1. Bayat A, Iqbal S, Borredy K, Amiel J, Zweier C, Barcia G, Kraus C, Weyhreter H, Bassuk AG, Chopra M, Rubboli G, Møller RS. PRICKLE2 revisited-further evidence implicating PRICKLE2 in neurodevelopmental disorders. European journal of human genetics : EJHG. 2021; 29(8): 1235-44.

PRICKLE2 encodes a member of a highly conserved family of proteins that are involved in the non-canonical Wnt and planar cell polarity signaling pathway. Prickle2 localizes to the post-synaptic density, and interacts with post-synaptic density protein 95 and the NMDA receptor. Loss-of-function variants in prickle2 orthologs cause seizures in flies and mice but evidence for the role of PRICKLE2 in human disease is conflicting. Our goal is to provide further evidence for the role of this gene in humans and define the phenotypic spectrum of PRICKLE2-related disorders. We report a cohort of six subjects from four unrelated families with heterozygous rare PRICKLE2 variants (NM_198859.4). Subjects were identified through an international collaboration. Detailed phenotypic and genetic assessment of the subjects were carried out and in addition, we assessed the variant pathogenicity using bioinformatic approaches. We identified two missense variants (c.122 C > T; p.(Pro41Leu), c.680 C > G; p.(Thr227Arg)), one nonsense variant (c.214 C > T; p.(Arg72*) and one frameshift variant (c.1286_1287delGT; p.(Ser429Thrfs*56)). While the p.(Ser429Thrfs*56) variant segregated with disease in a family with three affected females, the three remaining variants occurred de novo. Subjects shared a mild phenotype characterized by global developmental delay, behavioral difficulties ± epilepsy, autistic features, and attention deficit hyperactive disorder. Computational analysis of the missense variants suggest that the altered amino acid residues are likely to be located in protein regions important for function. This paper demonstrates that PRICKLE2 is involved in human neuronal development and that pathogenic variants in PRICKLE2 cause neurodevelopmental delay, behavioral difficulties and epilepsy in humans.

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2. Calver J, Balogh R, Rudoler D. Incidence of injury in children and adolescents with intellectual and developmental disability. Journal of safety research. 2021; 77: 56-60.

INTRODUCTION: Children and adolescents living with intellectual and developmental disability (IDD) have a higher risk of experiencing morbidities and premature death when compared to children and adolescents living without IDD. Childhood injuries are a leading cause of morbidity and death, yet there are limited studies that explore the prevalence of childhood injuries for individuals living with IDD. The purpose of this study was to analyze Ontario health administrative data to identify and compare rates of injury resulting in hospitalization in children and adolescents living with and without IDD. METHODS: This is a cross-sectional study of all Ontarians aged 0-19 years with and without IDD. The outcome of interest was the rate of injury resulting in hospitalization. RESULTS: This study found that children and adolescents with IDD had 1.79 (CI 1.66, 1.92) times higher rates of both intentional and unintentional injuries that resulted in hospitalization when compared to children and adolescents without IDD. Hospitalizations for self-harm related injuries were 3.16 (CI 3.09, 3.23) times higher in the IDD group. CONCLUSION: Children and adolescents with IDD have a higher risk of sustaining serious injuries, particularly injuries resulting from self-harm. Practical Applications: This study provides evidence of increased injury related hospitalizations for children and adolescents with IDD when compared to their peers without IDD.

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3. Chamak B. [Experiences of families of autistic children during a period of lockdown: Exploratory study]. Neuropsychiatrie de l’enfance et de l’adolescence. 2021; 69(5): 235-40.

OBJECTIVE: The lockdown periods associated with the Covid-19 pandemic are a particularly significant challenge for families of children with autism. Exchanges by e-mail and interviews were aimed at collecting testimonies from parents for a better understanding of their difficulties and the help provided by the mobilization of professionals. METHODS AND RESULTS: Eight parents of autistic children living in the Seine-Saint-Denis area agreed to testify about their experience, either in person, taking into account the barrier measures after the first lockdown, or by telephone during the second lockdown. By way of comparison, e-mails were exchanged with a mother and two fathers of autistic children from higher socio-economic backgrounds living in other parts of France or Belgium. While at the beginning of the first lockdown, some children may have felt soothed by being at home with their parents, the extension of the situation led to crises related to feelings of anxiety or boredom. Despite the closure of many medical-social facilities, professionals mobilized to continue helping families and children whose routines were disrupted. CONCLUSION: Depending on the conditions of lockdown, the families’ experiences differed and evolved over time. The major problems encountered by some families were the worsening of their child’s troubles (self-harm, tantrums, violence, and shouting). Pedagogical tools were adapted by the teachers, activity sheets were sent out, group workshops were organized, and consultations were given at a distance. The teams of the child psychiatry services and the medico-social services have mobilized themselves and have shown reactivity and inventiveness in order to ensure the care and follow-up of children and their families. Publisher: Abstract available from the publisher. fre.

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4. Čolić M, Araiba S, Lovelace TS, Dababnah S. Black Caregivers’ Perspectives on Racism in ASD Services: Toward Culturally Responsive ABA Practice. Behavior analysis in practice. 2021: 1-10.

Significant racial and ethnic disparities in health care and service access exist. In the present article, we reviewed qualitative studies investigating the racism-related experiences of Black caregivers of children with autism spectrum disorder (ASD) in the U.S. health care system. Specifically, we examined institutional racism (i.e., systemic racism) and individual racism directed toward Black families when they seek diagnoses and services for their children with ASD. Additionally, we summarized culturally responsive and context-specific practice guidelines to work collaboratively with Black caregivers of children with ASD for applied behavior analysis practitioners.

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5. Curtis JS, Kennedy SE, Attarha B, Edwards L, Jacob R. Upper Gastrointestinal Disorders in Adult Patients with Intellectual and Developmental Disabilities. Cureus. 2021; 13(6): e15384.

The purpose of this literature review is to address the diagnosis and treatment of upper gastrointestinal (GI) disorders in patients with intellectual and developmental disabilities (IDD). Manifestations of upper GI dysmotility and disorders include dysphagia, pulmonary aspiration, malnutrition, gastroesophageal reflux, and gastritis, all of which can impact a person’s quality of life and lead to chronic, life-threatening conditions. This article will explore the existing diagnostic methods and treatments for gastrointestinal disorders as they relate to patients with IDD.

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6. Dardani C, Riglin L, Leppert B, Sanderson E, Rai D, Howe LD, Davey Smith G, Tilling K, Thapar A, Davies NM, Anderson E, Stergiakouli E. Is genetic liability to ADHD and ASD causally linked to educational attainment?. International journal of epidemiology. 2021.

BACKGROUND: The association patterns of Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) with educational attainment (EA) are complex; children with ADHD and ASD are at risk of poor academic outcomes, and parental EA has been associated with risk of ADHD/ASD in the offspring. Little is known on the causal links between ADHD, ASD, EA and the potential contribution of cognitive ability. METHODS: Using the latest genome-wide association studies (GWAS) summary data on ADHD, ASD and EA, we applied two-sample Mendelian randomization (MR) to assess the effects of genetic liability to ADHD and ASD on EA. Reverse direction analyses were additionally performed. Multivariable MR was performed to estimate any effects independent of cognitive ability. RESULTS: Genetic liability to ADHD had a negative effect on EA, independently of cognitive ability (MVMRIVW: -1.7 months of education per doubling of genetic liability to ADHD; 95% CI: -2.8 to -0.7), whereas genetic liability to ASD a positive effect (MVMRIVW: 30 days per doubling of the genetic liability to ASD; 95% CI: 2 to 53). Reverse direction analyses suggested that genetic liability to higher EA had an effect on lower risk of ADHD, independently of cognitive ability (MVMRIVWOR: 0.33 per SD increase; 95% CI: 0.26 to 0.43) and increased risk of ASD (MRIVWOR: 1.51 per SD increase; 95% CI: 1.29 to 1.77), which was partly explained by cognitive ability (MVMRIVWOR per SD increase: 1.24; 95%CI: 0.96 to 1.60). CONCLUSIONS: Genetic liability to ADHD and ASD is likely to affect educational attainment, independently of underlying cognitive ability.

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7. Feng S, Huang H, Wang N, Wei Y, Liu Y, Qin D. Sleep Disorders in Children With Autism Spectrum Disorder: Insights From Animal Models, Especially Non-human Primate Model. Frontiers in behavioral neuroscience. 2021; 15: 673372.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder with deficient social skills, communication deficits and repetitive behaviors. The prevalence of ASD has increased among children in recent years. Children with ASD experience more sleep problems, and sleep appears to be essential for the survival and integrity of most living organisms, especially for typical synaptic development and brain plasticity. Many methods have been used to assess sleep problems over past decades such as sleep diaries and parent-reported questionnaires, electroencephalography, actigraphy and videosomnography. A substantial number of rodent and non-human primate models of ASD have been generated. Many of these animal models exhibited sleep disorders at an early age. The aim of this review is to examine and discuss sleep disorders in children with ASD. Toward this aim, we evaluated the prevalence, clinical characteristics, phenotypic analyses, and pathophysiological brain mechanisms of ASD. We highlight the current state of animal models for ASD and explore their implications and prospects for investigating sleep disorders associated with ASD.

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8. Feroe AG, Uppal N, Gutiérrez-Sacristán A, Mousavi S, Greenspun P, Surati R, Kohane IS, Avillach P. Medication Use in the Management of Comorbidities Among Individuals With Autism Spectrum Disorder From a Large Nationwide Insurance Database. JAMA pediatrics. 2021; 175(9): 957-65.

IMPORTANCE: Although there is no pharmacological treatment for autism spectrum disorder (ASD) itself, behavioral and pharmacological therapies have been used to address its symptoms and common comorbidities. A better understanding of the medications used to manage comorbid conditions in this growing population is critical; however, most previous efforts have been limited in size, duration, and lack of broad representation. OBJECTIVE: To use a nationally representative database to uncover trends in the prevalence of co-occurring conditions and medication use in the management of symptoms and comorbidities over time among US individuals with ASD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, population-based cohort study mined a nationwide, managed health plan claims database containing more than 86 million unique members. Data from January 1, 2014, to December 31, 2019, were used to analyze prescription frequency and diagnoses of comorbidities. A total of 26 722 individuals with ASD who had been prescribed at least 1 of 24 medications most commonly prescribed to treat ASD symptoms or comorbidities during the 6-year study period were included in the analysis. EXPOSURES: Diagnosis codes for ASD based on International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. MAIN OUTCOMES AND MEASURES: Quantitative estimates of prescription frequency for the 24 most commonly prescribed medications among the study cohort and the most common comorbidities associated with each medication in this population. RESULTS: Among the 26 722 individuals with ASD included in the analysis (77.7% male; mean [SD] age, 14.45 [9.40] years), polypharmacy was common, ranging from 28.6% to 31.5%. Individuals’ prescription regimens changed frequently within medication classes, rather than between classes. The prescription frequency of a specific medication varied considerably, depending on the coexisting diagnosis of a given comorbidity. Of the 24 medications assessed, 15 were associated with at least a 15% prevalence of a mood disorder, and 11 were associated with at least a 15% prevalence of attention-deficit/hyperactivity disorder. For patients taking antipsychotics, the 2 most common comorbidities were combined type attention-deficit/hyperactivity disorder (11.6%-17.8%) and anxiety disorder (13.1%-30.1%). CONCLUSIONS AND RELEVANCE: This study demonstrated considerable variability and transiency in the use of prescription medications by US clinicians to manage symptoms and comorbidities associated with ASD. These findings support the importance of early and ongoing surveillance of patients with ASD and co-occurring conditions and offer clinicians insight on the targeted therapies most commonly used to manage co-occurring conditions. Future research and policy efforts are critical to assess the extent to which pharmacological management of comorbidities affects quality of life and functioning in patients with ASD while continuing to optimize clinical guidelines, to ensure effective care for this growing population.

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9. Frampton SE, Munk GT, Shillingsburg LA, Shillingsburg MA. A Systematic Review and Quality Appraisal of Applications of Direct Instruction with Children with Autism Spectrum Disorder. Perspectives on behavior science. 2021; 44(2-3): 245-66.

Developed by Siegfried (« Zig ») Engelmann and colleagues, direct instruction (DI) has been recognized as an effective and replicable teaching model for decades. Although rooted in many principles of learning that behavior analysts utilize in daily practice, DI is not a common a component of behavior analytic services for learners with autism spectrum disorder (ASD). This may be attributed to behavior analysts’ unfamiliarity with research evaluating the efficacy of DI with learners with ASD. This article synthesizes findings across studies evaluating DI with learners with ASD. The review addresses the contributions of the studies to date and identifies additional areas of research that may lead to more learners with ASD benefitting from DI.

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10. Gong W, Qiao Y, Li B, Zheng X, Xu R, Wang M, Mi X, Li Y. The Alteration of Salivary Immunoglobulin A in Autism Spectrum Disorders. Frontiers in psychiatry. 2021; 12: 669193.

Objectives: Autism spectrum disorders (ASD) are neurodevelopmental disorders with changes in the gut and oral microbiota. Based on the intimate relationship between the oral microbiota and oral mucosal immunity, this study aimed to investigate changes in salivary immunoglobulin A (IgA) level in ASD and the underlying mechanism for any such changes. Methods: We recruited 36 children diagnosed with ASD and 35 normally developing children and measured their salivary IgA content using enzyme-linked immunosorbent assay (ELISA). The valproate (VPA) -treated ASD mouse model was established by prenatal exposure to valproate and mouse salivary IgA content was also quantified by ELISA. The submandibular glands of VPA and control mice were isolated and analyzed using qRT-PCR, immunofluorescence staining, and flow cytometry. ASD-related Streptococci were co-incubated with the human salivary gland (HSG) cell line, and western blotting was used to detect the levels of relevant proteins. Results: We found that salivary IgA content was significantly decreased in patients with ASD and had a significant ASD diagnostic value. The salivary IgA content also decreased in VPA mice and was significantly correlated with autistic-like behaviors among them. The mRNA and protein levels of the polymeric immunoglobulin receptor (Pigr) were downregulated in the submandibular glands of VPA mice and the Pigr mRNA level was positively correlated with mouse salivary IgA content. HSG cells treated with ASD-related Streptococci had reduced PIGR protein level. Conclusion: Therefore, protective IgA levels were reduced in the saliva of individuals with ASD, which correlated with the bacteria-induced downregulation of Pigr in salivary glands. This study suggests a new direction for ASD diagnosis and prevention of oral diseases in ASD cohorts and provides evidence for the ASD mucosal immunophenotype in the oral cavity.

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11. Görgülü FF, Koç AS. Is there any relationship between autism and pineal gland volume?. Polish journal of radiology. 2021; 86: e225-e31.

PURPOSE: Abnormalities in melatonin physiology and circadian rhythm are detected in patients with autism. Melatonin is produced predominantly in the pineal gland and the amount of melatonin released is proportional to the pineal gland volume. This study aimed to examine whether the pineal gland volume in children with autism is different from that in healthy children. MATERIAL AND METHODS: Brain magnetic resonance images (MRI) of 120 paediatric patients with autism and 82 control paediatric subjects were examined; pineal parenchymal volume (PPV), pineal cyst rate (PCR), and total pineal gland volume (TPGV) were measured using a multimodality viewer (MMV), but only the TPGVs were measured using a tumour tracking (TT) method. Measurements were taken by 2 separate radiologists. RESULTS: In patients with autism, the PPV and TPGV according to MMV, and the TPGV according to TT were significantly lower, and the PCR was significantly higher. Moreover, the ratio of PPV to TPGV was significantly lower in the autism patient group. In both groups, the TPGVs were significantly lower in the autism patient group than the controls among all age groups. CONCLUSIONS: Our study was the first to examine TPGVs in detail in paediatric patients with autism using 2 different methods. Low PPV-TPGV and high PCR have been observed in autism. This study also provides comparable reference values for pineal gland size in healthy children or autistic children aged 2-17 years. These results show promising potential for further research to understand the relationship between autism pathogenesis and the pineal gland.

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12. Gui A, Meaburn EL, Tye C, Charman T, Johnson MH, Jones EJH. Association of Polygenic Liability for Autism With Face-Sensitive Cortical Responses From Infancy. JAMA pediatrics. 2021; 175(9): 968-70.

This cohort study investigates whether N290 latency to faces vs nonfaces is associated with autism polygenic scores and cross-disorder polygenic scores in infants with and without a family history of autism.

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13. Habayeb S, Al-Harahsheh S, Ratto A, Verbalis A, Pugliese C, Nadwodny N, Al-Meer F, El-Akoum M. Meeting the needs of autistic adults in Qatar: Stakeholder perspectives on gaps in services and priorities for future programming. Autism : the international journal of research and practice. 2022; 26(1): 88-100.

Qatar is expanding the services that it offers for autistic people, but these services focus mainly on diagnosing and treating young children. Because there are not enough autism providers in Qatar and few opportunities for autistic youth to participate in the community, more and more autistic teens and young adults have unmet needs during their transition to adulthood. The goal of this study was to conduct a needs assessment of transition-age autistic youth in Qatar and their families in order to inform the development of an adult respite care and support center. Respite care is a service that provides families with stress relief and time to participate in activities that are more difficult to do when their loved one with a disability is with them. The objective of this study was to use family and stakeholder input to identify the needs and preferences for respite care for autistic youth in Qatar. The project was conducted with a local research team in Qatar and a team of clinical researchers in the United States specializing in autism. Stakeholders, including parents of autistic people and providers working with individuals with autism, completed surveys and participated in focus groups. Families and providers in Qatar were very interested increasing services for young adults with autism to improve quality of life, although wanted to make sure the service providers would be reliable and trustworthy. Implications from this study may substantially improve the lives of autistic adults in Qatar.

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14. High P, Silver EJ, Stein REK, Roizen N, Augustyn M, Blum N. Do Referral Factors Predict a Probable Autism Spectrum Disorder Diagnosis? A DBPNet Study. Academic pediatrics. 2022; 22(2): 271-8.

OBJECTIVE: To determine the proportion of children referred to academic medical centers with concerns about autism spectrum disorders (ASDs) who received a probable ASD diagnosis, identify factors predicting ASD diagnosis, and describe the children with ASD concerns who were not found to have autism. METHODS: A total of 55 developmental-behavioral pediatricians (DBP) at 12 academic sites in the DBPNet research network recorded data on ≤15 consecutive new patients. They coded presumed diagnoses after their first visit with the child. RESULTS: Of 784 new visits, 324 (41%) had concern for ASD; of these, 221 (68%) were presumptively ASD+; 103 (32%) were ASD-. In a mixed model accounting for clustering within site and covariates significant in bivariate analysis, significant predictors of receiving a presumptive ASD diagnoses were socialization concerns, languages other than English spoken in the home, and coming for second opinion. Also concern for « other behavior problems » (not mood, oppositionality, anxiety, attention, or repetitive behaviors) predicted not receiving ASD diagnoses. This model was not clinically useful because it misclassified 26.9% of children. ASD- children <4 years old had more language delay and less cognitive impairment and socialization concern than their ASD+ age peers. ASD- children ≥4 years old were more likely to have attention-deficit /hyperactivity disorder (ADHD) and learning disability with normal cognition than their ASD+ age peers. CONCLUSIONS: Two thirds of children referred to academic centers with concern for ASD received a presumptive diagnosis of ASD. While those with ASD were not easily distinguished from those without ASD at referral, virtually all children with ASD concerns had multiple DBP diagnoses made and required DBP follow-up care.

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15. Kolar D, Kleteckova L, Brozka H, Vales K. Mini-review: Brain energy metabolism and its role in animal models of depression, bipolar disorder, schizophrenia and autism. Neuroscience letters. 2021; 760: 136003.

Mitochondria are cellular organelles essential for energy metabolism and antioxidant defense. Mitochondrial impairment is implicated in many psychiatric disorders, including depression, bipolar disorder, schizophrenia, and autism. To characterize and eventually find effective treatments of bioenergetic impairment in psychiatric disease, researchers find animal models indispensable. The present review focuses on brain energetics in several environmental, genetic, drug-induced, and surgery-induced animal models of depression, bipolar disorder, schizophrenia, and autism. Most reported deficits included decreased activity in the electron transport chain, increased oxidative damage, decreased antioxidant defense, decreased ATP levels, and decreased mitochondrial potential. Models of depression, bipolar disorder, schizophrenia, and autism shared many bioenergetic deficits. This is in concordance with the absence of a disease-specific brain energy phenotype in human patients. Unfortunately, due to the absence of null results in examined literature, indicative of reporting bias, we refrain from making generalized conclusions. Present review can be a valuable tool for comparing current findings, generating more targeted hypotheses, and selecting fitting models for further preclinical research.

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16. Matsumoto A, Kojima K, Miya F, Miyauchi A, Watanabe K, Iwamoto S, Kawai K, Kato M, Takahashi Y, Yamagata T. Two cases of DYNC1H1 mutations with intractable epilepsy. Brain & development. 2021; 43(8): 857-62.

BACKGROUND: The DYNC1H1 gene encodes the heavy chain of cytoplasmic dynein 1, a core structure of the cytoplasmic dynein complex. Dominant DYNC1H1 mutations are implicated in Charcot-Marie-Tooth disease, axonal, type 20, spinal muscular atrophy, lower extremity-predominant 1, and autosomal dominant mental retardation 13 with neuronal migration defects. We report two patients with DYNC1H1 mutations who had intractable epilepsy and intellectual disability (ID), one with and one without pachygyria. CASE REPORTS: Patient 1 had severe ID. At the age of 2 months, she presented myoclonic seizures and tonic seizures, and later experienced atonic seizures and focal impaired-awareness seizures (FIAS). EEG showed slow waves in right central areas during myoclonic seizures. Brain MRI revealed pachygyria, predominantly in the occipital lobe. After callosal transection her atonic seizures disappeared, but FIAS remained. Patient 2 was diagnosed with autism spectrum disorder (ASD) and severe ID. At the age of 7 years, he presented generalized tonic-clonic seizures, myoclonic seizures, and FIAS. Interictal EEG showed generalized spike-and-wave complexes, predominantly in the left frontal area. Brain MRI was unremarkable. Exome sequencing revealed novel de novo mutations in DYNC1H1: c.4691A > T, p.(Glu1564Val) in Patient 1 and c.12536 T > C, p.(Leu4179Ser) in Patient 2. CONCLUSIONS: DYNC1H1 comprises a stem, stalk, and six AAA domains. Patient 2 is the second report of an AAA6 domain mutation without malformations of cortical development. The p.(Gly4072Ser) mutation in the AAA6 domain was also reported in a patient with ASD. It may be that the AAA6 domain has little effect on neuronal movement of DYNC1H1 along microtubules.

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17. Must A, Mulé CM, Linder DE, Cash SB, Folta SC. Animal-Assisted Intervention: A Promising Approach to Obesity Prevention for Youth With Autism Spectrum Disorder. Frontiers in veterinary science. 2021; 8: 646081.

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18. Rose SA, Wass SV, Jankowski JJ, Djukic A. Measures of attention in Rett syndrome: Internal consistency reliability. Neuropsychology. 2021; 35(6): 595-608.

OBJECTIVE: Rett syndrome (RTT), an x-linked neurodevelopmental disorder caused by spontaneous mutations in the MECP2 gene, is characterized by profound impairments in expressive language and purposeful hand use. We have pioneered the use of gaze-based tasks to by-pass these limitations and developed measures suitable for clinical trials with RTT. Here we estimated internal consistency reliability for three aspects of attention that are key to cognitive growth and that we previously identified as impaired in RTT. METHOD: Using a sample of 66 children with RTT (2-19 years), we assessed Sustained Attention (butterfly task: Butterfly traverses the screen only when fixated and distractors are ignored); Disengaging/Shifting Attention (« gap/overlap » task: Shifts of gaze from central to peripheral targets are compared in conditions where the central stimulus remains or disappears at the onset of the peripheral target); Selective Attention (search task: the target is embedded in arrays differing in size and distractor type). RESULTS: Reliability was acceptable to excellent on almost all key measures from tasks assessing Sustained Attention and Disengaging/Shifting Attention, with split-half coefficients and Cronbach alphas ranging from .70 to .93. Reliability increased as more trials were aggregated, with acceptable levels often reached with as few as six to nine trials. Measures from Selective Attention showed only limited reliability. CONCLUSION: Finding that critical aspects of attention can be reliably assessed in RTT with gaze-based tasks constitutes a major advance in the development of cognitive measures appropriate for clinical and translational work. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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19. Schaefer TL, Ashworth AA, Tiwari D, Tomasek MP, Parkins EV, White AR, Snider A, Davenport MH, Grainger LM, Becker RA, Robinson CK, Mukherjee R, Williams MT, Gibson JR, Huber KM, Gross C, Erickson CA. GABA(A) Alpha 2,3 Modulation Improves Select Phenotypes in a Mouse Model of Fragile X Syndrome. Frontiers in psychiatry. 2021; 12: 678090.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability. FXS is caused by functional loss of the Fragile X Protein (FXP), also known as Fragile X Mental Retardation Protein (FMRP). In humans and animal models, loss of FXP leads to sensory hypersensitivity, increased susceptibility to seizures and cortical hyperactivity. Several components of the GABAergic system, the major inhibitory system in the brain, are dysregulated in FXS, and thus modulation of GABAergic transmission was suggested and tested as a treatment strategy. However, so far, clinical trials using broad spectrum GABA(A) or GABA(B) receptor-specific agonists have not yielded broad improvement of FXS phenotypes in humans. Here, we tested a more selective strategy in Fmr1 knockout (KO) mice using the experimental drug BAER-101, which is a selective GABA(A) α2/α3 agonist. Our results suggest that BAER-101 reduces hyperexcitability of cortical circuits, partially corrects increased frequency-specific baseline cortical EEG power, reduces susceptibility to audiogenic seizures and improves novel object memory. Other Fmr1 KO-specific phenotypes were not improved by the drug, such as increased hippocampal dendritic spine density, open field activity and marble burying. Overall, this work shows that BAER-101 improves select phenotypes in Fmr1 KO mice and encourages further studies into the efficacy of GABA(A)-receptor subunit-selective agonists for the treatment of FXS.

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20. Sharaan S, MacPherson SE, Fletcher-Watson S. The Impact of Bilingualism on Everyday Executive Functions of English-Arabic Autistic Children: Through a Parent-Teacher Lens. Journal of autism and developmental disorders. 2022; 52(5): 2224-35.

There is evidence that autistic children may have reduced executive function skills, contributing to day-to-day difficulties, but much remains unknown regarding the influence of bilingualism. We investigated its influence on sustained attention, interference control, flexible switching and working memory, in Arabic-English autistic (n = 27) and typically developing peers (n = 53) children, aged 5 to 12 years old. Parents and teachers completed rating measures assessing children’s daily EF abilities. Results showed generalized positive effects for bilingual autistic children relative to their monolingual peers across all EF domains, but using parent ratings only. The findings indicate that bilingualism does not negatively impact the executive function skills of autistic children, and that it might mitigate difficulties faced on a day-to-day basis.

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21. Wang X, Xu J, Zhang B, Hou Y, Song F, Lyu H, Yue F. Genome-wide detection of enhancer-hijacking events from chromatin interaction data in rearranged genomes. Nature methods. 2021; 18(6): 661-8.

Recent efforts have shown that structural variations (SVs) can disrupt three-dimensional genome organization and induce enhancer hijacking, yet no computational tools exist to identify such events from chromatin interaction data. Here, we develop NeoLoopFinder, a computational framework to identify the chromatin interactions induced by SVs, including interchromosomal translocations, large deletions and inversions. Our framework can automatically resolve complex SVs, reconstruct local Hi-C maps surrounding the breakpoints, normalize copy number variation and allele effects and predict chromatin loops induced by SVs. We applied NeoLoopFinder in Hi-C data from 50 cancer cell lines and primary tumors and identified tens of recurrent genes associated with enhancer hijacking. To experimentally validate NeoLoopFinder, we deleted the hijacked enhancers in prostate adenocarcinoma cells using CRISPR-Cas9, which significantly reduced expression of the target oncogene. In summary, NeoLoopFinder enables identification of critical oncogenic regulatory elements that can potentially reveal therapeutic targets.

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22. Yao L, Cai K, Mei F, Wang X, Fan C, Jiang H, Xie F, Li Y, Bai L, Peng K, Deng W, Lai S, Wang J. Urine Nitric Oxide Is Lower in Parents of Autistic Children. Frontiers in psychiatry. 2021; 12: 607191.

Parents raising children with autism spectrum disorder (ASD) usually carry on their daily life under tremendous stress, but limited empirical research has been devoted to this population. It is known that parents’ health status directly impacts therapeutic outcome of ASD children. As an important regulator in cardiovascular, nervous and immune systems, nitric oxide (NO) levels haven’t been reported in parents of ASD children yet. In this study, we measured urine nitrite and nitrate from 43 ASD parents (ASD-P), and 43 healthy adults in the same range of age (Control) who didn’t have any ASD descendants. Comparison between the ASD-P and Control groups showed that NO2- , NO3- , and NO2- / NO3- were all significantly lower in the ASD-P group. Analysis on the interaction effect of sex and group indicated that urine NO3- of mothers in ASD-P was lower than that in females of the Control group, but no significant difference was observed between males in both groups. It is for the first time that urine nitric oxide metabolites (nitrite, nitrate) levels were precisely reported to differentiate parents of autistic children from other adults without ASD descendants. This phenomenon suggests that parents (especially mothers) of autistic children might have experienced more mental and physical stressors, which led to decreased NO levels during metabolism. Further investigations are necessary to uncover the etiology of low urine NO among parents of autistic children.

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23. Ye F, Gao X, Wang Z, Cao S, Liang G, He D, Lv Z, Wang L, Xu P, Zhang Q. Comparison of gut microbiota in autism spectrum disorders and neurotypical boys in China: A case-control study. Synthetic and systems biotechnology. 2021; 6(2): 120-6.

BACKGROUND: Autism spectrum disorders (ASDs) are a set of complex neurobiological disorders. Growing evidence has shown that the microbiota that resides in the gut can modulate brain development via the gut-brain axis. However, direct clinical evidence of the role of the microbiota-gut-brain axis in ASD is relatively limited. METHODS: A case-control study of 71 boys with ASD and 18 neurotypical controls was conducted at China-Japan Friendship Hospital. Demographic information and fecal samples were collected, and the gut microbiome was evaluated and compared by 16S ribosomal RNA gene sequencing and metagenomic sequencing. RESULTS: A higher abundance of operational taxonomic units (OTUs) based on fecal bacterial profiling was observed in the ASD group. Significantly different microbiome profiles were observed between the two groups. At the genus level, we observed a decrease in the relative abundance of Escherichia, Shigella, Veillonella, Akkermansia, Provindencia, Dialister, Bifidobacterium, Streptococcus, Ruminococcaceae UCG_002, Megasphaera, Eubacterium_coprostanol, Citrobacter, Ruminiclostridium_5, and Ruminiclostridium_6 in the ASD cohort, while Eisenbergiella, Klebsiella, Faecalibacterium, and Blautia were significantly increased. Ten bacterial strains were selected for clinical discrimination between those with ASD and the neurotypical controls. The highest AUC value of the model was 0.947. CONCLUSION: Significant differences were observed in the composition of the gut microbiome between boys with ASD and neurotypical controls. These findings contribute to the knowledge of the alteration of the gut microbiome in ASD patients, which opens the possibility for early identification of this disease.

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