Pubmed du 12/06/20

vendredi 12 juin 2020

1. Albizua I, Chopra P, Allen EG, He W, Amin AS, Sherman SL. Study of telomere length in men who carry a fragile X premutation or full mutation allele. Hum Genet ;2020 (Jun 12)

The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5’ UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS) ; those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual disabilities. In our study, we tested the hypothesis that men carrying a fragile X premutation or full mutation are "biologically older", as suggested by the associated age-related disorder in the presence of the fragile X premutation or the altered cellular pathology that affects both the fragile X premutation and full mutation carriers. Thus, we predicted that both groups would have shorter telomeres than men carrying the normal size repeat allele. Using linear regression models, we found that, on average, premutation carriers had shorter telomeres compared with non-carriers (n = 69 vs n = 36 ; p = 0.02) and that there was no difference in telomere length between full mutation carriers and non-carriers (n = 37 vs n = 29 ; p > 0.10). Among premutation carriers only, we also asked whether telomere length was shorter among men with vs without symptoms of FXTAS (n = 28 vs n = 38 and n = 27 vs n = 41, depending on criteria) and found no evidence for a difference (p > 0.10). Previous studies have shown that the premutation is transcribed whereas the full mutation is not, and the expanded repeat track in FMR1 transcript is thought to lead to the risk for premutation-associated disorders. Thus, our data suggest that the observed premutation-only telomere shortening may be a consequence of the toxic effect of the premutation transcript and suggest that premutation carriers are "biologically older" than men carrying the normal size allele in the same age group.

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2. Brazendale K, Brazendale AB, Garcia JM, Monroe CM, Weaver RG, Beets MW. Brief Report : Obesogenic Behaviors of Children with Developmental Disabilities During Summer. J Autism Dev Disord ;2020 (Jun 12)

The ’Structured Days Hypothesis’ suggests that children’s obesogenic behaviors (e.g., activity, diet, sleep, and screen time) are less favorable during times when there is less-structure to a child’s day (e.g., summer). To compare obesogenic behaviors of children with developmental disabilities (DD) during summer on days with differing amounts of ’structure’. Seventeen children with DD (mean age 9.8 years) attending a day camp wore a Fitbit(©) activity monitor on the non-dominant wrist during summer, and parents completed a survey packet, to capture obesogenic behaviors. Participants displayed improved physical activity levels, diets, and sleep timing on camp days versus other days. Providing children with DD ’structure’ over summer is a potential intervention approach requiring further investigation.

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3. Cheng B, Zhu J, Yang T, Wang S, Liu H, Wu Q, Zhang X, Chen J, Li T. Vitamin A deficiency exacerbates autism-like behaviors and abnormalities of the enteric nervous system in a valproic acid-induced rat model of autism. Neurotoxicology ;2020 (Jun 8)

The manifestations of autism spectrum disorder (ASD) are highly heterogeneous. As many individuals with ASD have gastrointestinal (GI) comorbidities, ASD with GI problems is considered to be a subtype of ASD. Vitamin A (VA) plays an important role in the development of both the central and peripheral nervous system. However, the relationship between VA deficiency (VAD) and ASD with GI comorbidities is still unclear. We established rat models with different VA levels based on the valproic acid-induced autism model. Compared to autism model rats with VA normal (VAN), autism model rats with gestational VAD showed more severe autism-like behavior, increased GI transit time, and impairment of the enteric nervous system (ENS). Besides, the expression levels of retinoic acid receptor α (RARα) and Ret in autism model rats with VAD were decreased compared with those in rats with VAN. Supplementation with VA was found to effectively ameliorate autism-like behaviors and impairments of GI motility and the ENS in autism model rats with VAD. Chromatin immunoprecipitation results suggested that RARa can bind to the promoter region of the Ret gene and regulate the Ret signaling pathway. We speculate that VAD in autism might lead to impairments of both the brain and ENS. VAD might be a factor that causes individuals to be more susceptible to ASD-related risk factors and aggravates a subtype of ASD with GI comorbidities.

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4. Fuller EA, Oliver K, Vejnoska SF, Rogers SJ. The Effects of the Early Start Denver Model for Children with Autism Spectrum Disorder : A Meta-Analysis. Brain Sci ;2020 (Jun 12) ;10(6)

This meta-analysis examined the effects of the Early Start Denver Model (ESDM) for young children with autism on developmental outcome measures. The 12 included studies reported results from 640 children with autism across 44 unique effect sizes. The aggregated effect size, calculated using a robust variance estimation meta-analysis, was 0.357 (p = 0.024), which is a moderate effect size with a statistically significant overall weighted averaged that favored participants who received the ESDM compared to children in control groups, with moderate heterogeneity across studies. This result was largely driven by improvements in cognition (g = 0.412) and language (g = 0.408). There were no significant effects observed for measures of autism symptomology, adaptive behavior, social communication, or restrictive and repetitive behaviors.

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5. Gevarter C, Horan K, Sigafoos J. Teaching Preschoolers With Autism to Use Different Speech-Generating Device Display Formats During Play : Intervention and Secondary Factors. Lang Speech Hear Serv Sch ;2020 (Jun 12):1-18.

Purpose Children with autism spectrum disorder (ASD) and complex communication needs are increasingly taught to use tablet-based speech-generating devices (SGDs). An important issue in designing such interventions is the selection of an appropriate format for displaying vocabulary. The purpose of this study was to determine (a) whether young children with ASD can be taught to use different SGD vocabulary display formats and (b) whether there are differences across the formats on a range of secondary measures (e.g., preference and generalization). Method Five preschoolers with ASD (and prior experience with simpler aided augmentative and alternative communication) were taught to use grid and visual scene display SGDs during a play-based intervention. Acquisition of functional responding was assessed using a single-case experimental design. Secondary variables included error types, antecedents for communication, preference, and generalization. Results All participants increased their use of functional target vocabulary using both the grid and the simple visual scene display. Of the five participants, three showed similar performance with both formats, whereas two had slightly higher rates of functional responding with the grid. Individualized differences across participants and formats were apparent across secondary variables (e.g., preference, error types, generalization). Conclusions Both simple grid and visual scene displays may be viable options when teaching functional use of SGDs to children with ASD who have prior aided augmentative and alternative communication experience. Analyzing secondary variables beyond device acquisition (e.g., generalization, preference) may have implications for individualizing intervention.

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6. Goldman SE, Gilmour AF. Educating Students with Autism Spectrum Disorders : Is Teacher Certification Area Associated with Academic Outcomes ?. J Autism Dev Disord ;2020 (Jun 12)

Although typically taught by special educators, few studies have examined if certification area is associated with academic outcomes for students with autism spectrum disorders (ASDs). The purpose of this study was to determine whether students with ASD scored better on language arts and mathematics state assessments depending on teacher certification, and whether these associations varied by assessment type. We analyzed 3 years of state administrative data from students with ASD in grades 4-8 receiving special education services. Results showed students taking the regular or alternate assessment had similar academic outcomes regardless of teacher certification. Students who were taught by special education certified teachers and took the modified assessment had lower academic outcomes. Implications for practice, policy, and research are discussed.

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7. Jaramillo TC, Xuan Z, Reimers JM, Escamilla CO, Liu S, Powell CM. Early Restoration of Shank3 Expression in Shank3 Knock-Out Mice Prevents Core ASD-Like Behavioral Phenotypes. eNeuro ;2020 (May/Jun) ;7(3)

Several genes are associated with increased risk for autism spectrum disorder (ASD), neurodevelopmental disorders that present with repetitive movements and restricted interests along with deficits in social interaction/communication. While genetic alterations associated with ASD are present early in life, ASD-like behaviors are difficult to detect in early infancy. This raises the issue of whether reversal of an ASD-associated genetic alteration early in life can prevent the onset of ASD-like behaviors. Genetic alterations of SHANK3, a well-characterized gene encoding a postsynaptic scaffolding protein, are estimated to contribute to ∼0.5% of ASD and remain one of the more replicated and well-characterized genetic defects in ASD. Here, we investigate whether early genetic reversal of a Shank3 mutation can prevent the onset of ASD-like behaviors in a mouse model. Previously, we have demonstrated that mice deficient in Shank3 display a wide range of behavioral abnormalities such as repetitive grooming, social deficits, anxiety, and motor abnormalities. In this study, we replicate many of these behaviors in Shank3 mutant mice. With early genetic restoration of wild-type (WT) Shank3, we rescue behaviors including repetitive grooming and social, locomotor, and rearing deficits. Our findings support the idea that the underlying mechanisms involving ASD behaviors in mice deficient in Shank3 are susceptible to early genetic correction of Shank3 mutations.

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8. Lilley R, Sedgwick M, Pellicano E. Inclusion, acceptance, shame and isolation : Attitudes to autism in Aboriginal and Torres Strait Islander communities in Australia. Autism ;2020 (Jun 12):1362361320928830.

There has been almost no research done about autism in Aboriginal and Torres Strait Islander communities in Australia. This article is the first detailed report on attitudes to autism in these communities. Understanding attitudes to autism is important because they influence whether or not children are diagnosed, as well as the kinds of support autistic people are getting. Twelve families who lived in different parts of Australia were interviewed. They told us that there is a range of attitudes to autism in Aboriginal and Torres Strait Islander communities. These include negative ideas such as sometimes feeling shame associated with children’s unusual behaviour, as well as feeling stigmatised and socially isolated. The negative attitudes reported may mean that some children are missing out on an autism diagnosis or being wrongly diagnosed with a different condition in these communities. They also included positive ideas such as the importance of looking after each other and of accepting autistic people and their differences. We can all learn from these positive attitudes. It will be interesting to know in future projects whether these accepting attitudes lead to better outcomes for autistic children and adults in these communities. This research helps us to understand how autism is thought about in different cultures and how attitudes impact diagnosis and support. It will also help people to plan supports that reflect what Aboriginal and Torres Strait Islander families actually want and need.

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9. Linnsand P, Gillberg C, Nilses Å, Hagberg B, Nygren G. A High Prevalence of Autism Spectrum Disorder in Preschool Children in an Immigrant, Multiethnic Population in Sweden : Challenges for Health Care. J Autism Dev Disord ;2020 (Jun 12)

This study examines the prevalence of autism spectrum disorder (ASD) in preschool children in an immigrant population. Possible risk factors for ASD and individual needs for the children and their families are described, as well as implications for health care. The estimated minimum prevalence for ASD in the area was 3.66% for children aged 2-5 years. Multiple risk factors and extensive individual needs for the children and their families were observed. The high prevalence of ASD and the plethora of needs in immigrant communities pose challenges for health care. A coordinated health care system is necessary to meet the many and individual needs.

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10. Lutz AK, Pfaender S, Incearap B, Ioannidis V, Ottonelli I, Föhr KJ, Cammerer J, Zoller M, Higelin J, Giona F, Stetter M, Stoecker N, Alami NO, Schön M, Orth M, Liebau S, Barbi G, Grabrucker AM, Delorme R, Fauler M, Mayer B, Jesse S, Roselli F, Ludolph AC, Bourgeron T, Verpelli C, Demestre M, Boeckers TM. Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles. Sci Transl Med ;2020 (Jun 10) ;12(547)

Heterozygous mutations of the gene encoding the postsynaptic protein SHANK3 are associated with syndromic forms of autism spectrum disorders (ASDs). One of the earliest clinical symptoms in SHANK3-associated ASD is neonatal skeletal muscle hypotonia. This symptom can be critical for the early diagnosis of affected children ; however, the mechanism mediating hypotonia in ASD is not completely understood. Here, we used a combination of patient-derived human induced pluripotent stem cells (hiPSCs), Shank3Δ11(-/-) mice, and Phelan-McDermid syndrome (PMDS) muscle biopsies from patients of different ages to analyze the role of SHANK3 on motor unit development. Our results suggest that the hypotonia in SHANK3 deficiency might be caused by dysfunctions in all elements of the voluntary motor system : motoneurons, neuromuscular junctions (NMJs), and striated muscles. We found that SHANK3 localizes in Z-discs in the skeletal muscle sarcomere and co-immunoprecipitates with α-ACTININ. SHANK3 deficiency lead to shortened Z-discs and severe impairment of acetylcholine receptor clustering in hiPSC-derived myotubes and in muscle from Shank3Δ11(-/-) mice and patients with PMDS, indicating a crucial role for SHANK3 in the maturation of NMJs and striated muscle. Functional motor defects in Shank3Δ11(-/-) mice could be rescued with the troponin activator Tirasemtiv that sensitizes muscle fibers to calcium. Our observations give insight into the function of SHANK3 besides the central nervous system and imply potential treatment strategies for SHANK3-associated ASD.

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11. Petersson Bloom L. Professional Development for Enhancing Autism Spectrum Disorder Awareness in Preschool Professionals. J Autism Dev Disord ;2020 (Jun 12)

The current study describes the design, implementation, and analysis of a professional development programme using a Lesson Study model to enhance awareness in preschool professionals regarding inclusive education for children with autism spectrum disorder. The mixed method approach included pre- and post-intervention questionnaires, audio-recordings of group seminars, and an interview. The results indicated an increase in autism awareness among the professionals, suggesting that professionals changed their practice as a result of the programme. This was particularly clear regarding making adjustments to the learning environment and taking measures to prevent challenging situations. In addition to describing the implementation of a professional development programme in a preschool, this paper emphasises the importance of appropriate conditions for such initiatives.

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12. Rajkumar D, Manokaran RK, Shubha S, Shruthi TK. Phenytoin Induced Status Dystonicus : A Rare Manifestation of Phenytoin Toxicity in a Child with Autism Spectrum Disorder. Indian J Pediatr ;2020 (Jun 12)

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13. Runge K, Tebartz van Elst L, Maier S, Nickel K, Denzel D, Matysik M, Kuzior H, Robinson T, Blank T, Dersch R, Domschke K, Endres D. Cerebrospinal Fluid Findings of 36 Adult Patients with Autism Spectrum Disorder. Brain Sci ;2020 (Jun 8) ;10(6)

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by difficulties with social interaction, repetitive behavior, and additional features, such as special interests. Its precise etiology is unclear. Recently, immunological mechanisms, such as maternal autoantibodies/infections, have increasingly been the subject of discussion. Cerebrospinal fluid (CSF) investigations play a decisive role in the detection of immunological processes in the brain. This study therefore retrospectively analyzed the CSF findings of adult patients with ASD. CSF basic measures (white blood cell count, total protein, albumin quotient, immunoglobulin G (IgG) index, and oligoclonal bands) and various antineuronal antibody findings of 36 adult patients with ASD, who had received lumbar puncture, were compared with an earlier described mentally healthy control group of 39 patients with idiopathic intracranial hypertension. CSF protein concentrations and albumin quotients of patients with ASD were significantly higher as compared to controls (age corrected : p = 0.003 and p = 0.004, respectively) ; 17% of the patients with ASD showed increased albumin quotients. After correction for age and gender, the group effect for total protein remained significant (p = 0.041) and showed a tendency for albumin quotient (p = 0.079). In the CSF of two ASD patients, an intrathecal synthesis of anti-glutamate decarboxylase 65 (GAD65) antibodies was found. In total, more of the ASD patients (44%) presented abnormal findings in CSF basic diagnostics compared to controls (18% ; p = 0.013). A subgroup of the patients with adult ASD showed indication of a blood-brain barrier dysfunction, and two patients displayed an intrathecal synthesis of anti-GAD65 antibodies ; thus, the role of these antibodies in patients with ASD should be further investigated. The results of the study are limited by its retrospective and open design. The group differences in blood-brain barrier markers could be influenced by a different gender distribution between ASD patients and controls.

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14. Saad K, Abdallah AM, Abdel-Rahman AA, Al-Atram AA, Abdel-Raheem YF, Gad EF, Abo-Elela MGM, Elserogy YM, Elhoufey A, Nigm DA, Nagiub Abdelsalam EM, Alruwaili TAM. Polymorphism of interleukin-1β and interleukin-1 receptor antagonist genes in children with autism spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry ;2020 (Jun 9):109999.

In this study, we first investigated interleukin-1 beta (IL-1β) and IL-1 receptor antagonist (IL-1RA) levels in a cohort of Egyptian children with autism spectrum disorder (ASD) and in healthy controls. Second, we examined the single-nucleotide polymorphisms (SNPs) at positions -31 and - 511 of the IL-1β gene promoter and IL1RA and assessed the association between IL1B and IL1RA polymorphisms with ASD. We examined IL1β promoter polymorphism at -511 (IL-1β-511) and - 31 (IL-1β-31) and IL1RA gene polymorphism in 80 children with ASD and 60 healthy children. The children with ASD had significantly higher levels of IL-1β and IL-1RA than the controls. The children with ASD also had significantly higher frequencies of homozygous (CC) and heterozygous (TC) genotype variants of IL-1β-511, and IL-1RA than the controls. Moreover, the frequency of the IL-1β-511 allele (C) was higher in the ASD group than in the controls (p = .001). The homozygous and heterozygous variants of IL-1RA allele II were also significantly higher in the ASD group than in the control group. There was no significant association between the IL-1β-31 genotype and autism classes. However, there were significant differences in the distribution of the IL-1RA heterogeneous genotype and allele II among children with severe autism. The inflammatory role of cytokines has been implicated in a variety of neuropsychiatric pathologies, including autism. Our data show alterations in the IL-1β system, with abnormally increased serum levels of IL-1β and IL-1RA in the children with ASD. Further, polymorphisms in the IL-1β-511 and IL-1RA genotype variants correlated positively with autism severity and behavioral abnormalities. IL-1β-511 and IL-1RA gene polymorphisms could impact ASD risk and may be used as potential biomarkers of ASD. Variations in the IL-1β and IL-1RA systems may have a role in the pathophysiology of ASD.

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15. Sun JM, Dawson G, Franz L, Howard J, McLaughlin C, Kistler B, Waters-Pick B, Meadows N, Troy J, Kurtzberg J. Infusion of human umbilical cord tissue mesenchymal stromal cells in children with autism spectrum disorder. Stem Cells Transl Med ;2020 (Jun 12)

Ongoing neuroinflammation may contribute to symptoms of autism spectrum disorder (ASD) in at least a portion of affected individuals. Mesenchymal stromal cells (MSCs) have demonstrated the capacity to modulate neuroinflammation, but safety and feasibility of MSC administration in children with ASD have not been well established. In this open-label, phase I study, 12 children with ASD between 4 and 9 years of age were treated with intravenous (IV) infusions of human cord tissue mesenchymal stromal cells (hCT-MSCs), a third-party MSC product manufactured from unrelated donor umbilical cord tissue. Children received one, two, or three doses of 2 × 10(6) cells per kilogram at 2-month intervals. Clinical and laboratory evaluations were performed in person at baseline and 6 months and remotely at 12 months after the final infusion. Aside from agitation during the IV placement and infusion in some participants, hCT-MSCs were well tolerated. Five participants developed new class I anti-human leukocyte antigen (HLA) antibodies, associated with a specific lot of hCT-MSCs or with a partial HLA match between donor and recipient. These antibodies were clinically silent and not associated with any clinical manifestations to date. Six of 12 participants demonstrated improvement in at least two ASD-specific measures. Manufacturing and administration of hCT-MSCs appear to be safe and feasible in young children with ASD. Efficacy will be evaluated in a subsequent phase II randomized, placebo-controlled clinical trial.

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16. Sysoeva OV, Molholm S, Djukic A, Frey HP, Foxe JJ. Atypical processing of tones and phonemes in Rett Syndrome as biomarkers of disease progression. Transl Psychiatry ;2020 (Jun 10) ;10(1):188.

Due to severe motor impairments and the lack of expressive language abilities seen in most patients with Rett Syndrome (RTT), it has proven extremely difficult to obtain accurate measures of auditory processing capabilities in this population. Here, we examined early auditory cortical processing of pure tones and more complex phonemes in females with Rett Syndrome (RTT), by recording high-density auditory evoked potentials (AEP), which allow for objective evaluation of the timing and severity of processing deficits along the auditory processing hierarchy. We compared AEPs of 12 females with RTT to those of 21 typically developing (TD) peers aged 4-21 years, interrogating the first four major components of the AEP (P1 : 60-90 ms ; N1 : 100-130 ms ; P2 : 135-165 ms ; and N2 : 245-275 ms). Atypicalities were evident in RTT at the initial stage of processing. Whereas the P1 showed increased amplitude to phonemic inputs relative to tones in TD participants, this modulation by stimulus complexity was absent in RTT. Interestingly, the subsequent N1 did not differ between groups, whereas the following P2 was hugely diminished in RTT, regardless of stimulus complexity. The N2 was similarly smaller in RTT and did not differ as a function of stimulus type. The P2 effect was remarkably robust in differentiating between groups with near perfect separation between the two groups despite the wide age range of our samples. Given this robustness, along with the observation that P2 amplitude was significantly associated with RTT symptom severity, the P2 has the potential to serve as a monitoring, treatment response, or even surrogate endpoint biomarker. Compellingly, the reduction of P2 in patients with RTT mimics findings in animal models of RTT, providing a translational bridge between pre-clinical and human research.

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17. Wright B, Teige C, Watson J, Hodkinson R, Marshall D, Varley D, Allgar V, Mandefield L, Parrott S, Kingsley E, Hargate R, Mitchell N, Ali S, McMillan D, Wang H, Hewitt C. Autism Spectrum Social Stories In Schools Trial 2 (ASSSIST2) : study protocol for a randomised controlled trial analysing clinical and cost-effectiveness of Social Stories™ in primary schools. BMC Psychol ;2020 (Jun 12) ;8(1):60.

BACKGROUND : Interventions designed to support children with a diagnosis of Autism Spectrum Conditions (ASC) can be time consuming, needing involvement of outside experts. Social Stories™ are a highly personalised intervention aiming to give children with ASC social information or describing an otherwise difficult situation or skill. This can be delivered daily by staff in education settings. Studies examining Social Story™ use have yielded mostly positive results but have largely been single case studies with a lack of randomised controlled trials (RCTs). Despite this numerous schools are utilising Social Stories™, and a fully powered RCT is timely. METHODS : A multi-site pragmatic cluster RCT comparing care as usual with Social Stories™ and care as usual. This study will recruit 278 participants (aged 4-11) with a clinical diagnosis of ASC, currently attending primary school in the North of England. Approximately 278 school based staff will be recruited to provide school based information about participating children with approximately 140 recruited to deliver the intervention. The study will be cluster randomised by school. Potential participants will be screened for eligibility prior to giving informed consent. Follow up data will be collected at 6 weeks and 6 months post randomisation and will assess changes in participants’ social responsiveness, goal based outcomes, social and emotional health. The primary outcome measure is the Social Responsiveness Scale Second Edition (SRS-2) completed by school based staff at 6 months. Approvals have been obtained from the University of York’s Research Governance Committee, Research Ethics Committee and the Health Research Authority. Study results will be submitted for publication in peer-reviewed journals and disseminated to participating families, educational staff, local authority representatives, community groups and Patient and Participant Involvement representatives. Suggestions will be made to NICE about treatment evidence dependent on findings. DISCUSSION : This study addresses a much used but currently under researched intervention and results will inform school based support for primary school children with a diagnosis of ASC. TRIAL REGISTRATION : The trial is registered on the ISRCTN registry (registration number : ISRCTN11634810). The trial was retrospectively registered on 23rd April 2019.

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