1. Balasubramanian H, Ahmed J, Ananthan A, Srinivasan L, Mohan D. Comparison of parent or caregiver-completed development screening tools with Bayley Scales of Infant Development: a systematic review and meta-analysis. Arch Dis Child;2024 (Aug 16);109(9):759-766.

BACKGROUND: Parent/caregiver-completed developmental testing (PCDT) is integral to developmental care in children; however, there is limited information on its accuracy. In this systematic review, we compared the diagnostic accuracy of PCDT with concurrently administered Bayley Scales of Infant Development for detection of developmental delay (DD) in children below 4 years of age. METHODS: We searched databases PubMed, Embase, CINAHL, PsycINFO and Google Scholar until November 2023. Bivariate and multiple thresholds summary receiver operating characteristics were used to obtain the summary sensitivity and specificity with 95% CIs. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used for risk of bias assessment. RESULTS: A total of 38 studies (31 in the meta-analysis) were included. Ages and Stages Questionnaire (ASQ) and Parent Report of Children’s Abilities-Revised (PARCA-R) were the most commonly evaluated PCDTs. ASQ score >2 SD below the mean had an overall sensitivity of 0.72 (0.6, 0.82) and 0.63 (0.50, 0.75) at a median specificity of 0.89 (0.82, 0.94) and 0.81 (0.76, 0.86) for diagnosing moderate to severe DD and severe DD, respectively. PARCA- R had an overall sensitivity of 0.69 (0.51, 0.83) at median specificity of 0.75 (0.64, 0.83) for predicting severe DD. Participant selection bias and partial verification bias were found in over 50% of the studies. The certainty of evidence was low for the studied outcomes. CONCLUSIONS: The most commonly studied parental tools, ASQ and PARCA-R, have moderate to low sensitivity and moderate specificity for detecting DD in young children. High risk of bias and heterogeneity in the available data can potentially impact the interpretation of our results. PROSPERO REGISTRATION NUMBER: CRD42021268629.

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2. Bednarczuk N, Housby H, Lee IO, Consortium I, Skuse D, Wolstencroft J. Behavioural and neurodevelopmental characteristics of SYNGAP1. J Neurodev Disord;2024 (Aug 15);16(1):46.

BACKGROUND: SYNGAP1 variants are associated with varying degrees of intellectual disability (ID), developmental delay (DD), epilepsy, autism, and behavioural difficulties. These features may also be observed in other monogenic conditions. There is a need to systematically compare the characteristics of SYNGAP1 with other monogenic causes of ID and DD to identify features unique to the SYNAGP1 phenotype. We aimed to contrast the neurodevelopmental and behavioural phenotype of children with SYNGAP1-related ID (SYNGAP1-ID) to children with other monogenic conditions and a matched degree of ID. METHODS: Participants were identified from the IMAGINE-ID study, a UK-based, national cohort study of neuropsychiatric risk in children with ID of known genetic origin. Thirteen children with SYNGAP1 variants (age 4-16 years; 85% female) were matched (2:1) with 26 controls with other monogenic causes of ID for chronological and mental age, sex, socio-economic deprivation, adaptive behaviour, and physical health difficulties. Caregivers completed the Development and Wellbeing Assessment (DAWBA) and physical health questionnaires. RESULTS: Our results demonstrate that seizures affected children with SYNGAP1-ID (84.6%) more frequently than the ID-comparison group (7.6%; p =  < 0.001). Fine-motor development was disproportionally impaired in SYNGAP1-ID, with 92.3% of children experiencing difficulties compared to 50% of ID-comparisons(p = 0.03). Gross motor and social development did not differ between the two groups. Children with SYNGAP1-ID were more likely to be non-verbal (61.5%) than ID-comparisons (23.1%; p = 0.01). Those children able to speak, spoke their first words at the same age as the ID-comparison group (mean = 3.25 years), yet achieved lower language competency (p = 0.04). Children with SYNGAP1-ID compared to the ID-comparison group were not more likely to meet criteria for autism (SYNGAP1-ID = 46.2%; ID-comparison = 30.7%; p = .35), attention-deficit hyperactivity disorder (15.4%;15.4%; p = 1), generalised anxiety (7.7%;15.4%; p = .49) or oppositional defiant disorder (7.7%;0%; p = .15). CONCLUSION: For the first time, we demonstrate that SYNGAP1-ID is associated with fine motor and language difficulties beyond those experienced by children with other genetic causes of DD and ID. Targeted occupational and speech and language therapies should be incorporated early into SYNGAP1-ID management.

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3. Carter A, Klinner C, Young A, Strnadová I, Wong H, Vujovich-Dunn C, Newman CE, Davies C, Skinner SR, Danchin M, Hynes S, Guy R. « I Thought It Was Better to Be Safe Than Sorry »: Factors Influencing Parental Decisions on HPV and Other Adolescent Vaccinations for Students with Intellectual Disability and/or Autism in New South Wales, Australia. Vaccines (Basel);2024 (Aug 16);12(8)

The uptake of human papilloma virus (HPV) and other adolescent vaccinations in special schools for young people with disability is significantly lower than in mainstream settings. This study explored the factors believed to influence parental decision making regarding vaccine uptake for students with intellectual disability and/or on the autism spectrum attending special schools in New South Wales, Australia, from the perspective of all stakeholders involved in the program. Focus groups and interviews were conducted with 40 participants, including parents, school staff, and immunisation providers. The thematic analysis identified two themes: (1) appreciating diverse parental attitudes towards vaccination and (2) educating parents and managing vaccination questions and concerns. While most parents were described as pro-vaccination, others were anti-vaccination or vaccination-hesitant, articulating a marked protectiveness regarding their child’s health. Reasons for vaccine hesitancy included beliefs that vaccines cause autism, concerns that the vaccination may be traumatic for the child, vaccination fatigue following COVID-19, and assumptions that children with disability will not be sexually active. Special school staff regarded the vaccination information pack as inadequate for families, and nurses described limited educational impact resulting from minimal direct communication with parents. More effective communication strategies are needed to address vaccine hesitancy among parents with children with disability.

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4. Casella R, Miniello A, Buta F, Yacoub MR, Nettis E, Pioggia G, Gangemi S. Atopic Dermatitis and Autism Spectrum Disorders: Common Role of Environmental and Clinical Co-Factors in the Onset and Severity of Their Clinical Course. Int J Mol Sci;2024 (Aug 16);25(16)

Increasing evidence suggests an association between atopic dermatitis, the most chronic inflammatory disease of the skin, and autism spectrum disorders, which are a group of neurodevelopmental diseases. Inflammation and immune dysregulation associated with genetic and environmental factors seem to characterize the pathophysiological mechanisms of both conditions. We conducted a literature review of the PubMed database aimed at identifying the clinical features and alleged risk factors that could be used in clinical practice to predict the onset of ASD and/or AD or worsen their prognosis in the context of comorbidities.

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5. Chapek M, Kessler J. The Prevalence of Persistent Toe Walking in Children with and without Autism Spectrum Disorder and the Odds of Subsequent Surgery. J Foot Ankle Surg;2024 (Aug 13)

Persistent toe walking is associated with autism spectrum disorder. The true prevalence of persistent toe walking and odds of progression to surgery in children with and without autism remains unclear. This retrospective descriptive study identified patients ages 3 – 17 years who were enrolled in our healthcare system over a two-year period. Using international classification of disease codes, we identified all children with autism and persistent toe walking, and excluded children with conditions that may independently cause toe walking. Data on Achilles lengthening surgeries, sex, race and body mass index was gathered. The toe walking prevalence amongst children with and without autism was calculated. Multivariable logistic regression analysis controlling for sex, race and body mass index was used to determine independent risk factors for persistent toe walking and surgery. Of the children who met inclusion criteria (N = 284,925), 4,622 (1.6%) had persistent toe walking. Prevalence of persistent toe walking was higher amongst children with autism (6.3% versus 1.5%, p < 0.01), as were odds of persistent toe walking (OR 4.13, 95% CI 3.74 - 4.56, p < 0.01). Males and White patients had higher odds of persistent toe walking compared to females and patients of any other race, respectively (p < 0.01 for all). Although children with autism and toe walking had higher rates of surgery than their counterparts without autism (4.3% versus 2.6%, p = 0.04), this difference was not significant after controlling for sex, race and BMI (OR 1.59, 95% CI 0.95 - 2.69, p > 0.05). LEVEL OF CLINICAL EVIDENCE: III.

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6. Charkaluk ML, Kana GD, Benhammou V, Guellec I, Letouzey M, Morgan AS, Nuytten A, Torchin H, Twilhaar S, Cambonie G, Marret S, Ancel PY, Pierrat V. Neurodevelopment at age 5.5 years according to Ages & Stages Questionnaire at 2 years’ corrected age in children born preterm: the EPIPAGE-2 cohort study. Arch Dis Child Fetal Neonatal Ed;2024 (Aug 16);109(5):519-526.

OBJECTIVE: To report neurodevelopment at age 5.5 years according to developmental delay screening with the Ages & Stages Questionnaire (ASQ) in late infancy in preterm-born children. DESIGN: Population-based cohort study, EPIPAGE-2. SETTING: France, 2011-2017. PARTICIPANTS: 2504 children born at 24-26, 27-31 and 32-34 weeks, free of cerebral palsy, deafness or blindness at 2 years’ corrected age. MAIN OUTCOME MEASURES: Moderate/severe, mild or no disability at age 5.5 years using gross and fine motor, sensory, cognitive and behavioural evaluations. Results of the ASQ completed between 22 and 26 months’ corrected age described as positive screening or not. RESULTS: Among 2504 participants, 38.3% had ASQ positive screening. The probability of having moderate/severe or mild disability was higher for children with ASQ positive versus negative screening: 14.2% vs 7.0%, adjusted OR 2.5 (95% CI 1.8 to 3.4), and 37.6% vs 29.7%, adjusted OR 1.5 (1.2 to 1.9). For children with ASQ positive screening, the probability of having neurodevelopmental disabilities at age 5.5 years was associated with the number of domain scores below threshold, very low gestational age and severe neonatal morbidities. For children with ASQ negative screening, this probability was increased for boys and children born small-for-gestational age. For both groups, maternal level of education was strongly associated with outcomes. CONCLUSION: In preterm-born children, ASQ screening at 2 years’ corrected age was associated with neurodevelopmental disabilities at age 5.5 years. However, other factors should be considered when interpreting the ASQ data to draw further follow-up. TRIAL REGISTRATION NUMBER: 2016-A00333-48.

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7. Hanzel M, Fernando K, Maloney SE, Horn Z, Gong S, Mätlik K, Zhao J, Pasolli HA, Heissel S, Dougherty JD, Hull C, Hatten ME. Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties. Proc Natl Acad Sci U S A;2024 (Aug 20);121(34):e2405901121.

Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in Astn2 cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.

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8. He HL, Lin XQ, Wang XL, Peng P, Xiao H, Yin F, Peng J. [Developmental and epileptic encephalopathy 33 caused by EEF1A2 gene mutation: a case report]. Zhongguo Dang Dai Er Ke Za Zhi;2024 (Aug 15);26(8):861-864.

A boy, aged 7 months, presented with severe global developmental delay (GDD), refractory epilepsy, hypotonia, nystagmus, ocular hypertelorism, a broad nasal bridge, everted upper lip, a high palatal arch, and cryptorchidism. Genetic testing revealed a de novo heterozygous missense mutation of c.364G>A(p.E122K) in the EEF1A2 gene, and finally the boy was diagnosed with autosomal dominant developmental and epileptic encephalopathy 33 caused by the EEF1A2 gene mutation. This case report suggests that for children with unexplained infancy-onset severe to profound GDD/intellectual disability and refractory epilepsy, genetic testing for EEF1A2 gene mutations should be considered. This is particularly important for those exhibiting hypotonia, nonverbal communication, and craniofacial deformities, to facilitate a confirmed diagnosis.

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9. Kang N, Sargsyan S, Chough I, Petrick L, Liao J, Chen W, Pavlovic N, Lurmann FW, Martinez MP, McConnell R, Xiang AH, Chen Z. Dysregulated metabolic pathways associated with air pollution exposure and the risk of autism: Evidence from epidemiological studies. Environ Pollut;2024 (Aug 13);361:124729.

Autism spectrum disorder (ASD) is a developmental disorder with symptoms that range from social and communication impairments to restricted interests and repetitive behavior and is the 4th most disabling condition for children aged 5-14. Risk factors of ASD are not fully understood. Environmental risk factors are believed to play a significant role in the ASD epidemic. Research focusing on air pollution exposure as an early-life risk factor of autism is growing, with numerous studies finding associations of traffic and industrial emissions with an increased risk of ASD. One of the possible mechanisms linking autism and air pollution exposure is metabolic dysfunction. However, there were no consensus about the key metabolic pathways and corresponding metabolite signatures in mothers and children that are altered by air pollution exposure and cause the ASD. Therefore, we performed a review of published papers examining the metabolomic signatures and metabolic pathways that are associated with either air pollution exposure or ASD risk in human studies. In conclusion, we found that dysregulated lipid, fatty acid, amino acid, neurotransmitter, and microbiome metabolisms are associated with both short-term and long-term air pollution exposure and the risk of ASD. These dysregulated metabolisms may provide insights into ASD etiology related to air pollution exposure, particularly during the perinatal period in which neurodevelopment is highly susceptible to damage from oxidative stress and inflammation.

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10. Kaya İ, Karayagmurlu A, Kitapçıoğlu S, Bakman N, Erbay MF, Dinçel M, Soylu N. Increased Hyperactivity with Decreased Parental Perceived Social Support Among Turkish Children with Autism Spectrum Disorder during Coronavirus Disease 2019 Pandemic. Alpha Psychiatry;2024 (Jun);25(3):350-355.

OBJECTIVE: The aim of the present study is to investigate the change in emotional/behavioral problems of children with autism spectrum disorder (ASD) and the perceived social support of parents during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A total of 51 children with ASD aged between 6 and 18 years took part in the study. The Aberrant Behavior Checklist (ABC), the Strengths and Difficulties Questionnaire (SDQ), and the Multidimensional Scale of Perceived Social Support (MSPSS) were used to evaluate ASD symptoms, emotional/behavioral problems, and perceived social support, respectively. The cases were assessed before and 6 months after the pandemic. RESULTS: Our findings indicated that after the onset of the pandemic hyperactivity scores of children with ASD increased, whereas perceived social support of their parents decreased, compared to their pre-pandemic levels (P-value < .05). The increase in hyperactivity and irritability levels among children were positively associated with the presence of a chronic illness in the family and medication discontinuation (P-value < .05). CONCLUSION: Quarantine in the COVID-19 pandemic may cause or worsen behavioral problems among children with ASD possibly due to problems related to poor medication adherence and lowered perceived social support among their parents. Clinicians working with children with special needs may be pro-active to assess and manage emotional/behavioral problems among this special population particularly during difficult times such as pandemic.

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11. Li PP, Zhou YY, Gao L, Lv JN, Xu SS, Zhao YW, Xu D, Huang R, Zhang X, Li P, Fu X, He Z. The de novo missense mutation F224S in GABRB2, identified in epileptic encephalopathy and developmental delay, impairs GABA(A)R function. Neuroscience;2024 (Aug 16);553:172-184.

Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABA(A)R) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671 T > C (p.F224S) was discovered in the GABRB2 gene, which encodes the β2 subunit of GABA(A)R. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABA(A)R channel function, we conducted transient expression experiments using GABA(A)R subunits in HEK293T cells. The GABA(A)Rs containing mutant β2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABA(A)R containing the β2 (F224S) subunit was significantly smaller compared to the wild type GABA(A)R. We propose that GABRB2 variant F224S is pathogenic and GABA(A)Rs containing this β2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.

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12. Litman A, Sauerwald N, Snyder LG, Foss-Feig J, Park CY, Hao Y, Dinstein I, Theesfeld CL, Troyanskaya OG. Decomposition of phenotypic heterogeneity in autism reveals distinct and coherent genetic programs. medRxiv;2024 (Aug 16)

Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory, and clinical manifestations of the many forms of the condition. Here, we leveraged broad phenotypic data from a large cohort with matched genetics to characterize classes of autism and their patterns of core, associated, and co-occurring traits, ultimately demonstrating that phenotypic patterns are associated with distinct genetic and molecular programs. We used a generative mixture modeling approach to identify robust, clinically-relevant classes of autism which we validate and replicate in a large independent cohort. We link the phenotypic findings to distinct patterns of de novo and inherited variation which emerge from the deconvolution of these genetic signals, and demonstrate that class-specific common variant scores strongly align with clinical outcomes. We further provide insights into the distinct biological pathways and processes disrupted by the sets of mutations in each class. Remarkably, we discover class-specific differences in the developmental timing of genes that are dysregulated, and these temporal patterns correspond to clinical milestone and outcome differences between the classes. These analyses embrace the phenotypic complexity of children with autism, unraveling genetic and molecular programs underlying their heterogeneity and suggesting specific biological dysregulation patterns and mechanistic hypotheses.

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13. Marks IR, Doyle LW, Mainzer RM, Spittle AJ, Clark M, Boland RA, Anderson PJ, Cheong JL. Neurosensory, cognitive and academic outcomes at 8 years in children born 22-23 weeks’ gestation compared with more mature births. Arch Dis Child Fetal Neonatal Ed;2024 (Aug 16);109(5):511-518.

Despite providing intensive care to more infants born <24 weeks' gestation, data on school-age outcomes, critical for counselling and decision-making, are sparse. OBJECTIVE: To compare major neurosensory, cognitive and academic impairment among school-aged children born extremely preterm at 22-23 weeks' gestation (EP22-23) with those born 24-25 weeks (EP24-25), 26-27 weeks (EP26-27) and term (≥37 weeks). DESIGN: Three prospective longitudinal cohorts. SETTING: Victoria, Australia. PARTICIPANTS: All EP live births (22-27 weeks) and term-born controls born in 1991-1992, 1997 and 2005. MAIN OUTCOME MEASURES: At 8 years, major neurosensory disability (any of moderate/severe cerebral palsy, IQ <-2 SD relative to controls, blindness or deafness), motor, cognitive and academic impairment, executive dysfunction and poor health utility. Risk ratios (RRs) and risk differences between EP22-23 (reference) and other gestational age groups were estimated using generalised linear models, adjusted for era of birth, social risk and multiple birth. RESULTS: The risk of major neurosensory disability was higher for EP22-23 (n=21) than more mature groups (168 EP24-25; 312 EP26-27; 576 term), with increasing magnitude of difference as the gestation increased (adjusted RR (95% CI) compared with EP24-25: 1.39 (0.70 to 2.76), p=0.35; EP26-27: 1.85 (0.95 to 3.61), p=0.07; term: 13.9 (5.75 to 33.7), p<0.001). Similar trends were seen with other outcomes. Two-thirds of EP22-23 survivors were free of major neurosensory disability. CONCLUSIONS: Although children born EP22-23 experienced higher rates of disability and impairment at 8 years than children born more maturely, many were free of major neurosensory disability. These data support providing active care to infants born EP22-23.

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14. Medeiros D, Polepalli L, Li W, Pozzo-Miller L. Altered activity of mPFC pyramidal neurons and parvalbumin-expressing interneurons during social interactions in a Mecp2 mouse model for Rett syndrome. bioRxiv;2024 (Aug 6)

Social memory impairments in Mecp2 knockout (KO) mice result from altered neuronal activity in the monosynaptic projection from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC). The hippocampal network is hyperactive in this model for Rett syndrome, and such atypically heightened neuronal activity propagates to the mPFC through this monosynaptic projection, resulting in altered mPFC network activity and social memory deficits. However, the underlying mechanism of cellular dysfunction within this projection between vHIP pyramidal neurons (PYR) and mPFC PYRs and parvalbumin interneurons (PV-IN) resulting in social memory impairments in Mecp2 KO mice has yet to be elucidated. We confirmed social memory (but not sociability) deficits in Mecp2 KO mice using a new 4-chamber social memory arena, designed to minimize the impact of the tethering to optical fibers required for simultaneous in vivo fiber photometry of Ca(2+)-sensor signals during social interactions. mPFC PYRs of wildtype (WT) mice showed increases in Ca(2+) signal amplitude during explorations of a novel toy mouse and interactions with both familiar and novel mice, while PYRs of Mecp2 KO mice showed smaller Ca(2+) signals during interactions only with live mice. On the other hand, mPFC PV-INs of Mecp2 KO mice showed larger Ca(2+) signals during interactions with a familiar cage-mate compared to those signals in PYRs, a difference absent in the WT mice. These observations suggest atypically heightened inhibition and impaired excitation in the mPFC network of Mecp2 KO mice during social interactions, potentially driving their deficit in social memory.

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15. Okkenhaug I, Jensen MR, Solhaug S. Barriers and Facilitators for Physical Activity Among Children and Youth With Autism-A Scoping Review. J Phys Act Health;2024 (Aug 16):1-15.

BACKGROUND: The purpose of this scoping review was to systematically synthesize barriers and facilitators for physical activity (PA) among children and youth with autism spectrum disorders (ASD) across the socioecological model. METHODS: Five electronic databases were searched in March 2022 for studies examining barriers and facilitators for PA among children and youth with ASD. An updated search was performed in April 2024. The framework synthesis method was utilized, and the socioecological model was the chosen framework. RESULTS: Fifty-four studies published from 2008 to 2024 were included. Among the included studies, 57% included the perspectives of children and youth with ASD alone or together with proxies (eg, parents, teachers, and coaches), while 43% included only the perspectives of proxies. Barriers and facilitators on the intrapersonal and interpersonal levels were most substantial. The analysis led to 2 main categories of barriers and facilitators, those unique to children and youth with ASD, and those similar to what had been identified through research on children and youth, both typically developing and with other disabilities. CONCLUSIONS: This comprehensive scoping review shows the complexity of factors contributing to barriers and facilitators for PA among children and youth with ASD, and highlights both the factors unique to this population and more general factors affecting PA participation. The findings from this synthesis might be used to guide the development of inclusive PA in physical education, organized sports, and other community PA arenas.

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16. Osaki T, Delepine C, Osako Y, Kranz D, Levin A, Nelson C, Fagiolini M, Sur M. Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cerebral organoids. bioRxiv;2024 (Aug 10)

Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MeCP2 mutations – a missense mutation (R306C) and a truncating mutation (V247X) – using calcium imaging with three-photon microscopy. Compared to isogenic controls, we found abnormal neuronal activity in Rett organoids and altered network function based on graph theoretic analyses, with V247X mutations impacting functional responses and connectivity more severely than R306C mutations. These changes paralleled EEG data obtained from patients with comparable mutations. Labeling DLX promoter-driven inhibitory neurons demonstrated differences in activity and functional connectivity of inhibitory and excitatory neurons in the two types of mutation. Transcriptomic analyses revealed HDAC2-associated impairment in R306C organoids and decreased GABA(A) receptor expression in excitatory neurons in V247X organoids. These findings demonstrate mutation-specific mechanisms of vulnerability in Rett syndrome and suggest targeted strategies for their treatment.

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17. Resnikoff AW, Colantuono V, Wieckowski AT, Chernak E, Plumb J, Baynard M, Sheridan E, Robins DL. Reported Barriers and Facilitators for Autistic Individuals, Persons with Other Intellectual and Developmental Disabilities, and Their Caregivers to Receive the COVID-19 Vaccine: A Pilot Study. J Autism Dev Disord;2024 (Aug 16)

Autistic individuals and persons with other intellectual or developmental disabilities (IDD) may experience challenges in social engagement, sensory processing, and behavior rigidity. This population is more likely to face barriers to successful preventative healthcare, including vaccines, compared to neurotypical peers. Autistic individuals and persons with other IDD may be at greater risk for COVID-19 infection due to sensory dysregulation that interferes with mitigation such as wearing masks, and challenges in social communication that impose difficulties in understanding and adhering to prevention measures. Adaptations are needed to make vaccine opportunities more accessible for neurodivergent individuals. A series of seven Sensory-Friendly COVID-19 Vaccine Clinics (SFVCs) were conducted between December 2021 and August 2022 in collaboration with the A.J. Drexel Autism Institute and the Academy of Natural Sciences of Drexel University. SFVCs examined perceived barriers and facilitators to vaccine experiences, based on feedback from autistic individual/persons with IDD and their caregivers. Surveys were administered to autistic individuals/persons with IDD or their caregivers (n = 35) from the larger sample who attended the clinic; 18 participants also complete a supplemental interview. Scaled survey questions were analyzed to determine the acceptability of the SFVCs. Open-ended survey questions and interview responses were coded thematically to identify barriers, facilitators, and areas of improvement. All individuals who came to a SFVC with intent to be vaccinated were successfully administered a COVID-19 vaccine. More than 90% of participants reported that experiences at the SFVCs were positive, promoted retention, and they would recommend clinics to others. Staff clinical expertise, sensory-friendly elements, and hosting clinics at a neutral location (free from past medical history) served as facilitators to successful vaccine administration, whereas factors such as ill-equipped pharmacy staff, behavioral challenges, and logistical issues may serve as barriers. Incorporating reported barriers, facilitators, and accommodations of SFVC experiences may lead to more successful preventative healthcare processes for neurodivergent individuals.

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18. Schlink A, Kasari C. Characterizing social communication among minimally verbal children with autism: An application of item response theory. Autism Res;2024 (Aug 16)

Minimally verbal children constitute a portion of the autism spectrum. The paucity of proper measurement tools that sensitively and accurately assess behaviors has been one limiting factor in the improved knowledge of these children. Short of creating and validating a new measurement tool for this subpopulation, this study took an alternative and more immediate approach: conduct a secondary data analysis and examine an existing social communication measure, the Early Social Communication Scales (ESCS), with item response theory. The final sample consisted of 453 minimally verbal children culled from four different completed studies. The IRT models analyzed the frequency of social communication gestures from the ESCS and returned an objective difficulty hierarchy regarding initiations of joint attention and behavior regulation gestures. The best-fitting and final model was a zero-inflated negative binomial model (ZINBM), which determined that joint attention gestures were, on average, more difficult than behavior regulation gestures. Joint attentional shows and gives were essentially absent in the children’s repertoire, and behavior regulation reaches were the easiest gestures for this sample. The ZINBM separately modeled children with some gestures and children who did not present with any gestures and determined that behavior regulation reaches and gives were likely the first gestures a child will eventually exhibit among children with no gestures. Methodological contributions and potential future applications of IRT are discussed.

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19. Shin YS, Christensen D, Wang J, Shirley DJ, Orlando AM, Romero RA, Wilkes BJ, Vaillancourt DE, Coombes S, Wang Z. Transcallosal white matter and cortical gray matter variations in autistic adults ages 30-73 years: A bi-tensor free water imaging approach. Res Sq;2024 (Aug 16)

Background: Autism spectrum disorder (ASD) has long been recognized as a lifelong condition, but brain aging studies in autistic adults aged >30 years are limited. Free water, a novel brain imaging marker derived from diffusion MRI (dMRI), has shown promise in differentiating typical and pathological aging and monitoring brain degeneration. We aimed to examine free water and free water corrected dMRI measures to assess white and gray matter microstructure and their associations with age in autistic adults. Methods: Forty-three autistic adults ages 30-73 years and 43 age, sex, and IQ matched neurotypical controls participated in this cross-sectional study. We quantified fractional anisotropy (FA), free water, and free water-corrected FA (fwcFA) across 32 transcallosal white matter tracts and 94 gray matter areas in autistic adults and neurotypical controls. Follow-up analyses assessed age effect on dMRI metrics of the whole brain for both groups and the relationship between dMRI metrics and clinical measures of ASD in regions that significantly differentiated autistic adults from controls. Results: We found globally elevated free water in 24 transcallosal tracts in autistic adults. We identified negligible differences in dMRI metrics in gray matter between the two groups. Age-associated FA reductions and free water increases were featured in neurotypical controls; however, this brain aging profile was largely absent in autistic adults. Additionally, greater autism quotient (AQ) total raw score was associated with increased free water in the inferior frontal gyrus pars orbitalis and lateral orbital gyrus in autistic adults. Limitations: All autistic adults were cognitively capable individuals, minimizing the generalizability of the research findings across the spectrum. This study also involved a cross-sectional design, which limited inferences about the longitudinal microstructural changes of white and gray matter in ASD. Conclusions: We identified differential microstructural configurations between white and gray matter in autistic adults and that autistic individuals present more heterogeneous brain aging profiles compared to controls. Our clinical correlation analysis offered new evidence that elevated free water in some localized white matter tracts may critically contribute to autistic traits in ASD. Our findings underscored the importance of quantifying free water in dMRI studies of ASD.

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20. Skvortsova L, Perfilyeva A, Bespalova K, Kuzovleva Y, Kabysheva N, Khamdiyeva O. 7p22.3 microdeletion: a case study of a patient with congenital heart defect, neurodevelopmental delay and epilepsy. Orphanet J Rare Dis;2024 (Aug 16);19(1):301.

BACKGROUND: Chromosome 7 has regions enriched with low copy repeats (LCRs), which increase the likelihood of chromosomal microdeletion disorders. Documented microdeletion disorders on chromosome 7 include both well-known Williams syndrome and more rare cases. It is noteworthy that most cases of various microdeletions are characterized by phenotypic signs of neuropsychological developmental disorders, which, however, have a different genetic origin. The localization of the microdeletions, the genes included in the region, as well as the structural features of the sequences of these genes have a cumulative influence on the phenotypic characteristics of the individuals for each specific case and the severity of the manifestations of disorders. The consideration of these features and their detailed analysis is important for a correct and comprehensive assessment of the disease. RESULTS: The article describes a clinical case of 7p22.3 microdeletion in a patient with congenital heart defect and neurological abnormalities – epilepsy, combined with moderate mental and motor developmental delay. CONCLUSIONS: Through detailed genetic analyses, we are improving the clinical description of the rare 7p22.3 microdeletion and thus creating a basis for future genetic counseling and research into targeted therapies.

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21. Turkstani H, Alfaifi A, Ramachandran M, Bushra A, Stoopler E, France K. Severe manifestation of plasma cell mucositis in a patient with autism spectrum disorder: A unique overlap illustrating challenges with diagnosis and management. Spec Care Dentist;2024 (Aug 16)

Plasma cell mucositis (PCM) is a rare inflammatory condition affecting the oral tissues, often triggered by allergens or inflammation. Autism spectrum disorder (ASD), a neurodevelopmental condition, poses unique challenges in oral care and hygiene due to behavioral and sensory issues. These conditions have not previously been reported in concert but may share risk factors including through the development of inflammation. We present a case of severe PCM in a 23-year-old male with ASD, illustrating diagnostic complexities and management strategies. The patient presented with widespread and severe lesions, raising the possibility of underlying causes. After multiple interventions, including topical steroids and trigger avoidance, the patient achieved near-complete resolution of the oral lesions. Immunohistochemical and serological investigations suggested an underlying monoclonal gammopathy, warranting hematological evaluation. Our case shows how PCM and ASD can affect each other, highlighting the importance of understanding how these conditions interact, and the need for tailored approaches to oral health in this population. Further research is needed to elucidate any pathophysiological or risk-based link between ASD and inflammatory oral conditions and to refine management strategies for PCM in patients with neurodevelopmental disorders.

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22. Vickers ML, Menhinnitt RS, Choi YK, Malacova E, Eriksson L, Churchill AW, Oddy B, Boon K, Randall C, Braun A, Taggart J, Marsh R, Pun P. Comorbidity rates of autism spectrum disorder and functional neurological disorders: A systematic review, meta-analysis of proportions and qualitative synthesis. Autism;2024 (Aug 16):13623613241272958.

Autism spectrum disorder (ASD) and functional neurological disorders (FND) are relatively common conditions, and there has been recent interest in the overlap between them. Both conditions share core features of alexithymia, impaired interoception and deficits in attentional focus. To date, relatively little is known about the comorbidity rates between ASD and FND. This is the first meta-analysis and qualitative synthesis on the subject. We found that around 10% of children presenting with functional seizures have a comorbid ASD diagnosis. People with ASD are more likely than the neurotypical population to have functional somatic disorders, and there is also evidence that ASD rates are higher for other FNDs such as functional motor disorders. Since FND comes with risks of unnecessary medical procedures and investigations, it is important to recognize the potential for people with ASD to have an FND comorbidity.

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23. Xie L, Li H, Xiao M, Chen N, Zang X, Liu Y, Ye H, Tang C. Epigenetic insights into Fragile X Syndrome. Front Cell Dev Biol;2024;12:1432444.

Fragile X Syndrome (FXS) is a genetic neurodevelopmental disorder closely associated with intellectual disability and autism spectrum disorders. The core of the disease lies in the abnormal expansion of the CGG trinucleotide repeat sequence at the 5’end of the FMR1 gene. When the repetition exceeds 200 times, it causes the silencing of the FMR1 gene, leading to the absence of the encoded Fragile X mental retardation protein 1 (FMRP). Although the detailed mechanism by which the CGG repeat expansion triggers gene silencing is yet to be fully elucidated, it is known that this process does not alter the promoter region or the coding sequence of the FMR1 gene. This discovery provides a scientific basis for the potential reversal of FMR1 gene silencing through interventional approaches, thereby improving the symptoms of FXS. Epigenetics, a mechanism of genetic regulation that does not depend on changes in the DNA sequence, has become a new focus in FXS research by modulating gene expression in a reversible manner. The latest progress in molecular genetics has revealed that epigenetics plays a key role in the pathogenesis and pathophysiological processes of FXS. This article compiles the existing research findings on the role of epigenetics in Fragile X Syndrome (FXS) with the aim of deepening the understanding of the pathogenesis of FXS to identify potential targets for new therapeutic strategies.

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24. Yilmaz Sukranli Z, Korkmaz Bayram K, Taheri S, Cuzin F, Ozkul Y, Rassoulzadegan M. Experimentally altering microRNA levels in embryos alters adult phenotypes. Sci Rep;2024 (Aug 16);14(1):19014.

We previously identified a unique genetic feature of Autism Spectrum Disorder (ASD) in human patients and established mouse models, a low to very low level of six microRNAs, miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p and miR-499a-5p. We attempted to interfere experimentally in mice with two of them, miR19a-3p and miR499a-5p by microinjecting into zygote pronuclei either the complementary sequence or an excess of the microRNA. Both resulted in low levels in the tissues and sperm of the targeted microRNAs and their pri and pre precursors. This method stably modify predetermined levels of miRNAs and identify miRNA alterations that cause changes in autistic behavior and predispose the individual to an inherited disease. Excess miRNA results in single-stranded miRNA variations in both free and DNA-bound RNA (R-loop) fractions in mouse models thus appearing to affect their own transcription. Analysis of miRNAs fractions in human patients blood samples confirm low level of six microRNAs also in R-loop fractions.

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