1. Ajjugal Y, Kolimi N, Rathinavelan T. Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS. Scientific reports. 2021; 11(1): 8163.

CGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.

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2. Chafouleas SM, Iovino EA. Comparing the initial impact of COVID-19 on burden and psychological distress among family caregivers of children with and without developmental disabilities. School psychology (Washington, DC). 2021; 36(5): 358-66.

The current COVID-19 pandemic is presenting challenges for families (Cluver et al., The Lancet, 2020), which may be exacerbated for caregivers of children with developmental disabilities (DDs; Center on the Developing Child, Stress, hope, and the role of science: Responding to the coronavirus pandemic, 2020). The purpose of this study was to explore caregiver burden and psychological distress among caregivers of children with DD as compared to caregivers of typically developing children across the United States as a result of COVID-19. Between 2 weeks and 1 month following COVID-19-related school closures, a total of 460 caregivers from across the U.S. completed an online survey via Qualtrics; recruitment and initial survey completion occurred simultaneously. Of the total sample of eligible participants (N = 407), 225 were the primary caregiver of a child with autism spectrum disorder (ASD)/attention-deficit/hyperactivity disorder (ADHD) and 182 were the primary caregiver of a child without ASD/ADHD. Participants across groups indicated varying levels of exposure to COVID-19 and an impact of COVID-19 at the community and individual or family levels. However, caregivers of children with ASD/ADHD reported significantly higher levels of burden, depression, anxiety, and stress. Overall, findings are consistent with anecdotal and preliminary reports that all caregivers are experiencing COVID-19-related challenges, with caregivers of children with ASD/ADHD experiencing even greater challenges, particularly with regard to burden and psychological distress. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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3. Halewa J, Marouillat S, Dixneuf M, Thépault RA, Ung DC, Chatron N, Gérard B, Ghoumid J, Lesca G, Till M, Smol T, Couque N, Ruaud L, Chune V, Grotto S, Verloes A, Vuillaume ML, Toutain A, Raynaud M, Laumonnier F. Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder. Human mutation. 2021; 42(7): 848-61.

The X-linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild-type and mutated forms of PTCHD1-GFP in HEK 293T and in Neuro-2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD.

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4. Lopez-Espejo MA, Nuñez AC, Moscoso OC, Escobar RG. Clinical characteristics of children affected by autism spectrum disorder with and without generalized hypotonia. European journal of pediatrics. 2021; 180(10): 3243-6.

In this cross-sectional study, we aimed to evaluate the association between generalized hypotonia (GH) and demographic features and clinical characteristics in toddlers (2 to 5 years) with autism spectrum disorder (ASD). Among 93 children, 32 (34.4%) had GH. These patients had a later onset of independent walking (17 vs. 15 months, p < 0.01), a higher proportion of motor stereotypies (65.6 vs. 27.9%, p < 0.01), a lower mean total score in the parental-reported Generic Core Scale of Pediatric Quality of Life Inventory 4.0 (71 vs. 76 points, p 0.03), and a higher mean total score in the Calibrated Severity Score of Autism Diagnostic Observation Schedule version 2 at diagnosis (6 vs. 5 points, p 0.02) compared to the group without GH.Conclusion: Hypotonia is associated with other motor abnormalities and could be an early marker for higher autistic symptom severity and lower quality of life in young children with ASD. What is Known: • Motor function is closely related to autism spectrum disorder (ASD) • Muscle hypotonia is present in 15% to 67% of children with ASD What is New: • Muscle hypotonia is associated with higher autistic symptom severity and lower quality of life in children with ASD • Children with ASD and muscle hypotonia have more commonly motor stereotypies and a later onset of independent walking.

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5. Lotan M, Downs J, Elefant C. A Pilot Study Delivering Physiotherapy Support for Rett Syndrome Using a Telehealth Framework Suitable for COVID-19 Lockdown. Developmental neurorehabilitation. 2021; 24(6): 429-34.

Background: Rett syndrome (RTT) is a genetically caused neurodevelopmental disorder associated with severe disability. We assessed the feasibility of a telehealth program supporting gross motor skills in RTT.Methods: Five girls with RTT were assessed and a home-based exercise program developed in response to functional goals. Families then participated in monthly Skype sessions for 6 months, guided by a physiotherapist to monitor progress and adjust the program as necessary. Goal Attainment Scaling was used to evaluate progress and a parental satisfaction questionnaire was administered.Results: Four goals were established for each participant and progress was greater than would be expected in 16 of 20 goals. Parents evaluated the program as feasible and useful for their daughters.Discussion: A telehealth model of home-based intervention supported individuals with RTT to achieve gross motor skills and was found to be feasible. This model is important at present times during COVID-19 outbreak and lockdown.

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6. Loth E. Are we ready for precision medicine for Autism? And who wants it?. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2021; 48: 32-3.

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7. MacDuffie KE, Estes AM, Harrington LT, Peay HL, Piven J, Pruett JR, Jr., Wolff JJ, Wilfond BS. Presymptomatic Detection and Intervention for Autism Spectrum Disorder. Pediatrics. 2021; 147(5).

Universal screening for autism spectrum disorder (ASD) is recommended during pediatric primary care visits in the first 2 years of life. However, many children are missed by initial screening and not diagnosed with ASD until years later. Research efforts are underway to develop and evaluate new objective measures of risk for ASD that can be used in infancy, before symptoms emerge. Initial studies with these tests, particularly MRI-based screening for infants at high familial risk, have shown promise but have not yet been evaluated in clinical trials. We present the study design for a hypothetical clinical trial that would combine presymptomatic detection and intervention for ASD and consider, through commentaries from diverse perspectives, the ethical issues that should be anticipated in advance of beginning such trials. Commentators Drs Pruett and Piven address the social value of the proposed research and importance of researcher-bioethicist collaborations. Drs Estes and Wolff discuss the clinical potential and challenges of developing presymptomatic interventions for infants at risk for ASD. Dr Harrington takes a neurodiversity view of presymptomatic prediction and intervention and their implications for autistic identity and quality of life. Finally, Drs MacDuffie, Peay and Wilfond consider the potential risks and benefits that must be evaluated and weighed in the next phases of research on presymptomatic detection and intervention for ASD.

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8. Maemonah S, Hamidah H, Notobroto HB, Sulystiono D, Widarti L. Factors affecting the ability to speak in children with autism spectrum disorders. Journal of public health research. 2021; 10(2).

BACKGROUND: Communication deficit is one of the characteristics of autism spectrum disorder. Some children with this condition cannot communicate verbally and some have very limited speech skills. This study aims to analyze the factors that affect speaking ability in children with autism, namely age, sex, emotions, attention, and memory. DESIGN AND METHODS: This study used a correlational analytical design with a retrospective cohort design. Data were obtained using questionnaires and scales. Furthermore, emotional factors, attention, memory, and age were analyzed for their effects on speaking ability using the Pearson test, while sex was analyzed for their effects on speaking ability using the Eta test. RESULTS: The results showed that there was a significant effect of attention and age on the speaking ability of children with autism spectrum disorders. Furthermore, it showed that there was a significant effect of emotion on attention. CONCLUSIONS: It was concluded that attention and age affect the speaking ability of children with autism spectrum disorder. Meanwhile, attention in affecting speaking ability is influenced by emotions. Therefore, to improve speaking ability, good emotional management and increased attention is required.

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9. Meral BF, Wehmeyer ML, Cinisli NA, Yilmaz E. The positive psychology constructs of parents of children with intellectual and developmental disabilities in Turkey. Journal of intellectual disability research : JIDR. 2021; 65(7): 638-54.

BACKGROUND: The purpose of this exploratory study was to examine positive psychology constructs (life orientation/optimism, life satisfaction, happiness, psychological well-being and personal well-being) that may predict the family quality of life (FQOL) of parents of children with intellectual and developmental disabilities (IDD) in Turkey. METHODS: Data were obtained from a convenience sample of 660 parents of children with IDD who responded to six assessments, including a measure of FQOL. An analysis using stepwise multiple regression was conducted to identify predictors of FQOL as rated by parents. RESULTS: The four constructs including personal well-being, psychological well-being, life orientation (optimism) and life satisfaction significantly explained 60% of the total variance of FQOL. The amount of explained variance, beta scores and correlations suggests that these positive psychology constructs are significant predictors of FQOL of parents of children with IDD in Turkey. CONCLUSION: The study findings suggested that positive psychological constructs at the individual level were positively related to FQOL at the group level. Personal well-being was the strongest predictor of FOQL of parents who have children with IDD in Turkey. The results also indicated that other constructs including psychological well-being, an optimistic life orientation and life satisfaction contribute significantly to the FQOL of parents of children with IDD.

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10. Peñuelas-Calvo I, Sareen A, Porras-Segovia A, Cegla-Schvatzman FB, Fernandez-Berrocal P. The Association Between Reading the Mind in the Eyes Test Performance and Intelligence Quotient in Children and Adolescents With Asperger Syndrome. Frontiers in psychiatry. 2021; 12: 642799.

Background: There has been an extensive debate about a potential association between intelligence and social cognition. In this study, we aimed to assess the association between social cognition as measured with the Reading the Mind in the Eyes test (RMET) and intelligence as measured with the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV) in children and adolescents diagnosed with Asperger Syndrome (AS). Methods: We conducted a cross-sectional study among 84 children diagnosed with AS aged 6-16 years (mean = 11.64; standard deviation = 2.75; 92.9% males). We analyzed the association between RMET performance and WISC-IV total score as well as the association between RMET performance and each of the four WISC-IV indexes (processing speed index, PSI; working memory index, WMI; perceptual reasoning index, PRI, and verbal comprehension index, VCI). Results: We found a positive correlation between RMET performance and full-scale intelligence quotient (r = 0.340; p < 0.01), VCI (r = 0.310; p < 0.01), PRI (r = 0.401; p < 0.01), and WMI (r = 0.292; p < 0.01). In the linear regression model, age was a significant predictor of RMET score (β = 0.409; p < 0.001) as was PRI (β = 0.309; p = 0.019). Conclusion: Our results suggest that intelligence quotient positively influences RMET performance, indicating that intelligence increases social cognition in individuals diagnosed with AS. However, weak-to-moderate size effects were found. This study contributes to understanding the mechanisms underlying the disturbance of social cognition in children and adolescents diagnosed with AS.

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11. Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, Vitiello B, Arango C. The pediatric psychopharmacology of autism spectrum disorder: A systematic review – Part I: The past and the present. Progress in neuro-psychopharmacology & biological psychiatry. 2021; 110: 110326.

Autism Spectrum Disorder (ASD) is a severe and lifelong neurodevelopmental disorder, with high social costs and a dramatic burden on the quality of life of patients and family members. Despite its high prevalence, reaching 1/54 children and 1/45 adults in the United States, no pharmacological treatment is still directed to core symptoms of ASD, encompassing social and communication deficits, repetitive behaviors, restricted interests, and abnormal sensory processing. The purpose of this review is to provide an overview of the state-of-the-art of psychopharmacological therapy available today for ASD in children and adolescents, in order to foster best practices and to organize new strategies for future research. To date, atypical antipsychotics such as risperidone and aripiprazole represent the first line of intervention for hyperactivity, impulsivity, agitation, temper outbursts or aggression towards self or others. Tricyclic antidepressants are less prescribed because of uncertain efficacy and important side effects. SSRIs, especially fluoxetine and sertraline, may be effective in treating repetitive behaviors (anxiety and obsessive-compulsive symptoms) and irritability/agitation, while mirtazapine is more helpful with sleep problems. Low doses of buspirone have shown some efficacy on restrictive and repetitive behaviors in combination with behavioral interventions. Stimulants, and to a lesser extent atomoxetine, are effective in reducing hyperactivity, inattention and impulsivity also in comorbid ASD-ADHD, although with somewhat lower efficacy and greater incidence of side effects compared to idiopathic ADHD. Clonidine and guanfacine display some efficacy on hyperactivity and stereotypic behaviors. For several other drugs, case reports and open-label studies suggest possible efficacy, but no randomized controlled trial has yet been performed. Research in the pediatric psychopharmacology of ASD is still faced with at least two major hurdles: (a) Great interindividual variability in clinical response and side effect sensitivity is observed in the ASD population. This low level of predictability would benefit from symptom-specific treatment algorithms and from biomarkers to support drug choice; (b) To this date, no psychoactive drug appears to directly ameliorate core autism symptoms, although some indirect improvement has been reported with several drugs, once the comorbid target symptom is abated.

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12. Shelly KE, Candelaria NR, Li Z, Allen EG, Jin P, Nelson DL. Ectopic expression of CGG-repeats alters ovarian response to gonadotropins and leads to infertility in a murine FMR1 premutation model. Human molecular genetics. 2021; 30(10): 923-38.

Women heterozygous for an expansion of CGG repeats in the 5’UTR of FMR1 risk developing fragile X-associated primary ovarian insufficiency (FXPOI) and/or tremor and ataxia syndrome (FXTAS). We show that expanded CGGs, independent of FMR1, are sufficient to drive ovarian insufficiency and that expression of CGG-containing mRNAs alone or in conjunction with a polyglycine-containing peptide translated from these RNAs contribute to dysfunction. Heterozygous females from two mouse lines expressing either CGG RNA-only (RNA-only) or CGG RNA and the polyglycine product FMRpolyG (FMRpolyG+RNA) were used to assess ovarian function in aging animals. The expression of FMRpolyG+RNA led to early cessation of breeding, ovulation and transcriptomic changes affecting cholesterol and steroid hormone biosynthesis. Females expressing CGG RNA-only did not exhibit decreased progeny during natural breeding, but their ovarian transcriptomes were enriched for alterations in cholesterol and lipid biosynthesis. The enrichment of CGG RNA-only ovaries for differentially expressed genes related to cholesterol processing provided a link to the ovarian cysts observed in both CGG-expressing lines. Early changes in transcriptome profiles led us to measure ovarian function in prepubertal females that revealed deficiencies in ovulatory responses to gonadotropins. These include impairments in cumulus expansion and resumption of oocyte meiosis, as well as reduced ovulated oocyte number. Cumulatively, we demonstrated the sufficiency of ectopically expressed CGG repeats to lead to ovarian insufficiency and that co-expression of CGG-RNA and FMRpolyG lead to premature cessation of breeding. However, the expression of CGG RNA-alone was sufficient to lead to ovarian dysfunction by impairing responses to hormonal stimulation.

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13. Sung MC, Ku B, Leung W, MacDonald M. The Effect of Physical Activity Interventions on Executive Function Among People with Neurodevelopmental Disorders: A Meta-Analysis. Journal of autism and developmental disorders. 2022; 52(3): 1030-50.

The current meta-analysis comprehensively examined the effects of physical activity interventions on executive function among people with neurodevelopmental disorders. The meta-analysis included 34 studies with 1058 participants aged 5-33 years. Results indicated an overall significant medium effect of physical activity interventions on improving executive function in people with neurodevelopmental disorders under the random-effect model (Hedges’ g = 0.56, p < .001). Significant moderators of the effects of physical activity intervention on executive function included age, intervention length and session time, executive function subdomains, and intervention dose (total minutes in the intervention). This meta-analysis provides support for the effectiveness of physical activity interventions on executive function among people with neurodevelopmental disorders. Future studies and limitations are discussed.

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14. Zhao J, Xue J, Zhu T, He H, Kang H, Jiang X, Huang W, Duan R. Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome. Neuroscience bulletin. 2021; 37(7): 973-84.

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, resulting from the lack of functional fragile X mental retardation protein (FMRP), an mRNA binding protein mainly serving as a translational regulator. Loss of FMRP leads to dysregulation of target mRNAs. The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network. Yet the FMRP targets involved in circadian regulation have not been identified. Here, we identified collapsing response mediator protein (CRMP) mRNA as a target of FMRP. Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons (ventral lateral neurons) in dfmr1 mutant flies. Furthermore, specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors. Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation. Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila.

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