1. Abadie V, Hamiaux P, Ragot S, Legendre M, Malecot G, Burtin A, Attie-Bitach T, Lyonnet S, Bilan F, Gilbert-Dussardier B, Vaivre-Douret L. {{Should autism spectrum disorder be considered part of CHARGE syndrome? A cross-sectional study of 46 patients}}. {Orphanet J Rare Dis};2020 (Jun 3);15(1):136.
BACKGROUND: Behavioral problems are an important issue for people with CHARGE syndrome. The similarity of their behavioral traits with those of people with autism raises questions. In a large national cross-sectional study, we used specific standardized tools for diagnosing autism (Autism Diagnostic Interview-Revised and Diagnostic and Statistical Manual of Mental Disorders, 5th edition, DSM-5) and evaluating behavioral disorders (Developmental Behavior Checklist-Parents, DBC-P) to investigate a series of individuals with CHARGE syndrome, defined by Verloes’s criteria. We evaluated their adaptive functioning level and sensory particularities and extracted several data items from medical files to assess as potential risk factors for autism and/or behavioral disorders. RESULTS: We investigated 64 individuals with CHARGE syndrome (35 females; mean age 10.7 years, SD 7.1 years). Among 46 participants with complete results for the Autism Diagnostic Interview-Revised (ADI-R), 13 (28%) had a diagnosis of autism according to the ADI-R, and 25 (54%) had a diagnosis of autism spectrum disorder (ASD) according to the DSM-5 criteria. The frequency of autistic traits in the entire group was a continuum. We did not identify any risk factor for ASD but found a negative correlation between the ADI-R score and adaptive functioning level. Among 48 participants with data for the DBC-P, 26 (55%) had behavioral disorders, which were more frequent in patients with radiological brain anomalies, impaired adaptive functioning, later independent walking, and more sensory particularities. CONCLUSIONS: ASD should be considered to be an independent risk requiring early screening and management in children born with CHARGE syndrome.
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2. Colizzi M, Sironi E, Antonini F, Ciceri ML, Bovo C, Zoccante L. {{Psychosocial and Behavioral Impact of COVID-19 in Autism Spectrum Disorder: An Online Parent Survey}}. {Brain Sci};2020 (Jun 3);10(6)
The 2019 coronavirus disease (COVID-19) outbreak could result in higher levels of psychological distress, especially among people suffering from pre-existing mental health conditions. Young individuals with autism spectrum disorders (ASD) are particularly at risk due to their vulnerability to unpredictable and complex changes. This study aimed to investigate the impact of the COVID-19 pandemic on ASD individuals, whether any pre-pandemic sociodemographic or clinical characteristics would predict a negative outcome, and to narratively characterize their needs. Parents and guardians of ASD individuals filled out an online survey consisting of 40 questions investigating socio-demographic and clinical characteristics of their children, impact of the COVID-19 outbreak on their wellbeing and needs to deal with the emergency. Data were available on 527 survey participants. The COVID-19 emergency resulted in a challenging period for 93.9% of families, increased difficulties in managing daily activities, especially free time (78.1%) and structured activities (75.7%), and, respectively, 35.5% and 41.5% of children presenting with more intense and more frequent behavior problems. Behavior problems predating the COVID-19 outbreak predicted a higher risk of more intense (odds ratio (OR) = 2.16, 95% confidence interval (CI) 1.42-3.29) and more frequent (OR = 1.67, 95% CI 1.13-2.48) disruptive behavior. Even though ASD children were receiving different types of support, also requiring specialist (19.1%) or emergency (1.5%) interventions in a relatively low proportion of cases, a number of needs emerged, including receiving more healthcare support (47.4%), especially in-home support (29.9%), as well as interventions to tackle a potentially disruptive quarantine (16.8%). The COVID-19 outbreak has undoubtedly resulted in increased difficulties among ASD individuals.
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3. Eissa N, Azimullah S, Jayaprakash P, Jayaraj RL, Reiner D, Ojha SK, Beiram R, Stark H, Łażewska D, Kieć-Kononowicz K, Sadek B. {{The Dual-Active Histamine H(3) Receptor Antagonist and Acetylcholine Esterase Inhibitor E100 Alleviates Autistic-Like Behaviors and Oxidative Stress in Valproic Acid Induced Autism in Mice}}. {Int J Mol Sci};2020 (Jun 3);21(11)
The histamine H3 receptor (H3R) functions as auto- and hetero-receptors, regulating the release of brain histamine (HA) and acetylcholine (ACh), respectively. The enzyme acetylcholine esterase (AChE) is involved in the metabolism of brain ACh. Both brain HA and ACh are implicated in several cognitive disorders like Alzheimer’s disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with autistic spectrum disorder (ASD). Therefore, the novel dual-active ligand E100 with high H3R antagonist affinity (hH3R: K(i) = 203 nM) and balanced AChE inhibitory effect (EeAChE: IC(50) = 2 µM and EqBuChE: IC(50) = 2 µM) was investigated on autistic-like sociability, repetitive/compulsive behaviour, anxiety, and oxidative stress in male C57BL/6 mice model of ASD induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, intraperitoneal (i.p.)). Subchronic systemic administration with E100 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently attenuated sociability deficits of autistic (VPA) mice in three-chamber behaviour (TCB) test (all p < 0.05). Moreover, E100 significantly improved repetitive and compulsive behaviors by reducing the increased percentage of marbles buried in marble-burying behaviour (MBB) (all p < 0.05). Furthermore, pre-treatment with E100 (10 and 15 mg/kg, i.p.) corrected decreased anxiety levels (p < 0.05), however, failed to restore hyperactivity observed in elevated plus maze (EPM) test. In addition, E100 (10 mg/kg, i.p.) mitigated oxidative stress status by increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and decreasing the elevated levels of malondialdehyde (MDA) in the cerebellar tissues (all p < 0.05). Additionally, E100 (10 mg/kg, i.p.) significantly reduced the elevated levels of AChE activity in VPA mice (p < 0.05). These results demonstrate the promising effects of E100 on in-vivo VPA-induced ASD-like features in mice, and provide evidence that a potent dual-active H3R antagonist and AChE inhibitor (AChEI) is a potential drug candidate for future therapeutic management of autistic-like behaviours. Lien vers le texte intégral (Open Access ou abonnement)
4. Keesler JM. {{From the DSP Perspective: Exploring the Use of Practices That Align With Trauma-Informed Care in Organizations Serving People With Intellectual and Developmental Disabilities}}. {Intellect Dev Disabil};2020 (Jun 1);58(3):208-220.
Trauma-informed care (TIC) is a systemwide approach that emphasizes organizational practices based upon principles of safety, choice, collaboration, empowerment, and trustworthiness. It is intended to influence an entire organization, with implications for clients and the workforce. The present study explored the extent to which IDD organizations utilize practices that align with TIC with their DSP workforce. Through an online survey, 380 DSPs (84% women; 82% white) responded to a trauma-informed organizational culture measure. Results demonstrated variability across items and significant differences between TIC principles with safety most strongly scored, and collaboration least strongly scored. Perception of organizational practices differed by ethnicity, with non-white DSPs having more favorable responses. Current practices with DSPs align with TIC, however, increased attention through explicit trauma-informed initiatives is warranted.
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5. Keifer CM, Mikami AY, Morris JP, Libsack EJ, Lerner MD. {{Prediction of social behavior in autism spectrum disorders: Explicit versus implicit social cognition}}. {Autism};2020 (Jun 2):1362361320922058.
Difficulties with social communication and interaction are a hallmark feature of autism spectrum disorder. These difficulties may be the result of problems with explicit social cognition (effortful and largely conscious processes) such as learning and recalling social norms or rules. Alternatively, social deficits may stem from problems with implicit social cognition (rapid and largely unconscious processes) such as the efficient integration of social information. The goal of this study was to determine how problems in explicit and implicit social cognition relate to social behavior in 34 youth with autism spectrum disorder. We measured aspects of implicit and explicit social cognition abilities in the laboratory using behavioral, cognitive, and brain (electrophysiological) measures. We then used those measures to predict « real-world » social behavior as reported by parents, clinicians, and independent observers. Results showed that overall better aspects of implicit and explicit social cognition predicted more competent social behavior. In addition, the ability to fluidly integrate social information (implicit social cognition) was more frequently related to competent social behavior that merely knowing what to do in social situations (explicit social cognition). These findings may help with the development of interventions focusing on improving social deficits.
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6. Khoury ES, Sharma A, Ramireddy RR, Thomas AG, Alt J, Fowler A, Rais R, Tsukamoto T, Blue ME, Slusher B, Kannan S, Kannan RM. {{Dendrimer-conjugated glutaminase inhibitor selectively targets microglial glutaminase in a mouse model of Rett syndrome}}. {Theranostics};2020;10(13):5736-5748.
Background: Elevated glutamate production and release from glial cells is a common feature of many CNS disorders. Inhibitors of glutaminase (GLS), the enzyme responsible for converting glutamine to glutamate have been developed to target glutamate overproduction. However, many GLS inhibitors have poor aqueous solubility, are unable to cross the blood brain barrier, or demonstrate significant toxicity when given systemically, precluding translation. Enhanced aqueous solubility and systemic therapy targeted to activated glia may address this challenge. Here we examine the impact of microglial-targeted GLS inhibition in a mouse model of Rett syndrome (RTT), a developmental disorder with no viable therapies, manifesting profound central nervous system effects, in which elevated glutamatergic tone, upregulation of microglial GLS, oxidative stress and neuroimmune dysregulation are key features. Methods: To enable this, we conjugated a potent glutaminase inhibitor, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenyl-acetamide (JHU29) to a generation 4 hydroxyl PAMAM dendrimer (D-JHU29). We then examined the effect of D-JHU29 in organotypic slice culture on glutamate release. We also examined GLS activity in microglial and non-microglial cells, and neurobehavioral phenotype after systemic administration of D-JHU29 in a mouse model of RTT. Results: We report successful conjugation of JHU29 to dendrimer resulting in enhanced water solubility compared to free JHU29. D-JHU29 reduced the excessive glutamate release observed in tissue culture slices in a clinically relevant Mecp2-knockout (KO) RTT mouse. Microglia isolated from Mecp2-KO mice demonstrated upregulation of GLS activity that normalized to wild-type levels following systemic treatment with D-JHU29. Neurobehavioral assessments in D-JHU29 treated Mecp2-KO mice revealed selective improvements in mobility. Conclusion: These findings demonstrate that glutaminase inhibitors conjugated to dendrimers are a viable mechanism to selectively inhibit microglial GLS to reduce glutamate production and improve mobility in a mouse model of RTT, with broader implications for selectively targeting this pathway in other neurodegenerative disorders.
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7. Lee CYQ, Franks AE, Hill-Yardin EL. {{Autism-associated synaptic mutations impact the gut-brain axis in mice}}. {Brain Behav Immun};2020 (May 30)
Interactions between the gut microbiome and the brain affect mood and behaviour in health and disease. Using preclinical animal models, recent discoveries begin to explain how bacteria in the gut influence our mood as well as highlighting new findings relevant to autism. Autism-associated gene mutations known to alter synapse function in the CNS also affect inflammatory response and modify the enteric nervous system resulting in abnormal gastrointestinal motility and structure. Strikingly, these mutations additionally affect the gut microbiome in mice. This review describes the changes in gut physiology and microbiota in mouse models of autism with modified synapse function. The rationale for different regions of the gastrointestinal tract having variable susceptibility to dysfunction is also discussed. To dissect underlying biological mechanisms involving gut-brain axis dysfunction in preclinical models, a range of multidisciplinary approaches are required. This research will provide insights into the role of the gut-brain axis in health and neurodevelopmental disorders including autism.
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8. Ma L, Hagerman PJ. {{Autofluorescence-based analyses of intranuclear inclusions of Fragile X-associated tremor/ataxia syndrome}}. {Biotechniques};2020 (Jun 3)
Intranuclear inclusions present in the brains of patients with Fragile X-associated tremor/ataxia syndrome (FXTAS) have historically been difficult to study due to their location and scarcity. The recent finding that these particles autofluoresce has complicated the use of immunofluorescence techniques, but also offers new opportunities for purification. We have ascertained the features of the autofluorescence, including its excitation/emission spectrum, similarities and differences compared with lipofuscin autofluorescence, and its presence/absence under various fixation, mounting and UV light exposure conditions. Immunofluorescence at various wavelengths was conducted to determine which conditions are ideal for minimizing autofluorescence confounds. We also present a technique for autofluorescence-based sorting of FXTAS inclusions using flow cytometry, which will allow researchers in the field to purify inclusions more successfully for unbiased analyses.
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9. Masson HL, Op de Beeck H, Boets B. {{Reduced task-dependent modulation of functional network architecture for positive versus negative affective touch processing in autism spectrum disorders}}. {Neuroimage};2020 (Jun 3):117009.
Individuals with autism spectrum disorders (ASD) experience impairments in social communication and interaction, and often show difficulties with receiving and offering touch. Despite the high prevalence of abnormal reactions to touch in ASD, and the importance of touch communication in human relationships, the neural mechanisms underlying atypical touch processing in ASD remain largely unknown. To answer this question, we provided both pleasant and unpleasant touch stimulation to male adults with and without ASD during functional neuroimaging. By employing generalized psychophysiological interaction analysis combined with an independent component analysis approach, we characterize stimulus-dependent changes in functional connectivity patterns for processing two tactile stimuli that evoke different emotions (i.e., pleasant vs. unpleasant touch). Results reveal that neurotypical male adults showed extensive stimulus-sensitive modulations of the functional network architecture in response to the different types of touch, both at the level of brain regions and large-scale networks. Conversely, far fewer stimulus-sensitive modulations were observed in the ASD group. These aberrant functional connectivity profiles in the ASD group were marked by hypo-connectivity of the parietal operculum and major pain networks and hyper-connectivity between the semantic and limbic networks. Lastly, individuals presenting more social deficits and a more negative attitude towards social touch showed greater hyper-connectivity between the limbic and semantic networks. These findings suggest that reduced stimulus-related modulation of this functional network architecture is associated with abnormal processing of touch in ASD.
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10. Merrick H, King C, McConachie H, Parr JR, Le Couteur A. {{Experience of transfer from child to adult mental health services of young people with autism spectrum disorder}}. {BJPsych Open};2020 (Jun 3);6(4):e58.
BACKGROUND: Transition from child-centred to adult mental health services has been reported as challenging for young people. It can be especially difficult for young people with autism spectrum disorder (ASD) as they manage the challenges of adolescence and navigate leaving child and adolescent mental health services (CAMHS). AIMS: This study examines the predictors of transfer to adult mental health services, and using a qualitative analysis, explores the young people’s experiences of transition. METHOD: A UK sample of 118 young people aged 14-21 years, with ASD and additional mental health problems, recruited from four National Health Service trusts were followed up every 12 months over 3 years, as they were discharged from CAMHS. Measures of mental health and rich additional contextual information (clinical, family, social, educational) were used to capture their experiences. Regression and framework analyses were used. RESULTS: Regression analysis showed having an attention-deficit hyperactivity disorder diagnosis and taking medication were predictors of transfer from child to adult mental health services. Several features of young people’s transition experience were found to be associated with positive outcomes and ongoing problems, including family factors, education transitions and levels of engagement with services. CONCLUSIONS: The findings show the importance of monitoring and identifying those young people that might be particularly at risk of negative outcomes and crisis presentations. Although some young people were able to successfully manage their mental health following discharge from CAMHS, others reported levels of unmet need and negative experiences of transition.
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11. Mills WR, Sender S, Lichtefeld J, Romano N, Reynolds K, Price M, Phipps J, White L, Howard S, Poltavski D, Barnes R. {{Supporting individuals with intellectual and developmental disability during the first 100 days of the COVID-19 outbreak in the USA}}. {J Intellect Disabil Res};2020 (Jun 3)
BACKGROUND: It is unknown how the novel Coronavirus SARS-CoV-2, the cause of the current acute respiratory illness COVID-19 pandemic that has infected millions of people, affects people with intellectual and developmental disability (IDD). The aim of this study is to describe how individuals with IDD have been affected in the first 100 days of the COVID-19 pandemic. METHODS: Shortly after the first COVID-19 case was reported in the USA, our organisation, which provides continuous support for over 11 000 individuals with IDD, assembled an outbreak committee composed of senior leaders from across the health care organisation. The committee led the development and deployment of a comprehensive COVID-19 prevention and suppression strategy, utilising current evidence-based practice, while surveilling the global and local situation daily. We implemented enhanced infection control procedures across 2400 homes, which were communicated to our employees using multi-faceted channels including an electronic resource library, mobile and web applications, paper postings in locations, live webinars and direct mail. Using custom-built software applications enabling us to track patient, client and employee cases and exposures, we leveraged current public health recommendations to identify cases and to suppress transmission, which included the use of personal protective equipment. A COVID-19 case was defined as a positive nucleic acid test for SARS-CoV-2 RNA. RESULTS: In the 100-day period between 20 January 2020 and 30 April 2020, we provided continuous support for 11 540 individuals with IDD. Sixty-four per cent of the individuals were in residential, community settings, and 36% were in intermediate care facilities. The average age of the cohort was 46 ± 12 years, and 60% were male. One hundred twenty-two individuals with IDD were placed in quarantine for exhibiting symptoms and signs of acute infection such as fever or cough. Sixty-six individuals tested positive for SARS-CoV-2, and their average age was 50. The positive individuals were located in 30 different homes (1.3% of total) across 14 states. Fifteen homes have had single cases, and 15 have had more than one case. Fifteen COVID-19-positive individuals were hospitalised. As of 30 April, seven of the individuals hospitalised have been discharged back to home and are recovering. Five remain hospitalised, with three improving and two remaining in intensive care and on mechanical ventilation. There have been three deaths. We found that among COVID-19-positive individuals with IDD, a higher number of chronic medical conditions and male sex were characteristics associated with a greater likelihood of hospitalisation. CONCLUSIONS: In the first 100 days of the COVID-19 outbreak in the USA, we observed that people with IDD living in congregate care settings can benefit from a coordinated approach to infection control, case identification and cohorting, as evidenced by the low relative case rate reported. Male individuals with higher numbers of chronic medical conditions were more likely to be hospitalised, while most younger, less chronically ill individuals recovered spontaneously at home.
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12. Nguyen TA, Wu K, Pandey S, Lehr AW, Li Y, Bemben MA, Badger JD, 2nd, Lauzon JL, Wang T, Zaghloul KA, Thurm A, Jain M, Lu W, Roche KW. {{A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y}}. {Neuron};2020 (Jun 3);106(5):759-768 e757.
Autism spectrum disorder (ASD) is more prevalent in males; however, the etiology for this sex bias is not well understood. Many mutations on X-linked cell adhesion molecule NLGN4X result in ASD or intellectual disability. NLGN4X is part of an X-Y pair, with NLGN4Y sharing ∼97% sequence homology. Using biochemistry, electrophysiology, and imaging, we show that NLGN4Y displays severe deficits in maturation, surface expression, and synaptogenesis regulated by one amino acid difference with NLGN4X. Furthermore, we identify a cluster of ASD-associated mutations surrounding the critical amino acid in NLGN4X, and these mutations phenocopy NLGN4Y. We show that NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations. Altogether, our data reveal a potential pathogenic mechanism for male bias in NLGN4X-associated ASD.
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13. Oser TK, Oser SM, Parascando JA, Grisolano LA, Krishna KB, Hale DE, Litchman M, Majidi S, Haidet P. {{Challenges and Successes in Raising a Child With Type 1 Diabetes and Autism Spectrum Disorder: Mixed Methods Study}}. {J Med Internet Res};2020 (Jun 3);22(6):e17184.
BACKGROUND: Self-management of type 1 diabetes (T1D) requires numerous decisions and actions by people with T1D and their caregivers and poses many daily challenges. For those with T1D and a developmental disorder such as autism spectrum disorder (ASD), more complex challenges arise, though these remain largely unstudied. OBJECTIVE: This study aimed to better understand the barriers and facilitators of raising a child with T1D and ASD. Secondary analysis of web-based content (phase 1) and telephone interviews (phase 2) were conducted to further expand the existing knowledge on the challenges and successes faced by these families. METHODS: Phase 1 involved a qualitative analysis of publicly available online forums and blog posts by caregivers of children with both T1D and ASD. Themes from phase 1 were used to create an interview guide for further in-depth exploration via interviews. In phase 2, caregivers of children with both T1D and ASD were recruited from Penn State Health endocrinology clinics and through the web from social media posts to T1D-focused groups and sites. Interested respondents were directed to a secure web-based eligibility assessment. Information related to T1D and ASD diagnosis, contact information, and demographics were collected. On the basis of survey responses, participants were selected for a follow-up telephone interview and were asked to complete the adaptive behavior assessment system, third edition parent form to assess autism severity and upload a copy of their child’s most recent hemoglobin A(1c) (HbA(1c)) result. Interviews were transcribed, imported into NVivo qualitative data management software, and analyzed to determine common themes related to barriers and facilitators of raising a child with both ASD and T1D. RESULTS: For phase 1, 398 forum posts and blog posts between 2009 and 2016 were analyzed. Common themes related to a lack of understanding by the separate ASD and T1D caregiver communities, advice on coping techniques, rules and routines, and descriptions of the health care experience. For phase 2, 12 eligible respondents were interviewed. For interviewees, the average age of the child at diagnosis with T1D and ASD was 7.92 years and 5.55 years, respectively. Average self-reported and documented HbA(1c) levels for children with T1D and ASD were 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol), respectively. Common themes from the interviews related to increased emotional burden, frustration surrounding the amount of information they are expected to learn, and challenges in the school setting. CONCLUSIONS: Caregivers of children with both T1D and ASD face unique challenges, distinct from those faced by caregivers of individuals who have either disorder alone. Understanding these challenges may help health care providers in caring for this unique population. Referral to the diabetes online community may be a potential resource to supplement the care received by the medical community.
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14. Shuai FR, Lin ZY. {{Effectiveness of social skills intervention for the management of children with autism spectrum disorder: A protocol for systematic review and meta-analysis}}. {Medicine (Baltimore)};2020 (May 29);99(22):e20331.
BACKGROUND: This study will investigate the effectiveness of and safety of social skills intervention (SSI) for the management of children with autism spectrum disorder (ASD). METHODS: All potential randomized controlled trials related to the effectiveness and safety of SSI for children with ASD will be retrieved from Cochrane Library, MEDLINE, EMBASE, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All these databases will be identified from inception to the present with no limitations of language and publication time. Two investigators will independently perform selection of study, data collection, and study quality assessment, respectively. A third investigator will help to solve any different views between 2 investigators. RevMan 5.3 software will be used for data pooling and statistical analysis. RESULTS: This study will provide synthesis of present evidence on assessing the effectiveness and safety of SSI for children with ASD. CONCLUSION: This study will provide helpful references for the effectiveness and safety of SSI on the management of ASD, which may benefit both patients and clinicians. STUDY REGISTRATION NUMBER: INPLASY202040090.
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15. Stanojlovic S, Milovancevic MP, Stankovic B. {{Is there a potential link between keratoconus and autism spectrum disorders?: A case report and literature review}}. {Medicine (Baltimore)};2020 (May 29);99(22):e20247.
RATIONALE: Eye rubbing (ER) is a proven factor that can trigger the onset and progression of keratoconus (KC). Apart from allergy, ER is a repetitive motor stereotypy. Eye rubbing is frequently observed in children with autism spectrum disorders (ASDs) and in individuals who may be at risk for developing KC. We present a child with ASD who developed progressive KC following standard corneal cross-linking (CXL), most likely because of abnormal ER associated with allergy and repetitive behavior due to ASD symptoms. PATIENT CONCERNS: A 14-year-old boy was referred to our clinic because of asymmetric visual acuity reduction. DIAGNOSIS: The child was diagnosed as having keratoconus. He had a strong ER habit. The child had been previously diagnosed as having ASD. INTERVENTIONS: Corneal cross-linking was performed in both the eyes. On account of keratoconus progression, most likely associated with persistent ER habit, he was retreated with CXL in the right eye. Behavioral modification intervention for ER habit reversal was also applied. OUTCOMES: Corneal cross-linking in combination with behavioral modification intervention for ER habit reversal prevented further KC progression. LESSONS: Behavioral interventions are likely to provide positive results in an ER habit reversal in children with ASD. Keratoconus treatment with CXL combined with behavioral management for ER reversal seemed effective in halting keratoconus progression in a young patient with ASD.
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16. Stathopoulos S, Gaujoux R, Lindeque Z, Mahony C, Van Der Colff R, Van Der Westhuizen F, O’Ryan C. {{DNA Methylation Associated with Mitochondrial Dysfunction in a South African Autism Spectrum Disorder Cohort}}. {Autism Res};2020 (Jun 3)
Autism spectrum disorder (ASD) is characterized by phenotypic heterogeneity and a complex genetic architecture which includes distinctive epigenetic patterns. We report differential DNA methylation patterns associated with ASD in South African children. An exploratory whole-epigenome methylation screen using the Illumina 450 K MethylationArray identified differentially methylated CpG sites between ASD and controls that mapped to 898 genes (P ≤ 0.05) which were enriched for nine canonical pathways converging on mitochondrial metabolism and protein ubiquitination. Targeted Next Generation Bisulfite Sequencing of 27 genes confirmed differential methylation between ASD and control in our cohort. DNA pyrosequencing of two of these genes, the mitochondrial enzyme Propionyl-CoA Carboxylase subunit Beta (PCCB) and Protocadherin Alpha 12 (PCDHA12), revealed a wide range of methylation levels (9-49% and 0-54%, respectively) in both ASD and controls. Three CpG loci were differentially methylated in PCCB (P ≤ 0.05), while PCDHA12, previously linked to ASD, had two significantly different CpG sites (P ≤ 0.001) between ASD and control. Differentially methylated CpGs were hypomethylated in ASD. Metabolomic analysis of urinary organic acids revealed that three metabolites, 3-hydroxy-3-methylglutaric acid (P = 0.008), 3-methyglutaconic acid (P = 0.018), and ethylmalonic acid (P = 0.043) were significantly elevated in individuals with ASD. These metabolites are directly linked to mitochondrial respiratory chain disorders, with a putative link to PCCB, consistent with impaired mitochondrial function. Our data support an association between DNA methylation and mitochondrial dysfunction in the etiology of ASD. LAY SUMMARY: Epigenetic changes are chemical modifications of DNA which can change gene function. DNA methylation, a type of epigenetic modification, is linked to autism. We examined DNA methylation in South African children with autism and identified mitochondrial genes associated with autism. Mitochondria are power-suppliers in cells and mitochondrial genes are essential to metabolism and energy production, which are important for brain cells during development. Our findings suggest that some individuals with ASD also have mitochondrial dysfunction.
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17. Tatavarty V, Torrado Pacheco A, Groves Kuhnle C, Lin H, Koundinya P, Miska NJ, Hengen KB, Wagner FF, Van Hooser SD, Turrigiano GG. {{Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1}}. {Neuron};2020 (Jun 3);106(5):769-777 e764.
Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which, in turn, may render them more vulnerable to such perturbations.
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18. Whitlock A, Fulton K, Lai MC, Pellicano E, Mandy W. {{Recognition of Girls on the Autism Spectrum by Primary School Educators: An Experimental Study}}. {Autism Res};2020 (Jun 3)
Autism has long been considered a predominantly male condition. It is increasingly understood, however, that autistic females are under-recognized. This may reflect gender stereotyping, whereby symptoms are missed in females, because it is assumed that autism is mainly a male condition. Also, some autistic girls and women may go unrecognized because there is a « female autism phenotype » (i.e., a female-typical autism presentation), which does not fit current, male-centric views of autism. Potential biases shown by educators, in their role as gatekeepers for an autism assessment, may represent a barrier to the recognition of autism in females. We used vignettes describing autistic children to test: (a) whether gender stereotyping occurs, whereby educators rate males as more likely to be autistic, compared to females with identical symptoms; (b) whether recognition is affected by sex/gender influences on autistic presentation, whereby children showing the male autism phenotype are rated as more likely to be autistic than those with the female phenotype. Ratings by primary school educators showed a significant main effect of both gender and presentation (male phenotype vs. female phenotype) on estimations of the child in the vignette being autistic: respondents showed a bias against girls and the female autism phenotype. There was also an interaction: female gender had an effect on ratings of the female phenotype, but not on the male phenotype vignette. These findings suggest that primary school educators are less sensitive to autism in girls, through under-recognition of the female autism phenotype and a higher sensitivity to autism in males. LAY SUMMARY: Educators have an important role in identifying children who need an autism assessment, so gaps in their knowledge about how autism presents in girls could contribute to the under-diagnosis of autistic girls. By asking educators to identify autism when presented with fictional descriptions of children, this study found that educators were less able to recognize what autism « looks like » in girls. Also, when given identical descriptions of autistic boys and girls, educators were more likely to identify autism in boys. These results suggest that primary school educators might need extra help to improve the recognition of girls on the autism spectrum.
