1. Bradshaw J, Platt E, Yurkovic-Harding J, Harding S, Fu X. Autonomic and attentional pathways in the emergence of autism: bridging mechanisms and real-world contexts in infancy. Adv Child Dev Behav;2025;69:99-133.

Autism spectrum disorder (ASD) unfolds over the first two years of life through complex interactions among developmental systems. Attention and autonomic nervous system (ANS) regulation represent foundational processes critical for adaptive engagement with the environment. Disruptions in these systems during early infancy may initiate developmental cascades that contribute to core ASD features, including social-communication challenges and restricted and repetitive behaviors, as well as the vast heterogeneity found within ASD. This chapter reviews our approach to integrating mechanistic research and real-world methodologies to explore autonomic and attentional pathways in the early development of ASD. We conduct prospective, longitudinal studies to track how ANS regulation and attention unfold in infancy in infants at elevated and low familial likelihood for ASD. By integrating multimethod approaches to study these functions in naturalistic contexts, we demonstrate that autonomically regulated attention mechanisms support key developmental milestones and may play an important role in the emergence of ASD. Findings presented provide preliminary support for the theory that infants later diagnosed with ASD exhibit early disruptions in parasympathetic modulation of arousal and attention across responses to social and nonsocial contexts. This work emphasizes the value of leveraging portable, non-invasive technologies to study early autonomic and attention processes in naturalistic contexts. By using this approach to uncover formative mechanisms underlying ASD, we enhance the translational potential of this research while addressing critical gaps in inclusivity and representation. Understanding autonomic and attentional systems in infancy provides an opportunity to identify cascading developmental divergences and promote adaptive developmental trajectories in ASD.

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2. Clarke L, Hodge DA, Walls SC, Santiago C. Caring for Patients with Intellectual or Developmental Disabilities – A Curriculum for Residents. N Engl J Med;2025 (Sep 6)

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3. Dali-Sahi M, Benguella-Benamnsour M, Amraoui N, Harek Y, Salmi T, Berrahoui S, Benosman C, Dennouni-Medjati N. Selenium deficiency and altered Cu/Se, Zn/Se and Cu/Zn ratios associated with GPx1 activity: non-invasive biomarkers of oxidative stress in autism spectrum disorders. Free Radic Biol Med;2025 (Sep 3)

Metal micronutrient dyshomeostasis appears to be involved in the risk of autism spectrum disorders (ASD). Selenium (Se), copper (Cu) and zinc (Zn) are essential for the defence against oxidative stress (OS), a key factor in the maintenance of synaptogenesis and neurogenesis. This study assessed plasma concentrations of Se, Cu, and Zn, along with their ratios, malondialdehyde (MDA) levels, and erythrocyte glutathione peroxidase (GPx1) activity in Algerian children with ASD. A total of 30 subjects diagnosed with ASD and 32 neurotypically developing (ND) children participated in this study. Trace element levels were measured using a polarographic analyzer. Plasma MDA was determined by UV spectrophotometry and erythrocyte GPx1 activity using a SPECORD® 210 plus dual beam spectrophotometer (Analytik Jena German). The Cu/Zn ratio was significantly lower in children with ASD (p<0.001), while no significant difference was found for MDA between the two study groups. However, in children with ASD, a positive correlation was found between MDA and the plasma Cu/Zn ratio (r = 0.6874, p = 0.005). Se levels and GPx1 erythrocyte activity were significantly lower in children with ASD compared with the ND children (p<0.001; p<0.05). Cu/Se and Zn/Se ratios were significantly higher in children with ASD (p<0.001). Sex-stratified analysis indicated a specific vulnerability to OS among boys with ASD, while no significant age-related differences were observed in children with ASD. These findings suggest that imbalances in micronutrient ratios and a decrease in GPx1 activity favor OS, potentially contributing to ASD pathogenesis in extreme western Algeria.

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4. Harbers M, Wei Z, Nakao H, Abe Y, Goto M, Tamano M, Sakai Y, Shimizu K, Nakao K, Sugaya Y, Itoh K, Kano M, Aiba A. FMR1 mutant marmosets show fragile X syndrome phenotypes. Cell Rep;2025 (Aug 27):116208.

Fragile X syndrome (FXS) is the foremost monogenic cause of autism spectrum disorder and intellectual disability, caused by FMR1 gene silencing. Here, we report that common marmosets carrying FMR1 mutation, a non-human primate model for FXS, share common features in behavioral and molecular phenotypes with patients with FXS. Founder mutants with markedly reduced fragile X messenger ribonucleoprotein expression display hyperactivity, spontaneous seizures, and transcriptome changes in synapse-related genes that overlap with those reported in patients with FXS. Although spontaneous seizures in these mutants lead to postnatal lethality, the lethality is rescued by introducing mutations into the GRM5 gene, suggesting that elevated mGluR5 signaling contributes to the phenotype. F1 heterozygous females carrying a uniform mutation exhibit phenotypes associated with FXS, including alterations in vocal development and social preferences, electroencephalographic abnormalities, and impaired motor skills. Thus, female marmosets heterozygous for the FMR1 mutation represent a valuable translational model for investigating FXS mechanisms and potential therapeutic strategies.

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5. Iannuzzelli CC, Iannuzzelli AL, Cunha B, Venkataraman V, Aita W. Exploring the impact of methylenetetrahydrofolate reductase (MTHFR) gene variations on autism spectrum disorder severity. J Osteopath Med;2025 (Sep 5)

CONTEXT: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by challenges in social communication and repetitive behaviors. Its etiology is influenced by a combination of genetic and environmental factors. Variations in the methylenetetrahydrofolate reductase (MTHFR) gene, which is implicated in folate metabolism and neurodevelopment, are widespread in the autism population. Understanding the relationship between MTHFR gene variations and ASD may be critical for early diagnosis and intervention. OBJECTIVES: This study aims to investigate the association between MTHFR gene variations and the severity of ASD symptoms in a clinical cohort. The goal is to determine whether reduced MTHFR activity correlates with increased symptom severity, thus offering insights into potential mechanisms and intervention strategies. METHODS: A cohort of 78 patients diagnosed with ASD who had previously undergone genetic testing to measure MTHFR activity levels were recruited. ASD severity was assessed utilizing DSM-5 criteria. Statistical analyses were performed to evaluate the relationship between MTHFR activity and ASD symptom severity. RESULTS: The analysis identified a significant negative correlation between MTHFR activity levels and ASD severity (p<0.05). Patients with lower MTHFR activity exhibited more severe ASD symptoms, as measured by DSM-5 classifications. These findings emphasize the potential link between MTHFR gene variations and neurodevelopmental outcomes in ASD. CONCLUSIONS: This study highlights the role of MTHFR gene variations in modulating ASD severity. The results support the potential for utilizing MTHFR activity as a biomarker for early screening and tailoring targeted interventions for individuals with MTHFR deficiencies. Due to a small sample size, any conclusions drawn from this study are limited and may be misleading in future studies. Further research is warranted to explore the underlying mechanisms and to develop clinical strategies that mitigate the impact of these genetic variations on ASD progression.

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6. Kilili-Lesta M, Voniati L. Concurrent developmental language level change for children with autism spectrum disorder using alternative and augmentative communication systems: a cross-sectional study in Cyprus. Disabil Rehabil Assist Technol;2025 (Sep 6):1-10.

We examined the concurrent change in developmental language phase (DLP) and linguistic status of children with Autism Spectrum Disorder (ASD)/autism, identified as Nonverbal/Minimally-Verbal (NV/MV), utilizing Augmentative/Alternative Communication (AAC) systems. We compared the linguistic output of NV/MV autistic children concurrently, with and without use of AAC systems. Additionally, we compared the linguistic level, characteristics, and early developmental milestones for AAC users and non-users. A sample of 23 autistic children (3-12 years-of-age) identified as NV/MV based on the DLP results by the Developmental/Verbal Language Phase parent-report questionnaire, participated in this cross-sectional study in Cyprus. Two groups formed based on AAC systems use (AAC users, AAC non-users). Parents completed the questionnaire through convenience sampling, determining the children’s overall DLP concurrently, with and without use of AAC systems. Only 52.0% of participants used aided AAC systems to support their communication. No significant differences were noted in demographic/other variables between the groups. When AAC systems use was included in measuring linguistic expression for AAC users, 75.0% of them displayed improved linguistic level (DLP), half of whom elevated to a verbal-linguistic status. AAC users in the DLP-2 First-Words phase/level were more likely to switch to DLP-3 Word-Combinations and thus to verbal status, than those in the DLP-1 Preverbal phase/level. AAC system use can be associated with improved communication level and status, especially for autistic children already verbalizing at the word-level. Most AAC users were at an advantage in their language skills through AAC systems use, compared to non-users. Children with autism spectrum disorder (ASD) who are identified as nonverbal/minimally verbal (NV/MV) have communication barriers that can be overcome with the use of appropriate augmentative and alternative communication (AAC) systems.Speech-language pathologists (SLPs) should incorporate the use of AAC systems when assessing the developmental language phase (DLP) and status of these children, just as they would incorporate a bilingual child’s both languages in their language assessment, regardless of means, e.g. parent report, language sample, formal test.The use of AAC systems for communication for children with ASD-NV/MV can advance their DLP and even propel them into a “verbal” status, providing access to more communication opportunities, social inclusion, and interaction, and thus, better quality of life.In this study, the advancement in language expression level for 75% of the children using AAC systems was found regardless of the early development milestone scores, age group, or socioeconomic background. SLPs, parents, and educators of children with ASD who are NV/MV are encouraged to attempt enforcing various AAC means, to find the optimal fit for each child, for the best possible outcome.In this study, children who were AAC users at the First Words DLP-2 were more likely to advance to verbal status compared to AAC users at the Preverbal DLP-1. SLPS need to target both verbal skills and AAC system use during intervention to maximize the potential for children with ASD to achieve verbal status. eng

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7. Song Q, Zhai J, Chen C, Li H, Cao A, Yuan B, An Y. Performance comparison of germline variant calling tools in sporadic disease cohorts. Mol Genet Genomics;2025 (Sep 6);300(1):90.

Accurate variant calling is essential for next-generation sequencing (NGS)-based diagnosis of rare diseases, yet most benchmarking studies have focused on standard cell lines or trio-based samples, with limited relevance to sporadic cases. Here, we systematically compared the performance of DeepVariant and GATK HaplotypeCaller in two Chinese cohorts of patients with sporadic epilepsy (EP) and autism spectrum disorder (ASD). DeepVariant exhibited higher precision and sensitivity in detecting single nucleotide variants (SNVs), while GATK showed a distinct advantage in identifying rare variants, which are often key to understanding the genetic basis of rare diseases. Comparative analyses based on disease-related gene panels further highlighted differences in the identification of potentially deleterious variants. These findings reveal important trade-offs between variant callers and emphasize the need to tailor variant-calling strategies to specific research and clinical contexts. Our study provides practical vision for optimizing germline variant detection pipelines in sporadic neurodevelopmental disorders, offering broader insights for precision medicine applications.

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8. Xin Y, Dou J, Yang R, Wang Y, Li P, Zhang X, Liu X, Yang J. Global, regional, and national burden of lead-attributable intellectual developmental disability in children and adolescents from 1990 to 2021, with projections up to 2040: the global burden of disease 2021 study. Eur J Pediatr;2025 (Sep 5);184(9):601.

Long-term lead exposure damages the central nervous system, with chronic poisoning strongly linked to intellectual developmental disability (IDD) and disproportionately affecting children and adolescents. Using the Global Burden of Disease (GBD) 2021 database, this study analyzed temporal, spatial, and population-specific trends in lead-attributable IDD burden among global children/adolescents (1990-2021) and projected trends to 2040 to inform global public health strategies. GBD 2021 data characterized global, regional, and national distributions of lead-attributable IDD burden. Associations with sex, age, and Socio-Demographic Index (SDI) were evaluated via Years Lived with Disability (YLDs) and Age-Standardized YLD Rate (ASYR). Joinpoint regression quantified annual burden changes, and the Nordpred model projected 2021-2040 trends. Globally, ASYR fell from 58.088 to 38.718 per 100,000 (AAPC = -1.297%, P < 0.001), with high-SDI countries seeing a 54.0% reduction (AAPC = -2.486%) versus 32.8% in low-SDI regions. Paradoxically, low-SDI YLDs rose by 39.7%. In 2021, ASYR peaked in 15-19-year-olds at 39.906 (males) and 41.146 (females). South Asia, led by India (119.30 per 100,000), remained a high-burden hotspot. SDI correlated negatively with ASYR (ρ = -0.76, P < 0.001), with projections showing global YLDs declining to 863,352 person-years by 2040 (ASYR = 33.057). CONCLUSION: While global progress has been made in reducing lead exposure-induced IDD, South Asia and low-SDI nations bear persistently high burdens. Strengthened international collaboration and targeted lead reduction policies are critical to advancing health equity for young people. WHAT IS KNOWN: • Trend of the global disease burden of IDD attributed to lead exposure in the total population from 1990 to 2019. WHAT IS NEW: • Trend of the global disease burden of IDD attributed to lead exposure in children and adolescents from 1990 to 2021, with projections up to 2040.

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