1. Adrien JL, Taupiac E, Thiébaut E, Paulais MA, Van-Gils J, Kaye K, Blanc R, Gattegno MP, Contejean Y, Michel G, Dean A, Barthélémy C, Lacombe D. A comparative study of cognitive and socio-emotional development in children with Rubinstein-Taybi syndrome and children with Autism Spectrum Disorder associated with a severe intellectual disability, and in young typically developing children with matched developmental ages. Research in developmental disabilities. 2021; 116: 104029.

BACKGROUND: Cognitive and socio-emotional profiles of children with CREBBP-related Rubinstein-Taybi syndrome (RSTS 1), children with Autism Spectrum Disorder (ASD) with severe intellectual disability and developmental ages (DA) under 24 months, and typically developing (TD) children with similar DA were compared. PARTICIPANTS: Thirty-one children with RSTS 1 (mean chronological age, CA = 59,8 months; 33-87) and thirty children with ASD, matched on CA and DA and developmental quotients (DQ), were compared to thirty TD children (CA ranged from 12 to 24 months). METHODS: Cognitive and socio-emotional developmental levels, DA and DQ were assessed with appropriated tests. RESULTS: More socio-emotional developmental similarities were observed between TD and RSTS 1 than between TD and ASD children. Clinical groups displayed similar developmental delays in cognitive (self-image, symbolic play, means-ends, and object permanence) and socio-emotional domains (language and imitation). Children with RSTS 1 exhibited higher developmental levels in behavior regulation, joint attention, affective relations, emotional expression domains, and a lower developmental level in spatial relations domain. CONCLUSIONS: Common interventions centered on symbolic play, self-image, language, and imitation for both clinical groups, and differentiated interventions centered on spatial abilities for RSTS 1 children and on social abilities for ASD could be used by caregivers were suggested.

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2. Borie AM, Theofanopoulou C, Andari E. The promiscuity of the oxytocin-vasopressin systems and their involvement in autism spectrum disorder. Handbook of clinical neurology. 2021; 182: 121-40.

Oxytocin and vasopressin systems have been studied separately in autism spectrum disorder (ASD). Here, we provide evidence from an evolutionary and neuroscience perspective about the shared mechanisms and the common roles in regulating social behaviors. We first discuss findings on the evolutionary history of oxytocin and vasopressin ligands and receptors that highlight their common origin and clarify the evolutionary background of the crosstalk between them. Second, we conducted a comprehensive review of the increasing evidence for the role of both neuropeptides in regulating social behaviors. Third, we reviewed the growing evidence on the associations between the oxytocin/vasopressin systems and ASD, which includes oxytocin and vasopressin dysfunction in animal models of autism and in human patients, and the impact of treatments targeting the oxytocin or the vasopressin systems in children and in adults. Here, we highlight the potential of targeting the oxytocin/vasopressin systems to improve social deficits observed in ASD and the need for further investigations on how to transfer these research innovations into clinical applications.

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3. Chien YL, Chen YC, Gau SS. Altered cingulate structures and the associations with social awareness deficits and CNTNAP2 gene in autism spectrum disorder. NeuroImage Clinical. 2021; 31: 102729.

BACKGROUNDS: Although evidence suggests that the activity of the anterior cingulate cortex involves social cognition, there are inconsistent findings regarding the aberrant cingulate gray matter (GM) and scanty evidence about altered cortical thickness and white matter (WM) of cingulate in individuals with autism spectrum disorder (ASD). Evidence supports the association between the genetic variants of CNTNAP2 and altered brain connectivity. This study investigated the cingulate substructure and its association with social awareness deficits and the CNTNAP2 variants in individuals with ASD and typically-developing controls (TDC). METHODS: We assessed 118 individuals with ASD and 122 TDC with MRI and clinical evaluation. The GM, WM volumes and cortical thickness of the cingulate gyrus were compared between ASD and TDC based on fine parcellation. Five SNPs of the CNTNAP2 linked to ASD and brain structural abnormality were genotyped, and rs2710102, rs2538991, rs2710126 passed quality control filters. RESULTS: ASD individuals showed thinner cortical thickness in bilateral cingulate subregions than TDC without significant group differences in GM and WM volumes. The WM volume of the right anterior cingulate gyrus was correlated with social awareness deficits in ASD. The CNTNAP2 variant demonstrated a main effect on the WM volumes of the right middle cingulate gyrus. Besides, the CNTNAP2 variants interacted with ASD diagnosis and age on the cortical thickness of the left anterior middle cingulate cortex. CONCLUSIONS: Our findings suggest that aberrant cingulate structure in ASD might be associated with the social awareness deficits and genetic variants of the CNTNAP2. These novel findings need validation.

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4. Davico C, Borgogno M, Campagna F, D’Alessandro R, Ricci F, Amianto F, Mussa A, Carli D, Ferrero GB, Vitiello B. Psychopathology and Adaptive Functioning in Children, Adolescents, and Young Adults with Noonan Syndrome. Journal of developmental and behavioral pediatrics : JDBP. 2022; 43(2): e87-e93.

OBJECTIVE: The objective of this study was to examine psychopathology and its impact on adaptive functioning in a sample of patients affected by Noonan syndrome (NS), a genetically heterogeneous condition with systemic manifestations. METHOD: Forty-two subjects affected by NS (23 males and 19 females), aged 5 to 21 years (mean 12.6 ± SD 5.1), were assessed for nonverbal cognitive abilities, with dimensional measures of psychopathology, adaptive functioning, and family quality of life. RESULTS: The nonverbal intelligence quotient (IQ) mean was 99.4 ± SD 22.2, with 3 subjects (8%, 95% confidence interval [CI], 1.6%-20.9%) showing cognitive impairment (IQ<70). The Parent Child Behavior Checklist (CBCL) total psychopathology score was in the clinical range in 10% of sample and borderline in another 10%. On the Conners' Parent Rating Scales, scores suggestive of attention-deficit/hyperactivity disorder (ADHD) were in the clinical range in 20%. On the autism quotient, autism spectrum disorder symptoms were reported in 10%. Higher scores on the Adaptive Behavioral Assessment System-Second Edition and on the World Health Organization Quality of Life (26 items) were associated with lower problems on the CBCL (r = -0.63, 95% CI, -0.78 to -0.40 and r = -0.48, 95% CI, -0.69 to -0.20, respectively). CONCLUSION: Psychopathology was common in patients with NS and negatively correlated with global functioning and family quality of life. Treatable psychopathology, such as ADHD, may constitute a treatment target for improving adaptive functioning.

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5. Davies C, Mishra D, Eshraghi RS, Mittal J, Sinha R, Bulut E, Mittal R, Eshraghi AA. Altering the gut microbiome to potentially modulate behavioral manifestations in autism spectrum disorders: A systematic review. Neuroscience and biobehavioral reviews. 2021; 128: 549-57.

There is a potential association between gastrointestinal (GI) symptoms and the severity of autism spectrum disorder (ASD). Given this correlation, the possible impact of probiotics and prebiotics have been explored in research studies to modify the gut microbiome and ameliorate behavioral manifestations of ASD via modulating the gut-brain-microbiome axis. This systematic review focuses on the interplay between these factors in altering the behavioral manifestations of ASD. Probiotic supplementation tended to mitigate some of the behavioral manifestations of ASD, with less of a discernible trend on the microbiome level. Studies supplementing multiple probiotic species, such as microbiota transfer therapy, or including prebiotics performed better than single strain supplementation. Our analysis suggests that gut dysbiosis may increase intestinal permeability, leading to more severe GI symptoms and a systemic inflammatory response, which can alter permeability across the blood-brain barrier and synaptogenesis in the brain. Future studies are warranted to understand the precise contribution of altering gut microbiome on clinical manifestations of ASD that will open up avenues to develop preventive and treatment modalities.

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6. Dhamrait GK, Christian H, O’Donnell M, Pereira G. Gestational age and child development at school entry. Scientific reports. 2021; 11(1): 14522.

Studies have reported a dose-dependent relationship between gestational age and poorer school readiness. The study objective was to quantify the risk of developmental vulnerability for children at school entry, associated with gestational age at birth and to understand the impact of sociodemographic and other modifiable risk factors on these relationships. Linkage of population-level birth registration, hospital, and perinatal datasets to the Australian Early Development Census (AEDC), enabled follow-up of a cohort of 64,810 singleton children, from birth to school entry in either 2009, 2012, or 2015. The study outcome was teacher-reported child development on the AEDC with developmental vulnerability defined as domain scores < 10(th) percentile of the 2009 AEDC cohort. We used modified Poisson Regression to estimate relative risks (RR) and risk differences (RD) of developmental vulnerability between; (i) preterm birth and term-born children, and (ii) across gestational age categories. Compared to term-born children, adjustment for sociodemographic characteristics attenuated RR for all preterm birth categories. Further adjustment for modifiable risk factors such as preschool attendance and reading status at home had some additional impact across all gestational age groups, except for children born extremely preterm. The RR and RD for developmental vulnerability followed a reverse J-shaped relationship with gestational age. The RR of being classified as developmentally vulnerable was highest for children born extremely preterm and lowest for children born late-term. Adjustment for sociodemographic characteristics attenuated RR and RD for all gestational age categories, except for early-term born children. Children born prior to full-term are at a greater risk for developmental vulnerabilities at school entry. Elevated developmental vulnerability was largely explained by sociodemographic disadvantage. Elevated vulnerability in children born post-term is not explained by sociodemographic disadvantage to the same extent as in children born prior to full-term.

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7. D’Souza NS, Nebel MB, Crocetti D, Robinson J, Wymbs N, Mostofsky SH, Venkataraman A. Deep sr-DDL: Deep structurally regularized dynamic dictionary learning to integrate multimodal and dynamic functional connectomics data for multidimensional clinical characterizations. NeuroImage. 2021; 241: 118388.

We propose a novel integrated framework that jointly models complementary information from resting-state functional MRI (rs-fMRI) connectivity and diffusion tensor imaging (DTI) tractography to extract biomarkers of brain connectivity predictive of behavior. Our framework couples a generative model of the connectomics data with a deep network that predicts behavioral scores. The generative component is a structurally-regularized Dynamic Dictionary Learning (sr-DDL) model that decomposes the dynamic rs-fMRI correlation matrices into a collection of shared basis networks and time varying subject-specific loadings. We use the DTI tractography to regularize this matrix factorization and learn anatomically informed functional connectivity profiles. The deep component of our framework is an LSTM-ANN block, which uses the temporal evolution of the subject-specific sr-DDL loadings to predict multidimensional clinical characterizations. Our joint optimization strategy collectively estimates the basis networks, the subject-specific time-varying loadings, and the neural network weights. We validate our framework on a dataset of neurotypical individuals from the Human Connectome Project (HCP) database to map to cognition and on a separate multi-score prediction task on individuals diagnosed with Autism Spectrum Disorder (ASD) in a five-fold cross validation setting. Our hybrid model outperforms several state-of-the-art approaches at clinical outcome prediction and learns interpretable multimodal neural signatures of brain organization.

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8. García-López C, Recio P, Pozo P, Sarriá E. Psychological Distress, Disorder Severity, and Perception of Positive Contributions in Couples Raising Individuals With Autism. Frontiers in psychology. 2021; 12: 694064.

Parents’ perception of the positive contributions associated with raising children with autism is considered to be a protective factor in the process of psychological adaptation. Thus, it is essential to unveil what factors are related to this perception. We explore how parents’ psychological distress (parental stress and anxiety) predicts the perception of positive contributions in fathers and mothers who raise individuals with different levels of autism severity. The sample comprises 135 couples (270 fathers and mothers) parenting individuals diagnosed with autism aged 3-38 years. Participants completed different self-report questionnaires, including measures of parental stress, anxiety, and positive contributions. To estimate the actor-partner interdependence model, data were analyzed using structural equation modeling (SEM) to explore transactional effects between fathers’ and mothers’ psychological distress and their perceptions of positive contributions associated with autism. Two separate multigroup models were tested, respectively, analyzing parental stress and anxiety. Each multigroup model considers two levels of disorder severity. The findings revealed that actor and partner effects of stress and anxiety were important predictors of the perception of positive contributions in both disorder severity groups. We conclude that it is necessary to develop family support programs that focus on controlling fathers’ and mothers’ stress and anxiety symptoms, as these mental states negatively impact the ability to perceive positive contributions.

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9. Gepner B, Charrier A, Arciszewski T, Tardif C. Slowness Therapy for Children with Autism Spectrum Disorder: A Blind Longitudinal Randomized Controlled Study. Journal of autism and developmental disorders. 2021.

The world often goes too fast for children with autism spectrum disorder (ASD) to process. We tested the therapeutic effectiveness of input slowing in children with ASD. Over 12 months, 12 children with ASD had weekly speech therapy sessions where stimuli were slowly played on a PC, while 11 age- and level-matched children with ASD had speech therapy using real-time stimuli. At the beginning and end of the study, all participants were assessed on communication, imitation, facial emotion recognition, behavior, and face exploration. Whereas communication and facial emotion recognition improved in both groups, imitation increased, inappropriate behaviors decreased, and time spent fixating mouth and eyes increased solely in the group using slowness. Slowness therapy seems very promising for ASD children.

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10. Goetzinger L, Starks RD, Dillahunt K, Major H, Nagy JM, Sidhu A. Interstitial duplication of 20q11.22q13.11: A case report and review of literature. Molecular genetics & genomic medicine. 2021; 9(8): e1755.

BACKGROUND: Reports of interstitial duplication of chromosome 20q11 are rare with only nine published patients to date. METHODS: We performed karyotype and chromosomal microarray analysis on a peripheral blood sample for our patient and reviewed the genes in the region to provide genotype-phenotype correlation. RESULTS: Clinical features of the patient include minor dysmorphic facial features, shorthands and feet, bilateral conductive hearing loss, global developmental delay, and behavioral issues with attention deficit hyperactivity disorder. Together with previously published cases of 20q11 duplication, we show that patients with overlapping duplications share a similar clinical phenotype of dysmorphic craniofacial features and developmental delay. CONCLUSION: We report an 8-year-old girl with a 9.1 Mb interstitial duplication of chromosome 20q11.22q13.11. Our observations suggest that a novel duplication syndrome and documentation of similar cases will further help clarify the phenotype.

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11. Higa LA, Wardley J, Wardley C, Singh S, Foster T, Shen JJ. CNKSR2-related neurodevelopmental and epilepsy disorder: a cohort of 13 new families and literature review indicating a predominance of loss of function pathogenic variants. BMC medical genomics. 2021; 14(1): 186.

BACKGROUND: Pathogenic variants in connector enhancer of kinase suppressor of Ras-2 (CNKSR2) located on the X chromosome (Xp22.12) lead to a disorder characterized by developmental delay and a characteristic seizure phenotype. To date, 20 affected males representing 13 different pathogenic variants have been published. CASE PRESENTATION: We identified an 8-year-old male with seizures, abnormal electroencephalogram (EEG) with epileptiform abnormalities in the right hemisphere, and developmental delay with notable loss of speech following seizure onset. Additional concerns include multiple nighttime awakenings, hyperactivity, and autism spectrum disorder. Genetic testing identified a de novo pathogenic nonsense variant in CNKSR2. Through an active family support group, an additional 12 males are described, each harboring a different CNKSR2 variant. The clinical presentation and natural history consistently show early developmental delay, sleep disturbances, and seizure onset in childhood that is initially intractable but later becomes better controlled. Virtually all of the pathogenic variants are predicted to be loss of function, including genomic deletions, nonsense variants, splice site mutations, and small insertions or deletions. CONCLUSIONS: This expanded knowledge, combined with functional studies and work with animal models currently underway, will enable a better understanding and improved ability to care for individuals with CNKSR2-related neurodevelopmental and epilepsy disorder.

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12. Inuzuka LM, Guerra-Peixe M, Macedo-Souza LI, Pedreira CC, Gurgel-Giannetti J, Monteiro FP, Ramos L, Costa LA, Crippa ACS, Lourenco CM, Pachito DV, Sukys-Claudino L, Gaspar LS, Antoniuk SA, Dutra LPS, Diniz SSL, Pires RB, Garzon E, Kok F. MECP2-related conditions in males: A systematic literature review and 8 additional cases. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2021; 34: 7-13.

OBJECTIVE: To present a cohort of 8 males and perform a systematic review of all published cases with a single copy of MECP2 carrying a pathogenic variant. METHODS: We reviewed medical records of males with a single copy of MECP2 carrying a pathogenic variant. We searched in Medline (Pubmed) and Embase to collect all articles which included well-characterized males with a single copy of MECP2 carrying a pathogenic or likely pathogenic variant in MECP2 (1999-2020). RESULTS: The literature search yielded a total of 3,185 publications, of which 58 were included in our systematic review. We were able to collect information on 27 published patients with severe neonatal encephalopathy, 47 individuals with isolated or familial mental retardation X-linked 13 (XLMR13), as well as 24 individuals with isolated or familial Pyramidal signs, parkinsonism, and macroorchidism (PPM-X). In our cohort, we met eight individuals aged 4 to 19-year-old at the last evaluation. Three MECP2-associated phenotypes were seen in male carriers of a single copy of the gene: severe neonatal encephalopathy (n = 5); X-linked intellectual deficiency 13 (n = 2); and pyramidal signs, parkinsonism, and macroorchidism (PPM-X) (n = 1). Two novel de novo variants [p.(Gly252Argfs∗7) and p.(Tyr132Cys)] were detected. CONCLUSION: In males, the MECP2 pathogenic variants can be associated with different phenotypes, including neonatal severe encephalopathy, intellectual deficiency, or late-onset parkinsonism and spasticity. The typical RS phenotype is not expected in males, except in those with Klinefelter syndrome or somatic mosaicism for MECP2.

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13. Johnson CN, Ramphal B, Koe E, Raudales A, Goldsmith J, Margolis AE. Cognitive correlates of autism spectrum disorder symptoms. Autism research : official journal of the International Society for Autism Research. 2021; 14(11): 2405-11.

Due to the diverse behavioral presentation of autism spectrum disorder (ASD), identifying ASD subtypes using patterns of cognitive abilities has become an important point of research. Some previous studies on cognitive profiles in ASD suggest that the discrepancy between verbal intelligence quotient (VIQ) and performance IQ (PIQ) is associated with ASD symptoms, while others have pointed to VIQ as the critical predictor. Given that VIQ is a component of the VIQ-PIQ discrepancy, it was unclear which was most driving these associations. This study tested whether VIQ, PIQ, or the VIQ-PIQ discrepancy was most associated with ASD symptoms in children and adults with ASD (N = 527). Using data from the Autism Brain Imaging Data Exchange (ABIDE), we tested the independent contribution of each IQ index and their discrepancy to ASD symptom severity using multiple linear regressions predicting ASD symptoms. VIQ was most associated with lower symptom severity as measured by the Autism Diagnostic Observation Schedule (ADOS) total score, and when VIQ was included in models predicting ASD symptoms, associations with PIQ and IQ discrepancy were not significant. An association between VIQ and ASD communication symptoms drove the association with ASD symptom severity. These results suggest that associations between ASD communication symptoms and IQ discrepancy or PIQ reported in prior studies likely resulted from variance shared with VIQ. Subtyping ASD on the basis of VIQ should be a point of future research, as it may allow for the development of more personalized approaches to intervention. LAY SUMMARY: Previous research on links between autism severity and verbal and nonverbal intelligence has produced mixed results. Our study examined whether verbal intelligence, nonverbal intelligence, or the discrepancy between the two was most related to autism symptoms. We found that higher verbal intelligence was most associated with less severe autism communication symptoms. Given the relevance of verbal intelligence in predicting autism symptom severity, subtyping autism on the basis of verbal intelligence could lead to more personalized treatments.

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14. Kala S, Rolison MJ, Trevisan DA, Naples AJ, Pelphrey K, Ventola P, McPartland JC. Brief Report: Preliminary Evidence of the N170 as a Biomarker of Response to Treatment in Autism Spectrum Disorder. Frontiers in psychiatry. 2021; 12: 709382.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by primary difficulties in social function. Individuals with ASD display slowed neural processing of faces, as indexed by the latency of the N170, a face-sensitive event-related potential. Currently, there are no objective biomarkers of ASD useful in clinical care or research. Efficacy of behavioral treatment is currently evaluated through subjective clinical impressions. To explore whether the N170 might have utility as an objective index of treatment response, we examined N170 before and after receipt of an empirically validated behavioral treatment in children with ASD. Method: Electroencephalography (EEG) data were obtained on a preliminary cohort of preschool-aged children with ASD before and after a 16-week course of PRT and in a subset of participants in waitlist control (16-weeks before the start of PRT) and follow-up (16-weeks after the end of PRT). EEG was recorded while participants viewed computer-generated faces with neutral and fearful affect. Results: Significant reductions in N170 latency to faces were observed following 16 weeks of PRT intervention. Change in N170 latency was not observed in the waitlist-control condition. Conclusions: This exploratory study offers suggestive evidence that N170 latency may index response to behavioral treatment. Future, more rigorous, studies in larger samples are indicated to evaluate whether the N170 may be useful as a biomarker of treatment response.

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15. Kaymakcalan H, Kaya İ, Cevher Binici N, Nikerel E, Özbaran B, Görkem Aksoy M, Erbilgin S, Özyurt G, Jahan N, Çelik D, Yararbaş K, Yalçınkaya L, Köse S, Durak S, Ercan-Sencicek AG. Prevalence and clinical/molecular characteristics of PTEN mutations in Turkish children with autism spectrum disorders and macrocephaly. Molecular genetics & genomic medicine. 2021; 9(8): e1739.

BACKGROUND: Phosphatase and tensin homolog (PTEN) germline mutations are associated with cancer syndromes (PTEN hamartoma tumor syndrome; PHTS) and in pediatric patients with autism spectrum disorder (ASD) and macrocephaly. The exact prevalence of PTEN mutations in patients with ASD and macrocephaly is uncertain; with prevalence rates ranging from 1% to 17%. Most studies are retrospective and contain more adult than pediatric patients, there is a need for more prospective pediatric studies. METHODS: We recruited 131 patients (108 males, 23 females) with ASD and macrocephaly between the ages of 3 and 18 from five child and adolescent psychiatry clinics in Turkey from July 2018 to December 2019. We defined macrocephaly as occipito-frontal HC size at or greater than 2 standard deviations (SD) above the mean for age and sex on standard growth charts. PTEN gene sequence analysis was performed using a MiSeq next generation sequencing (NGS) platform, (Illumina). CONCLUSION: PTEN gene sequence analyses identified three pathogenic/likely pathogenic mutations [NM_000314.6; p.(Pro204Leu), (p.Arg233*) and novel (p.Tyr176Cys*8)] and two variants of uncertain significance (VUS) [NM_000314.6; p.(Ala79Thr) and c.*10del]. We also report that patient with (p.Tyr176Cys*8) mutation has Grade 1 hepatosteatosis, a phenotype not previously described. This is the first PTEN prevalence study of patients with ASD and macrocephaly in Turkey and South Eastern Europe region with a largest homogenous cohort. The prevalence of PTEN mutations was found 3.8% (VUS included) or 2.29% (VUS omitted). We recommend testing for PTEN mutations in all patients with ASD and macrocephaly.

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16. Little ID, Gunter C. Mini-Review: Genetic Literacy and Engagement With Genetic Testing for Autism Spectrum Disorder. Frontiers in genetics. 2021; 12: 693158.

As genomic and personalized medicine is integrated into healthcare, the need for patients to understand and make decisions about their own genetic makeup increases. Genetic literacy, or one’s knowledge of genetic principles and their applications, measures an individual’s ability to apply genetic information to their own treatment. Increased genetic literacy can improve comprehension of genetic tests and therefore increase participation in testing to detect and treat genetic disorders. It can also help providers understand and explain genetic information to their patients. However, current research indicates that the population’s genetic literacy is generally low. Because many medical students, providers, and patients cannot adequately apply genetic information to their health, new and beneficial genetic technologies can be underused. More specifically, though genetic testing is recommended at the time of diagnosis for those affected by autism spectrum disorder (ASD), as few as 22% of families undergo genetic testing after diagnosis. While ASD, a neurodevelopmental condition characterized by impaired social communication and restricted interests, has both genetic and environmental risk, genetic testing can give clinicians useful information and help families avoid potentially painful and costly tests, even when many families do not receive a « positive » genetic result through microarrays or gene panels. Improving genetic literacy in populations affected by ASD can also improve attitudes toward genetic testing, thereby ensuring access to genetic health risk information. In this mini review, we discuss the current literature describing genetic literacy and genetic testing rates for ASD.

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17. Phan ML, Liu TT, Vollbrecht MS, Mansour MH, Nikodijevic I, Jadav N, Patibanda N, Dang J, Shekaran G, Reisler RC, Kim WS, Zhou X, DiCicco-Bloom E, Samuels BA. Engrailed 2 deficiency and chronic stress alter avoidance and motivation behaviors. Behavioural brain research. 2021; 413: 113466.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by impairments in social interaction, cognition, and communication, as well as the presence of repetitive or stereotyped behaviors and interests. ASD is most often studied as a neurodevelopmental disease, but it is a lifelong disorder. Adults with ASD experience more stressful life events and greater perceived stress, and frequently have comorbid mood disorders such as anxiety and depression. It remains unclear whether adult exposure to chronic stress can exacerbate the behavioral and neurodevelopmental phenotypes associated with ASD. To address this issue, we first investigated whether adult male and female Engrailed-2 deficient (En2-KO, En2-/-) mice, which display behavioral disturbances in avoidance tasks and dysregulated monoaminergic neurotransmitter levels, also display impairments in instrumental behaviors associated with motivation, such as the progressive ratio task. We then exposed adult En2-KO mice to chronic environmental stress (CSDS, chronic social defeat stress), to determine if stress exacerbated the behavioral and neuroanatomical effects of En2 deletion. En2-/- mice showed impaired instrumental acquisition and significantly lower breakpoints in a progressive ratio test, demonstrating En2 deficiency decreases motivation to exert effort for reward. Furthermore, adult CSDS exposure increased avoidance behaviors in En2-KO mice. Interestingly, adult CSDS exposure also exacerbated the deleterious effects of En2 deficiency on forebrain-projecting monoaminergic fibers. Our findings thus suggest that adult exposure to stress may exacerbate behavioral and neuroanatomical phenotypes associated with developmental effects of genetic En2 deficiency.

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18. Topal Z, Bahşi I, Karadag M, Sarp AS, Akkaya C, Gokcen C. Anthropometric Analysis of the Orbital Region in Children With Autism Spectrum Disorder and Healthy Controls. The Journal of craniofacial surgery. 2022; 33(1): 322-4.

It was aimed to examine the orbital region in children with autism spectrum disorder and comparison with the healthy controls in the present study. A total of 195 children and adolescents (101 of them were in the autism group, 94 of them were in healthy group) were evaluated. Anterior view photographs were taken, and endocanthion (en), exocanthion (ex), and pupil were determined bilaterally on the photographs. Outer canthal (ex-ex), intercanthal (ex-en), inner canthal (en-en) and interpupillary distances were measured and intercanthal index [(en-en / ex-ex) × 100] was calculated. There was a statistically significant difference between the groups for males for all parameters, while a statistically significant difference was not observed for females. All orbital region distances were higher in male autistic children. Although minor physical anomalies in children and adolescents with autism have been reported before, anthropometric measurements in individuals with autism may differ between genders. Further studies are needed to investigate the differences between genders in autism spectrum disorder.

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19. Wright B, Phillips H, Allgar V, Sweetman J, Hodkinson R, Hayward E, Ralph-Lewis A, Teige C, Bland M, Le Couteur A. Adapting and validating the Autism Diagnostic Interview – Revised for use with deaf children and young people. Autism : the international journal of research and practice. 2022; 26(2): 446-59.

Autism assessment processes need to improve for deaf children as they are currently being diagnosed later than their hearing counterparts and misdiagnosis can occur. We took one of the most commonly used parent developmental interviews for autism spectrum disorder the Autism Diagnostic Interview-Revised and adapted it using international expert advice. Modifications were proposed and agreed by the expert panel for 45% of items; the remaining 55% of items were unchanged. We then tested the revised version, adapted for deaf children (Autism Diagnostic Interview-Revised Deaf Adaptation), in a UK sample of 78 parents/carers of deaf children with autism spectrum disorder and 126 parents/carers with deaf children without autism spectrum disorder. When compared to National Institute for Health and Care Excellence guideline standard clinical assessments, the Autism Diagnostic Interview-Revised Deaf Adaptation diagnostic algorithm threshold scores could identify those deaf children with a definite diagnosis (true autism spectrum disorder positives) well (sensitivity of 89% (79%-96%)) and those deaf children who did not have autism spectrum disorder (true autism spectrum disorder negatives) well (specificity of 81% (70%-89%)). Our findings indicate that the Autism Diagnostic Interview-Revised Deaf Adaptation is likely to prove a useful measure for the assessment of deaf children with suspected autism spectrum disorder and that further research would be helpful.

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20. Xie Q, Zhang X, Rekik I, Chen X, Mao N, Shen D, Zhao F. Constructing high-order functional connectivity network based on central moment features for diagnosis of autism spectrum disorder. PeerJ. 2021; 9: e11692.

The sliding-window-based dynamic functional connectivity network (D-FCN) has been becoming an increasingly useful tool for understanding the changes of brain connectivity patterns and the association of neurological diseases with these dynamic variations. However, conventional D-FCN is essentially low-order network, which only reflects the pairwise interaction pattern between brain regions and thus overlooking the high-order interactions among multiple brain regions. In addition, D-FCN is innate with temporal sensitivity issue, i.e., D-FCN is sensitive to the chronological order of its subnetworks. To deal with the above issues, we propose a novel high-order functional connectivity network framework based on the central moment feature of D-FCN. Specifically, we firstly adopt a central moment approach to extract multiple central moment feature matrices from D-FCN. Furthermore, we regard the matrices as the profiles to build multiple high-order functional connectivity networks which further capture the higher level and more complex interaction relationships among multiple brain regions. Finally, we use the voting strategy to combine the high-order networks with D-FCN for autism spectrum disorder diagnosis. Experimental results show that the combination of multiple functional connectivity networks achieves accuracy of 88.06%, and the best single network achieves accuracy of 79.5%.

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21. Yoshitomi S, Hamano SI, Hayashi M, Sakuma H, Hirose S, Ishii A, Honda R, Ikeda A, Imai K, Jin K, Kada A, Kakita A, Kato M, Kawai K, Kawakami T, Kobayashi K, Matsuishi T, Matsuo T, Nabatame S, Okamoto N, Ito S, Okumura A, Saito A, Shiraishi H, Shirozu H, Saito T, Sugano H, Takahashi Y, Yamamoto H, Fukuyama T, Kuki I, Inoue Y. Current medico-psycho-social conditions of patients with West syndrome in Japan. Epileptic disorders : international epilepsy journal with videotape. 2021; 23(4): 579-89.

OBJECTIVE: To unveil current medical and psychosocial conditions of patients with West syndrome in Japan. METHODS: A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset. RESULTS: For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%. SIGNIFICANCE: The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.

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22. Zieminska E, Ruszczynska A, Augustyniak J, Toczylowska B, Lazarewicz JW. Zinc and Copper Brain Levels and Expression of Neurotransmitter Receptors in Two Rat ASD Models. Frontiers in molecular neuroscience. 2021; 14: 656740.

Zinc and copper are important trace elements necessary for the proper functioning of neurons. Impaired zinc and/or copper metabolism and signaling are implicated in many brain diseases, including autism (ASD). In our studies, autistic-like behavior in rat offsprings was induced by application to pregnant mothers valproic acid or thalidomide. Zinc and copper contents were measured in serum and brain structures: hippocampus, cerebral cortex, and cerebellum. Our research shows no interconnections in the particular metal concentrations measured in autistic animal brains and their sera. Based on patient researches, we studied 26 genes belonging to disturbed neurotransmitter pathways. In the same brain regions, we examined the expression of genes encoding proteins of cholinergic, adrenergic, serotonin, and dopamine receptors. In both rats’ ASD models, 17 out of the tested gene expression were decreased. In the cerebellum and cerebral cortex, expression of genes encoding cholinergic, adrenergic, and dopaminergic receptors decreased, whereas in the hippocampus only expression of serotoninergic receptors genes was downregulated. The changes in metals content observed in the rat brain can be secondary phenomena, perhaps elements of mechanisms that compensate for neurotransmission dysfunctions.

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