Pubmed du 07/01/20

mardi 7 janvier 2020

1. Alakhzami M, Huang A. Individuals with Autism Spectrum Disorders and Developmental Disorders in Oman : An Overview of Current Status. J Autism Dev Disord ;2020 (Jan 6)

This paper offers an overview of the current status of individuals with autism spectrum disorders (ASD) and developmental disorders (DD) in Oman. A review of demographic and background information about Oman is first presented, followed by an overview of the current status of individuals with autism and developmental disorders, in terms of disability-related legislation, prevalence and diagnosis, as well as treatment and education. In the last section of the paper, major challenges faced in the field are addressed, including lack of autism awareness, lack of healthcare and educational programs or related services, lack of highly qualified professionals to implement evidence-based practices, issues regarding early identification and early intervention, as well as issues pertaining secondary transition, independent living and employment. Corresponding recommendation is proposed at the end of each challenge.

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2. Apicella F, Costanzo V, Purpura G. Are early visual behavior impairments involved in the onset of autism spectrum disorders ? Insights for early diagnosis and intervention. Eur J Pediatr ;2020 (Jan 4)

A correct use of the visual behavior (VB), and its integration with motor function, represents the earliest mean used by infants to explore and act on the social and non-social surrounding environment. The aim of this mini review is to present influential evidence of abnormalities in the VB domain in ASD individuals and to discuss the implication of these findings for early identification and intervention. We analyzed the possible anomalies in oculomotor abilities, visual attention, and visual-motor integration, as parts of a wider visual behavior defect, that could affect children with autism spectrum disorders (ASD) since the early stages of development.Conclusion : According to the literature, difficulties in these three areas have been often reported in children with ASD, and the visual-perception deficit could have cascading effects on learning processes and on social development. Despite this evidence of atypical VB in ASD, their investigation is not yet included into diagnostic processes, and they are not yet considered a specific treatment target.What is Known :*Atypical social use of visual behavior is one the first symptoms in children with autism spectrum disorders*Individuals with autism spectrum disorders often show unusual visual exploration of the surrounding environmentWhat is New :*It is possible to hypothesize that early visual behavior abnormalities may affect experiences that permit learning processes and social and communicative development in infants*An early assessment of visual behavior, as a core symptom of ASD, might improve the diagnostic processes and might help to developing more individualized treatments.

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3. Di J, Li J, O’Hara B, Alberts I, Xiong L, Li X. The role of GABAergic Neural Circuits in the Pathogenesis of Autism Spectrum Disorder. Int J Dev Neurosci ;2020 (Jan 7)

Autism Spectrum Disorder (ASD) comprises a heterogeneous range of neurodevelopmental conditions represented by symptoms including, communication and language deficits, repetitive and restricted patterns of behavior and inadequate social interactions. Gamma-aminobutyric acid (GABA) is known to mediate inhibitory responses in the Central Nervous System (CNS) by interacting with GABA signaling receptors. In this context, several recent investigations suggest that imbalances in the GABAergic neurotransmission system may be implicated in the development of ASD as well as several other neurodevelopmental disorders, including Fragile X Syndrome and Rett Syndrome. This review initially expounds the functional role of the GABAergic system in the mature brain and during neurodevelopment. This will be followed by discussions concerning the impact of deficiencies in the system on ASD and the other above-mentioned neurodevelopment disorders. Finally, the connections between these deficiencies and behavioral features observed in the clinic will be considered.

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4. Edmondson DA, Xia P, McNally Keehn R, Dydak U, Keehn B. A Magnetic Resonance Spectroscopy Study of Superior Visual Search Abilities in Children with Autism Spectrum Disorder. Autism Res ;2020 (Jan 7)

Although diagnosed on the basis of deficits in social communication and interaction, autism spectrum disorder (ASD) is also characterized by superior performance on a variety of visuospatial tasks, including visual search. In neurotypical individuals, region-specific concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are associated with individual differences in attention and perception. While it has been hypothesized that ASD may be associated with an excitatory-inhibitory imbalance, it remains unclear how this may contribute to accelerated visual search performance in individuals with ASD. To investigate this, 21 children with ASD and 20 typically developing children participated in a visual search task and a magnetic resonance spectroscopy study to detect neurochemical concentrations, including GABA. Region-specific neurochemicals were examined in the right frontal eye fields, right temporal-parietal junction (rTPJ), and bilateral visual cortex (VIS). GABA concentrations did not differ between groups ; however, in children with ASD, greater GABA concentration in the VIS was related to more efficient search. Additionally, lower VIS GABA levels were also associated with increased social impairment. Finally, we found reduced N-acetyl aspartate, total creatine, glutamate and glutamine (Glx), GABA/Glx in the rTPJ, suggestive of neuronal dysfunction in a critical network hub. Our results show that GABA concentrations in the VIS are related to efficient search in ASD, thus providing further evidence of enhanced discrimination in ASD. Autism Res 2019, 00 : 1-13. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Children with autism spectrum disorder (ASD) often perform better than their non-ASD peers on visual search tasks ; however, it is unclear how they achieve this superior performance. Using magnetic resonance spectroscopy to measure neurochemicals in the brain, we found that the level of one, gamma-aminobutyric acid, in the visual cortex was directly related to search abilities in children with ASD. These results suggest that faster search may relate to enhanced perceptual functioning in children with ASD.

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5. ElMoazen D, Sobhy O, Abdou R, AbdelMotaleb H. Binaural interaction component of the auditory brainstem response in children with autism spectrum disorder. Int J Pediatr Otorhinolaryngol ;2019 (Dec 24) ;131:109850.

INTRODUCTION : There is ample evidence that auditory dysfunction is a common feature of autism spectrum disorder (ASD). Binaural interaction component (BIC) manifests binaural interaction and is valid and proven response which reflects ongoing binaural processing. OBJECTIVES : To investigate the differences in binaural interaction component of auditory brainstem response (ABR-BIC) between children with autism spectrum disorder (ASD) and normal peers and to correlate between ABR-BIC amplitudes and the acquired communication skills in ASD children. METHODS : ASD was diagnosed according to the criteria of 5th edition of diagnostic and statistical manual of mental disorders (DSM-V) and all children with ASD underwent test of acquired communication skills (TACS). Click evoked ABRs were elicited by left monaural, right monaural and binaural stimulation at intensity of 65 dBnHL in all participants. ABR-BIC was then calculated as the difference between the binaurally evoked ABR waveform and a predicted binaural waveform created by algebraically summing the left and right monaurally evoked ABRs. The difference in amplitudes that gives rise to ABR-BIC is at IV-VI waves. RESULTS : ABR-BIC amplitudes were demonstrated to be significantly reduced in the ASD group compared to the control group. There was significant positive correlation between ABR-BIC amplitude and the language and social scores in TACS. CONCLUSION : This study provided an objective evidence of binaural processing disorder in children with ASD.

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6. Fombonne E, Goin-Kochel RP, O’Roak BJ. Beliefs in vaccine as causes of autism among SPARK cohort caregivers. Vaccine ;2020 (Jan 7)

BACKGROUND : Fear of autism has led to a decline in childhood-immunization uptake and to a resurgence of preventable infectious diseases. Identifying characteristics of parents who believe in a causal role of vaccines for autism spectrum disorder (ASD) in their child may help targeting educational activities and improve adherence to the immunization schedule. OBJECTIVES : To compare caregivers of children with ASD who agree or disagree that vaccines play an etiological role in autism for 1) socio-demographics characteristics and 2) developmental and clinical profiles of their children. METHODS : Data from 16,525 participants with ASD under age 18 were obtained from SPARK, a national research cohort started in 2016. Caregivers completed questionnaires at registration that included questions on beliefs about the etiologic role of childhood immunizations and other factors in ASD. Data were available about family socio-demographic characteristics, first symptoms of autism, developmental regression, co-occurring psychiatric disorders, seizures, and current levels of functioning. RESULTS : Participants with ASD were 80.4% male with a mean age of 8.1years (SD=4.1). Overall, 16.5% of caregivers endorsed immunizations as perceived causes of autism. Compared to caregivers who disagreed with vaccines as a cause for ASD, those who believed in vaccine causation came disproportionately from ethnic minority, less educated, and less wealthy backgrounds. More often their children had experienced developmental regression involving language and other skills, were diagnosed earlier, had lost skills during the second year of life, and had worse language, adaptive, and cognitive outcomes. CONCLUSION : One in six caregivers who participate in a national research cohort believe that child immunizations could be a cause of autism in their child. Parent social background (non-White, less educated) and child developmental features (regression in second year, poorer language skills, and worse adaptive outcomes) index caregivers who are more likely to harbor these beliefs and could benefit from targeted educational activities.

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7. Frega M, Selten M, Mossink B, Keller JM, Linda K, Moerschen R, Qu J, Koerner P, Jansen S, Oudakker A, Kleefstra T, van Bokhoven H, Zhou H, Schubert D, Nadif Kasri N. Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype. Cell Rep ;2020 (Jan 7) ;30(1):173-186 e176.

Pathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3, or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features of both intellectual disability (ID) and autism spectrum disorder (ASD). To understand how these variants lead to the phenotypic convergence in KSS, we employ a loss-of-function approach to assess neuronal network development at the molecular, single-cell, and network activity level. KSS-gene-deficient neuronal networks all develop into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data reveal distinct regulatory mechanisms, KSS target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network communication, providing insights into the pathophysiology of KSS and phenotypically congruent disorders.

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8. Gong P, Xue J, Jiao XR, Zhang YH, Yang ZX. [Genotype and phenotype of children with KCNA2 gene related developmental and epileptic encephalopathy]. Zhonghua Er Ke Za Zhi ;2020 (Jan 2) ;58(1):35-40.

Objective : To investigate the genotype and phenotype of children with KCNA2 gene related developmental and epileptic encephalopathy (DEE). Methods : Clinical data including the manifestations and electroencephalogram of 8 children with KCNA2 variants treated in the Department of Pediatrics, Peking University First Hospital from March 2017 to June 2019 were collected and analyzed retrospectively. Results : Among the 8 epileptic patients with KCNA2 variants, 5 were males and 3 were females. The age of onset was from 1 day to 11 months. The age at last follow-up ranged from 4 months to 86 months. Two variants including c.1214C>T (loss-of-function) and c.1120A>G (gain-and loss-of-function) were identified. The variant of c.1214C>T was found in six patients (case 1-6). For these patients, the age of onset was from 5 to 11 months and they were characterized by multiple seizure types. All had focal seizures and had normal development before seizure onset with developmental regression after seizure onset. The first electroencephalogram showed epileptic discharges in Rolandic region in two, epileptic discharges in Rolandic region combined with generalized discharge in one, generalized discharge with posterior predominance in two (combined with or transferred to Rolandic region during the course) and epileptic discharges in posterior region combined with generalized discharge in one. And in 5 of them the Rolandic discharges developed into epileptic electrical status (ESES) during sleep. All the six patients were still treated with a combination of multiple antiepileptic drugs. Two of them had seizure controlled at 80 months and 68 months, respectively. The variant of c.1120A>G were identified in two of eight patients (case 7 and 8) and they had seizure onset on the 1st day after birth. Their epileptic seizures were frequent and difficult to control. They had remarkably developmental delay and microcephaly since birth. One case (case 8) had a wide forehead. They had frequent seizures up to the last follow-up. In case 7, the early electroencephalogram showed epileptic discharges in temporal region, and interictal electroencephalogram at 3 months of age showed multifocal discharge with posterior and temporal region predominance. In case 8, the early electroencephalogram was normal and electroencephalogram showed burst suppression at 2 months of age, and it developed epileptiform discharge in posterior region at 1 year of age. Conclusions : KCNA2 gene variants can lead to DEE with multiple seizures types. Among them, loss-of-function c.1214C>T is the most common, and these patients have seizure onset at infancy with Rolandic discharges tended to develop into to ESES pattern. The variant of c.1120A>G is a gain-of- and loss-of-function variant, patients with c.1120A>G have seizure onset in neonatal period, the phenotype overlaps with the former but is more severe.

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9. Gordon A, Geddert R, Hogeveen J, Krug MK, Obhi S, Solomon M. Not So Automatic Imitation : Expectation of Incongruence Reduces Interference in Both Autism Spectrum Disorder and Typical Development. J Autism Dev Disord ;2020 (Jan 4)

Research has observed evidence for both hypo-(supposedly due to a broken mirror neuron system) and hyper-(thought to be the result of deficits in adaptive control) imitation in autism spectrum disorder (ASD). This work sought to adjudicate between these findings using an automatic imitation (AI) paradigm with the novel manipulation of the need to engage adaptive control of imitation. Results demonstrated that ASD participants do not display a specific deficit in AI capability, are able to engage in proactive control of AI, and that relative to a well-matched effector condition, AI is not selectively associated with ASD symptom severity. These data cast doubt upon the notion of impairments in imitation or its control in ASD.

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10. Heifetz M, Lake J, Weiss J, Isaacs B, Connolly J. Dating and romantic relationships of adolescents with intellectual and developmental disabilities. J Adolesc ;2019 (Dec 31) ;79:39-48.

INTRODUCTION : Adolescents with intellectual and/or developmental disabilities (IDD) are at high risk for sexual exploitation, yet there is a paucity of research on their romantic relationships. The objectives of this study were to examine the romantic understanding and experiences of youth with IDD. METHODS : Thirty-one adolescents (16-19 years ; 21 males and 10 females) with IDD (12 participants with additional diagnosis of ASD) were recruited from a community health clinic. Individual interviews and questionnaires assessed cross-sectionally these youths’ : (1) romantic conceptualizations ; (2) romantic awareness (knowledge of : romantic relationships, sexual behaviours, initiating relationships) ; (3) involvement ; (4) social competence ; and (5) expectations for autonomy. Parent perspectives on these topics were also captured through questionnaires. RESULTS : While 85% reported an immediate desire for a romantic relationship, only 35% were currently in a relationship. Qualitative findings indicated that 14% of youth were unable to differentiate between a romantic relationship and a friendship. Among those who could make this distinction, romantic relationships were conceptualized as serious, commitment for life, and primarily for companionship. Adolescents with ASD, compared to those without ASD, showed weaker social competence and lower romantic awareness. Parents were adolescents’ primary source of information about relationships. Finally, parents and adolescents differed in their perception of the age at which they were ready to date. CONCLUSIONS : This study contributes to our understanding of the romantic experiences of youth with IDD. Prevention efforts focused on education may be important to help ensure these youth develop safe and healthy relationships.

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11. Hirsch MM, Deckmann I, Santos-Terra J, Staevie GZ, Fontes-Dutra M, Carello-Collar G, Korbes-Rockenbach M, Brum Schwingel G, Bauer-Negrini G, Rabelo B, Goncalves MCB, Correa-Velloso J, Naaldijk Y, Castillo AR, Schneider T, Bambini-Junior V, Ulrich H, Gottfried C. Effects of single-dose antipurinergic therapy on behavioral and molecular alterations in the valproic acid-induced animal model of autism. Neuropharmacology ;2020 (Jan 2):107930.

Autism spectrum disorder (ASD) is characterized by deficits in communication and social interaction, restricted interests, and stereotyped behavior. Environmental factors, such as prenatal exposure to valproic acid (VPA), may contribute to the increased risk of ASD. Since disturbed functioning of the purinergic system has been associated with the onset of ASD and used as a potential therapeutic target for ASD in both clinical and preclinical studies, we analyzed the effects of suramin, a non-selective purinergic antagonist, on behavioral, molecular and immunological in an animal model of autism induced by prenatal exposure to VPA. Treatment with suramin (20mg/kg, intraperitoneal) restored sociability in the three-chamber apparatus and decreased anxiety measured by elevated plus maze apparatus, but had no impact on decreased reciprocal social interactions or higher nociceptive threshold in VPA rats. Suramin treatment had no impact on VPA-induced upregulation of P2X4 and P2Y2 in hippocampus, and P2X4 in medial prefrontal cortex, but normalized an increased level of interleukin 6 (IL-6). Our results suggest an important role of purinergic modulation in behavioral, molecular, and immunological aberrations described in VPA model, and suggest that purinergic system might be a potential target for pharmacotherapy in preclinical studies of ASD.

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12. Karthikeyan R, Cardinali DP, Shakunthala V, Spence DW, Brown GM, Pandi-Perumal SR. Understanding the role of sleep and its disturbances in Autism spectrum disorder. Int J Neurosci ;2020 (Jan 14):1-14.

Background : Several studies have established a positive relationship between sleep difficulties and symptomatology in ASD children. The rationale for this review is to describe and discuss the sleep difficulties, which are one of the significant complications associated with autism spectrum disorder (ASD).Purpose : Many types of sleep disorders have been reported in ASD individuals, but still lack a comprehensive study and in-depth analysis. Despite the contribution of sleep problems to the overall symptoms of ASD, the symptoms of disturbed sleep experienced by many affected patients have only recently started to receive attention from clinicians and family members.Materials and methods : This narrative overview has been prepared based on searching standard research databases with specific keywords ; b. Additional search was made using the bibliographies of the retrieved articles ; and c. author’s collection of relevant peer-reviewed articles. Once selected, manuscripts are then compared and summarized based on the author’s perspective. Results are based on a qualitative rather than a quantitative level.Results : This article highlights the role of sleep in the brain and neural development of children and emphasizes that the intensity of sleep problems is associated with an increased occurrence of ASD symptoms. It also suggests the significance of treating sleep problems in ASD individuals.Conclusions : The review provides broader perspectives and a better understanding of sleep problems in pathophysiology, mechanism, and management with respect to ASD individuals. Finally, the implications for clinical practice and future agendas have also been discussed.

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13. Kobayashi A, Yokota S, Takeuchi H, Asano K, Asano M, Sassa Y, Taki Y, Kawashima R. Increased grey matter volume of the right superior temporal gyrus in healthy children with autistic cognitive style : A VBM study. Brain Cogn ;2019 (Dec 31) ;139:105514.

The empathizing-systemizing model describes human cognitive style using empathizing (the drive to identify another’s mental state and respond appropriately) and systemizing (the drive to assess or construct rule-based systems). ’Brain type’ was envisioned to explain individual differences in cognitive style based on the discrepancy of the two drives. In this model, individuals with autism spectrum disorder (ASD), a neurodevelopmental disorder, have extremely stronger systemizing. Revealing the underlying mechanisms of individual differences in cognitive style might contribute to elucidation of the pathology of ASD. We used voxel-based morphometry to compare the brain structures among the brain types (those who have stronger empathizing, those who have equally stronger drive to both, and those who have stronger systemizing) in 207 healthy children (age range : 5-15). Results showed that children with stronger systemizing had significantly greater grey matter volume of the right superior temporal gyrus (rSTG) than the others. The brain region, a distinctive brain structure of those with stronger systemizing, was overlapped with that of children with ASD. The rSTG is involved in detailed perceptual processing in social cognition, which is partially related to stronger systemizing. Our results contribute to elucidation of the underlying mechanisms of individual differences in cognitive style.

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14. Lecavalier L, Bodfish J, Harrop C, Whitten A, Jones D, Pritchett J, Faldowski R, Boyd B. Development of the Behavioral Inflexibility Scale for Children with Autism Spectrum Disorder and Other Developmental Disabilities. Autism Res ;2020 (Jan 6)

Behavior inflexibility (BI) refers to rigid patterns of behavior that contrast with the need to be adaptable to changing environmental demands. We developed a parent-reported outcome measure of BI for children with autism spectrum disorder (ASD) and other developmental disabilities with a multi-step iterative process. A pool of 62 candidate items was generated through expert panel feedback, review of existing scales and focus groups. A consensus process was used to generate the final 38 items. Parents of 943 children (age range, 3-18 years ; average, 11.4 years ; 79% boys) with ASD completed an online survey. One hundred thirty-three parents rated their child twice within 3 weeks (average = 16.5 days). A series of factor analyses suggested that the 38 items measured a single construct. Scores had a weak correlation with level of functioning (-0.12) and did not differ based on sex. Scores had a negligible correlation with age (-0.07), although measurement invariance was not supported. The mean total score for the Behavioral Inflexibility Scale (BIS) was normally distributed. Internal consistency was alpha = 0.97 and temporal stability was r = 0.92. Correlations with parent ratings on the subscales of the Repetitive Behavior Scale-Revised varied from 0.48 to 0.89. The correlation with parent ratings on the Social Communication Questionnaire total score was 0.52. Our data show that BI in children with ASD ranges significantly from mild to severe and that the 38-item BIS is valid and reliable. Autism Res 2020, 00 : 1-11. (c) 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY : We developed a parent-completed rating scale of behavior inflexibility (BI) for children with developmental disabilities using a multistep process. The Behavioral Inflexibility Scale (BIS) contains 38 questions rated on a 6-point scale. Parents of 943 children with autism spectrum disorder (ASD) completed an online survey. We examined associations between the BIS and other scales and demographic variables. The BIS is valid and reliable. BI in children with ASD ranges from mild to severe.

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15. MacLennan K, Roach L, Tavassoli T. The Relationship Between Sensory Reactivity Differences and Anxiety Subtypes in Autistic Children. Autism Res ;2020 (Jan 7)

Autistic children are at greater risk of developing anxiety than their nonautistic peers. Sensory reactivity differences have been implicated as one of the risk factors. Specifically, sensory hyperreactivity has previously been linked to anxiety, including separation anxiety and specific phobia ; however, minimal research has explored the influence of sensory hyporeactivity and seeking. Therefore, the present study examined the correlational relationship between sensory reactivity differences and anxiety subtypes in 41 autistic children aged between 3 and 14 years, using parent- and self-reported measures. We found positive correlations between sensory hyperreactivity and total anxiety, separation anxiety and physical injury fears. However, when controlling for autism traits, we found sensory hyperreactivity to be related to physical injury fears and specific phobia, and sensory hyporeactivity to be related to lower total and social anxiety. We found no significant relationships between sensory seeking and anxiety. These results indicate that sensory hyperreactivity and hyporeactivity might be implicated in specific anxiety symptomology. Our results also indicate minimal agreement between parent- and self-reported anxieties, which highlights the limitations of informant reports for anxiety and the pressing need for objective anxiety assessments for autistic children to be developed. Our findings have important implications for limiting the development of anxiety in autistic children and suggest that sensory reactivity differences should be considered when developing targeted interventions for certain anxiety disorders. Autism Res 2019, 00 : 1-11. (c) 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY : The present study found that when considering autism traits, greater sensory hyperreactivity, such as being oversensitive to sounds, was related to elevated phobia-related symptoms and sensory hyporeactivity, such as being under-responsive to touch, was related to lower total and social anxieties. Sensory seeking, such as a fascination with lights, was not related to anxiety. Our results have important implications for targeted anxiety interventions for autistic children. However, due to minimal agreement between the parent- and child-reported scores, developing more objective measures of anxiety would be beneficial.

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16. Madaan P, Jauhari P, Luhar ZM, Chakrabarty B, Gulati S. Autism, Epilepsy, and Neuroregression : Photosensitivity on Electroencephalography Solved the Riddle. Clin EEG Neurosci ;2020 (Jan 6):1550059419899327.

Autistic epileptiform regression is an uncommon but extensively described malady in children. The clinico-etiological spectrum of this entity ranges from electrical status epilepticus in sleep to various neurogenetic and neurodegenerative disorders. Identification of these disorders is crucial considering their therapeutic and prognostic implications. Simple investigations such as neuroimaging and electroencephalography with activation procedures can provide valuable diagnostic clues in resource-limited settings ; facilitating targeted genetic/metabolic testing. Here we report a 3.5-year-old girl with autistic regression and epilepsy. Neuronal ceroid lipofuscinosis was suspected as her electroencephalogram showed photoparoxysmal response on low-frequency (1-3 Hz) intermittent photic stimulation. A deficient leukocyte tripeptidyl peptidase 1 enzyme confirmed the diagnosis of late infantile neuronal ceroid lipofuscinosis.

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17. Markham VA, Giles AF, Roderique-Davies G, Adshead V, Tamiaki G, May RJ. Applications of within-stimulus errorless learning methods for teaching discrimination skills to individuals with intellectual and developmental disabilities : A systematic review. Res Dev Disabil ;2019 (Dec 31) ;97:103521.

Errorless learning is an instructional strategy used widely with individuals with intellectual and developmental disabilities. The present systematic review aims to update the literature on the application of ’within-stimulus’ errorless procedures. The protocol was registered with PROSPERO (CRD42018118385). Twenty-eight articles including 283 participants met the operationally defined inclusion criteria. In the majority of cases, the errorless learning procedures evaluated led to improvements in acquiring discrimination skills. Most of the reviewed studies evaluated stimulus fading. Results are discussed in relation to the selection of within-stimulus procedures. Areas identified for future research include further evaluations of other within-stimulus tactics, as well as further refinement of procedural parameters.

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18. McDiarmid TA, Belmadani M, Liang J, Meili F, Mathews EA, Mullen GP, Hendi A, Wong WR, Rand JB, Mizumoto K, Haas K, Pavlidis P, Rankin CH. Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation. Proc Natl Acad Sci U S A ;2020 (Jan 7) ;117(1):656-667.

A major challenge facing the genetics of autism spectrum disorders (ASDs) is the large and growing number of candidate risk genes and gene variants of unknown functional significance. Here, we used Caenorhabditis elegans to systematically functionally characterize ASD-associated genes in vivo. Using our custom machine vision system, we quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and habituation learning in 135 strains each carrying a mutation in an ortholog of an ASD-associated gene. We identified hundreds of genotype-phenotype relationships ranging from severe developmental delays and uncoordinated movement to subtle deficits in sensory and learning behaviors. We clustered genes by similarity in phenomic profiles and used epistasis analysis to discover parallel networks centered on CHD8*chd-7 and NLGN3*nlg-1 that underlie mechanosensory hyperresponsivity and impaired habituation learning. We then leveraged our data for in vivo functional assays to gauge missense variant effect. Expression of wild-type NLG-1 in nlg-1 mutant C. elegans rescued their sensory and learning impairments. Testing the rescuing ability of conserved ASD-associated neuroligin variants revealed varied partial loss of function despite proper subcellular localization. Finally, we used CRISPR-Cas9 auxin-inducible degradation to determine that phenotypic abnormalities caused by developmental loss of NLG-1 can be reversed by adult expression. This work charts the phenotypic landscape of ASD-associated genes, offers in vivo variant functional assays, and potential therapeutic targets for ASD.

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19. Nabgha EA, Eqani S, Khuram F, Alamdar A, Tahir A, Shah STA, Nasir A, Javed S, Bibi N, Hussain A, Rasheed H, Shen H. Environmental exposure pathway analysis of trace elements and autism risk in Pakistani children population. Sci Total Environ ;2020 (Jan 7) ;712:136471.

The pursuit of industrialization and urbanization in developing countries disrupt the fragile environment, resulting in biogeochemical extra-emission of the trace elements into human inhabitance causing serious health concerns. We aimed to determine the associations between Autism spectrum disorder (ASD) risk and exposure to trace elements (As, Zn, Ni, Pb, Hg, Cu, Cd, and Co), associations between the internal doses and environmental sources of these elements were also assessed. Genetic susceptibility to toxins was assessed through GSTT1 and GSTM1 null polymorphism analysis. Our results showed that lower BMI in children was significantly associated with ASD (p < 0.05, AOR = 0.86 ; 95% CI : 0.76, 0.98). As was significantly higher in both hair (p < 0.01, AOR = 18.29 ; 95% CI : 1.98, 169) and urine (p < 0.01, AOR = 1.04 ; 95% CI : 1.01, 1.06) samples from children with ASD ; urinary Hg (p < 0.05, AOR = 2.90 ; 95% CI : 1.39, 6.07) and Pb (p < 0.05, AOR = 1.95 ; 95% CI : 1.01, 3.77) were also positively associated with ASD. Regarding the genetic susceptibility, Cu was significantly associated with GSTM1 positive genotype (p < 0.05, AOR = 1.05 ; 95% CI : 1.00, 1.10). Children inhabiting the urban areas exposed to significantly higher levels of studied trace elements. The Estimated Daily Intake (EDI) values highlighted that the different land use settings resulted in children’s source specific exposure to studied trace elements. The exposure pathway analysis showed that the distal factors of land-use settings associated with children increased exposure risk for most of the investigated elements, noticeably As, Pb and Hg associated with ASD prevalence.

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20. Ribeiro MC, MacDonald JL. Sex differences in Mecp2-mutant Rett syndrome model mice and the impact of cellular mosaicism in phenotype development. Brain Res ;2020 (Jan 2) ;1729:146644.

There is currently no effective treatment for Rett syndrome (RTT), a severe X-linked progressive neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2. Because MECP2 is subjected to X-inactivation, most affected individuals are female heterozygotes who display cellular mosaicism for normal and mutant MECP2. Males who are hemizygous for mutant MECP2 are more severely affected than heterozygous females and rarely survive. Mecp2 loss-of-function is less severe in mice, however, and male hemizygous null mice not only survive until adulthood, they have been the most commonly studied model system. Although heterozygous female mice better recapitulate human RTT, they have not been as thoroughly characterized. This is likely because of the added experimental challenges that they present, including delayed and more variable phenotypic progression and cellular mosaicism due to X-inactivation. In this review, we compare phenotypes of Mecp2 heterozygous female mice and male hemizygous null mouse models. Further, we discuss the complexities that arise from the many cell-type and tissue-type specific roles of MeCP2, as well as the combination of cell-autonomous and non-cell-autonomous disruptions that result from Mecp2 loss-of-function. This is of particular importance in the context of the female heterozygous brain, composed of a mixture of MeCP2+ and MeCP2- cells, the ratio of which can alter RTT phenotypes in the case of skewed X-inactivation. The goal of this review is to provide a clearer understanding of the pathophysiological differences between the mouse models, which is an essential consideration in the design of future pre-clinical studies.

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21. Saitow F, Takumi T, Suzuki H. Change in serotonergic modulation contributes to the synaptic imbalance of neuronal circuit at the prefrontal cortex in the 15q11-13 duplication mouse model of autism. Neuropharmacology ;2019 (Dec 31) ;165:107931.

The prefrontal cortex (PFC) has been extensively studied in autism spectrum disorder (ASD) in an attempt to understand the deficits in executive and other higher brain functions related to sociability and emotion. Disruption of the excitatory/inhibitory (E/I) balance of cortical circuits is thought to underlie the pathophysiology of ASD. Recently, we showed that 15q dup mice (a model for ASD with human chromosome 15q11-13 paternal duplication) exhibit disruption of the E/I balance in layer 2/3 pyramidal neurons of the somatosensory cortex due to a decrease in the number of inhibitory synapses. However, whether there is a pathological abnormality in E/I balance in the PFC of 15q dup mice remains unknown. In this study, we found that 15q dup facilitates the activity-induced LTP of glutamate synapses onto layer 5 pyramidal neurons by shifting the E/I balance to an excitatory state, which this was associated with differences in synaptic glutamatergic and GABAergic inputs onto GABAergic fast-spiking interneurons (FSINs). Furthermore, we found that FSIN excitability was well-modulated and regulated by the constitutive activation of 5-HT2 receptors in PFC microcircuits. These results provide new insights into the cellular mechanisms underlying maintenance of optimal E/I balance in the PFC.

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22. Sokolowski MB. Functional testing of ASD-associated genes. Proc Natl Acad Sci U S A ;2020 (Jan 7) ;117(1):26-28.

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23. Zaidman-Zait A, Zwaigenbaum L, Duku E, Bennett T, Szatmari P, Mirenda P, Smith I, Vaillancourt T, Volden J, Waddell C, Kerns C, Elsabbagh M, Georgiades S, Ungar WJ, Fombonne E, Roberts W. Factor analysis of the children’s sleep habits questionnaire among preschool children with autism spectrum disorder. Res Dev Disabil ;2019 (Dec 31) ;97:103548.

BACKGROUND : Sleep problems are prevalent among young children with autism spectrum disorders (ASD). The Children’s Sleep Habits Questionnaire (CSHQ) is commonly used for assessment, but there are outstanding questions regarding its optimal measurement model. AIMS : To examine the factor structure of the CSHQ in preschool children with ASD, and relationships between CSHQ factors and children’s emotional, cognitive, and behavioral dysregulation. METHODS AND PROCEDURES : Participants included 4- to 5-year-olds with ASD (n=281). Confirmatory factor analysis was used to examine whether two previously reported CSHQ factor structures provided adequate fit to the sample data. Exploratory Factor Analysis (EFA) was used examine alternative models. Regression analyses were used to examine how CSHQ factor scores explained variance in dysregulation symptoms, measured by the Child Behavior Checklist. RESULTS : Previously reported factor models in children with ASD were not confirmed, but a novel five-factor model identified using EFA provided excellent fit to the sample data. Sleep factors were generally not correlated with autism symptoms but were associated with aggression, anxiety/depression and attention problems, with evidence of specificity in these relationships. CONCLUSIONS : The proposed CSHQ five-factor model may be useful in future studies of sleep problems in young children with ASD.

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