1. Amen NE, Eqani S, Bilal K, Ali N, Rajeh N, Adelman D, Shen H, Lohmann R. Molecularly tracing of children exposure pathways to environmental organic pollutants and the Autism Spectrum Disorder Risk. Environmental pollution (Barking, Essex : 1987). 2022; 315: 120381.

Organic pollutants (OPs) including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and polycyclic aromatic hydrocarbons (PAHs) have showed neuro-damaging effects, but studies concerning the autism spectrum disorder (ASD) risk are limited. A case-control study with ASD (n = 125) and healthy control (n = 125) children was conducted on the different land use settings across Punjab, Pakistan. Serum concentrations of 26 OCPs, 29 PCB congeners, 11 PBDEs and 32 PAHs were measured. Serum PCB77 (AOR = 2.00; 95% CI: 1.43, 2.18), PCB118 (AOR = 1.49; 95% CI: 1.00, 2.00), PCB128 (AOR = 1.65; 95% CI: 1.01, 1.91), PCB153 (AOR = 1.80; 95% CI: 1.55, 1.93) were significantly higher, but PCB187 (AOR = 0.37; 95% CI: 0.24, 0.49) was significantly lower in the ASD cases when compared to the controls. Serum BDE99 (AOR = 0.48; 95% CI: 0.26, 0.89) was significantly higher in the healthy controls than in the ASD cases. Among the analyzed OCPs, p,p’-DDE (AOR = 1.50; 95% CI: 1.00, 1.85) was significantly elevated in the ASD cases with comparison in the controls. For PAHs, serum dibenzothiophene (AOR = 7.30; 95% CI: 1.49, 35.85) was significantly higher in the ASD, while perylene (AOR = 0.25; 95% CI: 0.06, 1.10) and fluorene (AOR = 0.21; 95% CI: 0.06, 0.72) were significantly higher in the controls. In addition, many of the serum pollutants were significantly associated with GSTT1, GSTM1 (null/present polymorphism) and presented the genotypic variation to respond xenobiotics in children. The children living in proximity to urban and industrial areas had a greater exposure to most of the studied pollutants when compared to the rural children, however children residing in rural areas showed higher exposure to OCPs. This comprehensive study documents an association between environmental exposure risk of several organic pollutants (OPs) from some contaminated environmental settings with ASD risk in children from Pakistan.

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2. Dwyer P, Takarae Y, Zadeh I, Rivera SM, Saron CD. Multisensory integration and interactions across vision, hearing, and somatosensation in autism spectrum development and typical development. Neuropsychologia. 2022; 175: 108340.

Most prior studies of multisensory integration (MSI) in autism have measured MSI in only a single combination of modalities – typically audiovisual integration. The present study used onset reaction times (RTs) and 125-channel electroencephalography (EEG) to examine different forms of bimodal and trimodal MSI based on combinations of auditory (noise burst), somatosensory (finger tap), and visual (flash) stimuli presented in a spatially-aligned manner using a custom desktop apparatus. A total of 36 autistic and 19 non-autistic adolescents between the ages of 11-14 participated. Significant RT multisensory facilitation relative to summed unisensory RT was observed in both groups, as were significant differences between summed unisensory and multisensory ERPs. Although the present study’s statistical approach was not intended to test effect latencies, these interactions may have begun as early as ∼45 ms, constituting « early » (<100 ms) MSI. RT and ERP measurements of MSI appeared independent of one another. Groups did not significantly differ in multisensory RT facilitation, but we found exploratory evidence of group differences in the magnitude of audiovisual interactions in ERPs. Future research should make greater efforts to explore MSI in under-represented populations, especially autistic people with intellectual disabilities and nonspeaking/minimally-verbal autistic people.

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3. Friedel EBN, Schäfer M, Endres D, Maier S, Runge K, Bach M, Heinrich SP, Ebert D, Domschke K, Tebartz van Elst L, Nickel K. Electroretinography in adults with high-functioning autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2022; 15(11): 2026-37.

The electroretinogram (ERG) allows the investigation of retinal signaling pathways and has increasingly been applied in individuals with mental disorders in search for potential biomarkers of neurodevelopmental disorders. Preceding ERG examinations in individuals with autism spectrum disorders (ASD) showed inconsistent results, which might be due to the small number of participants, heterogeneity of the ASD population, differences in age ranges, and stimulation methods. The aim of this study was to investigate functional retinal responses in adults with ASD by means of the light-adapted (photopic) ERG. Light-adapted ERG measurements were obtained with the RETeval® system applying three different stimulation protocols. In the final analysis, the ERG parameters a-wave, b-wave, the photopic negative response (PhNR), the photopic hill parameters as well as additional amplitude ratios were compared between 32 adults with high-functioning ASD and 31 non-autistic controls. Both groups were matched with regard to sex and age. No significant functional retinal differences in amplitude or peak time of the a- or b-wave, PhNR, the photopic hill parameters or the ERG-amplitude ratios could be detected in individuals with ASD compared to non-autistic participants. The absence of electrophysiological functional retinal alterations in ASD, suggests that changes in visual perception, such as increased attention to detail or visual hypersensitivity in ASD, are not due to impairments at early levels of retinal signal processing.

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4. Li H, Shi B, Wang X, Cao M, Chen J, Liu S, Zhan X, Jin C, Gui Z, Jing J, Zhu Y. Associations of emotional/behavioral problems with accelerometer-measured sedentary behavior, physical activity and step counts in children with autism spectrum disorder. Frontiers in public health. 2022; 10: 981128.

BACKGROUND: The evidence for associations of emotional/behavioral status with sedentary behavior (SB), physical activity (PA) and step counts is scarce in children with autism spectrum disorder (ASD). Also, ASD-related deficiencies may affect actual levels of PA. We aimed to describe accelerometer-measured SB, PA and step counts in children with ASD, and to examine the associations of emotional/behavioral problems with SB, PA and step counts after assessing associations between accelerometer-measured SB, PA and step counts and ASD-related deficiencies. METHODS: A total of 93 ASD children, aged 6-9 years, were recruited from the Center for Child and Adolescent Psychology and Behavioral Development of Sun Yat-sen University in Guangzhou, China. Participants wore an accelerometer for seven consecutive days. Of the original 93, 78 participants’ accelerometer-measured valid PA were obtained, and the data were shown as time spent in SB, light, moderate, moderate-to-vigorous and vigorous PA, and step counts. Participants’ emotional/behavioral problems were assessed via the Strengths and Difficulties Questionnaire (SDQ), and anxiety symptoms were evaluated by the Screen for Child Anxiety Related Emotional Disorders (SCARED). ASD-associated deficiencies include restricted repetitive behaviors (Repetitive Behavior Scale-Revised), poor social competence (Social Responsiveness Scale Second Edition) and motor development restrictions (Developmental Coordination Disorder Questionnaire). RESULTS: Of the 78 participants, daily vigorous PA (VPA) and moderate-to-vigorous PA (MVPA) averaged 15.62 and 51.95 min, respectively. After adjustment for covariates, SDQ emotional symptoms (β = -0.060, p = 0.028) were inversely associated with the average daily minutes in VPA. Meanwhile, SDQ emotional symptoms (β = -0.033, p = 0.016) were inversely associated with the average daily MVPA minutes in the crude model. After adjustment for covariates, SCARED somatic/panic (β = -0.007, p = 0.040) and generalized anxiety (β = -0.025, p = 0.014) were negatively associated with the average daily VPA minutes; SCARED total anxiety (β = -0.006, p = 0.029) was conversely associated with daily MVPA duration. After adjustment for covariates, no significant associations between accelerometer-measured SB, PA and step counts and ASD-related deficiencies were found (p > 0.05). CONCLUSIONS: Accelerometer-measured SB, PA and step counts showed no associations with ASD-related deficiencies. On this basis, we further found that the emotional symptoms were inversely associated with VPA and MVPA. These results emphasize the importance of VPA and MVPA in children with ASD. The longitudinally investigations on the directionality of these associations between emotional symptoms with VPA and MVPA are needed in the future.

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5. Musich FD, Aragón-Daud AAD. [Psychological therapy adaptations for adults on the autism spectrum]. Vertex (Buenos Aires, Argentina). 2022; 33(157): 44-50.

The prevalence of autism spectrum conditions has been increasing in recent decades. However, this has not been reflected in an increase in clinical research, so there is insufficient evidence on the supports and adaptations that psychological treatments require for this population. Evidence-based psychological therapies are frequently goal-focused, usually short-term, such as cognitive behavioral therapy, which integrates cognitive and behavioral modalities. Due to the high rates of comorbidity in people with autism, various psychological therapies are in the process of adapting their delivery. This review explores research-suggested adaptations to implement psychological therapies in adults with autism without intellectual disability. Both formal and intervention techniques adaptations are required. Adaptations at each stage of psychological therapies are important to support the differences, needs, and preferences of the adult with autism. Professional training aimed at working with this particular population, and research on how to optimize the access of this population to mental health services are essential for its correct implementation.

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6. Sleyp Y, Valenzuela I, Accogli A, Ballon K, Ben-Zeev B, Berkovic SF, Broly M, Callaerts P, Caylor RC, Charles P, Chatron N, Cohen L, Coppola A, Cordeiro D, Cuccurullo C, Cuscó I, Janette d, Duran-Romaña R, Ekhilevitch N, Fernández-Alvarez P, Gordon CT, Isidor B, Keren B, Lesca G, Maljaars J, Mercimek-Andrews S, Morrow MM, Muir AM, Rousseau F, Salpietro V, Scheffer IE, Schnur RE, Schymkowitz J, Souche E, Steyaert J, Stolerman ES, Vengoechea J, Ville D, Washington C, Weiss K, Zaid R, Sadleir LG, Mefford HC, Peeters H. De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder. Genetics in medicine : official journal of the American College of Medical Genetics. 2022.

PURPOSE: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. METHODS: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. RESULTS: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. CONCLUSION: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.

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7. Srivastava S, Jo B, Zhang B, Frazier T, Gallagher AS, Peck F, Levin AR, Mondal S, Li Z, Filip-Dhima R, Geisel G, Dies KA, Diplock A, Eng C, Hanna R, Sahin M, Hardan A. A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome. Human molecular genetics. 2022; 31(20): 3393-404.

PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mechanistic target of rapamycin (mTOR) overactivity. Limited data suggest that mTOR inhibitors may be therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in humans with PHTS with/without autism. We conducted a 6-month phase II, randomized, double-blinded, placebo-controlled trial to examine the safety profile and efficacy of everolimus (4.5 mg/m2) in individuals (5-45 years) with PHTS. We measured several cognitive and behavioral outcomes, and electroencephalography (EEG) biomarkers. The primary endpoint was a neurocognitive composite derived from Stanford Binet-5 (SB-5) nonverbal working memory score, SB-5 verbal working memory, Conners’ Continuous Performance Test hit reaction time and Purdue Pegboard Test score. Forty-six participants underwent 1:1 randomization: n = 24 (everolimus) and n = 22 (placebo). Gastrointestinal adverse events were more common in the everolimus group (P < 0.001). Changes in the primary endpoint between groups from baseline to Month 6 were not apparent (Cohen's d = -0.10, P = 0.518). However, several measures were associated with modest effect sizes (≥0.2) in the direction of improvement, including measures of nonverbal IQ, verbal learning, autism symptoms, motor skills, adaptive behavior and global improvement. There was a significant difference in EEG central alpha power (P = 0.049) and central beta power (P = 0.039) 6 months after everolimus treatment. Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement. Several secondary efficacy endpoints moved in the direction of improvement. EEG measurements indicate target engagement following 6 months of daily oral everolimus. Trial Registration Information: ClinicalTrials.gov NCT02991807 Classification of Evidence: I.

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8. Stelzer JA, Yi JJ. A Scalable, Cell-based Method for the Functional Assessment of Ube3a Variants. Journal of visualized experiments : JoVE. 2022; (188).

The increased use of sequencing in medicine has identified millions of coding variants in the human genome. Many of these variants occur in genes associated with neurodevelopmental disorders, but the functional significance of the vast majority of variants remains unknown. The present protocol describes the study of variants for Ube3a, a gene that encodes an E3 ubiquitin ligase linked to both autism and Angelman syndrome. Duplication or triplication of Ube3a is strongly linked to autism, whereas its deletion causes Angelman syndrome. Thus, understanding the valence of changes in UBE3A protein activity is important for clinical outcomes. Here, a rapid, cell-based method that pairs Ube3a variants with a Wnt pathway reporter is described. This simple assay is scalable and can be used to determine the valence and magnitude of activity changes in any Ube3a variant. Moreover, the facility of this method allows the generation of a wealth of structure-function information, which can be used to gain deep insights into the enzymatic mechanisms of UBE3A.

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