1. Borghesi A, Plumari M, Rossi E, Viganò C, Cerbo RM, Codazzi AC, Valente EM, Gana S. PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum. American journal of medical genetics Part A. 2022; 188(2): 635-41.

PUS3 encodes the pseudouridylate synthase 3, an enzyme catalyzing the formation of tRNA pseudouridine, which plays a critical role in tRNA structure, function, and stability. Biallelic pathogenic variants of PUS3 have been previously associated with severe intellectual disability, microcephaly, epilepsy, and short stature. We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia. This patient further expands the phenotypic spectrum of PUS3-related disorders to include a more severe syndromic presentation.

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2. Bradshaw J, Shi D, Hendrix CL, Saulnier C, Klaiman C. Neonatal neurobehavior in infants with autism spectrum disorder. Developmental medicine and child neurology. 2022; 64(5): 600-7.

AIM: To investigate neurobehavioral maturation for neonates who are later diagnosed with autism spectrum disorder (ASD). METHOD: In a prospective longitudinal design, neonatal neurobehavior was examined monthly in 1- to 3-month-old infants at elevated and low familial likelihood of ASD (n=60). At 2 years, infants were seen for a clinical best-estimate evaluation, resulting in 18 infants with ASD and 36 typically developing infants. Repeated-measures analysis of variance models were conducted to examine the effects of age, diagnostic group, and their interactions. RESULTS: Neurobehavioral maturation of infants diagnosed with ASD was largely comparable to typically developing infants from 1 to 3 months, with the exception of the development of attention. Object-focused attention was significantly attenuated for infants with ASD beginning at 2 to 3 months and was predictive of social-communication skills 2 years later. INTERPRETATION: This is the first study to prospectively examine neonatal neurobehavior of infants at an elevated familial likelihood of ASD who later received a diagnosis. Despite relatively intact neurological and behavioral maturation in the neonatal period, attention to objects emerged as a key early indicator of ASD. This suggests a complex attentional vulnerability within the first 3 months of life that may be associated with cascading sequelae of social-communication challenges and the emergence of ASD.

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3. Houben F, van Hensbergen M, Den Heijer CDJ, Dukers-Muijrers N, Hoebe C. Barriers and facilitators to infection prevention and control in Dutch residential care facilities for people with intellectual and developmental disabilities: A theory-informed qualitative study. PloS one. 2021; 16(10): e0258701.

BACKGROUND: Care institutions are recognised to be a high-risk setting for the emergence and spread of infections and antimicrobial-resistant organisms, which stresses the importance of infection prevention and control (IPC). Accurate implementation is crucial for optimal IPC practice. Despite the wide promotion of IPC and research thereof in the hospital and nursing home setting, similar efforts are lacking in disability care settings. Therefore, this study aimed to assess perceived barriers and facilitators to IPC among professionals working at residential care facilities (RCFs) for people with intellectual and developmental disabilities (IDD), as well as to identify professional-reported recommendations to improve IPC. METHODS: This qualitative study involved semi-structured interviews (before COVID-19) with twelve professionals from five Dutch RCFs for people with IDD. An integrated theoretical approach was used to inform data collection and analysis. Thematic analysis using inductive and deductive approaches was conducted. This study followed the COnsolidated criteria for REporting Qualitative research (COREQ) guidelines. RESULTS: Our findings revealed barriers and facilitators at the guideline, client, professional, professional interaction, professional client interaction, client interaction, organisational, community, and societal level. Six main themes covering multiple barriers and facilitators were identified: (1) guidelines’ applicability to (work)setting; (2) professionals’ cognitions and attitude towards IPC (related to educational background); (3) organisational support and priority; (4) educational system; (5) time availability and staff capacity; and (6) task division and change coaches. The main professional-reported recommendations were the introduction of tailored and practical IPC guidelines, structural IPC education and training among all professionals, and client participation. CONCLUSIONS: To promote IPC, multifaceted and multilevel strategies should be implemented, with a preliminary need for improvements on the guideline, professional, and organisational level. Given the heterogeneous character, i.e., different professionals, clients and care needs, there is a need for a tailored approach to implement IPC and sustain it successfully in disability care. Our findings can inform future IPC practice improvements.

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4. Koganezawa N, Hanamura K, Schwark M, Krueger-Burg D, Kawabe H. Super-resolved 3D-STED microscopy identifies a layer-specific increase in excitatory synapses in the hippocampal CA1 region of Neuroligin-3 KO mice. Biochemical and biophysical research communications. 2021; 582: 144-9.

The chemical synapse is one type of cell-adhesion system that transmits information from a neuron to another neuron in the complex neuronal network in the brain. Synaptic transmission is the rate-limiting step during the information processing in the neuronal network and its plasticity is involved in cognitive functions. Thus, morphological and electrophysiological analyses of synapses are of particular importance in neuroscience research. In the current study, we applied super-resolved three-dimensional stimulated emission depletion (3D-STED) microscopy for the morphological analyses of synapses. This approach allowed us to estimate the precise number of excitatory and inhibitory synapses in the mouse hippocampal tissue. We discovered a region-specific increase in excitatory synapses in a model mouse of autism spectrum disorder, Neuroligin-3 KO, with this method. This type of analysis will open a new field in developmental neuroscience in the future.

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5. Lee J, Ha S, Ahn J, Lee ST, Choi JR, Cheon KA. The Role of Ion Channel-Related Genes in Autism Spectrum Disorder: A Study Using Next-Generation Sequencing. Frontiers in genetics. 2021; 12: 595934.

The clinical heterogeneity of autism spectrum disorder (ASD) is closely associated with the diversity of genes related to ASD pathogenesis. With their low effect size, it has been hard to define the role of common variants of genes in ASD phenotype. In this study, we reviewed genetic results and clinical scores widely used for ASD diagnosis to investigate the role of genes in ASD phenotype considering their functions in molecular pathways. Genetic data from next-generation sequencing (NGS) were collected from 94 participants with ASD. We analyzed enrichment of cellular processes and gene ontology using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). We compared clinical characteristics according to genetic functional characteristics. We found 266 genes containing nonsense, frame shift, missense, and splice site mutations. Results from DAVID revealed significant enrichment for « ion channel » with an enrichment score of 8.84. Moreover, ASD participants carrying mutations in ion channel-related genes showed higher total IQ (p = 0.013) and lower repetitive, restricted behavior (RRB)-related scores (p = 0.003) and mannerism subscale of social responsiveness scale scores, compared to other participants. Individuals with variants in ion channel genes showed lower RRB scores, suggesting that ion channel genes might be relatively less associated with RRB pathogenesis. These results contribute to understanding of the role of common variants in ASD and could be important in the development of precision medicine of ASD.

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6. Liu XM. [A clinical framework for the comprehensive evaluation and differential diagnosis of language delay language disorders and other childhood developmental disorders]. Zhonghua er ke za zhi = Chinese journal of pediatrics. 2021; 59(11): 901-4.

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7. Mathée-Scott J, Larson C, Venker C, Pomper R, Edwards J, Saffran J, Ellis Weismer S. Use of Mutual Exclusivity and its Relationship to Language Ability in Toddlers with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

To efficiently learn new words, children use constraints such as mutual exclusivity (ME) to narrow the search for potential referents. The current study investigated the use of ME in toddlers with autism spectrum disorder (ASD) and neurotypical (NT) peers matched on nonverbal cognition. Thirty-two toddlers with ASD and 26 NT toddlers participated in a looking-while-listening task. Images of novel and familiar objects were presented along with a novel or familiar label. Overall, toddlers with ASD showed less efficient looking toward a novel referent when a novel label was presented compared to NT toddlers, controlling for age and familiar word knowledge. However, toddlers with ASD and higher language ability demonstrated more robust use of ME than those with lower language ability.

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8. Melo X, Pinto R, Angarten V, Coimbra M, Correia D, Roque M, Reis J, Santos V, Fernhall B, Santa-Clara H. Training responsiveness of cardiorespiratory fitness and arterial stiffness following moderate-intensity continuous training and high-intensity interval training in adults with intellectual and developmental disabilities. Journal of intellectual disability research : JIDR. 2021; 65(12): 1058-72.

BACKGROUND: Cardiorespiratory fitness (CRF) prompts antiatherogenic adaptations in vascular function and structure. However, there is an extraordinary interindividual variability in response to a standard dose of exercise, wherein a substantial number of adults with intellectual and developmental disabilities (IDD) do not improve CRF. We (1) evaluated the effects of 12-month of moderate-intensity continuous training (MICT) on CRF and arterial stiffness and (2) tested whether an additional 3-month of high-intensity interval training (HIIT) would add to improvements in CRF responsiveness and arterial stiffness. METHODS: Fifteen adults with mild-to-moderate IDD (male adults = 9, 30.1 ± 7.5 years old) met 3 days per week for 30 min MICT for 12 months, after which the incidence of CRF responsiveness was calculated (≥5.0% change in absolute peak VO(2) ). Thereafter, responders and non-responders started HIIT for 3 months with identical daily training load/frequency. Peak VO(2) , local and regional indices of arterial stiffness were assessed prior to and after each period. RESULTS: Sixty per cent of the participants were non-responders following MICT, but the incidence dropped to 20% following HIIT (P = 0.03). Absolute peak VO(2) values reached significant difference from pre-intervention (+0.38 ± 0.08 L min(-1) , P = 0.001) only when HIIT was added. Lower limb pulse wave velocity (PWV) decreased following MICT (-0.8 ± 1.1 m s(-1) , P = 0.049), whereas central PWV only decreased following HIIT (-0.8 ± 0.9 m s(-1) , P = 0.013). CONCLUSIONS: Cardiorespiratory fitness responsiveness and reductions in PWV to a 12-month MICT period in adults with IDD improved following a period of HIIT programme inducing higher metabolic stress.

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9. Mertz L. AI, Virtual Reality, and Robots Advancing Autism Diagnosis and Therapy. IEEE pulse. 2021; 12(5): 6-10.

Autism spectrum disorder (ASD) is a challenge in multiple ways. Just getting diagnosed can take months of visits to doctors and specialists. After the diagnosis, children are often put on long waiting lists to begin therapy, which itself consists of frequent sessions that while helpful, are usually quite taxing for both the children and their parents. And while child-directed therapies are available, adults who are on the spectrum often find little continuing support. Recent technologies are using artificial intelligence (AI), machine learning (ML), virtual reality (VR), and other advanced methods to address all of those issues with faster and easier diagnostics, and in-home therapeutic approaches designed for all ages.

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10. Monlux KD, Pollard JS, Bujanda Rodriguez AY, Hall SS. Conducting In-Home Functional Analyses of Aggression and Self-Injury Exhibited by Boys with Fragile X Syndrome. Journal of developmental and behavioral pediatrics : JDBP. 2022; 43(4): e237-e45.

OBJECTIVE: Boys with fragile X syndrome (FXS) are at increased risk for exhibiting aggression and self-injury that can be extremely disruptive to families. Few studies, however, have examined the extent to which social-environmental factors can influence these behaviors, particularly in home settings. METHODS: Caregivers of 32 boys with FXS, aged 3 to 10 years, were coached by a board-certified behavior analyst to implement a functional analysis (FA) with their child in their home over 2 days. The functions identified in the FAs were validated by behavioral interventions conducted through telehealth over 12 weeks. RESULTS: Social functions for aggression and self-injury were identified in 29 (90.6%) cases, with the most common functions identified being escape from demands/transitions and/or tangible reinforcement. Subsequent function-based behavioral interventions (i.e., functional communication training) implemented for 22 cases by telehealth resulted in decreased rates of aggression and self-injury by 74% to 100%. CONCLUSION: These data underscore the significant impact that social-environmental factors can have on the development and maintenance of aggression and self-injury in FXS. Conducting early home-based behavioral interventions designed to increase functional communication skills may therefore be an effective solution for the treatment of aggression and self-injury in FXS in the long term.

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11. Moore K, Bullard A, Sweetman G, Ahearn WH. Assessing and Treating Anxiety in Individuals with Autism. Behavior modification. 2021: 1454455211051678.

Anxiety is a cluster of responses that can involve both operant and respondent behavior, which can be both public and/or private in nature, and occurs when an upcoming aversive stimulus is signaled. Despite the reported high comorbidity of autism and anxiety, there has been very limited research on how to directly assess and treat anxiety, especially with individuals who have limited communication skills. In Study 1, anxiety was assessed in five individuals with autism, ranging in age from 10 to 19 years old. Anxiety was assessed by measuring behavior during (1) a baseline (with no putative anxiety-provoking stimuli present), (2) signals for an upcoming aversive event, and (3) exposure to that aversive event. Anxiety presented in several different ways, as both conditioned activation and suppression, and both with and without problem behavior during the aversive event. In Study 2, individualized treatments involving differential reinforcement of alternative responses and stimulus fading were used to successfully reduce anxious responding in all four participants who displayed anxiety. These studies demonstrated a potentially useful means of assessing anxiety in individuals with autism which may not only help to measure anxious behavior and identify anxiety-provoking events, but may also lead to effective treatment.

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12. Song XK, So WC. The influence of child-based factors and parental inputs on expressive language abilities in children with autism spectrum disorder. Autism : the international journal of research and practice. 2021: 13623613211054597.

Language impairment is one of the early signs of Autism Spectrum Disorder (ASD) that alerts parents to take their children for early diagnosis and intervention. Little is known about how children’s autism traits, IQ, initial language abilities and parental inputs influence their language abilities. In addition, only a few studies have compared the relative influence of these factors. The present study addressed these issues by examining the structural language in parent-child spontaneous interactions. Forty-two Cantonese (Chinese)-speaking autistic children aged four to eight were recruited. Their expressive language skills grew rapidly more than 9 months, but their development trajectories varied. Initial expressive language ability is the only significant predictor of child language outcomes and language growth trajectories. In contrast, nonverbal cognition, autism traits, and parents’ input do not affect language outcomes in children with ASD. Therefore, early language intervention is crucial for autistic children at all severity and IQ levels.

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13. van den Bos N, Houwen S, Schoemaker M, Rosenblum S. Balancing Text Generative and Text Transcriptive Demands: Written Content and Handwriting Legibility and Speed of Children and Youth with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

The aim of this study was to assess text generation and text transcription of children and youth with Autism Spectrum Disorder (ASD, n = 67) and Typically Developing (TD) peers (n = 67). Participants (80.6% male, ages 9-14) produced a free-style handwriting task analysed for written content and handwriting legibility and speed. Findings showed children and youth with ASD perform significantly poorer than TD peers for written content and handwriting legibility and speed. For children and youth with ASD, poor handwriting legibility predicted poor written content. For TD peers, fast handwriting predicted good written content. Collapsing both groups, ASD group membership negatively predicted written content, after controlling for handwriting legibility and speed. Practical implementations for the educational context are provided.

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14. Wang Z, Peng D, Shang Y, Gao J. Autistic Spectrum Disorder Detection and Structural Biomarker Identification Using Self-Attention Model and Individual-Level Morphological Covariance Brain Networks. Frontiers in neuroscience. 2021; 15: 756868.

Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders, which brings enormous burdens to the families of patients and society. However, due to the lack of representation of variance for diseases and the absence of biomarkers for diagnosis, the early detection and intervention of ASD are remarkably challenging. In this study, we proposed a self-attention deep learning framework based on the transformer model on structural MR images from the ABIDE consortium to classify ASD patients from normal controls and simultaneously identify the structural biomarkers. In our work, the individual structural covariance networks are used to perform ASD/NC classification via a self-attention deep learning framework, instead of the original structural MR data, to take full advantage of the coordination patterns of morphological features between brain regions. The self-attention deep learning framework based on the transformer model can extract both local and global information from the input data, making it more suitable for the brain network data than the CNN- structural model. Meanwhile, the potential diagnosis structural biomarkers are identified by the self-attention coefficients map. The experimental results showed that our proposed method outperforms most of the current methods for classifying ASD patients with the ABIDE data and achieves a classification accuracy of 72.5% across different sites. Furthermore, the potential diagnosis biomarkers were found mainly located in the prefrontal cortex, temporal cortex, and cerebellum, which may be treated as the early biomarkers for the ASD diagnosis. Our study demonstrated that the self-attention deep learning framework is an effective way to diagnose ASD and establish the potential biomarkers for ASD.

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15. Wei QH, Zhang Y, He Y, Mu Y, Cheng Q. [Analysis of language of children with autism spectrum disorder at different developmental levels]. Zhonghua er ke za zhi = Chinese journal of pediatrics. 2021; 59(11): 922-7.

Objective: To explore the language characteristics of children with autism spectrum disorder (ASD) at different developmental levels. Methods: The clinical data of 103 children with ASD who attended the Children’s Hospital of Chongqing Medical University from January 2018 to December 2020 was analyzed retrospectively. They were divided into typical development and abnormal development (including mild and moderate or severe) groups based on developmental diagnostic scale results, and also devided into 2-3, 4-6, and 7-8 years of age groups based on age. The language characteristics of children with ASD at different developmental levels and different ages were compared by Pearson’s chi-square or Fisher’s exact probabilty test, t test, analysis of variance, or Kruskal-Wallis H test. The relationship between language ability and core symptoms of ASD was analyzed by Pearson correlation test. Results: Among 103 children with ASD, 86 were males and 17 were females, with an age of (5.5±1.5) years. A total of 61 children were charactered as typical development and 42 as abnormal (32 mild and 10 moderate or severe). There were no significant differences in developmental scale, overall language, receptive, expressive, syntax, and semantics scores among the three different age groups (all P>0.05). The detection rate of abnormal language ability in the typical development group was significantly lower than that in the abnormal development group (49.2% (30/61) vs. 100.0% (42/42), P<0.01). Receptive, expressive, semantics, and syntax scores of the typical development groups were significantly higher than those of the mildly and moderately or severely abnormal group (89±13 vs. 76±11 vs.71±8, F=18.61, P<0.01; 80±12 vs. 66±8 vs. 58±7, F=29.69, P<0.01; 92±14 vs.78±14 vs. 71±11, F=17.26, P<0.01; 83±10 vs. 71±8 vs. 64±5, F=29.35, P<0.01). Within the abnormal development group, there were no significant correlations between language ability and the core symptoms of ASD (r=-0.02-0.58, all P>0.05). Within the typical development group, there were no significant correlations between language ability and social interaction, repetitive stereotypes, and limited interests (r=0–0.22, all P>0.05). However, overall language, receptive, semantics, and expressive language abilities were negatively correlated with communication (r=-0.28–0.36, all P<0.05), and there was no significant correlation between syntax and communication (r=-0.24, P>0.05) in typical developmental group. Conclusions: The majority of children with ASD manifest language development disorders, mainly in the aspects of expressive and syntax language. Children with ASD with more delayed developmental level have more severe language disorder. About half children with ASD with normal development have language development disorders. The language ability of children with ASD is minimally correlated with ASD core symptoms.

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16. Yang C, Tian Y, Su F, Wang Y, Liu M, Wang H, Cui Y, Yuan P, Li X, Li A, Gong H, Luo Q, Zhu D, Cao P, Liu Y, Wang X, Luo MH, Xu F, Xiong W, Wang L, Li XY, Zhang C. Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome. Protein & cell. 2022; 13(3): 203-19.

Many people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1(KO)), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1(KO) mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABA(A) receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1(KO) mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

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17. Zacharov O, Huster RJ, Kaale A. Investigating Cognitive Flexibility in Preschool Children With Autism Spectrum Disorder. Frontiers in psychology. 2021; 12: 737631.

The current study investigated cognitive flexibility in preschool children with Autism Spectrum Disorder (ASD) and those with typical development using the Reverse Categorization (RC) task and the Dimensional Change Card Sort (DCCS) task. We further examined the relationship between non-verbal mental age (NVMA) and the performance on the two tasks. While no significant difference in performance on the RC task between the two groups was found, significantly more children in the typical developing group passed the DCCS task than children in the ASD group. NVMA was found to correlate with performance in both tasks in the typical developing group but not in the ASD group. When the children were matched on NVMA, no differences in task performance between the two groups were found. The current study found the disparity in performance in two groups on the RC and the DCCS tasks, hence illuminating the importance related to the selection of tasks when studying cognitive flexibility in preschool children with ASD. The study also cast some light on the involvement of NVMA in the performance on the RC and DCCS tasks.

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