1. Bekheet MHY, Mansour LA, Elkaffas RH, Kamel MA, Elmonem MA. Serum matrix metalloproteinase-9 (MMP9) and amyloid-beta protein precursor (APP) as potential biomarkers in children with Fragile-X syndrome: A cross sectional study. Clinical biochemistry. 2023: 110659.

INTRODUCTION: Fragile-X syndrome(FXS) is a neurological disease caused by abnormal repeats in the 5’untranslated region of the FMR1 gene leading to a defective fragile-X-messenger-ribonucleoprotein-1 (FMRP). Although relatively common in children, it is usually under-diagnosed especially in developing countries where genetic screening is not routinely practiced. So far, FXS lacks a laboratory biomarker that can be used for screening, severity scoring or therapeutic monitoring of potential new treatments. METHODS: 110 subjects were recruited; 80 male children with suspected FXS and 30 matched healthy children. We evaluated the clinical utility of serum matrix metalloproteinase-9(MMP9) and amyloid-beta protein precursor(APP) as potential biomarkers for FXS. RESULTS: Out of 80 suspected children, 14 had full mutation, 8 had the premutation and 58 children had normal genotypes. No statistically-significant difference was detected between children with different genotypes concerning age of onset(P = 0.658), main clinical presentation(P = 0.388), clinical severity-score(P = 0.799), patient’s disease-course(P = 0.719) and intellectual disability(P = 0.351). Both MMP9 and APP showed a statistically significant difference when comparing different genotype subgroups(P = 0.019 and < 0.001, respectively). Clinically, MMP9 levels were highest in children presenting with language defects, while APP was highest in children with neurodevelopmental delay. In receiver operating curve analysis, comparing full and premutation with the normal genotype group, MMP9 has an area-under-the-curve of 0.701(95 % CI 0.557-0.845), while APP was marginally better at 0.763(95 % CI 0.620-0.906). When combined together, elevated MMP9 or APP had excellent sensitivity > 95 % for picking-up FXS cases in the clinical setting. CONCLUSIONS: Screening for circulating biomarkers in the absence of FXS genetic diagnosis is justified. Our study is the first to evaluate both MMP9 and APP in FXS suspected children in a clinical setting and to assess their correlation with disease presentation and severity.

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2. Chatterjee I, Getselter D, Ghanayem N, Harari R, Davis L, Bel S, Elliott E. CHD8 regulates gut epithelial cell function and affects autism-related behaviors through the gut-brain axis. Translational psychiatry. 2023; 13(1): 305.

Autism is a neurodevelopmental disorder characterized by early-onset social behavioral deficits and repetitive behaviors. Chromodomain helicase DNA-binding protein (CHD8) is among the genes most strongly associated with autism. In addition to the core behavioral symptoms of autism, affected individuals frequently present with gastrointestinal symptoms that are also common among individuals harboring mutations in the gene encoding CHD8. However, little is known regarding the mechanisms whereby CHD8 affects gut function. In addition, it remains unknown whether gastrointestinal manifestations contribute to the behavioral phenotypes of autism. The current study found that mice haploinsufficient for the large isoform of Chd8 (Chd8L) exhibited increased intestinal permeability, transcriptomic dysregulation in gut epithelial cells, reduced tuft cell and goblet cell counts in the gut, and an overall increase in microbial load. Gut epithelial cell-specific Chd8 haploinsufficiency was associated with increased anxiety-related behaviors together with a decrease in tuft cell numbers. Antibiotic treatment of Chd8L haploinsufficient mice attenuated social behavioral deficits. Together, these results suggest Chd8 as a key determinant of autism-related gastrointestinal deficits, while also laying the ground for future studies on the link between GI deficits and autism-related behaviors.

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3. Fan L, Springfield C, Klein H, Ackerman RA, Sasson NJ, Pinkham AE. Assessing the diametrical model of schizotypal and autistic traits in emotion recognition and social functioning in a community sample. Schizophrenia research. 2023; 261: 194-202.

BACKGROUND: Some research suggests that schizotypal and autistic traits can produce opposing effects on the mentalizing domain of social cognition. Although such findings support a diametrical model proposing that psychotic and autistic traits represent opposite extremes of the social brain continuum, results from recent studies have been more inconsistent, and the applicability of this model to other social cognition domains remains unclear. To test the diametrical model more broadly, this study examined the interactions between schizotypal and autistic traits on emotion recognition and social functioning. METHOD: A total of 791 participants recruited from the general population self-reported schizotypal traits using the Schizotypal Personality Questionnaire-Brief Revised (SPQ-BR) and autistic traits using the Broad Autism Phenotype Questionnaire (BAPQ). Participants also completed the Emotion Recognition 40 task and the Specific Levels of Functioning (SLOF) scale. RESULTS: The SPQ subscales of interpersonal relationships and disorganized symptoms interacted significantly with social BAP on overall emotion recognition performance and the accuracy of identifying neutral faces. Supporting the diametrical model, elevated levels of both schizotypal and autistic traits contributed to higher emotion recognition accuracy compared to elevations on only one trait. For social functioning, however, the diametrical model was not supported. A main effect was found such that higher interpersonal relationship difficulties on SPQ predicted lower work skills on SLOF, and higher levels of both schizotypal and autistic traits combined to produce even lower social functioning. CONCLUSIONS: These findings suggest that the diametrical model may be more relevant to social cognition than to social functioning.

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4. Fernandez TV, Williams ZP, Kline T, Rajendran S, Augustine F, Wright N, Sullivan CAW, Olfson E, Abdallah SB, Liu W, Hoffman EJ, Gupta AR, Singer HS. Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene. PloS one. 2023; 18(10): e0291978.

Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children (« primary » stereotypies, pCMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with pCMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging DNA coding variants in pCMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in pCMS probands show significant overlap with those in Tourette syndrome, ASD, and those in ASD probands with high versus low stereotypy scores. An exploratory analysis of these pCMS gene expression patterns finds clustering within the cortex and striatum during early mid-fetal development. Exploratory gene ontology and network analyses highlight functional convergence in calcium ion transport, demethylation, cell signaling, cell cycle and development. Continued sequencing of pCMS trios will identify additional risk genes and provide greater insights into biological mechanisms of stereotypies across diagnostic boundaries.

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5. Gabay Y, Reinisch E, Even D, Binur N, Hadad BS. Intact Utilization of Contextual Information in Speech Categorization in Autism. Journal of autism and developmental disorders. 2023.

Current theories of Autism Spectrum Disorder (ASD) suggest atypical use of context in ASD, but little is known about how these atypicalities influence speech perception. We examined the influence of contextual information (lexical, spectral, and temporal) on phoneme categorization of people with ASD and in typically developed (TD) people. Across three experiments, we found that people with ASD used all types of contextual information for disambiguating speech sounds to the same extent as TD; yet they exhibited a shallower identification curve when phoneme categorization required temporal processing. Overall, the results suggest that the observed atypicalities in speech perception in ASD, including the reduced sensitivity observed here, cannot be attributed merely to the limited ability to utilize context during speech perception.

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6. Gunz S, Rozen-Knisbacher I, Blumenfeld A, Hendler K, Yahalom C. The prevalence of autism among children with albinism. European journal of ophthalmology. 2023: 11206721231206091.

BACKGROUND: The association between Autism spectrum disorders (ASD) and visual impairment has been mentioned in the literature. The aim of our study was to investigate the prevalence of autism among children with albinism compared to the prevalence of ASD in children with visual impairment secondary to other causes. METHODS: Retrospective study of children with albinism from January 2015 to December 2020. A control group was created with children with early onset visual impairment of similar visual range and age, secondary to diagnosis other than albinism. Patients with associated Autism were identified in both groups. RESULTS: Seven hundred and eight children aged 1-18 years with visual impairment were included in the study. 401 children had a diagnosis of albinism, of whom 14 were also diagnosed with ASD. In the control group, composed of 307 patients, only 3 had ASD (p: 0•03). CONCLUSIONS: The prevalence of ASD in patients with albinism was 1 in 28, while in children with visual impairment from other causes was 1 in 102. We aim to raise awareness of the higher prevalence of autism in children diagnosed with albinism in order to reach earlier diagnosis and support.

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7. Kilmer M, Hong M, Shah E. Relationship between caregiver adverse childhood events and age of autism spectrum diagnosis. Journal of pediatric nursing. 2023.

BACKGROUND: The age at which children are diagnosed with autism spectrum disorder (ASD) has not significantly decreased in the past 20 years. Adverse childhood events (ACEs) experienced by caregivers of autistic children may predict delays in caregivers attending ASD diagnostic evaluations, negatively impacting the age at which the child is diagnosed with ASD. The purpose of this study was to further explore the caregiver delay response by analyzing recurring events common in caregivers of children at risk for ASD. METHODS: We used a quantitative research design with convenience sampling to categorize caregivers of children referred for an ASD diagnostic evaluation into three groups based on their ACEs score and medical history. FINDINGS: A higher percentage of caregivers with four or more ACEs compared to the national average was noted. Parental separation or divorce, verbal aggression, emotional abuse, and parental alcohol or substance abuse occurred most frequently, and the latter predicted a prolonged time in attending the diagnostic evaluation. DISCUSSION: ACEs experienced by caregivers of children with ASD may delay the age of ASD diagnosis. Further investigation into the effect of ACEs on caregivers’ mental health status and executive functioning is warranted to develop best practice for assisting caregivers in ASD recognition, diagnosis, and care management. APPLICATION TO PRACTICE: Clinicians should consider caregiver ACEs score when referring a child for a diagnostic developmental evaluation. Resources to address caregiver mental health needs should be provided at the onset of the referral process to increase the likelihood of caregiver adherence.

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8. Kuruppath P, Xue L, Pouille F, Jones ST, Schoppa NE. Hyperexcitability in the olfactory bulb and impaired fine odor discrimination in the Fmr1 KO mouse model of fragile X syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023.

Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders in humans. FXS is caused by loss of expression of the Fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here we conducted experiments in wild-type and Fmr1 KO (Fmr1(-/y) ) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) in Fmr1 KO mice displayed greatly enhanced excitation under baseline conditions, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of spontaneous LLDs, which appeared to be due to a decrease in GABAergic synaptic inhibition in glomeruli leading to more feedforward excitation, caused a reduction in the reliability of stimulation-evoked responses in MCs. In addition, in a go/no-go operant discrimination paradigm, we found that Fmr1 KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the Fmr1 KO-induced reduction in MC response reliability is one plausible mechanism for the impaired fine odor discrimination.Significance StatementFragile X syndrome (FXS) in humans is associated with a range of debilitating deficits including aberrant sensory processing. One sensory system that has received comparatively little attention in studies in animal models of FXS is olfaction. Here, we report the first comprehensive physiological analysis of circuit defects in the olfactory bulb in the commonly-used Fmr1 knockout (KO) mouse model of FXS. Our studies indicate that Fmr1 KO alters the local excitation/inhibition balance in the bulb – similar to what Fmr1 KO does in other brain circuits – but through a novel mechanism that involves enhanced feedforward excitation. Furthermore, Fmr1 KO mice display behavioral impairments in fine odor discrimination, an effect that may be explained by changes in neural response reliability.

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9. Landes SD, Turk MA. Health equity for people with intellectual and developmental disability requires vast improvements to data collection: Lessons from the COVID-19 pandemic. Disability and health journal. 2023: 101539.

The COVID-19 pandemic drastically underscored the lack of proper health surveillance for people with intellectual and developmental disability (IDD) in the USA. This data equity failure resulted in researchers having to rely on nontraditional data sources to develop an understanding of how this population was faring during the pandemic. To begin addressing this data equity concern, in this commentary, we (1) discuss the difficulties in accessing data during the pandemic specifically related to people with IDD; (2) provide guidance regarding how existing data can be used to examine COVID-19 outcomes for people with IDD; and (3) provide recommendations for improving data collection for people with IDD in light of lessons learned during the pandemic. In sum, the data currently available to examine COVID-19 as well as other health outcomes among people with IDD are severely limited, compromising the ability to both understand and address health disparities among this population.

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10. Lu H, Wang S, Xue Z, Liu J, Niu X, Gao L, Guo X. Decreased functional concordance in male children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2023.

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental condition with altered function of the brain. At present, a variety of functional metrics from neuroimaging techniques have been used to explore ASD neurological mechanisms. However, the concordance of these functional metrics in ASD is still unclear. This study used resting-state functional magnetic resonance imaging data, which were obtained from the open-access Autism Brain Imaging Data Exchange database, including 105 children with ASD and 102 demographically matched typically developing (TD) children. Both voxel-wise and volume-wise functional concordance were calculated by combining the dynamic amplitude of low-frequency fluctuations, dynamic regional homogeneity, and dynamic global signal correlation. Furthermore, a two-sample t-test was performed to compare the functional concordance between ASD and TD groups. Finally, the relationship between voxel-wise functional concordance and Autism Diagnostic Observation Schedule subscores was analyzed using the multivariate support vector regression in the ASD group. Compared with the TD group, we found that ASD showed decreased voxel-wise functional concordance in the left superior temporal pole (STGp), right amygdala, and left opercular part of the inferior frontal gyrus (IFGoper). Moreover, decreased functional concordance was associated with restricted and repetitive behaviors in ASD. Our results found altered brain function in the left STGp, right amygdala, and left IFGoper in ASD by functional concordance, indicating that functional concordance may provide new insights into the neurological mechanisms of ASD.

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11. Perochon S, Di Martino JM, Carpenter KLH, Compton S, Davis N, Eichner B, Espinosa S, Franz L, Krishnappa Babu PR, Sapiro G, Dawson G. Early detection of autism using digital behavioral phenotyping. Nature medicine. 2023.

Early detection of autism, a neurodevelopmental condition associated with challenges in social communication, ensures timely access to intervention. Autism screening questionnaires have been shown to have lower accuracy when used in real-world settings, such as primary care, as compared to research studies, particularly for children of color and girls. Here we report findings from a multiclinic, prospective study assessing the accuracy of an autism screening digital application (app) administered during a pediatric well-child visit to 475 (17-36 months old) children (269 boys and 206 girls), of which 49 were diagnosed with autism and 98 were diagnosed with developmental delay without autism. The app displayed stimuli that elicited behavioral signs of autism, quantified using computer vision and machine learning. An algorithm combining multiple digital phenotypes showed high diagnostic accuracy with the area under the receiver operating characteristic curve = 0.90, sensitivity = 87.8%, specificity = 80.8%, negative predictive value = 97.8% and positive predictive value = 40.6%. The algorithm had similar sensitivity performance across subgroups as defined by sex, race and ethnicity. These results demonstrate the potential for digital phenotyping to provide an objective, scalable approach to autism screening in real-world settings. Moreover, combining results from digital phenotyping and caregiver questionnaires may increase autism screening accuracy and help reduce disparities in access to diagnosis and intervention.

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12. Sumathipala SH, Khan S, Kozol RA, Araki Y, Syed S, Huganir RL, Dallman JE. Context-dependent hyperactivity in syngap1a and syngap1b zebrafish autism models. bioRxiv : the preprint server for biology. 2023.

BACKGROUND AND AIMS: SYNGAP1 disorder is a prevalent genetic form of Autism Spectrum Disorder and Intellectual Disability (ASD/ID) and is caused by de novo or inherited mutations in one copy of the SYNGAP1 gene. In addition to ASD/ID, SYNGAP1 disorder is associated with comorbid symptoms including treatment-resistant-epilepsy, sleep disturbances, and gastrointestinal distress. Mechanistic links between these diverse symptoms and SYNGAP1 variants remain obscure, therefore, our goal was to generate a zebrafish model in which this range of symptoms can be studied. METHODS: We used CRISPR/Cas9 to introduce frameshift mutations in the syngap1a and syngap1b zebrafish duplicates ( syngap1ab ) and validated these stable models for Syngap1 loss-of-function. Because SYNGAP1 is extensively spliced, we mapped splice variants to the two zebrafish syngap1a and b genes and identified mammalian-like isoforms. We then quantified locomotory behaviors in zebrafish syngap1ab larvae under three conditions that normally evoke different arousal states in wild type larvae: aversive, high-arousal acoustic, medium-arousal dark, and low-arousal light stimuli. RESULTS: We show that CRISPR/Cas9 indels in zebrafish syngap1a and syngap1b produced loss-of-function alleles at RNA and protein levels. Our analyses of zebrafish Syngap1 isoforms showed that, as in mammals, zebrafish Syngap1 N- and C-termini are extensively spliced. We identified a zebrafish syngap1 α1-like variant that maps exclusively to the syngap1b gene. Quantifying locomotor behaviors showed that syngap1ab larvae are hyperactive compared to wild type but to differing degrees depending on the stimulus. Hyperactivity was most pronounced in low arousal settings, with overall movement increasing with the number of mutant syngap1 alleles. CONCLUSIONS: Our data support mutations in zebrafish syngap1ab as causal for hyperactivity associated with elevated arousal that is especially pronounced in low-arousal environments.

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