1. Al-Saei A, Nour-Eldine W, Rajpoot K, Arshad N, Al-Shammari AR, Kamal M, Akil AA, Fakhro KA, Thornalley PJ, Rabbani N. Validation of plasma protein glycation and oxidation biomarkers for the diagnosis of autism. Mol Psychiatry;2023 (Dec 22)

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder in children. It is currently diagnosed by behaviour-based assessments made by observation and interview. In 2018 we reported a discovery study of a blood biomarker diagnostic test for ASD based on a combination of four plasma protein glycation and oxidation adducts. The test had 88% accuracy in children 5-12 years old. Herein, we present an international multicenter clinical validation study (N = 478) with application of similar biomarkers to a wider age range of 1.5-12 years old children. Three hundred and eleven children with ASD (247 male, 64 female; age 5.2 ± 3.0 years) and 167 children with typical development (94 male, 73 female; 4.9 ± 2.4 years) were recruited for this study at Sidra Medicine and Hamad Medical Corporation hospitals, Qatar, and Hospital Regional Universitario de Málaga, Spain. For subjects 5-12 years old, the diagnostic algorithm with features, advanced glycation endproducts (AGEs)-N(ε)-carboxymethyl-lysine (CML), N(ω)-carboxymethylarginine (CMA) and 3-deoxyglucosone-derived hydroimidazolone (3DG-H), and oxidative damage marker, o,o’-dityrosine (DT), age and gender had accuracy 83% (CI 79 – 89%), sensitivity 94% (CI 90-98%), specificity 67% (CI 57-76%) and area-under-the-curve of receiver operating characteristic plot (AUROC) 0.87 (CI 0.84-0.90). Inclusion of additional plasma protein glycation and oxidation adducts increased the specificity to 74%. An algorithm with 12 plasma protein glycation and oxidation adduct features was optimum for children of 1.5-12 years old: accuracy 74% (CI 70-79%), sensitivity 75% (CI 63-87%), specificity 74% (CI 58-90%) and AUROC 0.79 (CI 0.74-0.84). We conclude that ASD diagnosis may be supported using an algorithm with features of plasma protein CML, CMA, 3DG-H and DT in 5-12 years-old children, and an algorithm with additional features applicable for ASD screening in younger children. ASD severity, as assessed by ADOS-2 score, correlated positively with plasma protein glycation adducts derived from methylglyoxal, hydroimidazolone MG-H1 and N(ε)(1-carboxyethyl)lysine (CEL). The successful validation herein may indicate that the algorithm modifiable features are mechanistic risk markers linking ASD to increased lipid peroxidation, neuronal plasticity and proteotoxic stress.

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2. Azmi AZ, Patrick S, Isa MIB, Ab Ghani S. A Multifaceted Presentation of Xerophthalmia in Autistic Patients. Cureus;2023 (Nov);15(11):e49172.

We report the manifestations of vitamin A deficiency (VAD) in three children with underlying autism of different stages. These children were under developmental paediatrician follow-up for autism, and the VAD was not detected until these children presented to Ophthalmology screening for varying stages of signs and symptoms. On further assessment, all of our patients have VAD secondary to poor dietary intake, as autistic patients are associated with having selective eating habits. In our case series, we discuss the spectrum of xerophthalmia presentations, which can be mild and can manifest as punctate epithelial erosions to the more blinding complications at the advanced stage of the disease, mainly irreversible optic neuropathy. The primary management is to address the dietary routine coupled with systemic administration of vitamin A.

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3. Chen Q, Liu XL, Lin LZ, Wang X, Li MH, Dai MX, Cao MQ, Li XH, Jin J, Xu HQ, Cai L. Associations of unintended pregnancy with autism spectrum disorders and the modification of folic acid supplements. Autism Res;2023 (Dec 22)

There is limited evidence on the associations of unintended pregnancy with autism spectrum disorders (ASD). This study aimed to examine this relationship and the modification of pre-conceptional and prenatal folic acid supplements. Six thousand and five toddlers aged 16 to 30 months from seven cities of six provinces in China were eligible for participation. Information on unintended pregnancy and folic acid supplements was obtained via questionnaires from caregivers of toddlers. The diagnosis of ASD was based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the Chinese version of the Childhood Autism Rating Scale (CARS). Of the 6005 toddlers in the study (3337 boys and 2668 girls), 71 (1.18%) received the diagnosis of ASD. Generalized linear models with a logit link function showed unintended pregnancy was positively associated with ASD (odds ratios [OR] = 1.69, 95% confidence interval [CI], 1.05-2.79). Stratified estimates indicated that the association remained stable among toddlers of mothers without pre-conceptional and prenatal folic acid supplements (OR = 2.75, 95% CI, 1.04-7.27; n = 1243, 20.70%). Unintended pregnancy was associated with higher odds of ASD in 16-30 months of toddlers, and the association was consistent among toddlers of mothers without prenatal folic acid supplements. Our findings emphasize the need to raise awareness of the risk of unintended pregnancy and the benefits of folic acid supplements among Chinese women.

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4. Cho CH, Deyneko IV, Cordova-Martinez D, Vazquez J, Maguire AS, Diaz JR, Carbonell AU, Tindi JO, Cui MH, Fleysher R, Molholm S, Lipton ML, Branch CA, Hodgson L, Jordan BA. ANKS1B encoded AIDA-1 regulates social behaviors by controlling oligodendrocyte function. Nat Commun;2023 (Dec 21);14(1):8499.

Heterozygous deletions in the ANKS1B gene cause ANKS1B neurodevelopmental syndrome (ANDS), a rare genetic disease characterized by autism spectrum disorder (ASD), attention deficit/hyperactivity disorder, and speech and motor deficits. The ANKS1B gene encodes for AIDA-1, a protein that is enriched at neuronal synapses and regulates synaptic plasticity. Here we report an unexpected role for oligodendroglial deficits in ANDS pathophysiology. We show that Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function, and recapitulate white matter abnormalities observed in ANDS patients. Selective loss of Anks1b from the oligodendrocyte lineage, but not from neuronal populations, leads to deficits in social preference and sensory reactivity previously observed in a brain-wide Anks1b haploinsufficiency model. Furthermore, we find that clemastine, an antihistamine shown to increase oligodendrocyte precursor cell maturation and central nervous system myelination, rescues deficits in social preference in 7-month-old Anks1b-deficient mice. Our work shows that deficits in social behaviors present in ANDS may originate from abnormal Rac1 activity within oligodendrocytes.

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5. Czech H. Herwig Czech: To assess Asperger’s knowledge on the Nazi ‘child euthanasia’ programme, his own words should matter (response to Tatzer et al.). Acta Paediatr;2023 (Dec 22)

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6. Dell’Osso L. Author’s response to commentary on « Autistic traits distribution in different psychiatric conditions: A cluster analysis on the basis of the adult autism subthreshold spectrum (AdAS Spectrum) questionnaire ». Psychiatry Res;2023 (Dec 22);332:115670.

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7. Ferrucci L, Cantando I, Cordella F, Di Angelantonio S, Ragozzino D, Bezzi P. Microglia at the Tripartite Synapse during Postnatal Development: Implications for Autism Spectrum Disorders and Schizophrenia. Cells;2023 (Dec 13);12(24)

Synapses are the fundamental structures of neural circuits that control brain functions and behavioral and cognitive processes. Synapses undergo formation, maturation, and elimination mainly during postnatal development via a complex interplay with neighboring astrocytes and microglia that, by shaping neural connectivity, may have a crucial role in the strengthening and weakening of synaptic functions, that is, the functional plasticity of synapses. Indeed, an increasing number of studies have unveiled the roles of microglia and astrocytes in synapse formation, maturation, and elimination as well as in regulating synaptic function. Over the past 15 years, the mechanisms underlying the microglia- and astrocytes-dependent regulation of synaptic plasticity have been thoroughly studied, and researchers have reported that the disruption of these glial cells in early postnatal development may underlie the cause of synaptic dysfunction that leads to neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia.

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8. Godbole N, Tirupathi SP, Nair S, Afnan L, Nallapu A, Nallapu A. Effectiveness of picture-based interventions of toothbrush training on improvement of oral hygiene in children with autism spectrum disorders: A systematic review and meta-analysis. Spec Care Dentist;2023 (Dec 21)

BACKGROUND: Children with autism exhibit a higher risk of poor oral health due to difficulty in the performance of simple tasks such as toothbrushing. AIM: This current systematic review aims to evaluate the effectiveness of Picture based intervention of toothbrush training on improvement of oral hygiene in children with autism spectrum disorders (ASD) MATERIALS AND METHODS: Prospero registered (CRD42023450156). PubMed, Cochrane, Scopus databases are searched from years January 1, 1980 to August 1, 2023 using broad search terms (brush) AND (autism). RESULTS: The search queries have identified 853 titles, from three databases (PubMed, Scopus, Cochrane), after application of filters for exclusion of systematic reviews and meta-analysis, duplicate exclusion and removal of irrelevant titles led to the final inclusion of 24 articles for full text screening. From the 24 included studies, 10 studies (four RCTs and six non-randomized clinical studies) sustained the final rigorous PICO search. Quantitative pooling of data were performed for limited articles. CONCLUSION: Low quality evidence suggest that picture-based intervention of toothbrush training has significant improvement (p ≤ .05) in improving toothbrushing habit as well as performance as indicated by the Plaque Index score (PI), Gingival index (GI) and Oral hygiene index score (OHI-S).

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9. Groen Y, Ebert WM, Dittner FM, Stapert AF, Henning D, Greaves-Lord K, Davids R, Castelein S, Baron Cohen S, Allison C, Van Balkom IDC, Piening S. Measuring the Autistic Women’s Experience (AWE). Int J Environ Res Public Health;2023 (Dec 6);20(24)

We developed a Dutch questionnaire called the Autistic Women’s Experience (AWE) and compared its psychometric properties to the Autism Spectrum Quotient (AQ). Whilst attenuated gender differences on the AQ have been widely replicated, this instrument may not fully capture the unique experience of autistic women. The AWE was co-developed with autistic women to include items that reflect autistic women’s experience. We investigated the AWE (49 items) and compared it with the AQ (50 items) in Dutch autistic individuals (N = 153, n = 85 women) and in the general population (N = 489, n = 246 women) aged 16+. Both the AQ and AWE had excellent internal consistency and were highly and equally predictive of autism in both women and men. Whilst there was a gender difference on the AQ among non-autistic people (men > women), there was no gender difference among autistic people, confirming all earlier studies. No gender differences were detected on the AWE overall scale, yet subtle gender differences were observed on the subscales. We conclude that the AQ is valid for both genders, but the AWE provides an additional useful perspective on the characteristics of autistic women. The AWE needs further validation in independent samples using techniques that allow for testing gender biases, as well as a confirmatory factor analysis in a larger sample.

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10. Jalil-Abkenar SS. Triple-P: Interaction of mother-adolescent with intellectual and developmental disability. J Intellect Disabil;2023 (Dec 21):17446295231224125.

This study aimed to investigate the effect of a Positive Parenting Program (Triple-P) on the interaction of the mother-adolescent with intellectual disability. The pre-test and post-test randomized experimental design was used for this research. Thirty-four mothers of adolescents with intellectual disability took part in the present research and were assigned to experimental and control groups, each comprised of 17 people. The experimental group took part in an 8-session Triple-P and each session lasted 75 minutes, but the control group did not participate in this intervention. The data were analyzed using MANCOVA. The findings revealed that Triple-P intervention significantly influenced dependency, closeness, conflict, and positive interaction between the mother and the child with intellectual disability. The present study emphasized that Triple-P will improve the interaction of mother-adolescent with intellectual disability; therefore, Triple-P is a useful intervention.

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11. Javik Dorantes-Barrios C, Reyes-Meza V, Camacho-Candia JA, Pfaus JG, González-Flores O. Influence of environmental enrichment on sexual behavior and the process of learning and memory in a rat model of autism with valproic acid. Brain Res;2023 (Dec 22);1827:148738.

Autism spectrum disorder (ASD) is a psychiatric disorder with severe behavioral consequences and no specific therapy. Its etiology is multifactorial, as it is caused by a complex interaction of genetic and environmental factors. In rats, prenatal exposure to the antiepileptic drug valproic acid (VPA) has been associated with an increased risk of autistic-like behaviors in offspring, including social behavior deficits, increased repetitive behaviors, and cognitive impairments. In addition, VPA-treated rats have shown altered sociosexual behaviors. However, the mechanisms underlying these alterations in reproductive processes in VPA-treated rats are not fully understood. Interestingly some abnormal behaviors in VPA autism models are improved by an enriched environment (EE). In the present study, we examined the effects of EE on memory performance and sexual behavior in male rats. We found that on postnatal day 90, EE reduced the time it took for both control and VPA-treated groups to find a hidden platform in the Morris water maze. On PND 100, prenatal exposure to VPA reduced total exploring time in object recognition tests. On PND 110, EE reduced mount and intromission latency and increased ejaculatory frequency in VPA-treated male rats. These results suggest that environmental stimuli significantly influence the onset of sexual behavior in VPA-treated male rats and that EE may be a potential tool for improving a variety of behavioral deficiencies in rodent models of autism.

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12. Josyfon E, Spain D, Blackmore C, Murphy D, Oakley B. Alexithymia in Adult Autism Clinic Service-Users: Relationships with Sensory Processing Differences and Mental Health. Healthcare (Basel);2023 (Dec 7);11(24)

Mental health difficulties commonly co-occur with autism, especially in autistic people accessing clinic services, impacting substantially on quality-of-life. Alexithymia (difficulty describing/identifying feelings) and sensory processing differences are prevalent traits in autism that have been associated with depression/anxiety in autistic community samples. However, it is important to better understand interrelationships between these traits in clinical populations to improve identification of service-user needs. In this study, 190 autistic adults (65.3% male), seen in a tertiary autism clinic, completed self-report measures of alexithymia (20-item Toronto Alexithymia Scale), sensory processing differences (Adolescent/Adult Sensory Profile) and depression/anxiety (Hospital Anxiety and Depression Scale). Multiple linear regression models and mediation analyses were used to examine associations between alexithymia, sensory processing differences, and depression/anxiety severity. Across the sample, 66.3% of individuals (N = 126) were classified as alexithymic (score ≥ 61). Total alexithymia and difficulty describing/identifying feelings were significantly associated with depression severity (β = 0.30-0.38, highest p < 0.002), and difficulty identifying feelings was significantly associated with anxiety severity (β = 0.36, p < 0.001). Sensory processing differences were also significantly associated with depression severity (β = 0.29, p = 0.002) and anxiety severity across all models (β = 0.34-0.48, highest p < 0.001) Finally, difficulty describing/identifying feelings partially mediated the relationships between sensory processing differences and both depression/anxiety severity. Overall, these results highlight that interventions adapted for and targeting emotional awareness and sensory-related uncertainty may improve mental health outcomes in autistic service-users.

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13. Kim J, Lee J, Jang DH. Combining chromosomal microarray and clinical exome sequencing for genetic diagnosis of intellectual disability. Sci Rep;2023 (Dec 20);13(1):22807.

Despite the current widespread use of chromosomal microarray analysis (CMA) and exome/genome sequencing for the genetic diagnosis of unexplained intellectual disability (ID) in children, gaining improved diagnostic yields and defined guidelines remains a significant challenge. This is a cohort study of children with unexplained ID. We analyzed the diagnostic yield and its correlation to clinical phenotypes in children with ID who underwent concurrent CMA and clinical exome sequencing (CES). A total of 154 children were included (110 [71.4%] male; mean [SD] age, 51.9 [23.1] months). The overall diagnosis yield was 26.0-33.8%, with CMA contributing 12.3-14.3% and CES contributing 13.6-19.4%, showing no significant difference. The diagnostic rate was significantly higher when gross motor delay (odds ratio, 6.69; 95% CI, 3.20-14.00; P < 0.001), facial dysmorphism (odds ratio, 9.34; 95% CI 4.29-20.30; P < 0.001), congenital structural anomaly (odds ratio 3.62; 95% CI 1.63-8.04; P = 0.001), and microcephaly or macrocephaly (odds ratio 4.87; 95% CI 2.05-11.60; P < 0.001) were presented. Patients with only ID without any other concomitant phenotype (63/154, 40.9%) exhibited a 6.3-11.1% diagnostic rate.

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14. Li X, Naveed Iqbal Qureshi M, Laplante DP, Elgbeili G, Paquin V, Lee Jones S, King S, Rosa-Neto P. Decreased amygdala-sensorimotor connectivity mediates the association between prenatal stress and broad autism phenotype in young adults: Project Ice Storm. Stress;2024 (Jan);27(1):2293698.

Studies show that prenatal maternal stress (PNMS) is related to risk for child autism, and to atypical amygdala functional connectivity in the autistic child. Yet, it remains unclear whether amygdala functional connectivity mediates the association between PNMS and autistic traits, particularly in young adult offspring. We recruited women who were pregnant during, or within 3 months of, the 1998 Quebec ice storm crisis, and assessed three aspects of PNMS: objective hardship (events experienced during the ice storm), subjective distress (post-traumatic stress symptoms experienced as a result of the ice storm) and cognitive appraisal. At age 19, 32 young adults (21 females) self-reported their autistic-like traits (i.e., aloof personality, pragmatic language impairment and rigid personality), and underwent structural MRI and resting-state functional MRI scans. Seed-to-voxel analyses were conducted to map the amygdala functional connectivity network. Mediation analyses were implemented with bootstrapping of 20,000 resamplings. We found that greater maternal objective hardship was associated with weaker functional connectivity between the left amygdala and the right postcentral gyrus, which was then associated with more pragmatic language impairment. Greater maternal subjective distress was associated with weaker functional connectivity between the right amygdala and the left precentral gyrus, which was then associated with more aloof personality. Our results demonstrate that the long-lasting effect of PNMS on offspring autistic-like traits may be mediated by decreased amygdala-sensorimotor circuits. The differences between amygdala-sensory and amygdala-motor pathways mediating different aspects of PNMS on different autism phenotypes need to be studied further.

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15. Lichtlé J, Devouche E, Dialahy IZ, de Gaulmyn A, Amestoy A, Coutelle R, Isnard P, Monestès JL, Mottron L, Cappe E. Development, psychometric evaluation, and factor analysis of an instrument measuring quality of life in autistic preschoolers. Int J Methods Psychiatr Res;2023 (Dec 22):e2002.

INTRODUCTION: Early interventions for autistic children should target their quality of life (QoL) but require adapted measures. The association of a child’s temperament and parental characteristics with the QoL of autistic children remains unknown. METHODS: We constructed an autism module based on a thematic analysis, a Delphi survey with experts, and a pre-test with parents to be completed alongside the proxy version of the PedsQL 4.0. We explored compliance, responsiveness, internal consistency, convergent validity, and factor structure with 157 parents of autistic preschool children. We examined the association between child and parental characteristics with the QoL of autistic children using correlation analysis, principal component analysis, hierarchical ascending classification, and linear regression. Sociodemographic information was collected via multiple choice questions, autism severity via Autism Diagnostic Observation Schedule (ADOS) scores, and parental acceptance and child’s temperament via the Acceptance and Action Questionnaire and the Emotionality, Activity, and Sociability. RESULTS: An autism module comprised of 27 items emerged. Psychometric evaluation resulted in a 24-item autism module with good internal consistency and significant convergent validity. ADOS total score was not significantly related to QoL, contrary to children’s sleep issues, children’s emotionality, and parental acceptance. CONCLUSIONS: The autism module is a reliable QoL proxy measure for autistic preschool children. Results suggest parental interventions targeting children’s QoL.

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16. Liu J, Wang Z, Qin H, Wang Y, Deng J, Li H, Xu Q, Xu X, Liu H. Social Recognition of Joint Attention Cycles in Children With Autism Spectrum Disorders. IEEE Trans Biomed Eng;2024 (Jan);71(1):237-246.

OBJECTIVE: Autism Spectrum Disorders (ASD) are characterized by impairments in joint attention (JA) comprising two components: responding to JA (RJA) and initiating JA (IJA). RJA and IJA are considered two interrelated aspects of JA, related to different stages of infant development. While recent technologies have been used to characterize RJA emerging in earlier childhood, only a limited number of studies have attempted to explore IJA, which progressively becomes evident as a hallmark of ASD. This study aims to achieve the social recognition of both RJA and IJA by vision-based human behavior perception through a multi-modal framework automatically and comprehensively. METHODS: The first three layers of this framework leverage localization, feature extraction, and activity recognition. On this basis, three critical activities in JA are recognized: attention estimation, spontaneous pointing, and showing actions. Then different behaviors are linked through the fourth layer, semantic interpretation, to model the JA event. The proposed framework is evaluated on experiments of four groups: 7 children with ASD, 5 children with mental retardation (MR), 5 children with developmental language disorder (DLD), and 3 typically developed children (TD). RESULTS: Experimental results compared with human codings demonstrate recognition reliability with an intra-class coefficient of 0.959. In addition, statistical analysis suggests significant group difference and correlations. CONCLUSIONS: The multi-modal human behavior perception-based framework is a feasible solution for the recognition of joint attention in unconstrained environments. SIGNIFICANCE: Thus the proposed approach has the potential to improve the clinical diagnosis of autism by offering quantitative monitoring and statistical analysis.

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17. Liu W, Shah N, Ma I, Rosenblau G. Strategic social decision making undergoes significant changes in typically developing and autistic early adolescents. Dev Sci;2023 (Dec 21):e13463.

Information sampling about others’ trustworthiness prior to cooperation allows humans to minimize the risk of exploitation. Here, we examined whether early adolescence or preadolescence, a stage defined as in between childhood and adolescence, is a significant developmental period for strategic social decisions. We also sought to characterize differences between autistic children and their typically developing (TD) peers. TD (N = 48) and autistic (N = 56) 8- to 12-year-olds played an online information sampling trust game. While both groups adapted their information sampling and cooperation to the various trustworthiness levels of the trustees, groups differed in how age and social skills modulated task behavior. In the TD group social skills were a stronger overall predictor of task behavior. In the autistic group, age was a stronger predictor and interacted with social skills. Computational modeling revealed that both groups used the same heuristic information sampling strategy-albeit older TD children were more efficient as reflected by decreasing decision noise with age. Autistic children had lower prior beliefs about the trustee’s trustworthiness compared to TD children. These lower priors indicate that children believed the trustees to be less trustworthy. Lower priors scaled with lower social skills across groups. Notably, groups did not differ in prior uncertainty, meaning that the priors of TD and autistic children were equally strong. Taken together, we found significant development in information sampling and cooperation in early adolescence and nuanced differences between TD and autistic children. Our study highlights the importance of deep phenotyping of children including clinical measures, behavioral experiments and computational modeling. RESEARCH HIGHLIGHTS: We specified how early adolescents with and without an autism diagnosis sampled information about their interaction partners and made cooperation decisions in a strategic game. Early adolescence is a significant developmental period for strategic decision making, marked by significant changes in information sampling efficiency and adaptivity to the partner’s behavior. Autistic and non-autistic groups differed in how age and social skills modulated task behavior; in non-autistic children behavior was more indicative of overall social skills. Computational modeling revealed differences between autistic and non-autistic groups in their initial beliefs about cooperation partners; autistic children expected their partners to be less trustworthy.

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18. Mensi MM, Guerini FR, Marchesi M, Chiappedi M, Bolognesi E, Borgatti R. SNAP-25 Polymorphisms in Autism Spectrum Disorder: A Pilot Study towards a Possible Endophenotype. Pediatr Rep;2023 (Dec 18);15(4):766-773.

While there is substantial agreement on the diagnostic criteria for autism spectrum disorder, it is also acknowledged that it has a broad range of clinical presentations. This can complicate the diagnostic process and aggravate the choice of the most suitable rehabilitative strategy for each child. Attentional difficulties are among the most frequently reported comorbidities in autism spectrum disorder. We investigated the role of SNAP-25 polymorphisms. Synaptosome-associated protein 25 (SNAP25) is a presynaptic membrane-binding protein; it plays a crucial role in neurotransmission and has already been studied in numerous psychiatric disorders. It was also seen to be associated with hyperactivity in children with autism spectrum disorder. We collected clinical, behavioral and neuropsychological data on 41 children with a diagnosis of autism spectrum disorder, and then genotyped them for five single-nucleotide polymorphisms of SNAP-25. Participants were divided into two groups according to the Autism Diagnostic Observation Schedule (ADOS-2) Severity Score. In the group with the highest severity score, we found significant associations of clinical data with polymorphism rs363050 (A/G): children with the GG genotype had lower total IQ, more severe autistic functioning and more attentional difficulties. Our research could be the starting point for outlining a possible endophenotype among patients with autism spectrum disorder who are clinically characterized by severe autistic functioning and significant attentional difficulties.

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19. Mussap M, Beretta P, Esposito E, Fanos V. Once upon a Time Oral Microbiota: A Cinderella or a Protagonist in Autism Spectrum Disorder?. Metabolites;2023 (Dec 5);13(12)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder evolving over the lifetime of individuals. The oral and gut microbial ecosystems are closely connected to each other and the brain and are potentially involved in neurodevelopmental diseases. This narrative review aims to identify all the available evidence emerging from observational studies focused on the role of the oral microbiome in ASD. A literature search was conducted using PubMed and the Cochrane Library for relevant studies published over the last ten years. Overall, in autistic children, the oral microbiota is marked by the abundance of several microbial species belonging to the Proteobacteria phylum and by the depletion of species belonging to the Bacteroidetes phylum. In mouse models, the oral microbiota is marked by the abundance of the Bacteroidetes phylum. Oral dysbiosis in ASD induces changes in the human metabolome, with the overexpression of metabolites closely related to the pathogenesis of ASD, such as acetate, propionate, and indoles, together with the underexpression of butyrate, confirming the central role of tryptophan metabolism. The analysis of the literature evidences the close relationship between oral dysbiosis and autistic core symptoms; the rebuilding of the oral and gut ecosystems by probiotics may significantly contribute to mitigating the severity of ASD symptoms.

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20. Okabe M, Miyamoto Y, Ikoma Y, Takahashi M, Shirai R, Kukimoto-Niino M, Shirouzu M, Yamauchi J. RhoG-Binding Domain of Elmo1 Ameliorates Excessive Process Elongation Induced by Autism Spectrum Disorder-Associated Sema5A. Pathophysiology;2023 (Nov 27);30(4):548-566.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger’s syndrome, and pervasive developmental disorder. ASD is characterized by poor interpersonal relationships and strong attachment. The correlations between activated or inactivated gene products, which occur as a result of genetic mutations affecting neurons in ASD patients, and ASD symptoms are now of critical concern. Here, for the first time, we describe the process in which that the respective ASD-associated mutations (Arg676-to-Cys [R676C] and Ser951-to-Cys [S951C]) of semaphorin-5A (Sema5A) localize Sema5A proteins themselves around the plasma membrane in the N1E-115 cell line, a model line that can achieve neuronal morphological differentiation. The expression of each mutated construct resulted in the promotion of excessive elongation of neurite-like processes with increased differentiation protein markers; R676C was more effective than S951C. The differentiated phenotypes were very partially neutralized by an antibody, against Plexin-B3 as the specific Sema5A receptor, suggesting that the effects of Sema5A act in an autocrine manner. R676C greatly increased the activation of c-Jun N-terminal kinase (JNK), one of the signaling molecules underlying process elongation. In contrast, the blocking of JNK signaling, by a chemical JNK inhibitor or an inhibitory construct of the interaction of RhoG with Elmo1 as JNK upstream signaling molecules, recovered the excessive process elongation. These results suggest that ASD-associated mutations of Sema5A, acting through the JNK signaling cascade, lead to excessive differentiated phenotypes, and the inhibition of JNK signaling recovers them, revealing possible therapeutic targets for recovering the potential molecular and cellular phenotypes underlying certain ASD symptoms.

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21. Özbaran NB, Kayan E. Catatonia in a 8-year-old child with autism spectrum disorder: Case report. Asian J Psychiatr;2023 (Dec 22);92:103893.

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22. Piening S, van Balkom IDC, Stapert AF, Henning D, Greaves-Lord K, Davids L, Castelein S, Groen Y. Perspectives on Autism Spectrum Disorder Diagnosis, Symptoms, Treatment and Gender Roles: A Qualitative Study of Similarities and Differences between Sexes. Int J Environ Res Public Health;2023 (Dec 15);20(24)

This study aims to compare the experiences of women and men of different age groups with regard to their first autism spectrum disorder (ASD) diagnosis, symptoms, treatment, and gender roles to inform our understanding in clinical practice of differences as well as similarities. Semi-structured interviews were conducted amongst 22 women (n = 12) and men (n = 10) in three adult age groups regarding their diagnostic process, symptoms, treatment, and gender roles. Participants also filled out questionnaires on gender traits, social support, coping, and quality of life. Framework analysis guidelines were followed to identify subthemes within the three pre-defined key themes of the semi-structured interviews, and quantitative analyses were performed on the questionnaire results. Women often had caregiver roles and were more focused on social and family-oriented life aspects than men. Family and societal expectations may have been different for women from an early age onward and were considered burdensome by some, but not all. Views on ASD diagnosis, symptoms, and treatment were largely individually determined. The questionnaire results mostly showed no significant sex differences. Perceived gender roles differed between participants. In diagnosis and treatment, awareness of general gender differences and gender roles is important, but inter-individual differences and similar experiences in men should not be overlooked.

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23. Santos E, Clark C, Biag HMB, Tang SJ, Kim K, Ponzini MD, Schneider A, Giulivi C, Montanaro FAM, Gipe JT, Dayton J, Randol JL, Yao PJ, Manolopoulos A, Kapogiannis D, Hwang YH, Hagerman P, Hagerman R, Tassone F. Open-Label Sulforaphane Trial in FMR1 Premutation Carriers with Fragile-X-Associated Tremor and Ataxia Syndrome (FXTAS). Cells;2023 (Dec 5);12(24)

Fragile X (FMR1) premutation is a common mutation that affects about 1 in 200 females and 1 in 450 males and can lead to the development of fragile-X-associated tremor/ataxia syndrome (FXTAS). Although there is no targeted, proven treatment for FXTAS, research suggests that sulforaphane, an antioxidant present in cruciferous vegetables, can enhance mitochondrial function and maintain redox balance in the dermal fibroblasts of individuals with FXTAS, potentially leading to improved cognitive function. In a 24-week open-label trial involving 15 adults aged 60-88 with FXTAS, 11 participants successfully completed the study, demonstrating the safety and tolerability of sulforaphane. Clinical outcomes and biomarkers were measured to elucidate the effects of sulforaphane. While there were nominal improvements in multiple clinical measures, they were not significantly different after correction for multiple comparisons. PBMC energetic measures showed that the level of citrate synthase was higher after sulforaphane treatment, resulting in lower ATP production. The ratio of complex I to complex II showed positive correlations with the MoCA and BDS scores. Several mitochondrial biomarkers showed increased activity and quantity and were correlated with clinical improvements.

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24. Shen YI, Cheng KC, Wei YJ, Lee IR. Structural Dynamics Role of AGG Interruptions in Inhibition CGG Repeat Expansion Associated with Fragile X Syndrome. ACS Chem Neurosci;2023 (Dec 22)

Abnormal expansion of trinucleotide CGG repeats is responsible for Fragile X syndrome. AGG interruptions in CGG repeat tracts were found in most healthy individuals, suggesting a crucial role in preventing disease-prone repeat expansion. Previous biophysics studies emphasize a difference in the secondary structure affected by AGG interruptions. However, the mechanism of how AGG interruptions impede repeat expansion remains elusive. We utilized single-molecule fluorescence resonance energy transfer spectroscopy to investigate the structural dynamics of CGG repeats and their AGG-interrupted variants. Tandem CGG repeats fold into a stem-loop hairpin structure with the capability to undergo a conformational rearrangement to modulate the length of the overhang. However, this conformational rearrangement is much more retarded when two AGG interruptions are present. Considering the significance of hairpin slippage in repeat expansion, we present a molecular basis suggesting that the internal loop created by two AGG interruptions acts as a barrier, obstructing the hairpin slippage reconfiguration. This impediment potentially plays a crucial role in curbing abnormal expansion, thereby contributing to the genomic stability.

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25. Smith M, Williams D, Lind S, Ferguson HJ. Revisiting the ownership effect in adults with and without autism. PLoS One;2023;18(12):e0293898.

Self-owned items are better remembered than other-owned items; this ownership effect reflects privileged processing of self-related information. The size of this ownership effect has been shown to decrease in neurotypical adults as the number of autistic traits increases, and is reduced in autistic adults. However, emerging evidence has questioned the reliability of these findings. This paper aimed to replicate previous work using well-powered, pre-registered designs, and Bayesian analyses. Experiment 1 (N = 100) found a significant ownership effect in neurotypical adults; however, the size of this was unrelated to individual differences in autistic traits. Experiment 2 (N = 56) found an ownership effect in neurotypical but not autistic adults. The findings suggest that individual differences in autistic traits in the neurotypical population do not impact the ownership effect, but a clinical diagnosis of autism might. We discuss how these findings can be explained by differences in psychological self-awareness in autism.

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26. Soueid J, Hamze Z, Bedran J, Chahrour M, Boustany RM. A novel autism-associated UBLCP1 mutation impacts proteasome regulation/activity. Transl Psychiatry;2023 (Dec 21);13(1):404.

The landscape of autism spectrum disorder (ASD) in Lebanon is unique because of high rates of consanguinity, shared ancestry, and increased remote consanguinity. ASD prevalence in Lebanon is 1 in 68 with a male-to-female ratio of 2:1. This study aims to investigate the impact of an inherited deletion in UBLCP1 (Ubiquitin-Like Domain-Containing CTD Phosphatase 1) on the ubiquitin-proteasome system (UPS) and proteolysis. Whole exome sequencing in a Lebanese family with ASD without pathogenic copy number variations (CNVs) uncovered a deletion in UBLCP1. Functional evaluation of the identified variant is described in fibroblasts from the affected. The deletion in UBLCP1 exon 10 (g.158,710,261CAAAG > C) generates a premature stop codon interrupting the phosphatase domain and is predicted as pathogenic. It is absent from databases of normal variation worldwide and in Lebanon. Wild-type UBLCP1 is widely expressed in mouse brains. The mutation results in decreased UBLCP1 protein expression in patient-derived fibroblasts from the autistic patient compared to controls. The truncated UBLCP1 protein results in increased proteasome activity decreased ubiquitinated protein levels, and downregulation in expression of other proteasome subunits in samples from the affected compared to controls. Inhibition of the proteasome by using MG132 in proband cells reverses alterations in gene expression due to the restoration of protein levels of the common transcription factor, NRF1. Finally, treatment with gentamicin, which promotes premature termination codon read-through, restores UBLCP1 expression and function. Discovery of an ASD-linked mutation in UBLCP1 leading to overactivation of cell proteolysis is reported. This, in turn, leads to dysregulation of proteasome subunit transcript levels as a compensatory response.

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27. Star J, Mo H, Glavin T, Ence W. Dental Desensitization to Increase Comfort with Preventive Dental Visits for Children with Autism Spectrum Disorder. Pediatr Dent;2023 (Nov 15);45(6):518-523.

Purpose: To evaluate the impact of a dental desensitization clinical program on the ability of children with autism spectrum disorder (ASD) to complete a routine preventive dental visit. Methods: English-speaking children with a diagnosis of ASD were enrolled in a prospective cohort study as part of a dental desensitization program. A task analysis (TA) and desensitization plan breaking down a routine dental visit into seven steps was designed and implemented. At each dental visit over a two-year period, the child’s comfort level with each step of the TA was collected. Results: Fifty-two patients participated in this program (average age equals 7.9±3.6 years, 80 percent male). Each participant completed, on average, 6.7 desensitization visits. Approximately half of the study participants were able to complete all steps of the TA during the study period. There was a statistically significant positive relationship between the number of desensitization visits and the number of steps of the dental visit the child could complete comfortably. Children with expressive and receptive language skills were more likely to complete all steps of the TA. Conclusion: Dental desensitization is a behavior guidance intervention that can support children with autism spectrum disorder to complete routine preventive dental visits.

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28. Waldhauser F, Tatzer E, Maleczek W. Response to the letter of H. Czech(1) : To assess Asperger’s knowledge on the NS Child Euthanasia programme, documents are decisive. Acta Paediatr;2023 (Dec 22)

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29. Whelan TP, Daly E, Puts NA, Malievskaia E, Murphy DGM, McAlonan GM. Editorial Perspective: Bridging the translational neuroscience gap in autism – development of the ‘shiftability’ paradigm. J Child Psychol Psychiatry;2023 (Dec 21)

Clinical trials of pharmacological candidates targeting the core features of autism have largely failed. This is despite evidence linking differences in multiple neurochemical systems to brain function in autism. While this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way to directly establish that a neurotransmitter or neuromodulator is involved in a candidate brain function is to change it and observe a shift in that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. Thus, our understanding of how neurochemical differences contribute to neurodiversity is limited, impeding our ability to translate findings from animal studies into humans. Here, we introduce our ‘shiftability’ paradigm, an approach to bridge the translational gap in autism research. We provide an overview of the guiding principles and methodologies we use to directly test the hypothesis that neurochemical systems function differently in autistic and non-autistic individuals.

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30. Xiao Q, Xu H, Chu Z, Feng Q, Zhang Y. Margin-Maximized Norm-Mixed Representation Learning for Autism Spectrum Disorder Diagnosis With Multi-Level Flux Features. IEEE Trans Biomed Eng;2024 (Jan);71(1):183-194.

Early diagnosis and timely intervention are significantly beneficial to patients with autism spectrum disorder (ASD). Although structural magnetic resonance imaging (sMRI) has become an essential tool to facilitate the diagnosis of ASD, these sMRI-based approaches still have the following issues. The heterogeneity and subtle anatomical changes place higher demands for effective feature descriptors. Additionally, the original features are usually high-dimensional, while most existing methods prefer to select feature subsets in the original space, in which noises and outliers may hinder the discriminative ability of selected features. In this article, we propose a margin-maximized norm-mixed representation learning framework for ASD diagnosis with multi-level flux features extracted from sMRI. Specifically, a flux feature descriptor is devised to quantify comprehensive gradient information of brain structures on both local and global levels. For the multi-level flux features, we learn latent representations in an assumed low-dimensional space, in which a self-representation term is incorporated to characterize the relationships among features. We also introduce mixed norms to finely select original flux features for the construction of latent representations while preserving the low-rankness of latent representations. Furthermore, a margin maximization strategy is applied to enlarge the inter-class distance of samples, thereby increasing the discriminative ability of latent representations. The extensive experiments on several datasets show that our proposed method can achieve promising classification performance (the average area under curve, accuracy, specificity, and sensitivity on the studied ASD datasets are 0.907, 0.896, 0.892, and 0.908, respectively) and also find potential biomarkers for ASD diagnosis.

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