that it stems from a complex interplay of genetic and environmental factors. In recent years, there has been increased focus on the role of gut microbiota and their metabolites, as studies show that ASD patients show a significant shift in their gut composition, characterized by an increase in specific bacteria and elevated levels of short-chain fatty acids (SCFAs), especially propionic acid (PPA). This review aims to provide an overview of the role of microbiota and SCFAs in the human body, as well as possible implications of microbiota shift. Also, it highlights current studies aiming to compare the composition of the gut microbiome of ASD-afflicted patients with neurotypical control. Finally, it highlights studies with rodents where ASD-like symptoms or molecular hallmarks of ASD are evoked, via the grafting of microbes obtained from ASD subjects or direct exposure to PPA.

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11. Malachowski T, Chandradoss KR, Boya R, Zhou L, Cook AL, Su C, Pham K, Haws SA, Kim JH, Ryu HS, Ge C, Luppino JM, Nguyen SC, Titus KR, Gong W, Wallace O, Joyce EF, Wu H, Rojas LA, Phillips-Cremins JE. Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome. Cell;2023 (Dec 21);186(26):5840-5858.e5836.

Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.

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12. McConkey R. Nurturing the Positive Mental Health of Autistic Children, Adolescents and Adults alongside That of Their Family Care-Givers: A Review of Reviews. Brain Sci;2023 (Nov 27);13(12)

The rising prevalence of autism internationally has been accompanied by an increased appreciation of the poorer mental health experienced by people with this condition and also of their family care-givers. In particular, higher incidences of anxiety and depression are reported in high-income nations and these conditions are likely to be under-recognised and under-reported in lower-resourced regions or countries. Mainstream mental health services seem to be ill-equipped to respond adequately to the needs of autistic persons and their care-givers. This literature review of 29 recently published reviews covering nearly 1000 journal articles summarises the insights and strategies that have been shown to promote the mental health and emotional wellbeing of autistic persons. In particular, a focus on family-centred, community-based supports is recommended that aim to enhance social communication, extend social connections and promote an individual’s self-esteem, self-determination and social motivation. These low-cost interventions are especially pertinent in low-resourced settings, but they can be used internationally to prevent mental illness and assist in the treatment of anxiety and depression in autistic persons and their family carers. The priority is to focus on primary-care responses with cross-sectoral working rather than investing in high-cost psychiatric provision.

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13. Mehmetbeyoglu E, Duman A, Taheri S, Ozkul Y, Rassoulzadegan M. From Data to Insights: Machine Learning Empowers Prognostic Biomarker Prediction in Autism. J Pers Med;2023 (Dec 15);13(12)

Autism Spectrum Disorder (ASD) poses significant challenges to society and science due to its impact on communication, social interaction, and repetitive behavior patterns in affected children. The Autism and Developmental Disabilities Monitoring (ADDM) Network continuously monitors ASD prevalence and characteristics. In 2020, ASD prevalence was estimated at 1 in 36 children, with higher rates than previous estimates. This study focuses on ongoing ASD research conducted by Erciyes University. Serum samples from 45 ASD patients and 21 unrelated control participants were analyzed to assess the expression of 372 microRNAs (miRNAs). Six miRNAs (miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p, and miR-499a-5p) exhibited significant downregulation in all ASD patients compared to healthy controls. The current study endeavors to identify dependable diagnostic biomarkers for ASD, addressing the pressing need for non-invasive, accurate, and cost-effective diagnostic tools, as current methods are subjective and time-intensive. A pivotal discovery in this study is the potential diagnostic value of miR-126-3p, offering the promise of earlier and more accurate ASD diagnoses, potentially leading to improved intervention outcomes. Leveraging machine learning, such as the K-nearest neighbors (KNN) model, presents a promising avenue for precise ASD diagnosis using miRNA biomarkers.

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14. Mezzelani A, Cupaioli FA. Progress in the Puzzle Resolution: The Molecular Genetics Underpinning Autism Spectrum Disorders. Brain Sci;2023 (Dec 7);13(12)

Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by impairments in social interaction, communication, and the presence of restricted, repetitive behaviors […].

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15. Omiya T, Deguchi NK, Asakura T. A Sense of Belonging and Help Seeking: Examining Factors Related to the Mental Health of High School Students with High Autistic Traits without Diagnosis. Children (Basel);2023 (Dec 14);10(12)

Certain individuals are clinically undiagnosed for Autism Spectrum Disorder (ASD) but exhibit strong ASD characteristics. This study examined the differences between a control group and a « high autistic traits » group involving individuals who scored 9 or higher on the Autism-Spectrum Quotient-16 Japanese Version, based on their sense of belonging, help-seeking style, and relationship with mental health. The participants were 608 Japanese public high school students. Of them, 129 (21.2%) and 479 (78.8%) were in the high autistic traits and control groups, respectively. A multiple regression analysis was performed using the General Health Questionnaire (GHQ) as the dependent variable for the groups. The analysis revealed no differences between the two groups regarding grade, gender, physical illness, insomnia, or mental health status; however, they differed regarding avoidant help-seeking style and teacher acceptance. Moreover, avoidant help-seeking scores in the high autistic traits group and teacher acceptance showed a significantly positive and significantly negative association with GHQ, respectively. The results indicated that children with autistic traits internally suppress them, experiencing distress. Teachers are aware that these students seek support from them, but the students seem reluctant to ask them for help. This can negatively impact the mental health of children with high autistic traits.

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16. Peristeri E, Andreou M, Ketseridou SN, Machairas I, Papadopoulou V, Stravoravdi AS, Bamidis PD, Frantzidis CA. Animacy Processing in Autism: Event-Related Potentials Reflect Social Functioning Skills. Brain Sci;2023 (Nov 29);13(12)

Though previous studies with autistic individuals have provided behavioral evidence of animacy perception difficulties, the spatio-temporal dynamics of animacy processing in autism remain underexplored. This study investigated how animacy is neurally encoded in autistic adults, and whether potential deficits in animacy processing have cascading deleterious effects on their social functioning skills. We employed a picture naming paradigm that recorded accuracy and response latencies to animate and inanimate pictures in young autistic adults and age- and IQ-matched healthy individuals, while also employing high-density EEG analysis to map the spatio-temporal dynamics of animacy processing. Participants’ social skills were also assessed through a social comprehension task. The autistic adults exhibited lower accuracy than controls on the animate pictures of the task and also exhibited altered brain responses, including larger and smaller N100 amplitudes than controls on inanimate and animate stimuli, respectively. At late stages of processing, there were shorter slow negative wave latencies for the autistic group as compared to controls for the animate trials only. The autistic individuals’ altered brain responses negatively correlated with their social difficulties. The results suggest deficits in brain responses to animacy in the autistic group, which were related to the individuals’ social functioning skills.

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17. Riviello FN, Daponte A, Ponzi E, Ficarella R, Orsini P, Bucci R, Ventura M, Antonacci F, Catacchio CR, Gentile M. A Rare Case of Concurrent 2q34q36 Duplication and 2q37 Deletion in a Neonate with Syndromic Features. Genes (Basel);2023 (Dec 10);14(12)

Large-scale genomic structural variations can have significant clinical implications, depending on the specific altered genomic region. Briefly, 2q37 microdeletion syndrome is a prevalent subtelomeric deletion disorder characterized by variable-sized deletions. Affected patients exhibit a wide range of clinical manifestations, including short stature, facial dysmorphism, and features of autism spectrum disorder, among others. Conversely, isolated duplications of proximal chromosome 2q are rare and lack a distinct phenotype. In this report, we provide an extensive molecular analysis of a 15-day-old newborn referred for syndromic features. Our analysis reveals an 8.5 Mb microdeletion at 2q37.1, which extends to the telomere, in conjunction with an 8.6 Mb interstitial microduplication at 2q34q36.1. Our findings underscore the prominence of 2q37 terminal deletions as commonly reported genomic anomalies. We compare our patient’s phenotype with previously reported cases in the literature to contribute to a more refined classification of 2q37 microdeletion syndrome and assess the potential impact of 2q34q36.1 microduplication. We also investigate multiple hypotheses to clarify the genetic mechanisms responsible for the observed genomic rearrangement.

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18. Romeo DM, Moro M, Pezone M, Venezia I, Mirra F, De Biase M, Polo A, Turrini I, Lala MR, Velli C, Sini F, Dragone D, Mercuri E, Brogna C. Relationship and New Prospectives in Joint Hypermobility in Children with Autism Spectrum Disorder: Preliminary Data. J Pers Med;2023 (Dec 18);13(12)

Autism spectrum disorder (ASD) and joint hypermobility (JH) are considered two different etiological and clinical entities that most often appear in childhood. Despite growing increased research showing a co-occurrence for both conditions, a link between them is rarely established in clinical settings, and the relationship between ASD and JH has not so far been completely investigated in all age groups of ASD children. This preliminary study examined a cohort of 67 non-syndromic ASD children aged 2-18 years (sex ratio M:F = 12:1) showing different degrees of cognitive impairment and autism severity, using the Beighton scale and its revised version. A total of 63% of ASD patients aged 2-4 years and 73% of ASD patients aged ≥5 years presented significant scores of hypermobility. No significant correlation was found comparing total laxity score and cognitive assessments and severity of autistic symptomatology (p > 0.05). The results suggest that JH could be considered as a clinical characteristic of ASD patients and it needs to be assessed in order to schedule a better rehabilitation program.

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19. Russell M, Baldwin CM, Quan SF. Exploring Sleep in Caregivers of Children with Autism Spectrum Disorder (ASD) and the Relationship to Health-Related Quality of Life (HRQoL) and Family Quality of Life (FQoL). Medicina (Kaunas);2023 (Dec 7);59(12)

Background and Objectives: To investigate (1) the prevalence of sleep disorder symptoms in caregivers of children with autism spectrum disorder (ASD) and (2) the relationships between caregiver sleep problems and their health-related quality of life and family quality of life. Materials and Methods: Descriptive cross-sectional study of caregivers (N = 62) of children aged 6 to 11 years old diagnosed with ASD and receiving care at a regional autism research and resource center. Results: Participants completed the Sleep Habits Questionnaire (SHQ), the Medical Outcomes Study (MOS) SF-12, and the Beach Center Family Quality of Life Scale (FQoL). Caregivers with longer sleep duration reported better mental health and better family quality of life. Caregivers who reported insomnia symptoms, non-restorative sleep, and insufficient sleep were more likely to report poorer mental health than caregivers who did not report these sleep disorder symptoms. Caregivers with obstructive sleep apnea and restless legs syndrome experienced worse physical quality of life. Conclusions: The physical and mental health of the primary caregiver is essential to the support of the child with ASD and to the functioning of the family. The study findings point to the importance of future research and interventions to enhance sleep health in order to improve quality of life for caregivers of children with ASD.

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20. Samra AI, Kamel AS, Abdallah DM, El Fattah MAA, Ahmed KA, El-Abhar HS. Preclinical Evidence for the Role of the Yin/Yang Angiotensin System Components in Autism Spectrum Disorder: A Therapeutic Target of Astaxanthin. Biomedicines;2023 (Nov 27);11(12)

Autism spectrum disorder (ASD) prevalence is emerging with an unclear etiology, hindering effective therapeutic interventions. Recent studies suggest potential renin-angiotensin system (RAS) alterations in different neurological pathologies. However, its implications in ASD are unexplored. This research fulfills the critical gap by investigating dual arms of RAS and their interplay with Notch signaling in ASD, using a valproic acid (VPA) model and assessing astaxanthin’s (AST) modulatory impacts. Experimentally, male pups from pregnant rats receiving either saline or VPA on gestation day 12.5 were divided into control and VPA groups, with subsequent AST treatment in a subset (postnatal days 34-58). Behavioral analyses, histopathological investigations, and electron microscopy provided insights into the neurobehavioral and structural changes induced by AST. Molecular investigations of male pups’ cortices revealed that AST outweighs the protective RAS elements with the inhibition of the detrimental arm. This established the neuroprotective and anti-inflammatory axes of RAS (ACE2/Ang1-7/MasR) in the ASD context. The results showed that AST’s normalization of RAS components and Notch signaling underscore a novel therapeutic avenue in ASD, impacting neuronal integrity and behavioral outcomes. These findings affirm the integral role of RAS in ASD and highlight AST’s potential as a promising treatment intervention, inviting further neurological research implications.

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21. Stojsavljević A, Lakićević N, Pavlović S. Mercury and Autism Spectrum Disorder: Exploring the Link through Comprehensive Review and Meta-Analysis. Biomedicines;2023 (Dec 18);11(12)

Mercury (Hg) is a non-essential trace metal with unique neurochemical properties and harmful effects on the central nervous system. In this study, we present a comprehensive review and meta-analysis of peer-reviewed research encompassing five crucial clinical matrices: hair, whole blood, plasma, red blood cells (RBCs), and urine. We assess the disparities in Hg levels between gender- and age-matched neurotypical children (controls) and children diagnosed with autism spectrum disorder (ASD) (cases). After applying rigorous selection criteria, we incorporated a total of 60 case-control studies into our meta-analysis. These studies comprised 25 investigations of Hg levels in hair (controls/cases: 1134/1361), 15 in whole blood (controls/cases: 1019/1345), 6 in plasma (controls/cases: 224/263), 5 in RBCs (controls/cases: 215/293), and 9 in urine (controls/cases: 399/623). This meta-analysis did not include the data of ASD children who received chelation therapy. Our meta-analysis revealed no statistically significant differences in Hg levels in hair and urine between ASD cases and controls. In whole blood, plasma, and RBCs, Hg levels were significantly higher in ASD cases compared to their neurotypical counterparts. This indicates that ASD children could exhibit reduced detoxification capacity for Hg and impaired mechanisms for Hg excretion from their bodies. This underscores the detrimental role of Hg in ASD and underscores the critical importance of monitoring Hg levels in ASD children, particularly in early childhood. These findings emphasize the pressing need for global initiatives aimed at minimizing Hg exposure, thus highlighting the critical intersection of human-environment interaction and neurodevelopment health.

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22. Um KB, Kwak S, Cheon SH, Kim J, Hwang SK. AST-001 Improves Social Deficits and Restores Dopamine Neuron Activity in a Mouse Model of Autism. Biomedicines;2023 (Dec 12);11(12)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social communication and social interaction, restricted and repetitive behavior, and interests. The core symptoms of ASD are associated with deficits in mesocorticolimbic dopamine pathways that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). AST-001 is an investigational product currently in a phase 3 clinical trial for treating the core symptoms of ASD, with L-serine as the API (active pharmaceutical ingredient). Because the causes of ASD are extremely heterogeneous, a single genetic ASD model cannot represent all autism models. In this paper, we used the VPA-exposed model, which is more general and widely used than a single genetic model, but this is also one of the animal models of autism. Herein, we conducted experiments to demonstrate the efficacy of AST-001 as L-Serine that alters the regulation of the firing rate in dopamine neurons by inhibiting small conductance Ca(2+)-activated K(+) channels (SK channels). Through these actions, AST-001 improved sociability and social novelty by rescuing the intrinsic excitabilities of dopamine neurons in VPA-exposed ASD mouse models that showed ASD-related behavioral abnormalities. It is thought that this effect of improving social deficits in VPA-exposed ASD mouse models is due to AST-001 normalizing aberrant SK channel activities that slowed VTA dopamine neuron firing. Overall, these findings suggest that AST-001 may be a potential therapeutic agent for ASD patients, and that its mechanism of action may involve the regulation of dopamine neuron activity and the improvement of social interaction.

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23. Waldhauser F, Tatzer E, Maleczek W. Response to the letter of H. Czech(1) : To assess Asperger’s knowledge on the NS Child Euthanasia programme, documents are decisive. Acta Paediatr;2023 (Dec 22)

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24. Wolpe SM, Johnson AR, Kim S. Navigating the Transition to Adulthood: Insights from Caregivers of Autistic Individuals. J Autism Dev Disord;2023 (Dec 23)

With many teens having to transition from a mainly educational system of support to a set of health and social service systems (Shattuck et al. in Autism Res Treat https://doi.org/10.1155/2014/924182 , 2017), there is a critical need to advance research and support services in the area of autism and transition to aid autistic* individuals and their families. This study aims to learn more about the experiences of caregivers of autistic young adults, their experiences navigating the transition process post-graduation, and what realistic steps could be undertaken by high schools, vocational schools, colleges, Regional Centers, and places of employment to ease this transition. Ten semi-structured interviews were conducted with caregivers of autistic young adults over the age of 18 focused on their experiences helping their children navigate the transition to adulthood. Using an iterative and inductive coding approach, three overarching themes were uncovered with twelve subthemes. The three major themes recurring in caregiver interviews were their experiences with navigating service receipt, exploring the landscape of opportunities available for their children, and the parent experiences specific to their role in their child’s transition into adulthood. Findings from this study provide a chance for stakeholders to learn from the lived experiences of caregivers navigating the frustration and confusion pertaining to transition for their autistic adult child due to the highly prohibitive access to service receipt, experiencing significant financial burdens, finding a niche for their children that fits their needs, desires, and talents, and managing their well-being.

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25. Wu X, Gao H, Duan S, Ding W, Yang X. [A review of the clinical progress on helminths and their derivative products in autoimmune disease]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi;2023 (Dec);39(12):1132-1140.

Traditional medications used for treating autoimmune diseases often come with a wide range of adverse effects. Current treatments focus mainly on symptom management, resulting in significant health issues and financial burdens for patients. Recently, clinical research has demonstrated the potential of helminths and their derivatives as effective therapies for autoimmune disorders. Helminths, being a near-natural immunomodulator, exhibit milder effects than broad-spectrum immunosuppressants and corticosteroids, thereby presenting a promising alternative for the treatment of autoimmune diseases. However, different helminths’ therapeutic efficacy and mechanisms and their derivatives in treating autoimmune diseases may vary. Therefore, we aim to review recent clinical advancements in the use of helminths and their derivatives for treating inflammatory bowel disease, multiple sclerosis, and autism spectrum disorder, with a view to offering novel clinical treatment approaches.

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26. Yang J, Hu M, Hu Y, Zhang Z, Zhong J. Diagnosis of Autism Spectrum Disorder (ASD) Using Recursive Feature Elimination-Graph Neural Network (RFE-GNN) and Phenotypic Feature Extractor (PFE). Sensors (Basel);2023 (Dec 6);23(24)

Autism spectrum disorder (ASD) poses as a multifaceted neurodevelopmental condition, significantly impacting children’s social, behavioral, and communicative capacities. Despite extensive research, the precise etiological origins of ASD remain elusive, with observable connections to brain activity. In this study, we propose a novel framework for ASD detection, extracting the characteristics of functional magnetic resonance imaging (fMRI) data and phenotypic data, respectively. Specifically, we employ recursive feature elimination (RFE) for feature selection of fMRI data and subsequently apply graph neural networks (GNN) to extract informative features from the chosen data. Moreover, we devise a phenotypic feature extractor (PFE) to extract phenotypic features effectively. We then, synergistically fuse the features and validate them on the ABIDE dataset, achieving 78.7% and 80.6% accuracy, respectively, thereby showcasing competitive performance compared to state-of-the-art methods. The proposed framework provides a promising direction for the development of effective diagnostic tools for ASD.

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27. Yip S, Calli K, Qiao Y, Trost B, Scherer SW, Lewis MES. Complex Autism Spectrum Disorder in a Patient with a Novel De Novo Heterozygous MYT1L Variant. Genes (Basel);2023 (Nov 24);14(12)

Autism spectrum disorder (ASD) comprises a group of complex neurodevelopmental features seen in many different forms due to variable causes. Highly impactful ASD-susceptibility genes are involved in pathways associated with brain development, chromatin remodeling, and transcription regulation. In this study, we investigate a proband with complex ASD. Whole genome sequencing revealed a novel de novo missense mutation of a highly conserved amino acid residue (NP_001289981.1:p.His516Gln; chr2:1917275; hg38) in the MYT1L neural transcription factor gene. In combination with in silico analysis on gene effect and pathogenicity, we described the proband’s phenotype and made comparisons with previously reported cases to explore the spectrum of clinical features in MYT1L single nucleotide variant (SNV) cases. The phenotype-genotype correlation showed a high degree of clinical similarity with previously reported cases of missense variants in MYT1L, indicating MYT1L as the causal gene for the observed phenotype in our proband. The variant was also predicted to be damaging according to multiple in silico pathogenicity predicting tools. This study expands the clinical description of SNVs on the MYT1L gene and provides insight into its contribution to ASD.

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28. Zoltowski AR, Failla MD, Quinde-Zlibut JM, Dunham-Carr K, Moana-Filho EJ, Essick GK, Baranek GT, Rogers B, Cascio CJ. Differences in temporal profile of brain responses by pleasantness of somatosensory stimulation in autistic individuals. Somatosens Mot Res;2023 (Dec 23):1-16.

Purpose/Aim. Autistic individuals may show either hyper- or hypo- responsiveness to touch compared to non-autistic individuals. These behavioural responses depend on perceptual and evaluative mechanisms, which unfold sequentially and thus can be distinguished by exploring the timing of neural responses. In this study, we examined neural response timing to pleasant, unpleasant, and affectively neutral textures, to determine whether these perceptual versus evaluative subprocesses differ in autism and how each subprocess contributes to behavioural responses.Materials and Methods. Our sample included n = 13 autistic and n = 14 non-autistic adults who completed functional magnetic resonance imaging. We analysed early, intermediate, and late phases of the tactile response, derived from studies of noxious tactile stimulation, to three different textures.Results. The autistic group showed distinct differences from the non-autistic group to each of the textures, showing earlier, somatosensory differences in response to the pleasantly and unpleasantly rated textures and later, frontomotor differences in response to the neutrally rated texture. Further, reduced early phase response to the pleasant texture correlated with increased sensory seeking behaviour.Conclusions. While preliminary, these results suggest distinct patterns between autistic and non-autistic individuals in how the neural response to touch unfolds and its correspondence with the perceived pleasantness of tactile experience. The findings suggest perceptual differences in response to affectively charged textures and evaluative differences in response to neutral, ambiguous textures. These temporal properties may inform future studies of tactile processing in autism, lending a better understanding of how individuals differ in their sensory experiences across contexts.

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