1. Bemmouna D, Coutelle R, Weibel S, Weiner L. Feasibility, Acceptability and Preliminary Efficacy of Dialectical Behavior Therapy for Autistic Adults without Intellectual Disability: A Mixed Methods Study. Journal of autism and developmental disorders. 2021: 1-18.

Self-harm and suicidal behaviors are prevalent among autistic adults without intellectual disability (ID). Emotion dysregulation (ED), the difficulty in modulating emotions, has been identified as an important risk factor. Dialectical behavior therapy (DBT) has been proved effective to treat ED in disorders other than autism spectrum disorder. Our study aimed at assessing the feasibility, acceptability and preliminary efficacy of DBT in seven autistic adults without ID exhibiting self-harm and/or suicidal behaviors linked to severe ED. Our results suggest that DBT is feasible and highly acceptable to autistic adults without ID. Additionally, mean scores on the Difficulties in Emotion Regulation Scale decreased significantly post-treatment and at 4-month follow-up, suggesting that DBT might be efficacious in reducing ED in this population.

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2. Camilleri LJ, Maras K, Brosnan M. Mothers’ and practitioners’ insights on the use of digitally-mediated social stories with children on the autism spectrum: A convergent mixed-methods study. Research in developmental disabilities. 2021; 119: 104104.

BACKGROUND: While end-user interest in digitally-mediated Social Story (SS) intervention for children on the autism spectrum is growing, research on the use of SSs in digital form is currently lacking. AIMS: This study aimed to investigate how digital-mediation can influence parents’ and practitioners’ attitudes towards the SS intervention as well as impact their perceived competence in their ability to administer the intervention. METHODS AND PROCEDURES: This study used a convergent mixed-method design. Nineteen participants (ten practitioners and nine mothers) participated in two focus group sessions. Participants then engaged with a digitally-mediated SS and completed a pre- and post-engagement survey measuring attitude, competence and user experience with the intervention. OUTCOMES AND RESULTS: The mothers’ perceived competence ratings improved after engaging with digitally-mediated SSs. Mothers and practitioners also indicated that digitally-mediated SSs increased their perceived efficiency, while mothers felt it improved their autonomy and further empowered them as end-users. CONCLUSION AND IMPLICATIONS: Digitally-mediated SS has the potential to effectively address challenges related to intervention implementation whilst also empowering further the end-user.

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3. Cao X, Li J, Song H, Zhu Y. [Identification of a novel TBR1 gene variant in a Chinese pedigree affected with intellectual developmental disorder with autism and speech delay]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2021; 38(10): 933-6.

OBJECTIVE: To describe a family with intellectual developmental disorder with autism and speech delay (IDDAS) caused by a splice variant of TBR1 gene. METHODS: A pregnant women with mental retardation, who also had a family history of mental retardation, was admitted to Prenatal Diagnosis Center of WanBei Coal and Electricity Group General Hospital Corporation in April 2019. Molecular genetic tests were performed on the pregnant women and ten other family members to analyze the pathogenic genotype. Functional assays of the pathogenic variant was carried out by minigene technology. With the determination of the genotype, prenatal diagnosis was carried out by amniotic fluid sampling. RESULTS: Through whole exome sequencing, a novel splicing variant (c.1129-1G>C) was identified in the TBR1 gene of the proband, which has co-segregated with the disease phenotype in the family. The results of minigene assay showed abnormal splicing of exon 5. The variant was not detected in the fetal amniotic fluid. Fetal growth and development were normal one year after the birth. CONCLUSION: The c.1129-1G>C variant of the TBR1 probably underlay the disease in of the pedigree. Timely prenatal genetic diagnosis and consultation can help to stop the transmission of the pathogenic variant.

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4. Carter SA, Rahman MM, Lin JC, Shu YH, Chow T, Yu X, Martinez MP, Eckel SP, Chen JC, Chen Z, Schwartz J, Pavlovic N, Lurmann FW, McConnell R, Xiang AH. In utero exposure to near-roadway air pollution and autism spectrum disorder in children. Environment international. 2022; 158: 106898.

IMPORTANCE: Previous studies have reported associations between in utero exposure to regional air pollution and autism spectrum disorders (ASD). In utero exposure to components of near-roadway air pollution (NRAP) has been linked to adverse neurodevelopment in animal models, but few studies have investigated NRAP association with ASD risk. OBJECTIVE: To identify ASD risk associated with in utero exposure to NRAP in a large, representative birth cohort. DESIGN, SETTING, AND PARTICIPANTS: This retrospective pregnancy cohort study included 314,391 mother-child pairs of singletons born between 2001 and 2014 at Kaiser Permanente Southern California (KPSC) hospitals. Maternal and child data were extracted from KPSC electronic medical records. Children were followed until: clinical diagnosis of ASD, non-KPSC membership, death, or December 31, 2019, whichever came first. Exposure to the complex NRAP mixture during pregnancy was assessed using line-source dispersion models to estimate fresh vehicle emissions from freeway and non-freeway sources at maternal addresses during pregnancy. Vehicular traffic load exposure was characterized using advanced telematic models combining traditional traffic counts and travel-demand models with cell phone and vehicle GPS data. Cox proportional-hazard models estimated hazard ratios (HR) of ASD associated with near-roadway traffic load and dispersion-modeled NRAP during pregnancy, adjusted for covariates. Non-freeway NRAP was analyzed using quintile distribution due to nonlinear associations with ASD. EXPOSURES: Average NRAP and traffic load exposure during pregnancy at maternal residential addresses. MAIN OUTCOMES: Clinical diagnosis of ASD. RESULTS: A total of 6,291 children (5,114 boys, 1,177 girls) were diagnosed with ASD. The risk of ASD was associated with pregnancy-average exposure to total NRAP [HR(95% CI): 1.03(1.00,1.05) per 5 ppb increase in dispersion-modeled NOx] and to non-freeway NRAP [HR(95% CI) comparing the highest to the lowest quintile: 1.19(1.11, 1.27)]. Total NRAP had a stronger association in boys than in girls, but the association with non-freeway NRAP did not differ by sex. The association of freeway NRAP with ASD risk was not statistically significant. Non-freeway traffic load exposure demonstrated associations with ASD consistent with those of NRAP and ASD. CONCLUSIONS: In utero exposure to near-roadway air pollution, particularly from non-freeway sources, may increase ASD risk in children.

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5. Cooper M, Gale K, Langley K, Broughton T, Massey TH, Hall NJ, Jones CRG. Neurological consultation with an autistic patient. Practical neurology. 2022; 22(2): 120-5.

Autism is a neurodevelopmental condition with a very heterogeneous presentation. Autistic people are more likely to have unmet healthcare needs, making it essential that healthcare professionals are ‘autism-aware’. In this article, we provide an overview of how autism presents and use case studies to illustrate how a neurological consultation in an outpatient clinic environment could prove challenging for a autistic person. We suggest how to improve communication with autistic patients in clinic and highlight the importance of a patient-centred and flexible approach.

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6. D CS, Zhang W, Moran M, Hardin J, McDermott S, Okoro C, Hollis N. Helpers help people with intellectual and developmental disabilities and hypertension to understand their condition and the need to adhere to anti-hypertensive medication. Disability and health journal. 2022; 15(1): 101219.

BACKGROUND: Recent evidence suggests that many adults with intellectual and developmental disabilities (IDD) do not adequately manage hypertension (HTN) medication. Known risk factors for insufficient prescription filling include age, residential placement, and lack of caregiver support. This is a first report of a randomized intervention trial designed to analyze the relationship of a brief educational intervention with increased knowledge about HTN and improvement in prescription filling for anti-hypertensive medication. OBJECTIVE/HYPOTHESIS: The objective was to test whether an educational flyer and regular messages about HTN and the importance of refilling medication would improve scores on knowledge surveys. Participants were Medicaid members with HTN and IDD (Member) or caregivers (Helpers) who chose to participate on behalf of a Member. METHODS: Recruitment letters explained that either the Member or their Helper could participate (not both). Participants were randomly assigned to the Case or Comparison group, and both were comprised of Members and Helpers. Only Case participants received a flyer and monthly HTN education messages for one year, but all participants completed knowledge surveys at baseline, six, and 12 months. Linear regression and log-binomial models were used to compare responses between groups. RESULTS: Case Helpers had statistically significant improvements on HTN knowledge from baseline through the first year, compared to Comparison Members and Comparison Helpers. Regardless of group assignment, Helpers scored better on surveys than did Members. CONCLUSIONS: This study suggests that it is beneficial to explicitly include Helpers in health care instruction and in management of chronic disease for adults with IDD.

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7. DeSpenza T, Jr., Carlson M, Panchagnula S, Robert S, Duy PQ, Mermin-Bunnell N, Reeves BC, Kundishora A, Elsamadicy AA, Smith H, Ocken J, Alper SL, Jin SC, Hoffman EJ, Kahle KT. PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets. Trends in neurosciences. 2021; 44(12): 961-76.

The lack of effective treatments for autism spectrum disorder (ASD) and congenital hydrocephalus (CH) reflects the limited understanding of the biology underlying these common neurodevelopmental disorders. Although ASD and CH have been extensively studied as independent entities, recent human genomic and preclinical animal studies have uncovered shared molecular pathophysiology. Here, we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as a common underlying mechanism that holds diagnostic, prognostic, and therapeutic promise for individuals with ASD and CH.

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8. Gardner EJ, Sifrim A, Lindsay SJ, Prigmore E, Rajan D, Danecek P, Gallone G, Eberhardt RY, Martin HC, Wright CF, FitzPatrick DR, Firth HV, Hurles ME. Detecting cryptic clinically relevant structural variation in exome-sequencing data increases diagnostic yield for developmental disorders. American journal of human genetics. 2021; 108(11): 2186-94.

Structural variation (SV) describes a broad class of genetic variation greater than 50 bp in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DDs). Individuals presenting with DDs are often referred for diagnostic testing with chromosomal microarrays (CMAs) to identify large copy-number variants (CNVs) and/or with single-gene, gene-panel, or exome sequencing (ES) to identify single-nucleotide variants, small insertions/deletions, and CNVs. However, individuals with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the tool InDelible, which interrogates short-read sequencing data for split-read clusters characteristic of SV breakpoints. We applied InDelible to 13,438 probands with severe DDs recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 63 rare, damaging variants in genes previously associated with DDs missed by standard SNV, indel, or CNV discovery approaches. Clinical review of these 63 variants determined that about half (30/63) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21 and 500 bp in size and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.9%. Of particular interest were seven confirmed de novo variants in MECP2, which represent 35.0% of all de novo protein-truncating variants in MECP2 among DDD study participants. InDelible provides a framework for the discovery of pathogenic SVs that are most likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.

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9. Grimm RP, Zhong N, Mazurek MO. Brief Report: Replication of the Five-Factor Structure of the Autism Impact Measure (AIM) in an Independent Sample. Journal of autism and developmental disorders. 2021.

The Autism Impact Measure is a caregiver-reported, behaviorally based measure designed to assess both frequency and functional impact of core ASD symptoms in children. This study used confirmatory factor analysis to determine if the factor structure of the AIM (Repetitive Behavior, Communication, Atypical Behavior, Social Reciprocity, and Peer Interaction), previously reported by Mazurek et al. (Journal of Autism and Developmental Disorders 50: 2307-2319, 2020), was supported in a large (n = 611), independent sample. The sample was diverse in age (2-16 years) and IQ (M = 76.6, SD = 22.7), but was composed of approximately 80% males. There were some nuanced differences between this study and Mazurek et al. (Journal of Autism and Developmental Disorders 50: 2307-2319, 2020), but findings generally provided further evidence supporting the psychometric properties of the AIM.

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10. Hansen AS, Christoffersen CH, Telléus GK, Lauritsen MB. Referral patterns to outpatient child and adolescent mental health services and factors associated with referrals being rejected. A cross-sectional observational study. BMC health services research. 2021; 21(1): 1063.

BACKGROUND: Outpatient child and adolescent mental health services (CAMHS) are faced with the challenge of balancing increasing demands with limited resources. An additional challenge is high rejection rates of referrals which causes frustration for referring agents and families. In order to effectively plan and allocate available resources within CAMHS there is a need for up-to-date knowledge on referral patterns and factors associated with rejection of referrals. METHODS: In this cross-sectional observational study we did a retrospective review of all referrals (n = 1825) for children (0-18) referred for assessment at the outpatient CAMHS of the North Denmark Region in 2018. RESULTS: The most common referral reasons to CAMHS were attention deficit disorder (ADHD/ADD) (27.9%), autism spectrum disorder (22.4%), affective disorders (14.0%) and anxiety disorders (11.6%). The majority of referrals came from general practitioners, but for neurodevelopmental disorders educational psychologists were the primary referral source. Re-referrals constituted more than a third of all referrals (35.9%). Children in care were overrepresented in this clinical sample and had an increased risk (Adj. OR 2.54) of having their referrals rejected by CAMHS. Referrals from general practitioners were also associated with an increased risk of rejection (Adj. OR 3.29). CONCLUSIONS: A high proportion of children with mental disorders have a repeated need for assessment by CAMHS. There is a need for future research on predictors of re-referral to outpatient services to identify potential targets for reducing re-referral rates as well as research on how to optimize service provision for children with a repeated need for assessment. General practitioners are the main gatekeepers to CAMHS and research on interventions to improve the referral process should be aimed towards general practitioners.

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11. Perche O, Lesne F, Patat A, Raab S, Twyman R, Ring RH, Briault S. Electroretinography and contrast sensitivity, complementary translational biomarkers of sensory deficits in the visual system of individuals with fragile X syndrome. Journal of neurodevelopmental disorders. 2021; 13(1): 45.

BACKGROUND: Disturbances in sensory function are an important clinical feature of neurodevelopmental disorders such as fragile X syndrome (FXS). Evidence also directly connects sensory abnormalities with the clinical expression of behavioral impairments in individuals with FXS; thus, positioning sensory function as a potential clinical target for the development of new therapeutics. Using electroretinography (ERG) and contrast sensitivity (CS), we previously reported the presence of sensory deficits in the visual system of the Fmr1(-/y) genetic mouse model of FXS. The goals of the current study were two-folds: (1) to assess the feasibility of measuring ERG and CS as a biomarker of sensory deficits in individuals with FXS, and (2) to investigate whether the deficits revealed by ERG and CS in Fmr1(-/y) mice translate to humans with FXS. METHODS: Both ERG and CS were measured in a cohort of male individuals with FXS (n = 20, 18-45 years) and age-matched healthy controls (n = 20, 18-45 years). Under light-adapted conditions, and using both single flash and flicker (repeated train of flashes) stimulation protocols, retinal function was recorded from individual subjects using a portable, handheld, full-field flash ERG device (RETeval®, LKC Technologies Inc., Gaithersburg, MD, USA). CS was assessed in each subject using the LEA SYMBOLS® low-contrast test (Good-Lite, Elgin, IL, USA). RESULTS: Data recording was successfully completed for ERG and assessment of CS in most individuals from both cohorts demonstrating the feasibility of these methods for use in the FXS population. Similar to previously reported findings from the Fmr1(-/y) genetic mouse model, individuals with FXS were found to exhibit reduced b-wave and flicker amplitude in ERG and an impaired ability to discriminate contrasts compared to healthy controls. CONCLUSIONS: This study demonstrates the feasibility of using ERG and CS for assessing visual deficits in FXS and establishes the translational validity of the Fmr1(-/y) mice phenotype to individuals with FXS. By including electrophysiological and functional readouts, the results of this study suggest the utility of both ERG and CS (ERG-CS) as complementary translational biomarkers for characterizing sensory abnormalities found in FXS, with potential applications to the clinical development of novel therapeutics that target sensory function abnormalities to treat core symptomatology in FXS. TRIAL REGISTRATION: ID-RCB number 2019-A01015-52 registered on the 17 May 2019.

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12. Rafiee F, Rezvani Habibabadi R, Motaghi M, Yousem DM, Yousem IJ. Brain MRI in Autism Spectrum Disorder: Narrative Review and Recent Advances. Journal of magnetic resonance imaging : JMRI. 2021.

Autism spectrum disorder (ASD) is neuropsychiatric continuum of disorders characterized by persistent deficits in social communication and restricted repetitive patterns of behavior which impede optimal functioning. Early detection and intervention in ASD children can mitigate the deficits in social interaction and result in a better outcome. Various non-invasive imaging methods and molecular techniques have been developed for the early identification of ASD characteristics. There is no general consensus on specific neuroimaging features of autism; however, quantitative magnetic resonance techniques have provided valuable structural and functional information in understanding the neuropathophysiology of ASD and how the autistic brain changes during childhood, adolescence, and adulthood. In this review of decades of ASD neuroimaging research, we identify the structural, functional, and molecular imaging clues that most accurately point to the diagnosis of ASD vs. typically developing children. These studies highlight the 1) exaggerated synaptic pruning, 2) anomalous gyrification, 3) interhemispheric under- and overconnectivity, and 4) excitatory glutamate and inhibitory GABA imbalance theories of ASD. The application of these various theories to the analysis of a patient with ASD is mitigated often by superimposed comorbid neuropsychological disorders, evolving brain maturation processes, and pharmacologic and behavioral interventions that may affect the structure and function of the brain. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 3.

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13. Smith DaWalt L, Hickey E, Hudock R, Esler A, Mailick M. Impact of Working Together for adults with autism spectrum disorder: a multifamily group intervention. Journal of neurodevelopmental disorders. 2021; 13(1): 44.

BACKGROUND: Adults with autism spectrum disorder (ASD) have lower engagement in their communities, higher rates of unemployment/underemployment, and continued difficulties with challenging behavior compared to their neurotypical peers. Multi-family psychoeducation emphasizes education and problem-solving with the goal of improving these outcomes for the individual with the disability. METHODS: Using a randomized waitlist control design, the present study evaluated a multi-family group psychoeducation intervention, Working Together, for adults on the autism spectrum without intellectual disability (n = 40). Five waves of data were collected at 3-month intervals. In this design, families in the intervention condition participated in intervention during the 6 months between baseline and time 3 data collection; the waitlist control condition received the intervention immediately after the time 3 data collection. We compared these two conditions, intervention group (n = 20) vs waitlist control group (n = 20), on key outcomes for the adults with ASD: engagement in work-related activities, engagement in meaningful activities, and behavior problems. RESULTS: Results indicated medium to large effect sizes associated with the Working Together intervention across key outcomes, including adults on the spectrum experiencing significant increases in meaningful activities and decreases in internalizing problems. Although increases in work-related activities were not statistically significant, an observed one-half of a standard deviation difference from before to after the intervention indicated clinically significant change. We also found maintenance of the treatment effect through 6 months post-treatment for the intervention group and replication of the treatment effect within the control group after they received the intervention. CONCLUSION: Working Together is a promising multi-family group psychoeducation intervention designed to improve functioning during adulthood. These findings highlight the need for more intervention services research during adulthood and specifically the need for family-centered supports.

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14. Taylor JL, Adams RE, Pezzimenti F, Zheng S, Bishop SL. Job loss predicts worsening depressive symptoms for young adults with autism: A COVID-19 natural experiment. Autism research : official journal of the International Society for Autism Research. 2022; 15(1): 93-102.

Adults with autism spectrum disorder (ASD) experience high rates of both unemployment and depression. Though job loss predicts increased risk of depression in the general population, studies have yet to directly examine this relationship among individuals with ASD. With the backdrop of rising unemployment due to COVID-19, we used a longitudinal design to examine whether employment changes predicted increasing depressive symptoms among young adults with ASD. Online surveys were collected from young adults with ASD at two times: just before widespread social distancing measures were adopted in the United States, and again 10 weeks later. Both time points included measurement of depressive symptoms (Beck Depression Inventory-2). At Time 2, COVID-related employment changes and the perceived impact of those changes on well-being were collected. Of the young adults who were employed at Time 1 (n = 144), over one-third (37.5%) reported employment changes during the first 2 months of COVID-19. Most of this change was job loss or reductions in hours or pay (« job loss/reduction »). Controlling for Time 1 depressive symptoms, young adults who experienced job loss/reduction had significantly higher depressive symptoms at Time 2 than those without an employment change. Individuals’ perceived impact of employment change also predicted depressive symptoms. These findings suggest that losing a job or experiencing reductions in hours or pay leads to worsening depressive symptoms among adults with ASD. Better supporting autistic adults in the workplace may not only decrease the likelihood of job loss, but also combat the exceedingly high rates of depression in this group. LAY SUMMARY: Though unemployment has been linked to mental health problems in the general population, this relationship is seldom considered among adults with autism. In this study, we found that adults on the autism spectrum who lost their jobs or experienced reductions in pay or hours during the first 2 months of COVID-19 had worsening depression compared to adults who did not have job changes. Our findings suggest that increasing access to employment may help alleviate poor mental health among autistic adults.

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15. Wang Z, Li C, Zhao Y, Li L, Lyu Y, Cui H. [Clinical and genetic analysis of a child with mental retardation and microcephaly with pontine and cerebellar hypoplasia]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2021; 38(10): 985-8.

OBJECTIVE: To analyze the clinical phenotype and pathogenic variant in a child diagnosed with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). METHODS: Clinical phenotype of the child was reviewed. Whole exome sequencing was carried out for the child. Candidate variant was verified by Sanger sequencing of the family member. RESULTS: The proband manifested dyskinesia, development delay, cerebellar hypoplasia and bilateral hearing impairment. WES results revealed that the proband has carried a pathogenic c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene, which was verified by Sanger sequencing to be a de novo variant. CONCLUSION: The c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene probably underlay the MICPCH in the proband. Above finding has provided a basis for genetic counseling. WES should be considered for the diagnosis of neurological dysplasia.

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