1. Baldwin AG, Foley DW, Collins R, Lee H, Jones DH, Wahab B, Waters L, Pedder J, Paine M, Feng GJ, Privitera L, Ashall-Kelly A, Thomas C, Gillespie JA, Schino L, Belelli D, Rocha C, Maussion G, Krahn AI, Durcan TM, Elkins JM, Lambert JJ, Atack JR, Ward SE. Discovery of MDI-114215: A Potent and Selective LIMK Inhibitor To Treat Fragile X Syndrome. J Med Chem. 2024.

LIMKs are serine/threonine and tyrosine kinases responsible for controlling cytoskeletal dynamics as key regulators of actin stability, ensuring synaptic health through normal synaptic bouton structure and function. However, LIMK1 overactivation results in abnormal dendritic synaptic development that characterizes the pathogenesis of Fragile X Syndrome (FXS). As a result, the development of LIMK inhibitors represents an emerging disease-modifying therapeutic approach for FXS. We report the discovery of MDI-114215 (85), a novel, potent allosteric dual-LIMK1/2 inhibitor that demonstrates exquisite kinome selectivity. 85 reduces phospho-cofilin in mouse brain slices and rescues impaired hippocampal long-term potentiation in brain slices from FXS mice. We also show that LIMK inhibitors are effective in reducing phospho-cofilin levels in iPSC neurons derived from FXS patients, demonstrating 85 to be a potential therapeutic candidate for FXS that could have broad application to neurological disorders or cancers caused by LIMK1/2 overactivation and actin instability.

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2. Breece E, Moreno RJ, Azzam Y, Rogers SJ, Ashwood P. Profiling of activated monocyte populations in autism and associations with increased severity and comorbid behaviors. Brain Behav Immun. 2024; 125: 111-6.

Immune dysfunction in autism spectrum disorder (ASD) has been widely reported and is associated with increased impairments in social interactions, communication, repetitive behaviors, anxiety and gastrointestinal problems. Several lines of evidence point towards increased activation of the innate immune system including activation of microglia, increases in innate inflammatory cytokines/chemokines in blood, brain tissue and CSF, activated dendritic cells and macrophages, and abnormal peripheral monocyte cell function. Monocytes are major players in innate immunity and have important functions in the phagocytosis of pathogens or debris, immune defense and cytokine/chemokine production. However, little is known about the frequencies of different circulating monocytes populations in ASD compared with similarly aged typically developing (TD) controls. In this study, the profile of circulating monocytes exhibiting different markers of activation were assessed in 77 children with ASD, and 49 TD controls who were enrolled as part of the Autism Phenome Project and were of a similar age, 2-4 years old. The frequencies of monocytes expressing the activation marker CD137 (4-1BB) were significantly increased in children with ASD and associated with greater behavioral impairments. In addition, although the frequencies of non-classical monocytes (CD14(+)CD16(+)) were not significantly different across groups, they were linked to worse behaviors in both the context of ASD and TD. Conversely classical monocytes were associated with better behavioral outcomes. These data further implicate monocytes and innate immune cells in the complex pathophysiology of ASD. Monocyte cells play key roles in modulating immune responses and differences in the activation profiles of these cells may result in immune dysfunction in children with ASD.

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3. Cordova M, Hau J, Schadler A, Wilkinson M, Alemu K, Shryock I, Baker A, Chaaban C, Churchill E, Fishman I, Müller RA, Carper RA. Structure of subcortico-cortical tracts in middle-aged and older adults with autism spectrum disorder. Cereb Cortex. 2024; 34(12).

Middle-aged and older adults with autism spectrum disorder may be susceptible to accelerated neurobiological changes in striato- and thalamo-cortical tracts due to combined effects of typical aging and existing disparities present from early neurodevelopment. Using magnetic resonance imaging, we employed diffusion-weighted imaging and automated tract-segmentation to explore striato- and thalamo-cortical tract microstructure and volume differences between autistic (n = 29) and typical comparison (n = 33) adults (40 to 70 years old). Fractional anisotropy, mean diffusivity, and tract volumes were measured for 14 striato-cortical and 12 thalamo-cortical tract bundles. Data were examined using linear regressions for group by age effects and group plus age effects, and false discovery rate correction was applied. Following false discovery rate correction, volumes of thalamocortical tracts to premotor, pericentral, and parietal regions were significantly reduced in autism spectrum disorder compared to thalamo-cortical groups, but no group by age interactions were found. Uncorrected results suggested additional main effects of group and age might be present for both tract volume and mean diffusivity across multiple subcortico-cortical tracts. Results indicate parallel rather than accelerated changes during adulthood in striato-cortical and thalamo-cortical tract volume and microstructure in those with autism spectrum disorder relative to thalamo-cortical peers though thalamo-cortical tract volume effects are the most reliable.

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4. Downs J, Pichard DC, Kaufmann WE, Horrigan JP, Raspa M, Townend G, Marsh ED, Leonard H, Motil K, Dietz AC, Garg N, Ananth A, Byiers B, Peters S, Beatty C, Symons F, Jacobs A, Youakim J, Suter B, Santosh P, Neul JL, Benke TA. International workshop: what is needed to ensure outcome measures for Rett syndrome are fit-for-purpose for clinical trials? June 7, 2023, Nashville, USA. Trials. 2024; 25(1): 845.

INTRODUCTION: The clinical, research and advocacy communities for Rett syndrome are striving to achieve clinical trial readiness, including having fit-for-purpose clinical outcome assessments. This study aimed to (1) describe psychometric properties of clinical outcome assessment for Rett syndrome and (2) identify what is needed to ensure that fit-for-purpose clinical outcome assessments are available for clinical trials. METHODS: Clinical outcome assessments for the top 10 priority domains identified in the Voice of the Patient Report for Rett syndrome were compiled and available psychometric data were extracted. The clinical outcome assessments measured clinical severity, functional abilities, comorbidities and quality of life, and electrophysiological biomarkers. An international and multidisciplinary panel of 29 experts with clinical, research, psychometric, biostatistical, industry and lived experience was identified through International Rett Syndrome Foundation networks, to discuss validation of the clinical outcome assessments, gaps and next steps, during a workshop and in a follow-up questionnaire. The identified gaps and limitations were coded using inductive content analysis. RESULTS: Variable validation profiles across 26 clinical outcome assessments of clinical severity, functional abilities, and comorbidities were discussed. Reliability, validity, and responsiveness profiles were mostly incomplete; there were limited content validation data, particularly parent-informed relevance, comprehensiveness and comprehensibility of items; and no data on meaningful change or cross-cultural validity. The panel identified needs for standardised administration protocols and systematic validation programmes. CONCLUSION: A pipeline of collaborative clinical outcome assessment development and validation research in Rett syndrome can now be designed, aiming to have fit-for-purpose measures that can evaluate meaningful change, to serve future clinical trials and clinical practice.

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5. Gudjonsdottir FJ, Halldorsson F, Ragnarsdottir B, Njardvik U, Hannesdottir DK. Peer Problems and Prosocial Behavior Among Icelandic Children and Adolescents with ADHD and/or Autism: Gender and Age Differences. J Autism Dev Disord. 2024.

Children with neurodevelopmental disorders tend to have more social difficulties than typically developing children. The aim of the current study was to examine parent and teacher-reported effects of age and gender on social functioning in a large clinical sample of children and adolescents with ADHD, autism, or co-occurring ADHD and autism using a cross-sectional study design. This nationwide clinical sample included 2132 Icelandic children and adolescents (35% girls, 65% boys) aged 5-18 years referred for a neurodevelopmental diagnostic assessment (ADHD and/or autism) in Iceland. Social functioning was measured using the Prosocial behavior and Peer problem subscales on the Strengths and Difficulties Questionnaire (SDQ) completed by parents and teachers. Results revealed that autistic youth and youth with co-occurring ADHD and autism experienced more peer problems and showed less prosocial behavior than youth with ADHD only. According to parents and teachers, girls were found to experience more social difficulties compared to boys. Interaction for age and gender, although only significant for teacher reports, indicated that younger girls with neurodevelopmental disorders experience more peer problems and show less prosocial behavior than older girls. In contrast, boys with neurodevelopmental disorders experience similar issues at all ages. The results suggest different patterns of social difficulties for boys and girls with neurodevelopmental disorders. Future research should examine different developmental pathways of social challenges for boys and girls. Implications for developing and providing clinical interventions appropriate developmental stages are discussed.

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6. İlgüy M, Yıldırım GK, Eyüboğlu D, Çarman KB, Yarar C. The relationship between serum phenylalanine levels, genotype, and developmental assessment test results in non-phenylketonuria mild hyperphenylalaninemia patients. Eur J Pediatr. 2024; 184(1): 99.

Phenylalanine (PA) levels below 360 µmol/L do not require treatment; however, cognitive deficits have been observed in patients with elevated PA levels, necessitating a safe upper limit for treatment and therapeutic objectives. The main purpose of this study is to evaluate the correlation between developmental assessments (Denver Developmental Screening Test-II [DDST-II] and Ankara Developmental Screening Inventory [ADSI]) and electroencephalogram (EEG) findings with blood PA levels and genotypic data in non-phenylketonuria mild Hyperphenylalaninemia (HPA) patients, to re-evaluate their treatment status based on potential adverse outcomes. This study encompassed 40 patients aged 1-5 years diagnosed with HPA and not on treatment, identified through initial blood PA levels, and monitored for a minimum of 1 year on an unrestricted diet. Data on demographics, serum PA levels during presentation and follow-up, and genetic mutations were retrieved from hospital records. Patients were categorized into two groups as well-controlled (120-240 µmol/L) and at-risk (240-360 µmol/L) based on average PA levels. Sleep-activated EEGs and developmental assessments using the DDST-II and ADSI were conducted to compare outcomes with PA levels and genetic findings. Developmental delays in the DDST-II were observed across language, gross motor, fine motor, and personal-social domains, predominantly in males. No significant difference in delays was noted between the well-controlled and at-risk groups based on PA levels. The ADSI revealed delays in similar developmental areas, with fine motor skills being particularly prominently affected in the at-risk group. Only a well-controlled patient showed abnormal EEG results deemed unrelated to HPA. CONCLUSION: Our findings indicate that children with untreated PA levels above 240 µmol/L are particularly susceptible to fine motor skill impairments, suggesting a need to reassess the PA level thresholds for initiating treatment. This study highlights the potential requirement for amending current guidelines to ensure early and appropriate intervention in non-PKU mild HPA patients, thereby mitigating the risk of developmental delays. WHAT IS KNOWN: • It is known that phenylalanine levels between 120 and 360 μmol/L typically do not require intervention in non-PKU mild HPA patients, but outcomes for levels near this threshold remain unclear. WHAT IS NEW: • Children with PA levels exceeding 240 µmol/L are at a higher risk of fine motor skill impairment, requiring a reassessment of safe PA levels to prevent developmental delays. • In addition, the Denver Developmental Screening Test II reveals developmental delays in multiple areas in children with non-PKU mild HPA, particularly in males, highlighting the need for gender-specific monitoring and intervention strategies.

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7. Kim H, Reinartz JM, Fabrizio J. Racial Disproportionality in Autism Over 20 Years: What It Means for Special Education Disability Classifications. J Autism Dev Disord. 2024.

PURPOSE: This study examines racial and ethnic disparities in autism prevalence using data from three National Longitudinal Transition Studies (NLTS) spanning two decades. This inquiry intends to explore: (1) changes in the educational labels assigned to students with a medical diagnosis of autism over time and (2) the disparities in these changes across different racial and ethnic groups. METHODS: A secondary data analysis of the NLTS was conducted using the SPSS Complex Samples module. We focused on percentage distribution over time utilizing longitudinal data from the NLTS surveys. RESULTS: The results reveal that students diagnosed with autism are often classified under various other special education categories. There are significant disparities observed in these autism categorizations, with variations in autism prevalence across different racial and ethnic groups. These disparities notably intersect with other special education categories including other health impairments, intellectual disabilities, speech and language impairment, and emotional disability. CONCLUSION: The study suggests that racial disproportionality in the special education autism category could stem from the mechanisms of special education disability designation, which may lead to an inaccurate representation of true autism prevalence.

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8. Kouroupa A, Irvine K, Mengoni SE, Sharma S. The Knowledge and Preferences of Parents/Carers of Autistic Children and Young People about Technology Devices. J Autism Dev Disord. 2024.

This study explored parents’/carers’ knowledge, interest, and preferences towards technology devices as support mediums for autistic children, the reasoning behind any choice and the factors associated with the most preferred technology device. Technology devices were conceptualised as smartphones, iPods, tablets, virtual reality, robots, and ‘other’ for participants to list their own further interpretations of technology devices. Survey data were collected from 267 parents/carers of autistic children aged 2-18 years internationally between May to October 2020. Parents/carers of autistic children and young people were aware of, interested in and mostly preferred the use of tablets because of their convenience and ease of use. They least preferred virtual reality followed by robots due to both being overwhelming, cold, inconvenient to transport and expensive. Robots, in particular, were unknown to respondents. The data suggested that some technology devices as a support medium are not widely known to families of autistic children and young people in support programmes. Technology devices need to be financially approachable and achieve a high standard of design to engage users. Future research should focus on gathering evidence from the autistic community about their preferences and views of technology devices as a medium in autism support programmes.

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9. Manoosi M, Rezaei B, Jenabi E, Soltanian AR, Rezaei M. The Persian Version of the Emotion Regulation and Social Skills Questionnaire: Psychometric Properties for Young People with Autism Spectrum Disorders. J Autism Dev Disord. 2024.

PURPOSE: The aim of the current study was to examine the psychometric properties of the Emotion Regulation and Social Skills Questionnaire (ERSSQ) among young Farsi-speaking individuals with Autism Spectrum Disorder (ASD) in Iran. METHODS: This cross-sectional study analyzed data from 108 children and teenagers (aged 7 to 14 years; mean age = 10.55 years, 91% male) with ASD, along with an equal number of neurotypical children, their families, and teachers. The assessment of the ERSSQ’s psychometric properties included evaluations of reliability, content validity, and face validity. Cronbach’s alpha coefficient was used to estimate the reliability of the ERSSQ-P and ERSSQ-T which were completed respectively by parents and teachers of children with autism spectrum disorders. RESULTS: The results indicated that the Persian versions of the ERSSQ-P and ERSSQ-T questionnaires exhibited adequate face and content validity (CVI = 0.92 and 0.88, respectively). Additionally, both ERSSQ-P and ERSSQ-T demonstrated acceptable internal consistency, with Cronbach’s alpha values of 0.95 and 0.70, respectively. DISCUSSION: This study confirms the effectiveness and validity of the ERSSQ-P and ERSSQ-T, which can be utilized by specialists in the field of autism for clinical and research applications. These instruments offer a straightforward and cost-effective means of assessing emotion regulation and social skills among Farsi-speaking children and adolescents with ASD.

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10. Moerkerke M, Daniels N, Van der Donck S, Tang T, Prinsen J, Yargholi E, Steyaert J, Alaerts K, Boets B. Impact of chronic intranasal oxytocin administration on face expression processing in autistic children: a randomized controlled trial using fMRI. Mol Autism. 2024; 15(1): 53.

BACKGROUND: Difficulties with (non-verbal) social communication, including facial expression processing, constitute a hallmark of autism. Intranasal administration of oxytocin has been considered a potential therapeutic option for improving social difficulties in autism, either by enhancing the salience of social cues or by reducing the social stress and anxiety experienced in social encounters. METHODS: We recorded fMRI brain activity while presenting neutral, fearful and scrambled faces, to compare the neural face processing signature of autistic children (n = 58) with that of matched non-autistic controls (n = 38). Next, in the autistic children group, we implemented this fMRI face processing task in a double-blind, placebo-controlled, multiple-dose oxytocin clinical trial, to evaluate the impact of four-week repeated oxytocin administration (24 IU daily dose) on brain activity in face processing regions. RESULTS: No significant diagnostic-group differences were identified between autistic versus non-autistic children with regard to neural face processing. Furthermore, no significant treatment effects were found in the oxytocin clinical trial. However, exploratory analyses (uncorrected for multiple comparisons) demonstrated decreases in brain activity in the left superior temporal sulcus (STS) and inferior frontal region in the oxytocin compared to the placebo group, and change-from-baseline analyses in the oxytocin group revealed significantly reduced neural activity in the core face-processing network (STS, inferior occipital, and posterior fusiform), as well as in amygdala and inferior frontal region. CONCLUSION: These findings suggest an attenuating effect of multiple-dose oxytocin administration on neural face processing, potentially supporting the anxiolytic account of oxytocin.

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11. Nimbley E, Maloney E, Gillespie-Smith K, Sharpe H, Buchan K, Kettley S, Bragg J, Shepherd A, Choat B, Long J, Whateley I, Booth O, Baker JA, Renton N, Nuttal E, Darling H, Fidgin L, Campbell L, Suratwala T, Temple C, MacDonald K, Carden S, Lazich B, Kerr-Gaffney J, Sader M, Waiter G, Tchanturia K, Duffy F. Conducting ethical, co-produced research with autistic individuals with an eating disorder: best practice guidelines. Eat Disord. 2024: 1-11.

There is a notable overlap between autism and eating disorders (EDs), and autistic individuals may experience poorer ED treatment outcomes than non-autistic peers. To make meaningful change in this field, it is imperative that we actively engage in co-production of research, however there are currently no guidelines to support co-production with autistic people with eating disorders. This paper reports on best practice guidelines that were co-produced across a series of workshops bringing together autistic people with EDs, researchers, clinicians, third-sector organisations, and parents/carers. The guidelines are intended to be used as a foundation for future co-produced autism and ED research. By creating a trusted, ethical co-production relationship, we hope to generate more clinically meaningful and translatable research. There is increasing awareness of an overlap between autism and eating disorders and concerns around the effectiveness of eating disorder treatment for this populationThere is a lack of research with autistic individuals with eating disorders and a pressing need to prioritise meaningful co-produced researchClinical practice should be informed by autism-affirming eating disorder research. eng.

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12. Polver S, Cantiani C, Bulf H, Piazza C, Turati C, Molteni M, Riva V. Gamma oscillations and auditory perception: A cluster-based statistic investigation in infants at higher likelihood of autism and developmental language disorder. J Exp Child Psychol. 2024; 252: 106132.

The ability to process auditory information is one of the foundations of the ability to appropriately acquire language. Moreover, early difficulties in basic auditory abilities have cascading effects on the appropriate wiring of brain networks underlying higher-order linguistic processes. Language impairments represent core difficulties in two different but partially overlapping disorders: developmental language disorder (DLD) and autism spectrum disorder (ASD). The aim of this study was to investigate basic auditory processes in 12-month-old infants at high likelihood (HL) of developing either DLD or ASD in response to standard tones embedded in a non-speech multi-feature oddball paradigm to discern early differences in how auditory processing relates to language acquisition. To do so, we focused on gamma-band oscillations due to the role of gamma activity in coordinating activity among neural assemblies and thus enabling both sensory and higher-order processing. Considering reported hemispheric asymmetries in auditory and linguistic processing, we chose to refer to a cluster-based method to investigate the whole scalp activity in the gamma range. Our results show that HL-ASD infants are characterized by differences in auditory gamma compared with their typically developing peers. These results may imply an enhanced sensitivity to auditory stimuli in HL-ASD infants that might negatively affect their ability to regulate responses.

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13. Shahrokhi H, Malek A, Norouzi S, Amiri S, Noorazar SG, Heidarabadi S, Bahari Gharehgoz A, Dastgiri S, Zali M, Gholipour K, Barzegar M, Shahrokhi R, Broumand S, Iezadi S. Design, methodology, and early findings of an autism registry program: ABBILAR project. Autism. 2024: 13623613241305723.

The autism spectrum disorder (ASD) registry program presents a unique opportunity to facilitate advanced research in various aspects of ASD, particularly in low-resource countries like Iran. Given the international significance of autism research, registry programs play a critical role in data sharing. ASD registry programs have been effectively established in high-income countries over a few decades; however, there are limited examples from low- and middle-income countries. This study presents a firsthand description of the design and primary findings of a 9-year established ASD registry program from the northwest of Iran. It elucidates the program’s feasibility for other low-income settings, providing valuable insights for researchers and policymakers.

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14. Tan MY, Chong SC, Chinnadurai A, Guruvayurappan S. Screening for Depression in Caregivers of Children with Developmental Disabilities: A Quality Improvement Initiative. J Pediatr Health Care. 2024.

INTRODUCTION: Screening for depression in caregivers of children with developmental disabilities is not routine, representing missed opportunities for support. METHOD: A quality improvement project was initiated in our pediatric clinic. Root causes of limited screening included unclear guidelines for support, caregiver perception that help is unavailable, and lack of a quick screening tool. A clinical pathway was constructed and integrated into existing practice using quality improvement methodology. RESULTS: Baseline screening rate was 5%-10%. During the 12-week pilot, weekly rates ranged from 46.0% to 91.0% (mean 70.2%). Monthly rates subsequently averaged 55.0%. Approximately 20% had a positive screen; over half were caregivers of children with autism. About 5% had moderate depression, of whom 40% required referral to social workers. DISCUSSION: Structured depression screening of caregivers of children with developmental disabilities is feasible and sustainable in a busy clinic. Further research is needed to measure the impact on child and family outcomes.

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