1. Daich Varela M, Motta FL, Webster AR, Arno G. A rare canonical splice-site variant in VPS13B causes attenuated Cohen syndrome. Ophthalmic genetics. 2022; 43(1): 110-5.

BACKGROUND: To describe a patient with a history of obesity, retinal dystrophy, type II diabetes, and mild cognitive impairment; found to harbour biallelic splice-site variants in VPS13B. MATERIALS & METHODS: A complete ophthalmic evaluation was performed at Moorfields Eye Hospital (London, United Kingdom), consisting of measurement of best-corrected visual acuity (BCVA), slit lamp and dilated fundus evaluation, colour, autofluorescence and near-infrared retinal imaging, spectral domain-optical coherence tomography, and electroretinogram (ERG). Whole-genome sequencing was performed as part of the UK’s 100,000 Genomes Project. RESULTS: A 26-year-old Pakistani man with normal appearance, stature, and head size presented with decreased BCVA and severely constricted visual fields to our Ophthalmic Genetics clinic. He had a history of obesity, type II diabetes, and mild cognitive impairment. His evaluation showed retina-wide, severe photoreceptor dysfunction in both eyes, with undetectable scotopic and photopic ERG waveforms. Genomic analysis identified a homozygous rare splice donor variant in the VPS13B gene (c.5024+2T>C) that was demonstrated to lead to skipping of the in-frame exon 31 (p.Gln1607_Ser1675delinsHis). CONCLUSIONS: Exon 31 skipping in VPS13B may lead to a hypomorphic change, with partial gene function and an incomplete, mild Cohen syndrome-like phenotype.

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2. Factor RS, Arriaga RI, Morrier MJ, Mathys JB, Dirienzo M, Miller CA, Southerland AM, Abowd GD, Ousley OY. Development of an interactive tool of early social responsiveness to track autism risk in infants and toddlers. Developmental medicine and child neurology. 2022; 64(3): 323-30.

AIM: To evaluate the psychometric properties of a 4-minute assessment designed to identify early autism spectrum disorder (ASD) status through evaluation of early social responsiveness (ESR). METHOD: This retrospective, preliminary study included children between 13 and 24 months (78 males, 79 females mean age 19.4mo, SD 3.1) from two independent data sets (an experimental/training sample [n=120] and a validation/test sample [n=37]). The ESR assessment examined social behaviors (e.g. eye contact, smiling, ease-of-social-engagement) across five common play activities (e.g. rolling a ball, looking at a book). Data analyses examined reliability and accuracy of the assessment in identifying ESR abilities and in discriminating children with and without ASD. RESULTS: Results indicated adequate internal consistency and test-retest reliability of the ESR assessment. Receiver operator curve analysis identified a cutoff score that discriminated infants with ASD-risk from peers in the training sample. This score yielded moderate sensitivity and high specificity for best-estimate ASD diagnosis in the validation sample. INTERPRETATION: Preliminary findings indicated that brief, systematic observation of ESR may assist in discriminating infants with and without ASD, providing concrete evidence to validate or supplement parents’, pediatricians’, or clinicians’ concerns. Future studies could examine the utility of ESR ‘growth curves’.

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3. Frewer V, Gilchrist CP, Collins SE, Williams K, Seal ML, Leventer RJ, Amor DJ. A systematic review of brain MRI findings in monogenic disorders strongly associated with autism spectrum disorder. Journal of child psychology and psychiatry, and allied disciplines. 2021; 62(11): 1339-52.

BACKGROUND: Research on monogenic forms of autism spectrum disorder (autism) can inform our understanding of genetic contributions to the autism phenotype; yet, there is much to be learned about the pathways from gene to brain structure to behavior. This systematic review summarizes and evaluates research on brain magnetic resonance imaging (MRI) findings in monogenic conditions that have strong association with autism. This will improve understanding of the impact of genetic variability on brain structure and related behavioral traits in autism. METHODS: The search strategy for this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias (ROB) assessment was completed on included studies using the Newcastle-Ottawa Scales. RESULTS: Of 4,287 studies screened, 69 were included pertaining to 13 of the top 20 genes with the strongest association with autism. The greatest number of studies related to individuals with PTEN variants and autism. Brain MRI abnormalities were reported for 12 of the 13 genes studied, and in 51.7% of participants across all 13 genes, including 100% of participants with ARID1B variants. Specific MRI findings were highly variable, with no clear patterns emerging within or between the 13 genes, although white matter abnormalities were the most common. Few studies reported specific details about methods for acquisition and processing of brain MRI, and descriptors for brain abnormalities were variable. ROB assessment indicated high ROB for all studies, largely due to small sample sizes and lack of comparison groups. CONCLUSIONS: Brain abnormalities are common in this population of individuals, in particular, children; however, a range of different brain abnormalities were reported within and between genes. Directions for future neuroimaging research in monogenic autism are suggested.

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4. Golos A, Chapani Itkin S, Ben-Zur H. The Structured Preschool Participation Observation (SPO) for Children with ASD: Adaptation, Initial Psychometric Properties, and Children’s Participation. Physical & occupational therapy in pediatrics. 2022; 42(2): 198-214.

Aims: Due to the lack of tools evaluating participation of children with ASD in the educational setting, this study aimed to adapt the Structured Preschool Participation Observation (SPO), which assess the participation of preschool children attending mainstream-educational settings to children with ASD attending non-inclusive special education (content validity), to measure its initial psychometric properties (internal reliability, inter-rater reliability), and to describe children’s participation characteristics, creating an effective tool to fill this gap.Methods: Content validity was evaluated by 21 experts using questionnaires. Thirty-five children with ASD were observed in their educational setting using the adapted tool (SPO-ASD).Results: Content validity was satisfactory regarding the items and their classification into occupational areas. Moderate to excellent internal consistency (α = .73-.92) and inter-rater reliability (ICC = .61-.95, p<.05) were found for all scales and most areas. Children's participation frequency was high in learning and activities of daily living (ADL), low in play and social participation. Performance level was low in social participation. Enjoyment level was low, and needed assistance in ADL was high.Conclusions: Based on our initial evaluation, the SPO-ASD may be suitable for assessing participation of children with ASD attending special education preschools. Additional studies are needed to more securely establish its psychometric properties.

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5. Harrop C, Dallman AR, Lecavalier L, Bodfish JW, Boyd BA. Behavioral Inflexibility Across Two Neurogenetic Conditions: Down Syndrome and Fragile X Syndrome. American journal on intellectual and developmental disabilities. 2021; 126(5): 409-20.

Behavioral inflexibility (BI) has been highlighted to occur across genetic and neurodevelopmental disorders. This study characterized BI in two common neurogenetic conditions: Fragile X syndrome (FXS) and Down syndrome (DS). Caregivers of children with FXS (N = 56; with ASD = 28; FXS only = 28) and DS (N = 146) completed the Behavioral Inflexibility Scale (BIS) via an online survey. Total BIS scores were higher in FXS+ASD than both FXS only and DS (p <.001). Most endorsed items were similar across the three groups, but scores were higher in the FXS+ASD group. In all groups, BI associated with other clinical variables (receptive behaviors, anxiety, social communication). The current data suggest that BI is variable across neurogenetic conditions and higher in individuals with comorbid ASD.

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6. Marsack-Topolewski CN, Wang F. Dimensions of Caregiver Burden between Compound and Noncompound Caregivers of Adults with Autism. Journal of gerontological social work. 2022; 65(4): 402-20.

The expanding population of adults with autism spectrum disorder (ASD) will increase the number of aging parents who often assume the role of primary caregivers. Among aging caregivers of adults with ASD, compound caregiving (caring for additional family members) has become an increasingly common scenario. However, limited research has examined the burden of compound caregivers and little is known about the specific dimensions of burden among this population. The present study aims to compare differences between compound 1, compound 2, and noncompound caregivers on specific dimensions of caregiver burden associated with adult children with ASD. Using a cross-sectional design, data were collected from 320 caregivers aged 50 and older through a web-based survey. Four dimensions of burden (time dependence, developmental, emotional, and financial) were compared using MANOVA. Compound 1 and noncompound caregivers experienced lower levels of time dependence burden than compound 2 caregivers. In terms of developmental burden, the social life of compound 2 caregivers was more affected by caregiving compared to noncompound caregivers. The findings have practice implications for identifying caregivers’ multiple responsibilities and the multi-faceted impact of caregiving, and prioritizing interventions for compound caregivers and its subpopulations to reduce their time and developmental burden.

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7. Minozzi S, Morgano GP, Scattoni ML, Cinquini M, Amato L. GRADE Notes 2: Criteria for searching non-randomized or indirect evidence should be defined early in the guideline production process. Journal of clinical epidemiology. 2021; 139: 210-3.

OBJECTIVE: To discuss two alternative approaches for complementing the body of direct evidence from Randomized Controlled Trials (RCTs) when it is judged insufficient from a guideline panel making recommendations. The approaches included expanding the evidence’s body to non-randomises studies on the population of interest or to RCTs on indirect populations. STUDY DESIGN AND SETTING: In this report, we adopt the perspective of an evidence review team developing guidelines following the GRADE approach. Our experience is based on the development of two evidence-based guidelines promoted by The Italian National Institute of Health (ISS) and focusing on diagnosis and treatment of Autism Spectrum Disorders (ASD) in children/adolescents and adults. RESULTS: We left panel members deciding case by case whether the direct evidence from RCTs was sufficient or not and indicating which alternative to implement. This strategy presented unanticipated challenges both from an organizational and methodological standpoint. CONCLUSION: We suggest an early-stage production of a research protocol to define the criteria for expanding the body of evidence. These criteria should be informed by considerations around the certainty in the evidence, the clinical applicability of the results, feasibility and conflict of interest.

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8. Nishat F, Lunsky Y, Tarasoff LA, Brown HK. Prenatal Care Adequacy Among Women With Disabilities: A Population-Based Study. American journal of preventive medicine. 2022; 62(1): 39-49.

INTRODUCTION: This study examines prenatal care adequacy among women with physical, sensory, and intellectual/developmental disabilities, compared with that among women without disabilities. METHODS: A population-based cohort study using linked health administrative data in Ontario, Canada was completed. The study population comprised women with physical (n=83,752), sensory (n=25,685), intellectual/developmental (n=1,219), and multiple (n=4,966) disabilities and women without disabilities (n=953,766), with a birth in 2003-2017. Analyses were conducted in 2020. Women with disabilities were identified using algorithms applied to healthcare encounters before conception. The main outcome was prenatal care adequacy, measured using the Revised Graduated Prenatal Care Utilization Index. Multivariable nominal logistic regression was used to compute the AORs and 95% CIs for no, inadequate, and intensive (versus adequate) care comparing each disability group with women without disabilities, adjusting for sociodemographic and health characteristics. RESULTS: Women with physical disabilities, compared with those without disabilities, had increased odds of intensive prenatal care (AOR=1.22, 95% CI=1.19, 1.24) and decreased odds of no prenatal care (AOR=0.94, 95% CI=0.89, 0.99) versus adequate care. Women with sensory disabilities had increased odds of intensive (AOR=1.11, 95% CI=1.08, 1.14), inadequate (AOR=1.06, 95% CI=1.02, 1.09), and no (AOR=1.24, 95% CI=1.14, 1.35) prenatal care. Women with intellectual/developmental disabilities had increased odds of inadequate (AOR=1.25, 95% CI=1.08, 1.44) and no (AOR=1.64, 95% CI=1.16, 2.34) prenatal care. Women with multiple disabilities had increased odds of intensive (AOR=1.41, 95% CI=1.32, 1.51) and inadequate (AOR=1.14, 95% CI=1.05, 1.22) prenatal care. CONCLUSIONS: There are variations in prenatal care adequacy by maternal disability status. Disparities in prenatal care access for women with disabilities, particularly those with intellectual/developmental disabilities, need to be addressed.

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9. Peteri UK, Pitkonen J, de Toma I, Nieminen O, Utami KH, Strandin TM, Corcoran P, Roybon L, Vaheri A, Ethell I, Casarotto P, Pouladi MA, Castrén ML. Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome. Glia. 2021; 69(12): 2947-62.

The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes. Levels of uPA were also increased in conditioned medium collected from FXS hiPSC-derived astrocyte cultures and correlated inversely with intracellular Ca(2+) responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase-Cγ1 (PLCγ1), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS-specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)-responsive astrocyte population. To conclude, our studies identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.

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10. Raulston TJ, Kosty D, McIntyre LL. Mindful Parenting, Caregiver Distress, and Conduct Problems in Children With Autism. American journal on intellectual and developmental disabilities. 2021; 126(5): 396-408.

Children with autism may display an externalizing problem behavior, which are associated with increased parenting stress and depression in caregivers. Mindful parenting is defined as having a non-judgmental moment-to-moment awareness during caregiver-child interactions. The extant literature is mixed, with some reporting that associations between child problem behavior and parenting stress and depression vary by level of mindful parenting, while others have not found these relations. We sought to extend these explorations. Participants who were caregivers of 75 children with autism spectrum disorder (ASD) ages 5-10, in the Pacific Northwestern region of the United States. Child conduct problems, parenting stress and caregiver depression, and mindful parenting were measured using caregiver-reported measures. Child conduct problems, parenting stress, and caregiver depression, and mindful parenting were all significantly correlated. The association between child conduct problems and parenting stress was significant for caregivers with high and low levels of mindful parenting. In contrast, the association between child conduct problems and caregiver depression was significant only for caregivers with low levels of mindful parenting. Our results suggest that mindful parenting may be a promising protective factor for the well-being of caregivers of children with autism. Implications are discussed.

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11. Samarasinghe RA, Miranda OA, Buth JE, Mitchell S, Ferando I, Watanabe M, Allison TF, Kurdian A, Fotion NN, Gandal MJ, Golshani P, Plath K, Lowry WE, Parent JM, Mody I, Novitch BG. Identification of neural oscillations and epileptiform changes in human brain organoids. Nature neuroscience. 2021; 24(10): 1488-500.

Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

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12. Sano M, Yoshimura Y, Hirosawa T, Hasegawa C, An KM, Tanaka S, Naitou N, Kikuchi M. Joint attention and intelligence in children with autism spectrum disorder without severe intellectual disability. Autism research : official journal of the International Society for Autism Research. 2021; 14(12): 2603-12.

In children with autism spectrum disorder (ASD), joint attention is regarded as a predictor of language function, social skills, communication, adaptive function, and intelligence. However, existing information about the association between joint attention and intelligence is limited. Most such studies have examined children with low intelligence. For this study, we investigated whether joint attention is related to intelligence in young children with autism spectrum disorder (ASD) without severe intellectual disability. We analyzed 113 children with ASD aged 40-98 months. Their Kaufman Assessment Battery (K-ABC) Mental Processing Index (MPI) scores are 60 and more (mean 93.4). We evaluated their intelligence using K-ABC and evaluated their joint attention using ADOS-2. After we performed simple regression analyses using K-ABC MPI and its nine subscales as dependent variables, using joint attention as the independent variable, we identified joint attention as a positive predictor of the MPI and its two subscales. From this result, we conclude that joint attention is related to intelligence in young children with ASD without severe intellectual disability. This result suggests a beneficial effect of early intervention targeting joint attention for children with ASD. LAY SUMMARY: Joint attention is the ability to coordinate visual attention with another person and then shift one’s gaze toward an object or event. Impairment of joint attention is regarded as an early marker of autism spectrum disorder (ASD). This study revealed impairment of joint attention as associated with lower intelligence in ASD children. These results are expected to constitute a rationale for future studies, particularly addressing beneficial effects of early intervention targeting joint attention for children with ASD.

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13. Shire SY, Worthman LB, Arbuckle S. A Technology-Enabled Adaptation of Face-to-Face Caregiver-Mediated JASPER Intervention: Preliminary Examination of Video Conferenced Caregiver Coaching. American journal on intellectual and developmental disabilities. 2021; 126(5): 421-34.

Family-centered practices that involve direct participation of caregivers as part of intervention is critical to effective early intervention. However, regularly scheduled, in person service delivery is not always possible in remote communities, prompting a need for adaptations to the delivery of services, such as the use of live video conferencing to coach caregivers in strategies to promote their children’s development. In this study, caregivers and their children ages 2-9 with autism who were living in rural and remote Canadian communities were included. A concurrent multiple baseline design across participants was applied to examine the effects of live video conference caregiver coaching on children’s time jointly engaged with caregivers and caregivers’ intervention strategy implementation. Results indicated that all children demonstrated greater time jointly engaged and caregivers demonstrated greater use of strategies in comparison to baseline. The results of this study offer preliminary evidence of the effectiveness of real time video conference coaching for caregivers engaging their children with ASD in play.

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14. Zdankiewicz-Ścigała E, Ścigała D, Sikora J, Kwaterniak W, Longobardi C. Relationship between interoceptive sensibility and somatoform disorders in adults with autism spectrum traits. The mediating role of alexithymia and emotional dysregulation. PloS one. 2021; 16(8): e0255460.

OBJECTIVE: The purpose of the study is to analyses the relationship between interoceptive sensibility and somatoform disorders among persons with Autism Spectrum Disorder (ASD). It has been assumed that the interoceptive sensibility is accompanied by a high level of alexithymia and emotion dysregulation in somatoform disorders. METHODS: Persons under the care of the foundation helping people with ASD were asked to participate in the study. In total, 205 people took part in the research. The participants aged from 18 to 63 (M = 34.91; SD = 8.44). The ASD group comprised 79 persons (38.5% of subjects). The control group comprised 126 individuals (61.5% of subjects). Participants completed self-report questionnaires measuring autism (AQ), interoceptive sensibility (BPQ), alexithymia (TAS20), emotional dysregulation (DERS), and somatoform disorder (SDQ). RESULTS: The analyses showed a moderation effect of the group, which indicates the existence of a relationship between interoceptive sensibility and somatoform disorders to the greater extent in the clinical group than in the control group. In addition, the serial multiple mediation model analysis allowed to verify the mediating effect of emotion dysregulation and alexithymia on the abovementioned relationship. The indirect effect, which assumed the mediating role of alexithymia turned out to be significant, contrary to the indirect effect where emotion dysregulation was a mediator in a situation where both variables were applied simultaneously. CONCLUSIONS: Interoceptive sensibility correlated with level of alexithymia, in particular, difficulties in identifying and verbalizing emotions and emotion dysregulation in the lack of emotional awareness and lack of emotional clarity and is associated with somatoform disorders in the investigated group regardless of participants’ belonging to the ASD or control group.

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15. Zhang B, Hu X, Li Y, Ni Y, Xue L. Identification of methylation markers for diagnosis of autism spectrum disorder. Metabolic brain disease. 2022; 37(1): 219-28.

Autism spectrum disorder (ASD) is a hereditary heterogeneous neurodevelopmental disorder characterized by social and speech dysplasia. We collected the expression profiles of ASD in GSE26415, GSE42133 and GSE123302 from the gene expression omnibus (GEO) database, as well as methylation data of GSE109905. Differentially expressed genes (DEGs) between ASD and controls were obtained by differential expression analysis. Enrichment analysis identified the biological functions and signaling pathways involved by common genes in three groups of DEGs. Protein-protein interaction (PPI) networks were used to identify genes with the highest connectivity as key genes. In addition, we identified methylation markers by associating differentially methylated positions. Key methylation markers were identified using the least absolute shrink and selection operator (LASSO) model. Receiver operating characteristic curves and nomograms were used to identify the diagnostic role of key methylation markers for ASD. A total of 57 common genes were identified in the three groups of DEGs. These genes were mainly enriched in Sphingolipid metabolism and PPAR signaling pathway. In the PPI network, we identified seven key genes with higher connectivity, and used qRT-PCR experiments to verify the expressions. In addition, we identified 31 methylation markers and screened 3 key methylation markers (RUNX2, IMMP2L and MDM2) by LASSO model. Their methylation levels were closely related to the diagnostic effects of ASD. Our analysis identified RUNX2, IMMP2L and MDM2 as possible diagnostic markers for ASD. Identifying different biomarkers and risk genes will contribute to the diagnosis of ASD and the development of new clinical and drug treatments.

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