1. Bang P, Andemichael DK, Pieslinger JF, Igelström K. Sensory symptoms associated with autistic traits and anxiety levels in children aged 6-11 years. J Neurodev Disord;2024 (Aug 12);16(1):45.

BACKGROUND: Autism spectrum conditions (ASC) and quantitative autistic traits (QATs) are associated with sensory symptoms, which may contribute to anxiety and adversely affect social and cognitive development. Although sensory symptoms can occur across all senses, the relative roles of specific sensory modalities as contributors to the autistic phenotype and to anxiety are not well understood. The objective of this study was to examine which sensory symptoms were most predictive of high anxiety. METHODS: We recruited 257 female primary caregivers of children aged 6 to 11 years (49% girls) to a questionnaire study comprising parent-report measures for classical QATs (social, communicative, and rigid), autism-related sensorimotor symptoms (visual, auditory, tactile, olfactory, gustatory, vestibular, proprioceptive, and motor), and anxiety symptoms. First, Bayesian stochastic search variable selection (SSVS) was used to identify the most probable sensorimotor predictors of specific QATs as well as diagnosed ASC. Then, the selected predictors were used in another SSVS, using anxiety symptoms as a dependent variable, to identify which of the autism-relevant sensorimotor symptoms were most robustly predictive of anxiety. Finally, the effect sizes of anxiety-related sensory symptoms were estimated with linear regressions. RESULTS: We found that auditory symptoms and motor difficulties were most predictive of ASC diagnosis. Developmental motor difficulties were also strongly related to all individual QATs, whereas auditory symptoms were more selectively predictive of rigid traits. Tactile symptoms robustly predicted social interaction QATs, and proprioceptive symptoms predicted communicative QATs. Anxiety outcomes were most strongly predicted by difficulties with auditory and olfactory processing. CONCLUSIONS: The results support the clinical importance of being alert to complaints about sounds and hearing in neurodevelopmental populations, and that auditory processing difficulties may be evaluated as an early marker of poor mental health in children with and without diagnosed autism. Olfactory processing differences appeared to be an anxiety marker less strongly associated with ASC or QATs, while motor difficulties were highly autism-relevant but not equally strongly associated with anxiety outcomes. We suggest that future studies may focus on the mechanisms and consequences of neurodevelopmental central auditory processing dysfunction and its potential relationship to anxiety disorders.

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2. Bausela-Herreras E. Autism Spectrum Disorder and BRIEF-P: A Review and Meta-Analysis. Children (Basel);2024 (Aug 13);11(8)

BACKGROUND: This research can facilitate the development of early detection tools for ASD by identifying specific patterns of deficits in executive functioning, validating the use of the BRIEF-P as a detection tool, and complementing information obtained from other evaluation instruments (Autism Diagnostic Interview-ADI-and Autism Diagnostic Observation Schedule-ADOS). AIMS: To gain knowledge of the application and usefulness of the BRIEF-P in the evaluation of executive functions (EFs) in people with ASD in the early years of the life cycle. METHOD: In order to systematically examine this hypothesis, a meta-analysis was conducted to identify the executive profile (strengths and weaknesses) of children with ASD. Out of a total of 161,773 potentially eligible published articles from different databases, 13 appropriate articles were revised and 4 articles were selected. Studies that were included evaluated samples involving individuals with ASD aged 2 to 8 years and were published in English or Spanish during the period of 2012-2022. RESULTS: The executive profile obtained from the application of the BRIEF-P in individuals with ASD was analyzed. It was identified that children with ASD, compared to typically developing children, show significantly clinical scores on the flexibility, inhibition, and global executive functioning scales. The results support the hypothesis of an executive deficit, with flexibility and inhibition being diagnostic markers for early and prompt identification of autism. CONCLUSIONS AND DISCUSSION: The results confirm deficits in flexibility, although they are not conclusive. This may be due to aspects related to methodology, whereby the studies (i) include very large and heterogeneous age groups, (ii) do not discriminate based on the level of competence, and (iii) use instruments for evaluating executive functions that are not validated or adapted for people with ASD. Another reason is the lack of consensus in the very operational definition of the executive functions construct, with the studies focusing mainly on the cold dimension while ignoring the hot dimension. From the perspective of therapeutic and treatment implications, executive dysfunction can impact adaptive skills in daily life and consequently the person’s autonomy.

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3. Bögl K, Bayer M, Walter H, Dziobek I. Influences of heart rate feedback and autistic traits on affective mindreading. Sci Rep;2024 (Aug 13);14(1):18783.

Although mindreading is an important prerequisite for successful social interactions, the underlying mechanisms are still matter of debate. It is unclear, for example, if inferring others’ and own mental states are distinct processes or are based on a common mechanism. Using an affect-induction experimental set-up with an acoustic heart rate feedback that addresses affective mindreading in self and others, we investigated if non-autistic study participants relied on similar information for self- and other-directed mindreading. We assumed that due to altered mindreading capacities in autism, mainly individuals with low autistic traits would focus on additional sensory cues, such as heart rate, to infer their own and their gambling partner’s affective states. Our analyses showed that the interpretation of a heart rate signal differed in self- and other-directed mindreading trials. This effect was modulated by autistic traits suggesting that individuals with higher autistic traits might not have interpreted the heart rate feedback for gambling partner ratings and differentiated less between self- and other-directed mindreading trials. We discuss these results in the context of a common mechanism underlying self- and other-directed mindreading and hypothesize that the weighting of internal and external sensory information might contribute to how we make sense of our and others’ mental states.

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4. Carbone PS, Stipelman CH, Villalobos ME, Ellzey A, Stuart A, Stoddard GJ, Campbell K. A Comparison of Parent-Reported Severe Autism With Mild/Moderate Autism Among US Children. J Dev Behav Pediatr;2024 (Aug 13)

OBJECTIVE: An expert commission has proposed the term « profound » autism for children on the spectrum who are minimally verbal or nonverbal and have intellectual disability (ID), behavioral challenges, and co-occurring conditions. It is unknown whether parents’ rating of « severe » autism aligns with the definition of « profound » autism. Using the National Survey of Children’s Health, we sought to (1) estimate the prevalence of parent-reported severe autism, (2) identify child characteristics that are associated with severe autism, (3) compare health care utilization, and (4) compare caregiver stress and resilience between families of children with severe versus mild/moderate autism. METHODS: Parent responses on the 2018 to 2019 NSCH were used to compare school-age children with parent-reported severe autism and those with mild/moderate autism. Descriptive statistics, χ2 tests, and logistic regression were used for statistical analysis. RESULTS: Among parents of 1,368 US children with autism, 10.1% characterized their child’s autism as severe, a prevalence of 1 in 333. Parents of children with severe autism were more likely to report ID (45% vs 12.1%, p < 0.001), language delay (88% vs 58.7%, p < 0.001), and difficulties in dressing and bathing (67% vs 19.2%, p < 0.001). Children with severe autism had more behavioral problems and co-occurring conditions but were no more likely to see specialists or receive autism-specific behavioral therapy. Their caregivers reported more stress and less resilience. CONCLUSION: The characteristics of "profound" autism and parent-reported "severe" autism significantly overlap, allowing the use of the NSCH for studies of this vulnerable population. Children with profound/severe autism could benefit from more behavioral therapy, specialty care, and family support.

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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. Cherewick M, Cruz CM, Giri P, Matergia M, Rai RP. Relationships between autistic traits, self-efficacy, and internalizing symptoms in a nonclinical sample of Indian early adolescents. Brain Behav;2024 (Aug);14(8):e3646.

INTRODUCTION: Having more « autistic traits » is associated with an increased risk of mental health conditions. However, few studies have examined autistic traits in nonclinical samples. This study aims to analyze the relationship between autistic traits and internalizing symptoms among early adolescents and to examine the moderating effect of self-efficacy. METHODS: Survey data were collected from early adolescents ages 10-14 living in Darjeeling, India (n = 274) to assess autistic traits, self-efficacy, and internalizing symptoms. RESULTS: Higher internalizing symptoms were significantly associated with a higher report of autistic traits. Academic, social, and emotional dimensions of self-efficacy moderated the relationship between autistic traits and internalizing symptoms. CONCLUSION: The moderation effects between social and emotional self-efficacy among youth with high versus low autism trait scores suggest the need for social-emotional learning interventions designed for and with neurodivergent youth. Such interventions aim to reduce internalizing symptoms during early adolescence and improve future mental health trajectories.

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7. Daghmash RM, Khanfar MS, Darweesh RS. Risperidone Pellets, Pycnogenol(®), and Glucomannan Gummy Formulation for Managing Weight Gain and ADHD in Autistic Children. Pharmaceutics;2024 (Aug 13);16(8)

Gummy formulations are defined as gradually or slowly released solid oral dosage forms. Risperidone is an atypical antipsychotic medication used to treat schizophrenia and autism-related irritability. This study presents the development of visually appealing, patient-tailored medicated gummies that act as a novel pharmaceutical form of Risperidone for pediatrics. In this study, two gummy bases were used, one containing Glucomannan and the other containing Gelatin as a gelling agent, where these gummy bases were loaded with coated Risperidone pellets with a controlled release layer. The final products were evaluated for their pH, viscosity, content uniformity, drug content, and dissolution profile. Both formulas showed proper rheology and met content and weight uniformity standards. The release rates for F1 and F2 in the acidic media were 25% and 11%, respectively, after 2 h. At the same time, a full-release profile for Risperidone was noticed in both formulae at pH 6.8 where the release lasts for 24 h. It can be concluded that the chewable semi-solid dosages (gummies) filled with coated pellets are suitable for pediatric patients since pediatrics have drug-related problems which can be solved using high gastro-resistance coated pellets, which also shows a proper release profile for the drug.

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8. Dennison CA, Shakeshaft A, Eyre O, Tilling K, Rice F, Thapar A. Investigating the neurodevelopmental correlates of early adolescent-onset emotional problems. J Affect Disord;2024 (Nov 1);364:212-220.

BACKGROUND: Emotional problems (EPs) increase sharply after mid-adolescence. Earlier EPs are associated with poorer long-term outcomes, and their underlying mechanisms may differ to later-onset EPs. Given an established relationship between ADHD, autism, and later depression, we aimed to examine associations between neurodevelopmental conditions and correlates and early adolescent-onset EPs. METHODS: Adolescents in two UK population cohorts, Avon Longitudinal Study of Parents and Children (ALSPAC) and Millennium Cohort Study (MCS), were included. Individuals scoring >6 on the Strengths and Difficulties Questionnaire (SDQ) emotional problems subscale between ages 11-14 were defined as having early adolescent-onset EP, whilst those scoring >6 for the first time at 16-25 were defined as having later-onset EP. We tested associations between early adolescent-onset EP (total cases = 887, controls = 19,582) and ICD-10/DSM-5 neurodevelopmental conditions and known correlates, including: sex, birth complications, low cognitive ability, special educational needs (SEND), and epilepsy. Analyses were conducted separately in ALSPAC and MCS then meta-analysed. RESULTS: In the meta-analysis of both cohorts, early adolescent-onset EPs were associated with female sex and greater likelihood of low cognitive ability, SEND, autism, ADHD, and reading difficulties. Compared to later-onset EP, early adolescent-onset EPs were associated with male sex, low cognitive ability, SEND, epilepsy, ASD, ADHD, and reading difficulties. LIMITATIONS: A clinical definition of depression/anxiety was available only in ALSPAC, instead we primarily defined EP via questionnaires, which capture a broader phenotype. CONCLUSIONS: Individuals with early adolescent-onset EP are likely to have a co-occurring neurodevelopmental condition. Clinicians should consider assessing for neurodevelopmental conditions in young adolescents with EPs.

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9. Friedman L, Moser C, Thurman AJ, Taylor JL, Abbeduto L, Klusek J. Description and predictors of self-determination in males and females with fragile X syndrome on the verge of adulthood. J Intellect Disabil Res;2024 (Aug 12)

BACKGROUND: Self-determination refers to setting goals and making decisions regarding one’s own life with support from others as needed. Research on people with intellectual and developmental disabilities has established the importance of self-determination for quality of life outcomes, such as increased independence and life satisfaction. However, self-determination has not been characterised specifically in fragile X syndrome (FXS), the leading inherited cause of intellectual disability. Relative to youth with other forms of intellectual and developmental disabilities, youth with FXS may face exceptional barriers to the development of self-determined behaviour. In addition to intellectual disability, the FXS behavioural profile is characterised by high rates of autism and anxiety that may further limit opportunities for youth with FXS. The heritable nature of the condition can also yield a distinctive family environment, with siblings and parents also living with fragile X or its associated conditions. Considering these unique challenges, the present study examined self-determination in young adult males and females with FXS and explored whether factors such as language skills, adaptive behaviour and autism traits were associated with self-determination capacity and opportunities. METHODS: The present study included 9 females and 36 males with FXS between the ages of 17 and 25 years. Caregivers (mothers or fathers) completed the American Institute for Research Self-Determination Assessment, which is a questionnaire that yields three scores: self-determination capacity, opportunities for self-determination at home and opportunities for self-determination at school. RESULTS: Caregivers endorsed a wide range of self-determination capacity and opportunities, with ratings for opportunities at home and school exceeding ratings of capacity. Better adaptive behaviour skills were associated with more self-determination capacity, and the presence of more autism traits was associated with fewer opportunities at school. CONCLUSIONS: Results from this study contribute to our understanding of avenues to best support young adults with FXS as they transition to adulthood. Our findings also have implications for practice, such that interventions targeting adaptive behaviours and self-determination may be an effective approach for promoting autonomy and independence for young adults with FXS. Additionally, caregivers and educators should continue to provide opportunities to practise self-determination, regardless of their perception of capacity.

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10. Fuchs C, t Hoen PAC, Müller AR, Ehrhart F, Van Karnebeek CDM. Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?. Front Med (Lausanne);2024;11:1425038.

Rett syndrome (RTT) and Rett-like syndromes [i.e., CDKL5 deficiency disorder (CDD) and FOXG1-syndrome] represent rare yet profoundly impactful neurodevelopmental disorders (NDDs). The severity and complexity of symptoms associated with these disorders, including cognitive impairment, motor dysfunction, seizures and other neurological features significantly affect the quality of life of patients and families. Despite ongoing research efforts to identify potential therapeutic targets and develop novel treatments, current therapeutic options remain limited. Here the potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored. Leveraging existing drugs for new therapeutic purposes, DR presents an attractive strategy, particularly suited for neurological disorders given the complexities of the central nervous system (CNS) and the challenges in blood-brain barrier penetration. The current landscape of DR efforts in these syndromes is thoroughly examined, with partiuclar focus on shared molecular pathways and potential common drug targets across these conditions.

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11. Gharavi M, Salem K, Adabdokht R, Ghasemi M. Effectiveness of two visual-pedagogical methods for toothbrushing skills in autistic children: A randomized clinical trial. Spec Care Dentist;2024 (Aug 12)

AIM: This study aimed to compare the effectiveness of two visual pedagogy methods, video modeling and educational posters, on improving tooth-brushing autonomy in 10-12-year-old children with mild autism. METHODS: Sixty-four autistic children were randomly assigned to either the video or poster groups using the Rand function in Excel. Toothbrushing skills were divided into five stages: preparation, buccal, occlusal, lingual surfaces, and the end. These five stages comprised a total of 20 steps, with each step scored from 1 (not done at all) to 5 (done independently). The final score was calculated by averaging the scores of the five stages. The FONES method of toothbrushing was used for training. Follow-up assessments were conducted after 1 and 3 months. The data were analyzed using SPSS V26, including t-tests, Mann-Whitney U tests, and repeated-measures ANOVA. RESULTS: After 3 months, there were significant improvements in autonomy scores for both groups, with the video group showing greater benefits (4.37 ± 0.43) compared to the poster group (4.11 ± 0.49) (p = .03), with an effect size of η(2) = .07. CONCLUSION: Both video and poster methods were effective in improving tooth-brushing skills, but video modeling was associated with a higher total autonomy score.

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12. Heyne H. Rare developmental disorder caused by variants in a small RNA gene. Nature;2024 (Aug);632(8026):747-748.

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13. Kacimi FE, Didou L, Ed Day S, Azzaoui FZ, Ramchoun M, Berrougui H, Khalki H, Boulbaroud S. Gut microbiota, vitamin A deficiency and autism spectrum disorder: an interconnected trio – a systematic review. Nutr Neurosci;2024 (Aug 13):1-11.

Accumulating evidence proves that children with autism have gastrointestinal problems. However, a significant difference in gut microbiota (GM) exists between autistic and non-autistic children. These changes in the GM may stem from several factors. Recently, researchers focused on nutritional factors, especially vitamin deficiency. Thus, our systematic review investigates the connections among autism, GM alterations, and vitamin A deficiency (VAD), by analyzing studies sourced from PubMed and Embase databases spanning from 2010 to 2022. Adhering to PRISMA guidelines, we meticulously selected 19 pertinent studies that established links between autism and GM changes or between autism and VAD. Our findings uniformly point to significant alterations in the GM of individuals with autism, indicating these changes as promising biomarkers for the disorder. Despite the consistent association of GM alterations with autism, our analysis revealed no notable differences in GM composition between individuals with autism and those experiencing VAD. This suggests that VAD, especially when encountered early in life, might play a role in the onset of autism. Furthermore, our review underscores a distinct correlation between reduced levels of retinoic acid in children with autism, a disparity that could relate to the severity of autism symptoms. The implications of our findings are twofold: they not only reinforce the significance of GM alterations as potential diagnostic markers but also spotlight the critical need for further research into nutritional interventions. Specifically, vitamin A supplementation emerges as a promising avenue for alleviating autism symptoms, warranting deeper investigation into its therapeutic potential.

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14. Kalani L, Kim BH, de Chavez AR, Roemer A, Mikhailov A, Merritt JK, Good KV, Chow RL, Delaney KR, Hendzel MJ, Zhou Z, Neul JL, Vincent JB, Ausió J. Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms. Hum Mol Genet;2024 (Aug 14)

Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms.

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15. 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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16. Kaufmann WE, Percy AK, Neul JL, Downs J, Leonard H, Nues P, Sharma GD, Bartolotta TE, Townend GS, Curfs LMG, Mariotti O, Buda C, O’Leary HM, Oberman LM, Vogel-Farley V, Barnes KV, Missling CU. Burden of illness in Rett syndrome: initial evaluation of a disorder-specific caregiver survey. Orphanet J Rare Dis;2024 (Aug 13);19(1):296.

BACKGROUND: Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder associated with multiple neurologic impairments. Previous studies have shown challenges to the quality of life of individuals with RTT and their caregivers. However, instruments applied to quantify disease burden have not adequately captured the impact of these impairments on affected individuals and their families. Consequently, an international collaboration of stakeholders aimed at evaluating Burden of Illness (BOI) in RTT was organized. METHODS: Based on literature reviews and qualitative interviews with parents of children and adults with RTT, a caregiver questionnaire was constructed to evaluate 22 problems (inclusive of core characteristics, functional impairments, and comorbidities) often experienced with RTT, rated mainly with a 5-level Likert scale. The questionnaire was administered anonymously online to an international sample of 756 caregivers (predominantly parents) of girls and women with RTT. Descriptive statistics were used to identify problems of high frequency and impact on affected individuals and caregivers. Chi-square tests characterized the relationship between problem severity and impact responses, while nonparametric ANOVAs of raw and z-score adjusted scores identified agreement between severity and impact on individual and caregiver. Secondary inferential tests were used to determine the roles of age, clinical type, and country of residence on BOI in RTT. RESULTS: There was variability in reported frequency of problems, with the most prevalent, severe and impactful being those related to the core features of RTT (i.e., communication and fine and gross motor impairments). Chi-square analyses demonstrated interdependence between severity and impact responses, while ANOVAs showed that many problems had disproportionately greater impact than severity, either on affected individuals (e.g., hand stereotypies) or their caregivers (e.g., sleep difficulties, seizures, pain, and behavioral abnormalities). With certain exceptions (e.g., breath-holding, seizures), age, clinical type, or country of residence did not influence these BOI profiles. CONCLUSIONS: Our data demonstrate that core features and related impairments are particularly impactful in RTT. However, problems with mild severity can also have disproportionate impact on affected individuals and, particularly, on their caregivers. Future analyses will examine the role of factors such as treatment outcomes, healthcare services, and healthcare provider’s perspectives, in these BOI profiles.

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17. Lob K, Sawka DM, Gaitanis JN, Liu JS, Nie DA. Genetic Diagnostic Yield in Autism Spectrum Disorder (ASD) and Epilepsy Phenotypes in Children with Genetically Defined ASD. J Autism Dev Disord;2024 (Aug 13)

We compared the epilepsy phenotypes in children with genetically defined versus undefined autism spectrum disorder (ASD). A single-center retrospective study was conducted to investigate diagnostic yields of different genetic testing for children with ASD. Patients with at least one testing modality were included and classified as having genetically defined ASD or not based on updated genotype-phenotype correlation. Of the 523 patients included, 79 (15.1%) had results explaining their ASD diagnosis. WES (whole exome sequencing) outperformed CMA (chromosomal microarray) on diagnostic yield (23.0% versus 8.3%). Compared to those with non-diagnostic test(s), children with genetically defined ASD were associated with higher rates for microcephaly, hypotonia, dysmorphic features, and developmental delay/regression. The prevalence of epilepsy was significantly higher in children with genetically defined ASD than those without a genetic diagnosis (35.4% versus 16.4%, p < 0.001, power = 0.97). Furthermore, children with genetically defined ASD had a younger age of epilepsy onset (median 2.2 versus 5.0 years, p = 0.002, power = 0.90) and a higher rate of drug-resistant epilepsy although not reaching statistical significance (35.7% versus 21.9%, p = 0.20). Our study has provided further evidence to support WES as first-tier test for children with ASD and that an early genetic diagnosis has the potential to inform further surveillance and management for ASD comorbid conditions including epilepsy.

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18. Manville RW, Block SD, Illeck CL, Kottmeier J, Sidlow R, Abbott GW. A novel autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel activation, deactivation and inactivation. Front Cell Neurosci;2024;18:1438101.

KCNB1, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human KCNB1 mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C>A), p. (S114R) in KCNB1, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings’ father demonstrated autistic features and was determined to be an obligate KCNB1 c. 342 C>A carrier based on familial genetic testing results. Functional investigation of Kv2.1-S114R using cellular electrophysiology revealed slowing of channel activation, deactivation, and inactivation, resulting in increased net current after longer membrane depolarizations. To our knowledge, this is the first study of its kind that compares the presentation of siblings each with a KCNB1 disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying KCNB1-linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue.

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19. Miniscalco C, Reinholdson AC, Gillberg C, Johnels J. Speech sound error patterns may signal language disorder in Swedish preschool children with autism. Int J Lang Commun Disord;2024 (Aug 13)

BACKGROUND: Within cohorts of children with autism spectrum disorder (ASD) there is considerable variation in terms of language ability. In the past, it was believed that children with ASD either had delayed articulation and phonology skills or excelled in those areas compared to other language domains. Very little is known about speech sound ability in relation to language ability and non-verbal ability in Swedish preschool children with ASD. AIM: The current study aimed to describe language variation in a group of 4-6-year-old children with ASD, focusing on in-depth analyses of speech sound error patterns with and without non-phonological language disorder and concomitant non-verbal delays. METHOD & PROCEDURES: We examined and analysed the speech sound skills (including consonant inventory, percentage of correct consonants and speech sound error patterns) in relation to receptive language skills in a sample of preschool children who had screened positive for ASD in a population-based screening at 2.5 years of age. Seventy-three children diagnosed with ASD participated and were divided into subgroups based on their receptive language (i.e., non-phonological language) and non-verbal abilities. OUTCOMES & RESULTS: The subgroup division revealed that 29 children (40%) had language delay/disorder without concurrent non-verbal general cognitive delay (ALD), 27 children (37%) had language delay/disorder with non-verbal general cognitive delay (AGD), and 17 children (23%) had language and non-verbal abilities within the normal range (ALN). Results revealed that children with ALD and children with AGD both had atypical speech sound error patterns significantly more often than the children with ALN. CONCLUSIONS & IMPLICATIONS: This study showed that many children who had screened positive for ASD before age 3 years – with or without non-verbal general cognitive delays – had deficits in language as well as in speech sound ability. However, individual differences were considerable. Our results point to speech sound error patterns as a potential clinical marker for language problems (disorder/delay) in preschool children with ASD. WHAT THIS PAPER ADDS: What is already known on the subject Children with autism spectrum disorder (ASD) have deficits in social communication, restricted interests and repetitive behaviour. They show very considerable variation in both receptive and expressive language abilities. Previously, articulation and phonology were viewed as either delayed in children with ASD or superior compared with other (non-phonological) language domains. What this paper adds to existing knowledge Children with ASD and language disorders also have problems with speech sound error patterns. What are the potential or actual clinical implications of this work? About 75% of children with ASD experience language delays/disorders, as well as speech sound problems, related to speech sound error patterns. Understanding/acknowledging these phonological patterns and their implications can help in the diagnosis and intervention of speech sound disorders in children with ASD. Direct intervention targeting phonology might lead to language gains, but more research is needed.

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20. Pollick SA, Pesch MH, Spellun A, Betances EM, Wiley S, Geer LC, Prout KK, Hu M, Nyp SS. Hearing Loss and Autism Spectrum Disorder. J Dev Behav Pediatr;2024 (Aug 13)

Gretta is a 3.5-year-old girl with a history of congenital cytomegalovirus, congenital bilateral profound sensorineural hearing loss (SNHL), and bilateral vestibular dysfunction, resulting in frequent falls. She underwent cochlear implantation at 12 months of age and was diagnosed with autism spectrum disorder at 2.5 years of age.On presentation for follow-up in the developmental-behavioral pediatrics (DBP) clinic, Gretta’s mother reports that Gretta has refused to wear her cochlear implants for the past 5 months. Before that, she seemed to enjoy having access to sound and like dancing to music, and her receptive and expressive language skills, including speech, were progressing. Initially, the rejection of her devices occurred only at preschool. When frustrated or overwhelmed, she would close her eyes and remove her devices for up to 5 minutes before allowing them to be reapplied. Over time, this progressed to a complete refusal to wear her devices at school and then at home, rendering her without access to sound and spoken language.Gretta’s mood has become sullen, and she is now having tantrums at school. She physically startles when attempts are made to reintroduce her devices. Her ability to participate in classroom learning or interact with her classmates is limited, as she attends a spoken-language-focused preschool program. A board-certified behavioral analyst, hired by the family, recommended that Gretta not be allowed to participate in classroom activities unless she wears her devices. She now becomes visibly anxious even when in the same room as her devices and repetitively states « no implant, no implant. » Her mother is worried about her inability to communicate and has « no idea » what may have changed or sparked her initial refusal to wear the devices.What factors would you consider when determining the cause and function of Gretta’s refusal to wear the cochlear implants? How would you guide her parents, teachers, and clinicians to ensure the best developmental and behavioral outcomes for her?

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21. Reyes-Martín J, Simó-Pinatella D, Andrés A. Emotional Reactions of Professionals to Challenging Behaviors in People with Intellectual and Developmental Disability. Behav Sci (Basel);2024 (Aug 13);14(8)

Professionals working with people with intellectual and developmental disability (IDD) can be exposed to challenging behaviors (CBs), which may result in professionals exhibiting emotional reactions that can impact their practices. This study examined these reactions and analyzed how they are influenced by the individual characteristics of people with IDD (gender, age, and level of IDD) and the variables related to CB (type of behavior and its frequency and behavioral function). A total of 125 professionals assessed 293 people with IDD who exhibited CBs. The professionals were asked to complete the Behavior Problems Inventory-Short Form, the Emotional Reactions to Challenging Behavior Scale, and the Questions About Behavior Function measure. It was revealed that positive emotional reactions predominated over negative ones. Significant results were found regarding the level of disability and the age of people with IDD. Emotional reactions were related to the severity of CBs, especially self-injurious and aggressive/destructive behavior, as well as certain behavioral functions. The severity of CBs and the age of people with IDD emerge as key predictors of the emotional reactions of professionals. In short, these reactions vary according to different variables, highlighting the importance of interventions that address professionals’ emotional needs.

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22. Royston R, Absoud M, Ambler G, Barnes J, Hunter R, Kyriakopoulos M, Ondruskova T, Oulton K, Paliokosta E, Panca M, Sharma A, Slonim V, Summerson U, Sutcliffe A, Thomas M, Qu C, Hassiotis A. Evaluation of adapted parent training for challenging behaviour in pre-school children with moderate to severe intellectual developmental disabilities: A randomised controlled trial. PLoS One;2024;19(8):e0306182.

OBJECTIVES: There is limited evidence on the effectiveness of parenting interventions to improve disruptive behaviour in children with intellectual developmental disabilities. This clinical trial evaluated whether an adapted group parenting intervention for preschool children with intellectual developmental disabilities who display challenging behaviour is superior to treatment as usual in England. STUDY DESIGN: 261 children aged 30-59 months with moderate to severe intellectual developmental disabilities and challenging behaviour were randomised to either the intervention (Stepping Stones Triple P) and treatment as usual or treatment as usual alone. The primary outcome was the parent-rated Child Behaviour Checklist at 52 weeks after randomisation. A health economic evaluation was also completed. RESULTS: We found no significant difference between arms on the primary outcome (mean difference -4.23; 95% CI: -9.99 to 1.53; p = 0.147). However, a subgroup analysis suggests the intervention was effective for participants randomised before the COVID-19 pandemic (mean difference -7.12; 95% CI: -13.44 to -0.81; p = 0.046). Furthermore, a complier average causal effects analysis (mean difference -11.53; 95% CI: -26.97 to 3.91; p = 0.143) suggests the intervention requires participants to receive a sufficient intervention dose. The intervention generated statistically significant cost savings (-£1,057.88; 95% CI -£3,218.6 to -£46.67) but the mean point estimate in Quality Adjusted Life Years was similar in both groups. CONCLUSION: This study did not find an effect of the intervention on reducing challenging behaviour, but this may have been influenced by problems with engagement. The intervention could be considered by services as an early intervention if families are supported to attend, especially given its low cost.

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23. Sannar EM, Winter JR, Franke RK, Werner E, Rochowiak R, Romani PW, Miller OS, Bainbridge JL, Enabulele O, Thompson T, Natvig C, Mikulich-Gilbertson SK, Tartaglia NR. Cannabidiol for treatment of Irritability and Aggressive Behavior in Children and Adolescents with ASD: Background and Methods of the CAnnabidiol Study in Children with Autism Spectrum DisordEr (CASCADE) Study. medRxiv;2024 (Aug 13)

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder commonly associated with behavioral challenges. There are few evidence based pharmacological interventions available for the treatment of behavioral symptoms associated with ASD. Cannabidiol (CBD), the non-psychoactive component of cannabis, has potential neuroprotective, antiepileptic, anxiolytic, and antipsychotic effects and may be useful in treating the behavioral symptoms of ASD. METHODS: We describe the research methods of a 27-week double-blind placebo-controlled cross-over trial of cannabidiol for the treatment of irritability and aggression associated with ASD, utilizing the irritability subscale of the Aberrant Behavior Checklist-2nd edition (ABC-2) as the primary outcome measure. Adverse effects and safety monitoring protocols are included. Several secondary and exploratory outcomes measures also include anxiety, communication, repetitive behaviors, attention, hyperactivity, autism family experience, and telehealth functional behavior assessment. CONCLUSION: There is a significant need for clinical research exploring alternative medications for the treatment of behavioral symptoms of ASD. Cannabidiol (CBD) is being studied for the management of irritability, aggression, and other problem behaviors associated with ASD.

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24. Srinivasan AP, Nishiguchi EP, Gonzalez C, Jimenez ME, Zuckerman KE, Lion KC. Toward More Equitable Care: A Closer Look at Autism Clinic Intake Practices and Paperwork. J Dev Behav Pediatr;2024 (Aug 13)

OBJECTIVE: To describe intake requirements among autism clinics and to assess how well intake paperwork aligns with national standards for enhancing language and literacy accessibility. METHODS: This was a survey of 126 autism clinics in the Children’s Hospital Association, assessing intake processes and intake paperwork readability conducted between November 2021 and August 2022. Descriptive analyses characterized intake requirements and paperwork components. Free-text responses about intake support strategies were categorized into themes. Logistic regression models examined associations between clinic patient demographics and odds of requiring intake paperwork. Intake packet length, content, and reading grade level were examined. RESULTS: Of the invited clinics, 73% completed the survey. Among the participating clinics, 55% required intake paperwork before scheduling appointments, 34% offered English forms only, and 89% had no plain language forms. Clinic patient demographics were not associated with intake paperwork requirements. Analyzed intake packets (n = 67) averaged 11 pages long, and most were written above the fifth-grade reading level. Most packets solicited medical, developmental, and educational/therapy history. Many also requested psychoeducational evaluations and teacher rating forms. Reported intake support strategies for families with language or literacy needs included making ad hoc exceptions to the usual process, task shifting to outside organizations, providing support at family’s request, and delegating to support staff. CONCLUSION: Many autism clinics nationwide require intake paperwork before diagnostic evaluation. Many clinics offer intake paperwork in English only, and paperwork often does not meet health literacy standards. Reducing paperwork requirements and providing more routine and robust intake support may facilitate equitable access to autism diagnostic evaluations.

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25. Tafolla M, Amador R, Oyeyemi MJ, Algaze Z, Pandey J, Goin-Kochel RP, Sarver DE, Gulsrud A. Barriers, motivators and strategies to increase participation in genetic research among Asian and Black families of autistic individuals. J Community Genet;2024 (Aug 13)

Genetic research can help advance our knowledge of autism and positively impact the progress of care for individuals with autism. Asian American and Pacific Islander (AAPI) and Black participants remain significantly underrepresented in genetic research in autism in the United States, including nationwide, multisite, genetic consortiums like Simons Foundation Powering Autism Research for Knowledge (SPARK). Few studies have explored the unique motivators and barriers that influence participation in genetics research across underrepresented groups with autism and strategies to increase participation. Therefore, the aim of this study was to understand the perspectives of AAPI and Black parents of individuals with autism about participating in genetic research, specifically motivators (e.g., desire to know more about the relationship between autism and genetics) and/or barriers (e.g., mistrust of research staff) that may impact their decision to participate in genetic research. Using a mixed-methods approach, we collected surveys (n = 134) across the United States and conducted three focus groups with parents of individuals with autism (n = 16) who identified as AAPI and Black from two large metropolitan cities. No significant differences were observed in the survey data but findings from the focus groups elucidate shared motivators for participation (e.g., to help advance the autism field for future generations) and nuanced differences in barriers that influence Black and AAPI parents’ decision to participate (e.g., different beliefs about the source of autism). Practical suggestions to improve outreach and study engagement in genetic research in autism were identified and discussed.

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26. Tuan Y, Chen LC, Chen IC, Tsai SJ, Chen TJ, Chen MH. Effect of Parental Severe Mental Disorders on the Timing of Autism Diagnosis: A Family Linkage Study. J Autism Dev Disord;2024 (Aug 13)

The mean diagnosis age of autism was about 5 years in Taiwan. Whether the delayed diagnosis of autism (≥ 6 years) was associated with parental severe mental disorders remained unknown. The parents of 22,859 autistic individuals and 228,590 age- and sex-matched nonautistic individuals were assessed for the presence of severe mental disorders (schizophrenia, bipolar disorder, major depressive disorder, alcohol use disorder, and substance use disorder). The timing of autism diagnosis was classified into three age categories: < 6 years, 6-11 years, and ≥ 12 years. Logistic regression models were used to examine associations between parental severe mental disorders and these age categories of autism diagnosis. Parental schizophrenia and substance use disorders were associated with the delayed diagnosis of autism, both diagnosis at ≥ 12 years (odds ratio [OR]: 2.14; 1.57) and at 6-11 years (1.87; 1.38). Parental bipolar disorder and major depressive disorder were also associated with the delayed diagnosis of autism, especially diagnosis at 6-11 years (OR 1.98; 1.86). Our findings underscore the need for clinicians to monitor the neurodevelopmental conditions of offspring born to parents with severe mental disorders during the early stages of their life.

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27. Vannelli A, Mariano V, Bagni C, Kanellopoulos AK. Activation of the 5-HT1A Receptor by Eltoprazine Restores Mitochondrial and Motor Deficits in a Drosophila Model of Fragile X Syndrome. Int J Mol Sci;2024 (Aug 13);25(16)

Neurons rely on mitochondrial energy metabolism for essential functions like neurogenesis, neurotransmission, and synaptic plasticity. Mitochondrial dysfunctions are associated with neurodevelopmental disorders including Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, which also presents with motor skill deficits. However, the precise role of mitochondria in the pathophysiology of FXS remains largely unknown. Notably, previous studies have linked the serotonergic system and mitochondrial activity to FXS. Our study investigates the potential therapeutic role of serotonin receptor 1A (5-HT1A) in FXS. Using the Drosophila model of FXS, we demonstrated that treatment with eltoprazine, a 5-HT1A agonist, can ameliorate synaptic transmission, correct mitochondrial deficits, and ultimately improve motor behavior. While these findings suggest that the 5-HT1A-mitochondrial axis may be a promising therapeutic target, further investigation is needed in the context of FXS.

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