1. Capal JK, Williams ME, Pearson DA, Kissinger R, Horn PS, Murray D, Currans K, Kent B, Bebin M, Northrup H, Wu JY, Sahin M, Krueger DA. Profile of Autism Spectrum Disorder in Tuberous Sclerosis Complex: Results from a Longitudinal, Prospective, Multisite Study. Annals of neurology. 2021; 90(6): 874-86.

OBJECTIVE: Tuberous sclerosis complex (TSC) is highly associated with autism spectrum disorder (ASD). Objectives of the study were to characterize autistic features in young children with TSC. METHODS: Participants included 138 children followed from ages 3 to 36 months with TSC from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study aimed at understanding the underlying mechanisms of ASD in TSC. Developmental and autism-specific assessments were administered, and a clinical diagnosis of ASD was determined for all participants at 36 months. Further analyses were performed on 117 participants with valid autism assessments based on nonverbal mental age greater than 15 months. RESULTS: Prevalence of clinical diagnosis of ASD at 36 months was 25%. Nearly all autistic behaviors on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R) were more prevalent in children diagnosed with ASD; however, autism-specific behaviors were also observed in children without ASD. Overall quality of social overtures, facial expressions, and abnormal repetitive interests and behaviors were characteristics most likely to distinguish children with ASD from those without an ASD diagnosis. Participants meeting ADOS-2 criteria but not a clinical ASD diagnosis exhibited intermediate developmental and ADOS-2 scores compared to individuals with and without ASD. INTERPRETATION: ASD is highly prevalent in TSC, and many additional individuals with TSC exhibit a broad range of subthreshold autistic behaviors. Our findings reveal a broader autism phenotype that can be identified in young children with TSC, which provides opportunity for early targeted treatments. ANN NEUROL 2021;90:874-886.

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2. Galligan ML, Heyman M, Bolourian Y, Stavropoulos K, Blacher J. Brief Report: Emotional and Behavioral Problems Among Young Children with ASD: An Exploratory Study of ADOS E-Codes and Child Characteristics. Journal of autism and developmental disorders. 2021.

Emotional and behavioral problems (EBPs), such as anxiety, overactivity, and aggression, can influence the diagnosis of autism spectrum disorder (ASD). The gold standard diagnostic tool for ASD, the Autism Diagnostic Observation Schedule-Second Edition, includes three items (« E-codes ») for EBPs that are frequently associated with ASD. Few empirical investigations have explored the use of E-codes. This study examined the relationship between E-codes and child characteristics (e.g., cognitive abilities, ASD symptom severity) in a sample of young children with ASD (N = 233). Findings indicated that E-codes positively correlated with ASD symptom severity and negatively associated with IQ. Symptom severity also significantly accounted for the variance in EBPs. Implications for ASD assessment as well as future research are discussed.

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3. Gevarter C, Groll M, Stone E, Medina Najar A. A parent-implemented embedded AAC intervention for teaching navigational requests and other communicative functions to children with Autism spectrum disorder. Augmentative and alternative communication (Baltimore, Md : 1985). 2021; 37(3): 180-93.

This study evaluated the effectiveness of an embedded naturalistic intervention for teaching augmentative and alternative communication (AAC) application responses to three preschool-aged males with autism spectrum disorder (ASD). Parents were taught to embed opportunities for their child to communicate with a grid-based AAC application during every-day routines such as play or mealtime. Communication targets included requesting objects using two-step taxonomic navigational responses, and requesting assistance, rejecting items, or making social comments/responses using a two-step message-strip response. During intervention, parents used strategies such as time delay, prompting, reinforcement, and device proximity (faded over time) to encourage target responses. Display formats and intervention targets were selected in consideration of prior dynamic assessment results. Effects of intervention were evaluated using a multiple probe across participants design. For functional navigational AAC item requesting, all three participants showed an immediate increase in responding that maintained at high levels. Functional AAC responding for other communicative purposes also increased, but at a more gradual pace. All three participants showed generalized responding when new items were added to displays, and when display pages with a larger array of folders and vocabulary items were introduced. Generalization to labeling tasks was mixed.

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4. Kamate M, Goudar N, Hattiholi V. Antenatal presentation and supratentorial brain abnormalities in a child with Poretti-Boltshauser syndrome. Brain & development. 2022; 44(2): 139-41.

Autosomal recessively inherited Poretti-Boltshauser syndrome (PBS) with loss-of-function variants in the LAMA1 gene are characterized by motor and speech developmental delay, high myopia, and cerebellar dysplasia with cysts without any supratentorial abnormalities on neuroimaging. There is no muscular involvement. We report an eight months child with genetically confirmed PBS who presented with antenatally detected ventriculomegaly and had global developmental delay, focal seizures, myopic degeneration of fundi. Neuroimaging showed asymmetric ventriculomegaly and lissencephaly in bilateral temporal horns along with cerebellar dysplasia and cysts. These supratentorial abnormalities and antenatal presentation as ventriculomegaly have not been reported earlier. Child also had a small subaortic ventricular septal defect.

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5. Moerman F, Warreyn P, Demurie E, Boterberg S, Vermeirsch J, Roeyers H. Play in Relation to Autism Traits in Young Children at Elevated Likelihood for Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

Play of younger siblings of children with autism spectrum disorder (ASD) (siblings; n = 44), very preterm children (preterms; n = 44), and children at typical likelihood for ASD (n = 36) was observed at 24 months. Children with ASD and atypical development engaged less in spontaneous (pre-)symbolic play than typically developing children. Total duration of spontaneous and elicited (pre-)symbolic play was associated with later ASD traits in siblings. However, no association between most play variables and ASD traits was found in preterms. This suggests possible different ASD-trajectories between siblings and preterms. Thus, spontaneous (pre-)symbolic play may be indicative of developmental challenges across several populations, and results highlight the need to move beyond studying only siblings in order to broaden our understanding of ASD.

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6. Oliveira KSC, Fontes DE, Longo E, Leite HR, Camargos ACR. Motor Skills are Associated with Participation of Children with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

Children with autism spectrum disorder (ASD) generally have a delay in the development of motor skills when compared to typical children, however, to date, no study has investigated whether motor limitations can interfere in the participation of these children. The objectives of this study were: verify if the motor skills can explain the frequency, the percentage of number of activities, the involvement and the desire to change in participation at home, school and community of children with autism spectrum disorder (ASD) and; identify if contextual factors would modify the association between motor skills and participation outcomes. The participation and the motor skills were evaluated in 30 children with ASD between 5 and 10 years old. Participation outcomes were measured by the Participation and Environment Measure-Children and Youth (PEM-CY) and the motor skills were assessed by the Timed Up and Go, Timed Up and Down Stairs, Test of Gross Motor Development-2nd edition and Pediatric Balance Scale. The results of the study demonstrated that the motor skills of the locomotion, objects control, change position and balance explained participation outcomes of children with ASD classified from mild to moderate, between 5 and 10 years old. Moreover, the sex variable modified the association between the motor skills and the school participation, with girls performing less activities at this setting.

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7. Omotosho IO, Akinade AO, Lagunju IA, Yakubu MA. Oxidative stress indices in ASD children in Sub-Sahara Africa. Journal of neurodevelopmental disorders. 2021; 13(1): 50.

BACKGROUND: The pathogenesis of autism spectrum disorder (ASD) remains a medical challenge even in the developed world. Although genetics and epigenetic factors have been variously indicted as major causes of the disorder, development of oxidative stress especially in the formative years of children has equally gained prominence as an etiological basis of the disorder. Oxidative stress is characterized by the production of excessive amounts of free radicals, decreased levels of antioxidants with the attendant imbalance in oxidant/antioxidant ratio. This study was designed to determine the levels of essential metals [magnesium (Mg), zinc (Zn), and copper (Cu)] and toxic metal, lead (Pb), and generation of oxidative stress by their abnormal interaction. METHOD: Twenty-five children clinically diagnosed for ASD according to DSM-IV-TR and 25 neuro-typical (NT) children (controls), (aged 5.96 ± 1.40 years and 6.18 ± 2.59 years respectively) were recruited for this study. Essential and toxic metals were analyzed using induction-coupled plasma-mass spectrometry (ICP-MS); oxidative stress markers [malondialdehyde (MDA), total plasma peroxidase (TPP), and total antioxidant capacity (TAC)] were determined using appropriate biochemical methods. Oxidative stress index (OSI) was calculated. RESULTS: The levels of TPP and TAC were significantly reduced while MDA was higher in ASD compared to NT. Although OSI was higher in ASD, the difference was not significant. Pb (lead) concentration was significantly increased while Mg, Zn, and Cu levels were reduced significantly in ASD compared to NT. A significant negative correlation between Mg and OSI (r = – 0.438; p = 0.029) was observed in NT. CONCLUSION: Reduction in Zn and Mg levels with a concurrent increase in Pb in children with ASD in this study may be the basis of inadequate TAC manifesting as increased MDA and reduced TPP levels. The attendant imbalance in oxidant/antioxidant ratio may result in abnormality in neuronal transduction leading to the abnormal cognitive and speech functions characteristic of ASD.

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8. Pagani M, Barsotti N, Bertero A, Trakoshis S, Ulysse L, Locarno A, Miseviciute I, De Felice A, Canella C, Supekar K, Galbusera A, Menon V, Tonini R, Deco G, Lombardo MV, Pasqualetti M, Gozzi A. mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity. Nature communications. 2021; 12(1): 6084.

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism.

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9. Peltekova I, Yusuf A, Frei J, Savion-Lemieux T, Joober R, Howe J, Scherer SW, Elsabbagh M. Predictors of empowerment in parents of children with autism and related neurodevelopmental disorders who are undergoing genetic testing. Molecular genetics & genomic medicine. 2021; 9(11): e1803.

BACKGROUND: There is limited empirical data quantifying the utility of genetic testing for families of children with autism spectrum disorder (ASD) or related neurodevelopmental disorders (NDD). We assessed the utility of clinical chromosomal microarray analysis (CMA), defined by diagnostic yield and parental empowerment, in population-based sample of parents of affected children; and explored child, family, and health services factors predictive of empowerment. METHODS: Participants were families of children undergoing diagnostic assessments, between 2016 and 2019. Diagnostic yield of CMA in affected children was determined. Parental empowerment was measured through adapted version of the Genetics Counseling Outcome Scale-24. Parents completed questionnaires to capture child, family, and health service factors. RESULTS: The diagnostic yield of CMA was 2.8% for pathogenic variants. Parental empowerment was significantly correlated with family functioning and aspects of perceived family-centeredness of care. The model accounted for 49.8% of the variation in parental empowerment, F (10,37) = 3.67, p = 0.002. After accounting for other predictors, parental perception of the provision of general information remained significantly associated with empowerment. CONCLUSION: The informational needs of families play an important role in their empowerment during genetic testing. Meeting these needs and monitoring empowerment can aid genomic technologies integration in personalized healthcare for ASD/NDD.

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10. Rybicki AJ, Galea JM, Schuster BA, Hiles C, Fabian C, Cook JL. Intact predictive motor sequence learning in autism spectrum disorder. Scientific reports. 2021; 11(1): 20693.

Atypical motor learning has been suggested to underpin the development of motoric challenges (e.g., handwriting difficulties) in autism. Bayesian accounts of autistic cognition propose a mechanistic explanation for differences in the learning process in autism. Specifically, that autistic individuals overweight incoming, at the expense of prior, information and are thus less likely to (a) build stable expectations of upcoming events and (b) react to statistically surprising events. Although Bayesian accounts have been suggested to explain differences in learning across a range of domains, to date, such accounts have not been extended to motor learning. 28 autistic and 35 non-autistic controls (IQ > 70) completed a computerised task in which they learned sequences of actions. On occasional « surprising » trials, an expected action had to be replaced with an unexpected action. Sequence learning was indexed as the reaction time difference between blocks which featured a predictable sequence and those that did not. Surprise-related slowing was indexed as the reaction time difference between surprising and unsurprising trials. No differences in sequence-learning or surprise-related slowing were observed between the groups. Bayesian statistics provided anecdotal to moderate evidence to support the conclusion that sequence learning and surprise-related slowing were comparable between the two groups. We conclude that individuals with autism do not show atypicalities in response to surprising events in the context of motor sequence-learning. These data demand careful consideration of the way in which Bayesian accounts of autism can (and cannot) be extended to the domain of motor learning.

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11. Tsirgiotis JM, Young RL, Weber N. A Mixed-Methods Investigation of Diagnostician Sex/Gender-Bias and Challenges in Assessing Females for Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

Despite the importance of clinical judgement in autism spectrum disorder (ASD) assessment, little is currently known about challenges faced by diagnosticians when the client is female, any sex/gender biases during the assessment process, and how these issues affect diagnostic outcomes. Forty-seven ASD diagnosticians completed a questionnaire containing two hypothetical case studies (a ‘male’ and ‘female’ ASD presentation), with sex/gender randomly assigned within each. Diagnosticians reported greater ASD symptom severity when female sex/gender pseudonyms were allocated to the case studies, but their confidence in ASD diagnosis was similar regardless of condition. Diagnosticians identified a large number of challenges associated with assessing females for ASD. Many of these related to sex/gender differences in ASD presentation and limitations of diagnostic instruments.

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