1. Alvarez-Mora MI, Agusti I, Wijngaard R, Martinez-Barrios E, Barcos T, Borras A, Peralta S, Guimera M, Goday A, Manau D, Rodriguez-Revenga L. Evaluation of FMR4, FMR5 and FMR6 Expression Levels as Non-Invasive Biomarkers for the Diagnosis of Fragile X-Associated Primary Ovarian Insufficiency (FXPOI). Journal of clinical medicine. 2022; 11(8).

Female FMR1 (Fragile X mental retardation 1) premutation carriers are at risk for developing fragile X-associated primary ovarian insufficiency (FXPOI), a condition characterized by amenorrhea before age 40 years. Not all women with a FMR1 premutation suffer from primary ovarian insufficiency and nowadays there are no molecular or other biomarkers that can help predict the occurrence of FXPOI. Long non-coding RNAs (lncRNAs) comprise a group of regulatory transcripts which have versatile molecular functions, making them important regulators in all aspects of gene expression. In recent medical studies, lncRNAs have been described as potential diagnostic biomarkers in many diseases. The present study was designed to determine the expression profile of three lncRNAs derived from the FMR1 locus, FMR4, FMR5 and FMR6, in female FMR1 premutation carriers in order: (i) to determine a possible role in the pathogenesis of FXPOI and (ii) to investigate whether they could serve as a biomarker for the diagnosis of FXPOI. FMR4, FMR5 and FMR6 transcripts levels were evaluated in total RNA extracted from peripheral blood by digital droplet PCR and compared between FMR1 premutation carriers with FXPOI and without FXPOI. The diagnostic value of lncRNAs was evaluated by receiver operating characteristic (ROC) analysis. Results revealed a significant association between FXPOI and high expression levels of FMR4. No association was obtained for FMR5 or FMR6. ROC curve analysis revealed that FMR4 can distinguish FMR1 premutation carrier with FXPOI with a diagnostic power of 0.67. These findings suggest a potential role of FMR4 as a possible biomarker for FXPOI.

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2. Aspra Q, Cabrera-Mendoza B, Morales-Marín ME, Márquez C, Chicalote C, Ballesteros A, Aguilar M, Castro X, Gómez-Cotero A, Balboa-Verduzco AM, Albores-Gallo L, Nafate-López O, Marcín-Salazar CA, Sánchez P, Lanzagorta-Piñol N, López-Armenta FO, Nicolini H. Epigenome-Wide Analysis Reveals DNA Methylation Alteration in ZFP57 and Its Target RASGFR2 in a Mexican Population Cohort with Autism. Children (Basel, Switzerland). 2022; 9(4).

Autism Spectrum Disorders (ASD) comprise a group of heterogeneous and complex neurodevelopmental disorders. Genetic and environmental factors contribute to ASD etiology. DNA methylation is particularly relevant for ASD due to its mediating role in the complex interaction between genotype and environment and has been implicated in ASD pathophysiology. The lack of diversity in DNA methylation studies in ASD individuals is remarkable. Since genetic and environmental factors are likely to vary across populations, the study of underrepresented populations is necessary to understand the molecular alterations involved in ASD and the risk factors underlying these changes. This study explored genome-wide differences in DNA methylation patterns in buccal epithelium cells between Mexican ASD patients (n = 27) and age-matched typically developing (TD: n = 15) children. DNA methylation profiles were evaluated with the Illumina 450k array. We evaluated the interaction between sex and ASD and found a differentially methylated region (DMR) over the 5’UTR region of ZFP57 and one of its targets, RASGRF2. These results match previous findings in brain tissue, which may indicate that ZFP57 could be used as a proxy for DNA methylation in different tissues. This is the first study performed in a Mexican, and subsequently, Latin American, population that evaluates DNA methylation in ASD patients.

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3. Bernardini N, Skroza N, Marraffa F, Prevete E, Mambrin A, Proietti I, Tolino E, Caviglia M, Di Guardo A, Rossi G, Volpe S, Bersani G, Potenza C. A case of twins affected by psoriasis, psoriatic arthritis and autism: Five years of efficacious and safe treatment with Secukinumab. Dermatologic therapy. 2022: e15533.

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4. Bin Eid W, Lim M, Gabrieli G, Kölbel M, Halstead E, Esposito G, Dimitriou D. Alterations in Cortisol Profiles among Mothers of Children with ASD Related to Poor Child Sleep Quality. Healthcare (Basel, Switzerland). 2022; 10(4).

Caregivers of children with autism spectrum disorder (ASD) experience poorer sleep, but studies have not yet used objective measures to investigate how child and caregiver sleep affect each other. In this study, 29 mothers and their child with ASD aged between 6 and 16 years were recruited. Questionnaires measuring child autism, maternal depression, and maternal and child sleep quality were administered. Cortisol salivary samples were also obtained from the mothers over the course of a day. Results revealed that maternal depression is significantly correlated with their subjective sleep quality, sleep latency and daytime dysfunction. Child sleep quality was also found to be significantly correlated with ASD severity. In terms of maternal cortisol profiles, a significant number of mothers showed a flattened diurnal cortisol expression, and children of mothers with a flattened cortisol profile had significantly more sleep problems. Overall, results suggest that maternal and child sleep are affected by the child’s disability but also are mutually related. Future studies may consider employing measures such as actigraphy or somnography to quantify sleep quality and establish causal pathways between sleep, cortisol expression and caregiver and child outcomes. The present study has clinical implications in examining family sleep when considering treatment for ASD.

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5. Bove M, Schiavone S, Tucci P, Sikora V, Dimonte S, Colia AL, Morgese MG, Trabace L. Ketamine administration in early postnatal life as a tool for mimicking Autism Spectrum Disorders core symptoms. Progress in neuro-psychopharmacology & biological psychiatry. 2022; 117: 110560.

Autism Spectrum Disorders (ASD) core symptoms include deficits of social interaction, stereotyped behaviours, dysfunction in language and communication. Beyond them, several additional symptoms, such as cognitive impairment, anxiety-like states and hyperactivity are often occurring, mainly overlapping with other neuropsychiatric diseases. To untangle mechanisms underlying ASD etiology, and to identify possible pharmacological approaches, different factors, such as environmental, immunological and genetic ones, need to be considered. In this context, ASD animal models, aiming to reproduce the wide range of behavioural phenotypes of this uniquely human disorder, represent a very useful tool. Ketamine administration in early postnatal life of mice has already been studied as a suitable animal model resembling psychotic-like symptoms. Here, we investigated whether ketamine administration, at postnatal days 7, 9 and 11, might induce behavioural features able to mimic ASD typical symptoms in adult mice. To this aim, we developed a 4-days behavioural tests battery, including Marble Burying, Hole Board, Olfactory and Social tests, to assess repetitive and stereotyped behaviour, social deficits and anxiety-like symptoms. Moreover, by using this mouse model, we performed neurochemical and biomolecular analyses, quantifying neurotransmitters belonging to excitatory-inhibitory pathways, such as glutamate, glutamine and gamma-aminobutyric acid (GABA), as well as immune activation biomarkers related to ASD, such as CD11b and glial fibrillary acidic protein (GFAP), in the hippocampus and amygdala. Possible alterations in levels of brain-derived neurotrophic factor (BDNF) expression in the hippocampus and amygdala were also evaluated. Our results showed an increase in stereotyped behaviours, together with social impairments and anxiety-like behaviour in adult mice, receiving ketamine administration in early postnatal life. In addition, we found decreased BDNF and enhanced GFAP hippocampal expression levels, accompanied by elevations in glutamate amount, as well as reduction in GABA content in amygdala and hippocampus. In conclusion, early ketamine administration may represent a suitable animal model of ASD, exhibiting face validity to mimic specific ASD symptoms, such as social deficits, repetitive repertoire and anxiety-like behaviour.

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6. Carli E, Pasini M, Pardossi F, Capotosti I, Narzisi A, Lardani L. Oral Health Preventive Program in Patients with Autism Spectrum Disorder. Children (Basel, Switzerland). 2022; 9(4).

The aim of the study was to evaluate clinical hygienic parameters, patient collaboration, and dental habits in patients with ASD (autism spectrum disorder) before and after a tailored prevention program. A total of 100 patients (78 males and 22 females, mean age 8 ± 0.7 years old) was recruited, with ages ranging from 7 to 16 years old, and diagnoses of ASD. We evaluated the plaque index (IP), gingival index (IG), the dmft/DMFT, the frequency of tooth brushing, and the frequency of snacks for each patient. Patient behaviour was evaluated with the Frankl scale, and each patient was individually reassessed after five visits from the first one by the same operator. The t test was used to compare the parameters before and after the inclusion in the dedicated dental pathway. From T1 to T2 we found a significant improvement of the IP (p < 0.001), IG (p < 0.001), and the frequency of tooth brushing (p < 0.001). Concerning the frequency of snacks and the parameter dmft/DMFT, the differences in the observed averages were not significant (p > 0.05). The difference in collaboration between T1 and T2 evaluated by the Frankl scale was statistically significant (p < 0.001). It was found that the prevention program allowed a significant improvement in both clinical parameters and patient behaviour. The personalized digital supports can have a key role for success in familiarization and desensitization processes of patients affected by ASD, leading an increase in their collaboration.

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7. Carreira LD, Matias FC, Campos MG. Clinical Data on Canabinoids: Translational Research in the Treatment of Autism Spectrum Disorders. Biomedicines. 2022; 10(4).

Translational research made with Cannabis sativa L. and its biocompounds provides data for some targeted diseases, as also symptoms associated with Autism Spectrum Disorders (ASDs). The main compounds ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are capable of modulating the endocannabinoid system since its dysregulation interferes with the pathophysiology of ASDs there are clinical evidence for its potential use in the treatment of the disease. Conventional therapy still has limitations, as it does not always treat the central symptoms, and there are many patients who do not respond to treatment, which demands more research on new therapies. Through the analysis of published literature on this topic, it is verified that cannabinoids, in particular CBD, improves symptoms associated with common comorbidities in ASDs. Some studies also demonstrate the therapeutic potential of these compounds in the treatment of central symptoms of autism. In addition, cannabinoid therapy to ASDs is associated with low adverse effects and a reduction in concomitant medication. Although it appears to be promising, it is essential to do the translation of this data into clinical research and some of its potential and critical gaps are discussed in this review pointing to large-scale and long-term clinical trials that should include more patients and homogeneous samples.

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8. D’Haenens E, Vergult S, Menten B, Dheedene A, Kooy RF, Callewaert B. Expanding the Phenotype of B3GALNT2-Related Disorders. Genes. 2022; 13(4).

Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) that include a broad phenotypic spectrum ranging from late-onset limb-girdle muscular dystrophy to severe muscle-eye-brain disease, Walker-Warburg syndrome, and Fukuyama congenital muscular dystrophy. In addition to clinical heterogeneity, CMDs are characterized by genetic heterogeneity. To date, 18 genes have been associated with CMDs. One of them is B3GALNT2, which encodes the β-1,3-N-acetylgalactosaminyltransferase 2 that glycosylates α-dystroglycan. In this study, using exome sequencing, we identify a homozygous frameshift variant in B3GALNT2 due to a mixed uniparental disomy of chromosome 1 in a 7-year-old girl with global developmental delay, severely delayed active language development, and autism spectrum disorder but without any symptoms of muscular dystrophy. In addition to this case, we also provide an overview of all previously reported cases, further expanding the phenotypic spectrum.

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9. D’Incal C, Broos J, Torfs T, Kooy RF, Vanden Berghe W. Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network. Cells. 2022; 11(8).

Absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) causes autism spectrum disorders and intellectual disability, commonly referred to as the Fragile X syndrome. FMRP is a negative regulator of protein translation and is essential for neuronal development and synapse formation. FMRP is a target for several post-translational modifications (PTMs) such as phosphorylation and methylation, which tightly regulate its cellular functions. Studies have indicated the involvement of FMRP in a multitude of cellular pathways, and an absence of FMRP was shown to affect several neurotransmitter receptors, for example, the GABA receptor and intracellular signaling molecules such as Akt, ERK, mTOR, and GSK3. Interestingly, many of these molecules function as protein kinases or phosphatases and thus are potentially amendable by pharmacological treatment. Several treatments acting on these kinase-phosphatase systems have been shown to be successful in preclinical models; however, they have failed to convincingly show any improvements in clinical trials. In this review, we highlight the different protein kinase and phosphatase studies that have been performed in the Fragile X syndrome. In our opinion, some of the paradoxical study conclusions are potentially due to the lack of insight into integrative kinase signaling networks in the disease. Quantitative proteome analyses have been performed in several models for the FXS to determine global molecular processes in FXS. However, only one phosphoproteomics study has been carried out in Fmr1 knock-out mouse embryonic fibroblasts, and it showed dysfunctional protein kinase and phosphatase signaling hubs in the brain. This suggests that the further use of phosphoproteomics approaches in Fragile X syndrome holds promise for identifying novel targets for kinase inhibitor therapies.

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10. Doddato G, Fabbiani A, Scandurra V, Canitano R, Mencarelli MA, Renieri A, Ariani F. Identification of a Novel SHANK2 Pathogenic Variant in a Patient with a Neurodevelopmental Disorder. Genes. 2022; 13(4).

Genetic defects in the SHANK2 gene, encoding for synaptic scaffolding protein, are associated with a variety of neurodevelopmental conditions, including autism spectrum disorders and mild to moderate intellectual disability. Until now, limited patient clinical descriptions have been published. Only 13 unrelated patients with SHANK2 pathogenic variations or microdeletions have been reported worldwide. By Exome Sequencing, we identified a de novo stop-gain variant, c.334C>T, p.(Gln112*), in an Italian patient with a neurodevelopmental disorder. The patient (9 years old) presented the following facial features: a flat profile, thick eyebrows, long eyelashes, a bulbous nasal tip and a prominent columella, retracted ears, dental anomalies. The patient showed speech delay and mild neuromotor delay but not autism spectrum disorder. In conclusion, this patient with a novel pathogenic variant in SHANK2 enlarges the phenotypic spectrum of SHANK2-mutated patients and demonstrates that the severity of SHANK2-associated disorders is highly variable.

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11. Falcone N, Ranieri A, Vitale A, Pastore L, Lombardo B. Identification of a De Novo Deletion by Using A-CGH Involving PLNAX2: An Interesting Candidate Gene in Psychomotor Developmental Delay. Medicina (Kaunas, Lithuania). 2022; 58(4).

Psychomotor developmental delay is a disorder with a prevalence of 12-18% in the pediatric population, characterized by the non-acquisition of motor, cognitive and communication skills during the child’s development, in relation to chronological age. An appropriate neuropsychomotor evaluation and the use of new technologies, such as Array Comparative Genomic Hybridization (a-CGH) and Next-generation sequencing (NGS), can contribute to early diagnosis and improving the quality of life. In this case, we have analyzed a boy aged 2 years and 8 months, with a diagnosis of psychomotor developmental delay, mainly in the area of communication and language. The a-CGH analysis identified three de novo deletions of uncertain clinical significance, involving PLXNA2 (1q32.2), PRELID2, GRXCR2 and SH3RF2 (5q32), RIMS1 (6q13), and a heterozygous duplication of maternal origin involved three genes: HELZ, PSMD12 and PITPNC1 (17q24.2). Among all these alterations, our attention focused on the PLXNA2 gene because of the central function that plexin 2 carries out in the development of the central nervous system. However, all genes detected in the analysis could contribute to the phenotypic characteristics of the patient.

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12. Hajdúk M, Pinkham AE, Penn DL, Harvey PD, Sasson NJ. Heterogeneity of social cognitive performance in autism and schizophrenia. Autism research : official journal of the International Society for Autism Research. 2022.

Autistic adults and those with schizophrenia (SCZ) demonstrate similar levels of reduced social cognitive performance at the group level, but it is unclear whether these patterns are relatively consistent or highly variable within and between the two conditions. Seventy-two adults with SCZ (52 male, M(age) = 28.2 years) and 94 with diagnoses on the autism spectrum (83 male, M(age) = 24.2 years) without intellectual disability completed a comprehensive social cognitive battery. Latent profile analysis identified four homogeneous subgroups that were compared on their diagnosis, independent living skills, neurocognition, and symptomatology. Two groups showed normative performance across most social cognitive tasks but were differentiated by one having significantly higher hostility and blaming biases. Autistic participants were more likely to demonstrate fully normative performance (46.8%) than participants with SCZ, whereas normative performance in SCZ was more likely to co-occur with increased hostility and blaming biases (36.1%). Approximately 43% of participants in the full sample were classified into the remaining two groups showing low or very low performance. These participants tended to perform worse on neurocognitive tests and have lower IQ and fewer independent living skills. The prevalence of low performance on social cognitive tasks was comparable across clinical groups. However, nearly half of autistic participants demonstrated normative social cognitive performance, challenging assumptions that reduced social cognitive performance is inherent to the condition. Subgrouping also revealed a meaningful distinction between the clinical groups: participants with SCZ were more likely to demonstrate hostility biases than autistic participants, even when social cognitive performance was otherwise in the typical range. LAY SUMMARY: Social cognition refers to the perception and interpretation of social information. Previous research has shown that both autistic people and those with schizophrenia demonstrate reduced performance on traditional social cognitive tasks, which we replicate here at the group level. However, we also found that almost half of autistic participants performed in the normal range. Over a third of participants with schizophrenia did as well, but for them this performance was accompanied by a hostility bias not commonly found in the autistic sample. Taken together, findings challenge assumptions that difficulties in social cognition are a uniform characteristic of these clinical conditions in those without intellectual disability.

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13. Idris S, van Pelt BJ, Jagersma G, Duvekot J, Maras A, van der Ende J, van Haren N, Greaves-Lord K. A randomized controlled trial to examine the effectiveness of the Dutch version of the Program for the Education and Enrichment of Relational Skills (PEERS®). BMC psychiatry. 2022; 22(1): 293.

BACKGROUND: This study examines the effectiveness of the culturally adapted Dutch version of The Program for the Education and Enrichment of Relational Skills (PEERS®), utilizing a randomized control trial (RCT) with an active treatment control condition. METHODS: 106 adolescents with ASD, aged 12-18 years, were randomly assigned to one of two group interventions: the experimental condition (PEERS®; n = 54) or the active treatment control condition (Regulation, Organization and Autonomy Didactics; ROAD; n = 52). Effects of interventions on social skills were primarily assessed using an observational measure (CASS – Contextual Assessment Social Skills). Secondary indices of social skills were self, parent and teacher reported questionnaire data (i.e., Social Responsiveness Scale; SRS, and Social Skills Improvement System; SSIS). Treatment satisfaction was also obtained from adolescents and their parents. RESULTS: Results on the observational measure of social skills revealed improvements in positive affect, overall quality of rapport, as well as starting and ending a conversation, irrespective of condition. Compared to ROAD, PEERS® participants showed increased overall self-reported social skills (SSIS). Parent reports showed decreased overall social skill impairment (SRS) as well as improved social communication (SSIS subscale), with significantly more progress in the PEERS® group. Furthermore, parents of adolescents in the PEERS® group were significantly more satisfied with the intervention (M = 8.20, SD = 1.46) than parents of adolescents in the ROAD group (M = 7.52, SD = 1.45). The self-reported treatment satisfaction of adolescents did not differ between conditions. Teacher data showed decreased social skill impairment as measured with the SRS, irrespective of condition. CONCLUSIONS: This study reveals promising indications that the Dutch version of PEERS® enhances social skills in adolescents with ASD. Yet, further research is needed into how effectiveness can be optimized. TRIAL REGISTRATION: Dutch trail register NTR6255 (NL6117) 08/02/2017 https://www.trialregister.nl/trial/6117.

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14. Isaac J, Jeremias D, Rocha Almeida C, Albuquerque R. Beyond what clinicians see: missed diagnosis and misdiagnosis of a woman with autism spectrum disorder. BMJ case reports. 2022; 15(4).

A young woman with autism spectrum disorder was admitted to the hospital via the emergency care unit. On being admitted, she was improperly diagnosed with a psychotic disorder due to her erratic behaviour and incomprehensible refusal to eat. As a result, the patient was hospitalised against her will. For accurate and correct diagnosis and treatment, it was necessary to collect the patient’s detailed clinical history, while being hospitalised.

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15. Ji C, Yang J, Lin L, Chen S. Executive Function Improvement for Children with Autism Spectrum Disorder: A Comparative Study between Virtual Training and Physical Exercise Methods. Children (Basel, Switzerland). 2022; 9(4).

This study evaluated and compared the effects of virtual training and physical exercise on the executive function of children with autism spectrum disorder (ASD). After screening, the final analysis of this study was conducted on three groups: a virtual training group (n = 34), a physical exercise group (n = 33), and a control group (n = 33). The experiment was conducted for nine weeks, of which the virtual training group and physical exercise group were conducted three times a week for one hour each time during the first six weeks, while the control group did not conduct virtual training nor physical exercise. During the last three weeks (week 6 to week 9), virtual training and physical exercise were not performed on all three groups. The three main components of executive function (working memory, inhibition, flexibility) of children with ASD were measured before the intervention, after the intervention (week 1 to week 6) and in the last three weeks (week 6 to week 9). The final results are that firstly, the executive function of the virtual training and physical exercise groups were simultaneously improved after the intervention. Secondly, after the intervention stopped, the executive function of the virtual training and physical exercise groups showed a downward trend. Therefore, the study concludes that the application of virtual training and physical exercise can effectively enhance the executive function of children with ASD.

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16. Ji Y, Chen R, Wang Q, Wei Q, Tao R, Li B. A Bayesian framework to integrate multi-level genome-scale data for Autism risk gene prioritization. BMC bioinformatics. 2022; 23(1): 146.

BACKGROUND: Autism spectrum disorder (ASD) is a group of complex neurodevelopment disorders with a strong genetic basis. Large scale sequencing studies have identified over one hundred ASD risk genes. Nevertheless, the vast majority of ASD risk genes remain to be discovered, as it is estimated that more than 1000 genes are likely to be involved in ASD risk. Prioritization of risk genes is an effective strategy to increase the power of identifying novel risk genes in genetics studies of ASD. As ASD risk genes are likely to exhibit distinct properties from multiple angles, we reason that integrating multiple levels of genomic data is a powerful approach to pinpoint genuine ASD risk genes. RESULTS: We present BNScore, a Bayesian model selection framework to probabilistically prioritize ASD risk genes through explicitly integrating evidence from sequencing-identified ASD genes, biological annotations, and gene functional network. We demonstrate the validity of our approach and its improved performance over existing methods by examining the resulting top candidate ASD risk genes against sets of high-confidence benchmark genes and large-scale ASD genome-wide association studies. We assess the tissue-, cell type- and development stage-specific expression properties of top prioritized genes, and find strong expression specificity in brain tissues, striatal medium spiny neurons, and fetal developmental stages. CONCLUSIONS: In summary, we show that by integrating sequencing findings, functional annotation profiles, and gene-gene functional network, our proposed BNScore provides competitive performance compared to current state-of-the-art methods in prioritizing ASD genes. Our method offers a general and flexible strategy to risk gene prioritization that can potentially be applied to other complex traits as well.

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17. Karpur A, Vasudevan V, Frazier TW, Shih AJ. Food insecurity in households of children with ASD in COVID-19 pandemic: A comparative analysis with the Household Pulse Survey data using stabilized inverse probability treatment weights. Disability and health journal. 2022: 101323.

BACKGROUND: Before the COVID-19 pandemic, households of children on the autism spectrum were more likely to be food insecure than households of children without disabilities. With the unprecedented social, public health, and economic disruption caused by the pandemic, food insecurity has likely increased among families of children on the autism spectrum. OBJECTIVE: This analysis aims to compare the prevalence of food insecurity between [Author’s organization] survey administered during the Fall of 2020 and a nationally representative sample from the Household Pulse Survey (HPS) data collected during a similar timeframe. METHODS: A propensity score analysis was utilized to create stabilized inverse probability treatment weights for adjusting background differences between the two groups. A logistic regression model was computed to estimate the odds of food insecurity in the [Author’s organization] survey participants compared with those in the HPS data. RESULTS: After adjusting for background differences, households of children on the autism spectrum in the [Author’s organization] survey were about four times more likely to be food insecure than households in the general population contained in the HPS data (OR = 3.7; 95% CI: 3.1-4.4). CONCLUSIONS: The breakdown of social and economic supports during the COVID-19 pandemic contributed to a significantly higher likelihood of food insecurity among families of children on the autism spectrum.

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18. Kong Q, Chen Q, Mao X, Wang G, Zhao J, Zhang H, Chen W. Bifidobacterium longum CCFM1077 Ameliorated Neurotransmitter Disorder and Neuroinflammation Closely Linked to Regulation in the Kynurenine Pathway of Autistic-like Rats. Nutrients. 2022; 14(8).

The kynurenine pathway (KP) is abnormal in autistic patients and model animals. According to studies on the brain-gut axis, probiotics can help ameliorate the metabolic abnormalities of the KP in patients and model animals with neurological diseases. This study was aimed at evaluating the ability of Bifidobacterium longum (B. longum) CCFM077 to enhance the gut microbiome and KP metabolism and regulate the neurotransmitter levels and neuroinflammation of autistic rats. The KP metabolism of autistic rats was significantly disordered and significantly related to the regulation of neurotransmitter (excitation and inhibition) and neuroglia states. B. longum CCFM1077 could effectively alleviate autistic-like behaviours (repetitive stereotyped behaviour, learning and memory ability, and despair mood) and regulate the KP metabolism in the periphery system (gut and blood) and brain. In particular, B. longum CCFM1077 could significant regulate the quinolinic acid (QUIN) level in the brain and markedly regulate glutamic acid (Glu) and Glu/γ-aminobutyric acid (GABA) levels in the brain while alleviating microglia activity in the cerebellum. Through a correlation analysis, the QUIN level in the brain was strongly related with autistic-like behaviours and neurotransmitter levels (GABA and Glu). The QUIN level may thus be a potential therapeutic marker for treating autism through the intestinal and neural pathways.

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19. Kreysa H, Schneider D, Kowallik AE, Dastgheib SS, Doğdu C, Kühn G, Ruttloff JM, Schweinberger SR. Psychosocial and Behavioral Effects of the COVID-19 Pandemic on Children and Adolescents with Autism and Their Families: Overview of the Literature and Initial Data from a Multinational Online Survey. Healthcare (Basel, Switzerland). 2022; 10(4).

Since COVID-19 has become a pandemic, everyday life has seen dramatic changes affecting individuals, families, and children with and without autism. Among other things, these changes entail more time at home, digital forms of communication, school closures, and reduced support and intervention. Here, we assess the effects of the pandemic on quality of life for school-age autistic and neurotypical children and adolescents. First, we provide a comprehensive review of the current relevant literature. Next, we report original data from a survey conducted in several countries, assessing activities, well-being, and social life in families with autism, and their changes over time. We focus on differences between children with and without autism from within the same families, and on different outcomes for children with high- or low-functioning autism. While individuals with autism scored lower in emotional and social functioning than their neurotypical siblings, both groups of children showed comparable decreases in well-being and increases in anxiety, compared to before the pandemic. By contrast, decreases in adaptability were significantly more pronounced in autistic children and adolescents compared to neurotypical children and adolescents. Overall, although individual families reported some positive effects of pandemic restrictions, our data provide no evidence that these generalize across children and adolescents with autism, or even just to individuals with high-functioning autism. We discuss the increased challenges that need to be addressed to protect children and adolescents’ well-being under pandemic conditions, but also point out potentials in the present situation that could be used towards social participation and success in older children and young adults with autism.

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20. Li DJ, Tsai CS, Hsiao RC, Chen YL, Yen CF. Associations between Allergic and Autoimmune Diseases with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder within Families: A Population-Based Cohort Study. International journal of environmental research and public health. 2022; 19(8).

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are commonly comorbid with allergic and autoimmune diseases in children. The aim of the current study was to investigate the association between children’s and first-degree relatives’ (i.e., mother, father, and full sibling) allergic and autoimmune diseases and children’s ASD and ADHD. We enrolled participants from Taiwan’s Maternal and Child Health Database. We used the Cox regression model to examine the associations of familial, siblings’ and children’s allergic and autoimmune diseases with children’s ASD and/or ADHD. In total, we included 1,386,260 children in the current study. We found the significant association between familial allergic or autoimmune disease and development of ASD or ADHD among children. We also identified the predominant impact of familial aggregation on the above associations. The associations between some parental diagnoses of autoimmune or allergic diseases in children’s ASD and/or ADHD were stronger in mothers than those in fathers. Early assessment of the possibility of ASD and ADHD is required for children who have a parent with an allergic or autoimmune disease.

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21. MacFarlane H, Salem AC, Chen L, Asgari M, Fombonne E. Combining voice and language features improves automated autism detection. Autism research : official journal of the International Society for Autism Research. 2022.

Variability in expressive and receptive language, difficulty with pragmatic language, and prosodic difficulties are all features of autism spectrum disorder (ASD). Quantifying language and voice characteristics is an important step for measuring outcomes for autistic people, yet clinical measurement is cumbersome and costly. Using natural language processing (NLP) methods and a harmonic model of speech, we analyzed language transcripts and audio recordings to automatically classify individuals as ASD or non-ASD. One-hundred fifty-eight participants (88 ASD, 70 non-ASD) ages 7 to 17 were evaluated with the autism diagnostic observation schedule (ADOS-2), module 3. The ADOS-2 was transcribed following modified SALT guidelines. Seven automated language measures (ALMs) and 10 automated voice measures (AVMs) for each participant were generated from the transcripts and audio of one ADOS-2 task. The measures were analyzed using support vector machine (SVM; a binary classifier) and receiver operating characteristic (ROC). The AVM model resulted in an ROC area under the curve (AUC) of 0.7800, the ALM model an AUC of 0.8748, and the combined model a significantly improved AUC of 0.9205. The ALM model better detected ASD participants who were younger and had lower language skills and shorter activity time. ASD participants detected by the AVM model had better language profiles than those detected by the language model. In combination, automated measurement of language and voice characteristics successfully differentiated children with and without autism. This methodology could help design robust outcome measures for future research. LAY SUMMARY: People with autism often struggle with communication differences which traditional clinical measures and language tests cannot fully capture. Using language transcripts and audio recordings from 158 children ages 7 to 17, we showed that automated, objective language and voice measurements successfully predict the child’s diagnosis. This methodology could help design improved outcome measures for research.

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22. Marcotulli D, Davico C, Somà A, Teghille G, Ravaglia G, Amianto F, Ricci F, Puccinelli MP, Spada M, Vitiello B. Association between EEG Paroxysmal Abnormalities and Levels of Plasma Amino Acids and Urinary Organic Acids in Children with Autism Spectrum Disorder. Children (Basel, Switzerland). 2022; 9(4).

Abnormalities in the plasma amino acid and/or urinary organic acid profile have been reported in autism spectrum disorder (ASD). An imbalance between excitatory and inhibitory neuronal activity has been proposed as a mechanism to explain dysfunctional brain networks in ASD, as also suggested by the increased risk of epilepsy in this disorder. This study explored the possible association between presence of EEG paroxysmal abnormalities and the metabolic profile of plasma amino acids and urinary organic acids in children with ASD. In a sample of 55 children with ASD (81.8% male, mean age 53.67 months), EEGs were recorded, and 24 plasma amino acids and 56 urinary organic acids analyzed. EEG epileptiform discharges were found in 36 (65%) children. A LASSO regression, adjusted by age and sex, was applied to evaluate the association of plasma amino acids and urinary organic acids profiles with the presence of EEG epileptiform discharges. Plasma levels of threonine (THR) (coefficient = -0.02, p = 0.04) and urinary concentration of 3-Hydroxy-3-Methylglutaric acid (HMGA) (coefficient = 0.04, p = 0.02) were found to be associated with the presence of epileptiform discharges. These results suggest that altered redox mechanisms might be linked to epileptiform brain activity in ASD.

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23. Matsushima K, Matsubayashi J, Toichi M, Funabiki Y, Kato T, Awaya T, Tsuchida R, Kato T. Atypical Physiological Response to Less Controllable Sensory Stimulation in Children with ASD. Research on child and adolescent psychopathology. 2022.

Atypical sensory features are frequently observed in individuals with autism spectrum disorder (ASD) as uncontrollable and less predictable sensory stimuli are thought to be stressful for them. To quantify distal indicators of cardiac vagus nerve activity, which is associated with top-down self-regulatory capacity, during sensory tasks as a stress state in children with ASD, we conducted an exploratory study to measure phasic high-frequency components of heart rate variability (phasic HF-HRV) during less controllable tactile/auditory sensory tasks in 37 children with ASD (aged 6-12 years) and 37 typically developing (TD) children. Only children with ASD showed increased HF-HRV values from the resting state to the task (i.e., phasic HF-HRV augmentation) during both less controllable tactile/auditory sensory tasks. In TD children, decreased phasic HF-HRV values were observed to cope with the task demand during the less-controllable-tactile task. These findings suggest that increased phasic HF-HRV values in response to less controllable sensory stimuli may reflect atypical physiological regulation during sensory stimulation in children with ASD.

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24. Montagut-Asunción M, Crespo-Martín S, Pastor-Cerezuela G, D’Ocon-Giménez A. Joint Attention and Its Relationship with Autism Risk Markers at 18 Months of Age. Children (Basel, Switzerland). 2022; 9(4).

(1) Joint attention is the ability to coordinate attention to share a point of reference with another person. It has an early onset and is a clear indicator of understanding the representations of others, and it is essential in the development of symbolic thought and the acquisition of language. Deficiencies in this prelinguistic early communication skill are strong markers of the risk of autism spectrum disorder (ASD); (2) this longitudinal study aimed to evaluate joint attention skills in a group of 32 infants at two developmental moments (8 and 12 months) in order to explore whether their performance on this skill was related to the presence of early signs of ASD at 18 months. Logistic multiple regressions were carried out for the data analysis; (3) results of the analysis showed that the variables of initiating joint attention at 8 months and responding to joint attention at 12 months were linked to the risk of ASD at 18 months of age; (4) in conclusion, early joint attention skills had a pivotal role in defining early manifestations of ASD.

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25. Neklyudova A, Smirnov K, Rebreikina A, Martynova O, Sysoeva O. Electrophysiological and Behavioral Evidence for Hyper- and Hyposensitivity in Rare Genetic Syndromes Associated with Autism. Genes. 2022; 13(4).

Our study reviewed abnormalities in spontaneous, as well as event-related, brain activity in syndromes with a known genetic underpinning that are associated with autistic symptomatology. Based on behavioral and neurophysiological evidence, we tentatively subdivided the syndromes on primarily hyper-sensitive (Fragile X, Angelman) and hypo-sensitive (Phelan-McDermid, Rett, Tuberous Sclerosis, Neurofibromatosis 1), pointing to the way of segregation of heterogeneous idiopathic ASD, that includes both hyper-sensitive and hypo-sensitive individuals. This segmentation links abnormalities in different genes, such as FMR1, UBE3A, GABRB3, GABRA5, GABRG3, SHANK3, MECP2, TSC1, TSC2, and NF1, that are causative to the above-mentioned syndromes and associated with synaptic transmission and cell growth, as well as with translational and transcriptional regulation and with sensory sensitivity. Excitation/inhibition imbalance related to GABAergic signaling, and the interplay of tonic and phasic inhibition in different brain regions might underlie this relationship. However, more research is needed. As most genetic syndromes are very rare, future investigations in this field will benefit from multi-site collaboration with a common protocol for electrophysiological and event-related potential (EEG/ERP) research that should include an investigation into all modalities and stages of sensory processing, as well as potential biomarkers of GABAergic signaling (such as 40-Hz ASSR).

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26. Ranieri A, Veneruso I, La Monica I, Pascale MG, Pastore L, D’Argenio V, Lombardo B. Combined aCGH and Exome Sequencing Analysis Improves Autism Spectrum Disorders Diagnosis: A Case Report. Medicina (Kaunas, Lithuania). 2022; 58(4).

Background and Objectives: The development and standardization of genome-wide technologies able to carry out high-resolution, genomic analyses in a cost- and time-affordable way is increasing our knowledge regarding the molecular bases of complex diseases like autism spectrum disorder (ASD). ASD is a group of heterogeneous diseases with multifactorial origins. Genetic factors seem to be involved, albeit they remain still largely unknown. Here, we report the case of a child with a clinical suspicion of ASD investigated by using such a genomic high-resolution approach. Materials and Methods: Both array comparative genomic hybridization (aCGH) and exome sequencing were carried out on the family trio. aCGH was performed using the 4 × 180 K SurePrint G3 Human CGH Microarray, while the Human All Exon V7 targeted SureSelect XT HS panel was used for exome sequencing. Results: aCGH identified a paternally inherited duplication of chromosome 7 involving the CNTNAP2 gene, while 5 potentially clinically-relevant variants were identified by exome sequencing. Conclusions: Within the identified genomic alterations, the CNTNAP2 gene duplication may be related to the patient’s phenotype. Indeed, this gene has already been associated with brain development and cognitive functions, including language. The paternal origin of the alteration cannot exclude an incomplete penetrance. Moreover, other genomic factors may act as phenotype modifiers combined with CNTNAP2 gene duplication. Thus, the case reported herein strongly reinforces the need to use extensive genomic analyses to shed light on the bases of complex diseases.

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27. Samadi SA, McConkey R, Nuri H, Abdullah A, Ahmad L, Abdalla B, Biçak CA. Screening Children for Autism Spectrum Disorders in Low- and Middle-Income Countries: Experiences from the Kurdistan Region of Iraq. International journal of environmental research and public health. 2022; 19(8).

Screening tools for the early identification of developmental disabilities are strongly advised, yet culturally valid tools are not readily available for use in low- and middle-income countries. The present study describes the context and the processes used to develop a suitable screening procedure for use in the Kurdistan region of Iraq. This was based on an autism rating scale-GARS-3-developed in the USA for use primarily with children’s parents. It was administered to three groups of children: those with a pre-existing diagnosis of ASD; those with a confirmed diagnosis of a developmental disability; and those who were typically developing-735 participants in all. The 10 items from the 58 items in the full GARS-3 scale that best discriminated the three groups of children were identified. Subsequent analysis confirmed that the ten-item summary scores had reasonable internal reliabilities, with a good specificity and sensitivity in distinguishing children with ASD from those that were typically developing but less so for children with other developmental disabilities. The study confirms the universality of autism symptoms but also the different emphasis Kurdish parents may place on them. Nevertheless, screening procedures need to be developed in the context of support services that can undertake follow-up diagnostic assessments and provide suitable interventions for use by parents to promote their child’s development. The study provides an example of how this can be possible in low- and middle-income countries.

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28. Santos-Terra J, Deckmann I, Carello-Collar G, Nunes GD, Bauer-Negrini G, Schwingel GB, Fontes-Dutra M, Riesgo R, Gottfried C. Resveratrol Prevents Cytoarchitectural and Interneuronal Alterations in the Valproic Acid Rat Model of Autism. International journal of molecular sciences. 2022; 23(8).

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by several alterations, including disorganized brain cytoarchitecture and excitatory/inhibitory (E/I) imbalance. We aimed to analyze aspects associated with the inhibitory components in ASD, using bioinformatics to develop notions about embryonic life and tissue analysis for postnatal life. We analyzed microarray and RNAseq datasets of embryos from different ASD models, demonstrating that regions involved in neuronal development are affected. We evaluated the effect of prenatal treatment with resveratrol (RSV) on the neuronal organization and quantity of parvalbumin-positive (PV+), somatostatin-positive (SOM+), and calbindin-positive (CB+) GABAergic interneurons, besides the levels of synaptic proteins and GABA receptors in the medial prefrontal cortex (mPFC) and hippocampus (HC) of the ASD model induced by valproic acid (VPA). VPA increased the total number of neurons in the mPFC, while it reduced the number of SOM+ neurons, as well as the proportion of SOM+, PV+, and CB+ neurons (subregion-specific manner), with preventive effects of RSV. In summary, metabolic alterations or gene expression impairments could be induced by VPA, leading to extensive damage in the late developmental stages. By contrast, due to its antioxidant, neuroprotective, and opposite action on histone properties, RSV may avoid damages induced by VPA.

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29. Stafford CF, Sanchez-Lara PA. Impact of Genetic and Genomic Testing on the Clinical Management of Patients with Autism Spectrum Disorder. Genes. 2022; 13(4).

Research has shown that genetics play a key role in the development of autism spectrum disorder (ASD). ASD has been linked to many genes and is a prominent feature in numerous genetic disorders. A genetic evaluation should be offered to any patient who receives a diagnosis of ASD, including deep phenotyping and genetic testing when clinically indicated. When insurance does not cover genetic testing for ASD patients, the lack of medical utility is often cited as a reason for prior authorization request denial. However, ample evidence exists that genetic testing has the power to change clinical management in many of these patients. Genetic testing that results in a diagnosis guides clinicians to screen for associated medical conditions and can direct targeted medical interventions. Given the potential for clinically actionable results, it is important that genetic testing be available and accessible to all patients with ASD.

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30. Steinkellner H, Kempaiah P, Beribisky AV, Pferschy S, Etzler J, Huber A, Sarne V, Neuhaus W, Kuttke M, Bauer J, Arunachalam JP, Christodoulou J, Dressel R, Mildner A, Prinz M, Laccone F. TAT-MeCP2 protein variants rescue disease phenotypes in human and mouse models of Rett syndrome. International journal of biological macromolecules. 2022; 209(Pt A): 972-83.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by pathogenic variants leading to functional impairment of the MeCP2 protein. Here, we used purified recombinant MeCP2e1 and MeCP2e2 protein variants fused to a TAT protein transduction domain (PTD) to evaluate their transduction ability into RTT patient-derived fibroblasts and the ability to carry out their cellular function. We then assessed their transduction ability and therapeutic effects in a RTT mouse model. In vitro, TAT-MeCP2e2-eGFP reversed the pathological hyperacetylation of histones H3K9 and H4K16, a hallmark of abolition of MeCP2 function. In vivo, intraperitoneal administration of TAT-MeCP2e1 and TAT-MeCP2e2 extended the lifespan of Mecp2(-/y) mice by >50%. This was accompanied by rescue of hippocampal CA2 neuron size in animals treated with TAT-MeCP2e1. Taken together, these findings provide a strong indication that recombinant TAT-MeCP2 can reach mouse brains following peripheral injection and can ameliorate the phenotype of RTT mouse models. Thus, our study serves as a first step in the development of a potentially novel RTT therapy.

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31. Vallogini G, Festa P, Matarazzo G, Gentile T, Garret-Bernardin A, Zanette G, Galeotti A. Conscious Sedation in Dentistry for the Management of Pediatric Patients with Autism: A Narrative Review of the Literature. Children (Basel, Switzerland). 2022; 9(4).

(1) Background: the variety of autism spectrum disorder makes the definition of guidelines for dental care a challenging task. The aim of this review was to evaluate the literature concerning the use of conscious sedation for dental treatments in pediatric autistic patients. (2) Methods: we searched MEDLINE/PubMed, EMBASE, Cochrane databases in order to identify pertinent studies. The search strategy was based on these areas of interest: autistic spectrum disorder, pediatric patients, dentistry, tranquilizing agents, and conscious sedation. (3) Results: the search yielded 177 non-duplicated articles, of which 24 articles were retrieved for full text review, and 2 were found to address our review aim. The first paper was a retrospective study that included 83 autistic patients sedated either with an oral premedication combined with nitrous oxide/oxygen inhalation or with nitrous oxide/oxygen inhalation alone; the second article was a prospective trial on the effectiveness of 0.3 mg/kg of oral diazepam with 0.5 mg/kg of oral midazolam in 13 sedated uncooperative autistic patients. (4) Conclusions: this review highlights the insufficiency of studies that can provide concrete indications for the dental treatment in conscious sedation of pediatric patients with autism. New studies are needed to better define the appropriate drugs, dosages, sedation level and evaluate patient cooperation.

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32. Wallis KE, Nekrasova E, Bennett AE, Fiks AG, Gerdes M, Jenssen BP, Miller JS, Shu D, Guthrie W. Autism Spectrum Disorder Screening during the COVID-19 Pandemic in a Large Primary Care Network. Academic pediatrics. 2022.

OBJECTIVE: To assess the impact of the COVID-19 pandemic on screening for autism spectrum disorder (ASD) and screening equity among eligible children presenting for well-child care in a large primary care pediatric network, we compared rates of ASD screening completion and positivity during the pandemic to the year prior, stratified by socio-demographic factors. METHODS: Patients who presented for in-person well-child care at 16-26 months between 3/1/2020 and 2/28/2021 (COVID-19 cohort, n=24,549) were compared to those who presented between 3/1/2019 and 2/29/2020 (pre-COVID-19 cohort, n= 26,779). Demographics and rates of completion and positivity of the Modified Checklist for Autism in Toddlers with Follow-up (M-CHAT/F) were calculated from the electronic health record (EHR) and compared by cohort using logistic regression models. RESULTS: Total eligible visits decreased by 8.3% between cohorts, with a greater decline in Black and publicly insured children. In the pre-COVID-19 cohort, 89.0% of eligible children were screened at least once, compared to 86.4% during the pandemic (p<0.001). Significant declines in screening completion were observed across all socio-demographic groups except among Asian children, with the sharpest declines among non-Hispanic White children. Socio-demographic differences were not observed in screen-positive rates by cohort. CONCLUSIONS: Well-child visits and ASD screenings declined across groups, but with different patterns by race and ethnicity during the COVID-19 pandemic. Findings regarding screen-completion rates should not be interpreted as a decline in screening disparities, given differences in who presented for care. Strategies for catch-up screening for all children should be considered.

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33. Westmark CJ, Filon MJ, Maina P, Steinberg LI, Ikonomidou C, Westmark PR. Effects of Soy-Based Infant Formula on Weight Gain and Neurodevelopment in an Autism Mouse Model. Cells. 2022; 11(8).

Mice fed soy-based diets exhibit increased weight gain compared to mice fed casein-based diets, and the effects are more pronounced in a model of fragile X syndrome (FXS; Fmr1(KO)). FXS is a neurodevelopmental disability characterized by intellectual impairment, seizures, autistic behavior, anxiety, and obesity. Here, we analyzed body weight as a function of mouse age, diet, and genotype to determine the effect of diet (soy, casein, and grain-based) on weight gain. We also assessed plasma protein biomarker expression and behavior in response to diet. Juvenile Fmr1(KO) mice fed a soy protein-based rodent chow throughout gestation and postnatal development exhibit increased weight gain compared to mice fed a casein-based purified ingredient diet or grain-based, low phytoestrogen chow. Adolescent and adult Fmr1(KO) mice fed a soy-based infant formula diet exhibited increased weight gain compared to reference diets. Increased body mass was due to increased lean mass. Wild-type male mice fed soy-based infant formula exhibited increased learning in a passive avoidance paradigm, and Fmr1(KO) male mice had a deficit in nest building. Thus, at the systems level, consumption of soy-based diets increases weight gain and affects behavior. At the molecular level, a soy-based infant formula diet was associated with altered expression of numerous plasma proteins, including the adipose hormone leptin and the β-amyloid degrading enzyme neprilysin. In conclusion, single-source, soy-based diets may contribute to the development of obesity and the exacerbation of neurological phenotypes in developmental disabilities, such as FXS.

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