1. Ahmad A, Nkosi D, Iqbal MA. PARK2 Microdeletion or Duplications Have Been Implicated in Different Neurological Disorders Including Early Onset Parkinson Disease. Genes (Basel);2023 (Feb 27);14(3)

The PARK2 gene is located on 6q26, encodes ubiquitin-E3- ligase, and is a transcriptional repressor of p53. It contains 12 exons. PARK2 copy number variants has been reported in various types of neurodevelopmental disorders, namely schizophrenia, Parkinson’s disease (PD), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). In this retrospective study, nine cases (five with microdeletion and four with microduplication) are reported with 6q26 deletion disrupting the PARK2 gene. Microdeletion sizes ranged between 215 Kb and 356 Kb, and duplication between 279 Kb and 726 Kb. These were present within the exons 7-10. Family follow up with FISH probes revealed paternal inheritance in two cases, maternal in two cases, and de novo origin in one case. Our results support previous studies showing that patients with PARK2 CNVs involving exons 5-12 might be more deleterious and cause a unique syndrome. Comprehensive analysis of additional case studies is needed to have a full characterization of this neurological disorder syndrome.

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2. Alghafis B, Alharbi A, Al-Haj Ali S, Alsineedi F, Alsudairi O. Dental Treatment Characteristics of Autistic Children and Differences in Dental Procedures under General Anesthesia Relative to Healthy Counterparts. Children (Basel);2023 (Feb 26);10(3)

Here, we assess the dental treatment characteristics among children with autism spectrum disorder (ASD) and compare the dental procedures delivered under general anesthesia (GA) with those of healthy-matched counterparts. In this retrospective cohort study, we collected data from medical records of ASD children (n = 82) which included demographic profile, medical status (including the severity of the ASD and associated comorbidities), and dental history (including dental visits, behavior, care approach, and dental procedures provided). For those children who received dental GA (DGA) (n = 64), we compared all procedures delivered and the number of repeat sessions with healthy children (n = 64). Our results reveal that most ASD children (78%) received DGA, mainly with one repeat session (63.4%). The dental procedures provided to the children differed significantly according to the severity of the ASD and the behavior of the children. Furthermore, increasing severity led to significantly worse behavior of the children, increased need for DGA and repeat sessions. Comparison of the dental procedures under GA with healthy children revealed a significantly lower mean of almost all dental procedures in ASD children, except fissure-sealed teeth (p < 0.05). Considering these findings, DGA is unavoidable for ASD children with moderate-to-severe conditions or negative behavior in the dental office, even when their dental needs are lower than healthy children. The severity of ASD was the most important factor affecting the behavior of the children and the care approach they received. Along with children's behavior, they most influenced the dental procedures delivered and the need for repeat DGA.

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3. Alshamrani AA, Alshehri S, Alqarni SS, Ahmad SF, Alghibiwi H, Al-Harbi NO, Alqarni SA, Al-Ayadhi LY, Attia SM, Alfardan AS, Bakheet SA, Nadeem A. DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) Phthalate. Metabolites;2023 (Mar 22);13(3)

Autism spectrum disorder (ASD) is a multidimensional disorder in which environmental, immune, and genetic factors act in concert to play a crucial role. ASD is characterized by social interaction/communication impairments and stereotypical behavioral patterns. Epigenetic modifications are known to regulate genetic expression through various mechanisms. One such mechanism is DNA methylation, which is regulated by DNA methyltransferases (DNMTs). DNMT transfers methyl groups onto the fifth carbon atom of the cytosine nucleotide, thus converting it into 5-methylcytosine (5mC) in the promoter region of the DNA. Disruptions in methylation patterns of DNA are usually associated with modulation of genetic expression. Environmental pollutants such as the plasticizer Di(2-ethylhexyl) phthalate (DEHP) have been reported to affect epigenetic mechanisms; however, whether DEHP modulates DNMT1 expression, DNA methylation, and inflammatory mediators in the neutrophils of ASD subjects has not previously been investigated. Hence, this investigation focused on the role of DNMT1 and overall DNA methylation in relation to inflammatory mediators (CCR2, MCP-1) in the neutrophils of children with ASD and typically developing healthy children (TDC). Further, the effect of DEHP on overall DNA methylation, DNMT1, CCR2, and MCP-1 in the neutrophils was explored. Our results show that the neutrophils of ASD subjects have diminished DNMT1 expression, which is associated with hypomethylation of DNA and increased inflammatory mediators such as CCR2 and MCP-1. DEHP further causes downregulation of DNMT1 expression in the neutrophils of ASD subjects, probably through oxidative inflammation, as antioxidant treatment led to reversal of a DEHP-induced reduction in DNMT1. These data highlight the importance of the environmental pollutant DEHP in the modification of epigenetic machinery such as DNA methylation in the neutrophils of ASD subjects.

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4. Anchesi SD, Corallo F, Di Cara M, Quartarone A, Catalioto R, Cucinotta F, Cardile D. Autism and ADHD: A Literature Review Regarding Their Impacts on Parental Divorce. Children (Basel);2023 (Feb 23);10(3)

INTRODUCTION: The change in family structure as a consequence of divorce can be a traumatic event for a child that can undermine his or her emotional security. For this reason, it becomes a major health concern. Many divorce-related risk factors have been identified, including attention deficits or autism spectrum disorder (ASD) in children. The aim of this review is to evaluate if and how a diagnosis of ASD or attention deficit hyperactivity disorder (ADHD) in children is associated with an increase in divorce within families. METHOD: Searches were performed in two databases evaluating studies focusing on articles pertaining to the topic. A total of 20 articles were found, but only 8 were included in the study according to the criteria. RESULTS: The results showed that divorce does not appear to be specifically related to a diagnosed pathology of the child, but rather presents itself as a risk factor in certain situations. In particular, this occurs when the coping strategies required to deal with the diagnosis are dysfunctional. However, it would appear that families in which there are children with ADHD have a greater chance of divorce than families in which there is a child with a diagnosis of ASD. It may be hypothesised that in the latter case, parents receiving a diagnosis early in the child’s life have more time to develop adaptive strategies to cope with the condition than parents with children with ADHD who mostly find themselves having to deal with their child’s behavioural problems at a school age. Moreover, ASD is a disorder more likely genetic than environment-related, so parents receive more socio-medical support, and they are less likely to blame themselves or be blamed by others.

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5. Andrade C. Gestational Exposure to Benzodiazepines and Z-Hypnotics and the Risk of Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder in Offspring. J Clin Psychiatry;2023 (Mar 27);84(2)

Two recent cohort studies, one from Norway and the other from Taiwan, examined for perhaps the first time whether gestational exposure to benzodiazepines and to z-hypnotics was associated with a clinical diagnosis of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in offspring. The studies had important methodological strengths that are not often seen; these included actual assessment during pregnancy of whether drugs prescribed were used, and, if so, when; adjustment of analyses for postbaseline time-varying covariates; inclusion of discordant sibling pair and paternal exposure analyses; inclusion of pre-pregnancy vs intrapregnancy analyses; and others. The studies also had important limitations; these included inadequate statistical power resulting in a failure to identify potential associations in even unadjusted analyses; lack of information on intermittent use vs daily dosing; and others. The strengths and limitations are identified and explained to empower readers to identify similar issues in other studies. Important findings apparent in these studies are that benzodiazepine exposure may be associated with an increased risk of both ASD and ADHD, regardless of the trimester of exposure. The magnitude of increased risk is small and diminishes to statistical nonsignificance in adjusted analyses. The risks appear elevated in association with paternal exposure. In discordant sibling pair analyses, risks do not appear to be significantly higher in the exposed sib relative to the unexposed sib. These findings imply that observed associations, if any, between gestational exposure to benzodiazepines and ASD or ADHD in offspring may be due to maternal and paternal genetic factors, to family environmental variables, and to confounding by indication, rather than to benzodiazepine exposure itself. Nevertheless, decision-making should be tailored to individual context and shared between prescriber and patient. Finally, no conclusions can be drawn regarding the neurodevelopmental safety of z-drug exposure during pregnancy.

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6. Begum-Ali J, Gossé LK, Mason L, Pasco G, Charman T, Johnson MH, Jones EJH. Infant sleep predicts trajectories of social attention and later autism traits. J Child Psychol Psychiatry;2023 (Mar 29)

BACKGROUND: Children with neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) often experience sleep disturbances, but little is known about when these sleep differences emerge and how they relate to later development. METHODS: We used a prospective longitudinal design in infants with a family history of ASD and/or ADHD to examine infant sleep and its relation to trajectories of attention and later neurodevelopmental disorders. We formed factors of Day and Night Sleep from parent-reported measures (including day/night sleep duration, number of naps in the day, frequency of night awakenings and sleep onset problems). We examined sleep in 164 infants at 5-, 10- and 14-months with/without a first-degree relative with ASD and/or ADHD who underwent a consensus clinical assessment for ASD at age 3. RESULTS: By 14-months, infants with a first-degree relative with ASD (but not ADHD) showed lower Night Sleep scores than infants with no family history of ASD; lower Night Sleep scores in infancy were also associated with a later ASD diagnosis, decreased cognitive ability, increased ASD symptomatology at 3-years, and developing social attention (e.g., looking to faces). We found no such effects with Day Sleep. CONCLUSIONS: Sleep disturbances may be apparent at night from 14-months in infants with a family history of ASD and also those with later ASD, but were not associated with a family history of ADHD. Infant sleep disturbances were also linked to later dimensional variation in cognitive and social skills across the cohort. Night Sleep and Social Attention were interrelated over the first 2 years of life, suggesting that this may be one mechanism through which sleep quality influences neurodevelopment. Interventions targeted towards supporting families with their infant’s sleep problems may be useful in this population.

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7. Black MH, Greenwood DL, Hwa JCC, Pivac J, Tang J, Clarke PJF. What Are You Worried About? Content and Extent of Worry in Autistic Adults. J Autism Dev Disord;2023 (Mar 29):1-15.

Autistic adults commonly experience anxiety and worry, although knowledge on how worry presents and the content, extent, and experiences among autistic adults is limited. A convergent parallel mixed-methods approach was used to explore the presentation and experiences of worry in autistic and non-autistic adults. Quantitative surveys were used to compare the content and extent of worry in autistic adults to non-autistic adults, with semi-structured interviews also conducted with autistic adults to gain a deeper understanding of the experiences, impacts and content of worry in autistic adults. Findings indicated that autistic adults demonstrated clinically significant levels of worry which were substantially higher than non-autistic adults. Autistic adults described worry as a cycle of negative thoughts impacting their daily life. Findings indicate that autistic adults may worry more than non-autistic adults, impacting on participation in activities of daily living, sleep, and mental health.

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8. Blume J, Dhanasekara CS, Kahathuduwa CN, Mastergeorge AM. Central Executive and Default Mode Networks: An Appraisal of Executive Function and Social Skill Brain-Behavior Correlates in Youth with Autism Spectrum Disorder. J Autism Dev Disord;2023 (Mar 29)

Atypical connectivity patterns have been observed for individuals with autism spectrum disorders (ASD), particularly across the triple-network model. The current study investigated brain-behavior relationships in the context of social skills and executive function profiles for ASD youth. We calculated connectivity measures from diffusion tensor imaging using Bayesian estimation and probabilistic tractography. We replicated prior structural equation modeling of behavioral measures with total default mode network (DMN) connectivity to include comparisons with central executive network (CEN) connectivity and CEN-DMN connectivity. Increased within-CEN connectivity was related to metacognitive strengths. Our findings indicate behavior regulation difficulties in youth with ASD may be attributable to impaired connectivity between the CEN and DMN and social skill difficulties may be exacerbated by impaired within-DMN connectivity.

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9. Chouery E, Makhlouf J, Daoud Khatoun W, Mehawej C, Megarbane A. PCDH19 in Males: Are Hemizygous Variants Linked to Autism?. Genes (Basel);2023 (Feb 27);14(3)

BACKGROUND: Autism spectrum disorder (ASD) is a complex developmental disability that impairs the social communication and interaction of affected individuals and leads to restricted or repetitive behaviors or interests. ASD is genetically heterogeneous, with inheritable and de novo genetic variants in more than hundreds of genes contributing to the disease. However, these account for only around 20% of cases, while the molecular basis of the majority of cases remains unelucidated as of yet. MATERIAL AND METHODS: Two unrelated Lebanese patients, a 7-year-old boy (patient A) and a 4-year-old boy (patient B), presenting with ASD were included in this study. Whole-exome sequencing (WES) was carried out for these patients to identify the molecular cause of their diseases. RESULTS: WES analysis revealed hemizygous variants in PCDH19 (NM_001184880.1) as being the candidate causative variants: p.Arg787Leu was detected in patient A and p.Asp1024Asn in patient B. PCDH19, located on chromosome X, encodes a membrane glycoprotein belonging to the protocadherin family. Heterozygous PCDH19 variants have been linked to epilepsy in females with mental retardation (EFMR), while mosaic PCDH19 mutations in males are responsible for treatment-resistant epilepsy presenting similarly to EFMR, with some reported cases of comorbid intellectual disability and autism. Interestingly, a hemizygous PCDH19 variant affecting the same amino acid that is altered in patient A was previously reported in a male patient with ASD. CONCLUSION: Here, we report hemizygous PCDH19 variants in two males with autism without epilepsy. Reporting further PCDH19 variants in male patients with ASD is important to assess the possible involvement of this gene in autism.

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10. Çıtar Dazıroğlu ME, Sağdıçoğlu Celep AG. Determination of Nutrient Intake and Dietary Antioxidant Capacity in Autism Spectrum Disorder: A Case-Control Study. J Autism Dev Disord;2023 (Mar 30)

The aim of this study was to evaluate the nutrient intake and dietary antioxidant capacity of children and adolescents with ASD. The study included 38 children and adolescents with ASD aged 6-18 years and 38 gender and age-matched peers without ASD. Caregivers of participants who met inclusion criteria completed a questionnaire form, three-day food consumption record and antioxidant nutrient questionnaire. There were 26 (68.4%) boys and 12 (31.6%) girls in both groups and mean age of participants with and without ASD was 10.9 ± 4.03 years versus 11.1 ± 4.09 years, respectively. The average intake of carbohydrates, vitamin D, calcium, sodium and selenium was lower in participants with ASD than in participants without ASD (p < 0.05). In both groups, dietary fiber, vitamin D, potassium, calcium and selenium intake insufficiency were high, and there was a significant difference between the two groups in terms of carbohydrate, omega 3, vitamin D and sodium intake insufficiency. Considering the antioxidant intakes of the participants, the median value of dietary antioxidant capacity from food consumption record of participants with and without ASD was 3.2 (1.9) mmol versus 4.3 (1.9) mmol, respectively, whereas the dietary antioxidant capacity from antioxidant nutrient questionnaire was 3.5 (2.9) mmol versus 4.8 (2.7) mmol, respectively (p < 0.05). It is predicted that providing nutritional counseling and regulation of diet, especially keeping the antioxidant capacity of diets high, may be effective in reducing some of the symptoms of ASD.

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11. Colomar L, San José Cáceres A, Álvarez-Linera J, González-Peñas J, Huertas Patón A, Martín de Blas D, Polo Arrondo AP, Solís A, Jones E, Parellada M. Role of cortical excitatory/inhibitory imbalance in autism spectrum disorders from a symptom severity trajectories framework: a study protocol. BMC Psychiatry;2023 (Mar 29);23(1):213.

BACKGROUND: There is considerable evidence reporting an excitatory/inhibitory (E/I) cortical imbalance in autism spectrum disorders (ASD). However, previous findings on the direction of this imbalance and its relationship to ASD symptomatology are heterogeneous. Some factors contributing to these mixed results might be the methodological differences between studies assessing the E/I ratio and the intrinsic variability within the autistic spectrum. Studying the evolution of ASD symptoms and the factors that modulate it might help to explain and reduce this variability. Here we present a study protocol to explore the longitudinal role of E/I imbalance in ASD symptoms, combining different approaches to measure the E/I ratio and using the trajectories of symptom severity as a framework. METHODS: This observational two time-point prospective study assesses the E/I ratio and the evolution of the behavioural symptoms in a sample of at least 98 participants with ASD. Participants are enrolled at 12 to 72 months of age and followed from 18 to 48 months after. A comprehensive battery of tests is applied to evaluate ASD clinical symptoms. The E/I ratio is approached from electrophysiology, magnetic resonance, and genetics. We will calculate the individual change for the main ASD symptoms and, based on that, we will define the trajectories of symptom severity. Then, we will investigate the correlation between measures of excitation/inhibition balance and autistic symptomatology cross-sectionally, as well as the ability of these measurements to predict changes in symptoms over time. DISCUSSION: This study presents a robust multisystemic approach to the E/I imbalance theory in autism and its relation to divergent symptom trajectories. That setting will allow us to relate and compare the neurobiological information coming from different sources and its impact on behavioural symptoms while accounting for the high variability in ASD. The findings derived from this study could contribute to the ASD biomarkers research and might provide valuable evidence for the development of more personalized treatments in ASD.

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12. Cope EC, Wang SH, Waters RC, Gore IR, Vasquez B, Laham BJ, Gould E. Activation of the CA2-ventral CA1 pathway reverses social discrimination dysfunction in Shank3B knockout mice. Nat Commun;2023 (Mar 29);14(1):1750.

Mutation or deletion of the SHANK3 gene, which encodes a synaptic scaffolding protein, is linked to autism spectrum disorder and Phelan-McDermid syndrome, conditions associated with social memory impairments. Shank3B knockout mice also exhibit social memory deficits. The CA2 region of the hippocampus integrates numerous inputs and sends a major output to the ventral CA1 (vCA1). Despite finding few differences in excitatory afferents to the CA2 in Shank3B knockout mice, we found that activation of CA2 neurons as well as the CA2-vCA1 pathway restored social recognition function to wildtype levels. vCA1 neuronal oscillations have been linked to social memory, but we observed no differences in these measures between wildtype and Shank3B knockout mice. However, activation of the CA2 enhanced vCA1 theta power in Shank3B knockout mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can invoke latent social memory function.

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13. Cremone IM, Carpita B, Nardi B, Casagrande D, Stagnari R, Amatori G, Dell’Osso L. Measuring Social Camouflaging in Individuals with High Functioning Autism: A Literature Review. Brain Sci;2023 (Mar 10);13(3)

In the recent years, growing attention has been paid to the use of camouflaging strategies by adult populations suffering from autism spectrum disorder (ASD) with milder manifestations and without intellectual impairment, which may lead to a delay in diagnosis or even a misdiagnosis. In fact, high-functioning ASD individuals were reported to be more aware of their communication difficulties and were more likely make considerable efforts to adjust their behavior to conventional rules of non-autistic individuals, learning to imitate other non-ASD individuals. Moreover, females reported a higher frequency of camouflaging strategies, suggesting a role of camouflaging in the gender gap of the ASD diagnosis. Although camouflaging strategies can sometimes grant a better level of adjustment, even resulting in a hyper-adaptive behavior, they are also often correlated with negative mental health consequences due to the long-term stress associated with continuous attempts to adapt in day-to-day life. In this framework, the aim of the present work was to review the available studies that assessed the presence and correlates of camouflaging strategies in individuals with ASD. Although the literature available on the topic is still scarce, some interesting correlations between camouflaging and anxious and depressive symptoms, as well as suicidality, were highlighted. In particular, the controversial and sometime opposite thoughts and results about camouflaging may be clarified and integrated in light of a dimensional approach to psychopathology.

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14. Davico C, Marcotulli D, Succi E, Canavese C, Bodea AF, Pellegrino M, Cuffari E, Cudia VF, Svevi B, Amianto F, Ricci F, Vitiello B. Working with Children with Autism Undergoing Health-Care Assessments in a Day Hospital Setting: A Perspective from the Health-Care Professionals. Children (Basel);2023 (Feb 27);10(3)

BACKGROUND: Hospitals can be especially stressful for children with autism spectrum disorder (ASD) due to the communication and social skills deficits, lower capacity to adapt to disruption, and sensory hypersensitivity that are typical of these patients. PURPOSE: This study investigated how health-care professionals (HPs) experienced the clinical care and management of children with ASD undergoing medical testing in a day hospital setting, and assessed the rate of successful completion of laboratory tests and instrumental examinations. METHODS: A cross-sectional questionnaire was administered to 45 HPs, inquiring about their experience in obtaining blood and urine tests, ECG, audiometry, and EEG from children with ASD. The clinical sample included 153 consecutively referred children with ASD (74.5% males, mean age 5.6 years) undergoing a medical diagnostic work-up as part of their diagnostic evaluation. The success rate of completing the various assessments was examined. RESULTS: HPs identified aggressive behavior and communication deficits as the major challenges when providing care to children with ASD. The parents were seen as an important resource for managing the children. The completion rate of the laboratory tests and instrumental examinations was high (between 88.5% and 98.4% according to the specific type of examination). The lowest non-completion rate was found for the EEG (12.5%). CONCLUSIONS: Despite considerable challenges being reported by HPs in managing children with ASD, the scheduled assessments could be completed in the large majority of cases. Targeted approaches to preventing aggressive behaviors and obviating the communication barriers in children with ASD undergoing hospital exams are warranted.

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15. de Belen RA, Pincham H, Hodge A, Silove N, Sowmya A, Bednarz T, Eapen V. Eye-tracking correlates of response to joint attention in preschool children with autism spectrum disorder. BMC Psychiatry;2023 (Mar 29);23(1):211.

BACKGROUND: A number of differences in joint attention behaviour between children with autism spectrum disorder (ASD) and typically developing (TD) individuals have previously been documented. METHOD: We use eye-tracking technology to assess response to joint attention (RJA) behaviours in 77 children aged 31 to 73 months. We conducted a repeated-measures analysis of variance to identify differences between groups. In addition, we analysed correlations between eye-tracking and clinical measures using Spearman’s correlation. RESULTS: The children diagnosed with ASD were less likely to follow gaze compared to TD children. Children with ASD were less accurate at gaze following when only eye gaze information was available, compared to when eye gaze with head movement was observed. Higher accuracy gaze-following profiles were associated with better early cognition and more adaptive behaviours in children with ASD. Less accurate gaze-following profiles were associated with more severe ASD symptomatology. CONCLUSION: There are differences in RJA behaviours between ASD and TD preschool children. Several eye-tracking measures of RJA behaviours in preschool children were found to be associated with clinical measures for ASD diagnosis. This study also highlights the construct validity of using eye-tracking measures as potential biomarkers in the assessment and diagnosis of ASD in preschool children.

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16. Dell’Osso L, Chiarantini I, Bonelli C, Cappellato G, Carpita B. A comprehensive perspective of autistic traits and catatonic symptoms in a patient with Fronto-Temporal Dementia and Bipolar Disorder: a case report. BMC Psychiatry;2023 (Mar 30);23(1):216.

BACKGROUND: Fronto-Temporal Dementia (FTD) is a neurodegenerative disorder featuring frontotemporal lobe atrophy which leads to profound changes in behavior and cognition in the affected subjects. Considering that the onset of this type of dementia is typically characterized by the development of affective symptoms, differential diagnosis between FTD and Bipolar Disorder (BD) is particularly difficult. An important overlapping feature between BD and FTD is the presence of catatonic symptoms: Catatonia is extremely frequent in FTD, and, on the other hand, BD is the psychiatric disease with the highest frequency of association with catatonic states. In this framework, it should be noted that also Autism Spectrum conditions have been reported to show high rates of comorbidity and overlapping features with BD. In addition, subjects with autistic traits were reported to show an increased vulnerability towards the development of mood and anxiety disorders, as well as increase the risk of mood episodes with mixed features, suicidal thoughts and catatonic symptoms. CASE PRESENTATION: We reported the case of a patient with a diagnosis of both BD and FTD who showed catatonic symptoms. OBJECTIVES: The aim of this case report is to evaluate the possible role of autistic traits in the illness trajectory of BD and FTD. CONCLUSION: This case confirms the presence of a continuum between psychiatric and neurological conditions, which should be considered as expressions of a same neurobiological system and further investigated in light of an integrative model.

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17. Dossaji Z, Khattak A, Tun KM, Hsu M, Batra K, Hong AS. Efficacy of Fecal Microbiota Transplant on Behavioral and Gastrointestinal Symptoms in Pediatric Autism: A Systematic Review. Microorganisms;2023 (Mar 22);11(3)

Background and Aims: There is a high prevalence of gastrointestinal-related (GI) symptoms among children with autism spectrum disorder (ASD), which is associated with the severity of behavioral symptoms. Fecal microbiota transplantation (FMT) is a proposed therapeutic strategy that aims to address the dysregulation of the gut microbiome among children with ASD. Our study performed the first systematic review aimed to evaluate the benefits of FMT on the behavioral and gastrointestinal symptoms of pediatric patients with autism. Methods: A literature search was performed using variations of the keywords « pediatrics » and « fecal microbiota transplantation » in PubMed, EMBASE, CINAHL, Cochrane, and Web of Science from inception to 30 June 2022. Four studies that met the eligibility criteria were included in the systematic review. The efficacy of FMT on behavioral symptoms was measured by the difference in Aberrant Behavior Checklist (ABC) and Child Autism Rating Scale (CARS) scores before and after FMT. Results: We found a statistically significant improvement (p < 0.05) in ABC and CARS scores following FMT, with a statistically significant decrease in scores observed across all studies. In addition, substantial improvements in gastrointestinal symptoms were observed across all studies. Conclusion: Our findings suggest that FMT may offer a promising intervention for treating both behavioral and gastrointestinal symptoms in pediatric patients with autism.

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18. Esposito M, Mirizzi P, Fadda R, Pirollo C, Ricciardi O, Mazza M, Valenti M. Food Selectivity in Children with Autism: Guidelines for Assessment and Clinical Interventions. Int J Environ Res Public Health;2023 (Mar 14);20(6)

Autisms Spectrum Disorders (ASD) are characterized by core symptoms (social communication and restricted and repetitive behaviors) and related comorbidities, including sensory anomalies, feeding issues, and challenging behaviors. Children with ASD experience significantly more feeding problems than their peers. In fact, parents and clinicians have to manage daily the burden of various dysfunctional behaviors of children at mealtimes (food refusal, limited variety of food, single food intake, or liquid diet). These dysfunctional behaviors at mealtime depend on different factors that are either medical/sensorial or behavioral. Consequently, a correct assessment is necessary in order to program an effective clinical intervention. The aim of this study is to provide clinicians with a guideline regarding food selectivity concerning possible explanations of the phenomenon, along with a direct/indirect assessment gathering detailed and useful information about target feeding behaviors. Finally, a description of evidence-based sensorial and behavioral strategies useful also for parent-mediated intervention is reported addressing food selectivity in children with ASD.

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19. Frye RE, Nanda H, Pleasure SJ, Casanova MF, Boles RG, Lewine J, Gaitanis J, Adams JB. Synchrony 2022: Epilepsy and Seizures in Autism Spectrum Disorder Roundtable. J Pers Med;2023 (Mar 20);13(3)

The BRAIN Foundation (Pleasanton, CA, USA) hosted Synchrony 2022, a translational medicine conference focused on research into treatments for individuals with neurodevelopmental disorders (NDD), including those with autism spectrum disorders (ASD) […].

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20. Gehdu BK, Tsantani M, Press C, Gray KL, Cook R. Recognition of facial expressions in autism: Effects of face masks and alexithymia. Q J Exp Psychol (Hove);2023 (Mar 30):17470218231163007.

It is often assumed that the recognition of facial expressions is impaired in autism. However, recent evidence suggests that reports of expression recognition difficulties in autistic participants may be attributable to co-occurring alexithymia-a trait associated with difficulties interpreting interoceptive and emotional states-not autism per se. Due to problems fixating on the eye-region, autistic individuals may be more reliant on information from the mouth region when judging facial expressions. As such, it may be easier to detect expression recognition deficits attributable to autism, not alexithymia, when participants are forced to base expression judgements on the eye-region alone. To test this possibility, we compared the ability of autistic participants (with and without high levels of alexithymia) and non-autistic controls to categorise facial expressions (a) when the whole face was visible, and (b) when the lower portion of the face was covered with a surgical mask. High-alexithymic autistic participants showed clear evidence of expression recognition difficulties: they correctly categorised fewer expressions than non-autistic controls. In contrast, low-alexithymic autistic participants were unimpaired relative to non-autistic controls. The same pattern of results was seen when judging masked and unmasked expression stimuli. In sum, we find no evidence for an expression recognition deficit attributable to autism, in the absence of high levels of co-occurring alexithymia, either when participants judge whole-face stimuli or just the eye-region. These findings underscore the influence of co-occurring alexithymia on expression recognition in autism.

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21. Genovese A, Butler MG. The Autism Spectrum: Behavioral, Psychiatric and Genetic Associations. Genes (Basel);2023 (Mar 9);14(3)

Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene-protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed.

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22. He X, Liu W, Tang F, Chen X, Song G. Effects of Probiotics on Autism Spectrum Disorder in Children: A Systematic Review and Meta-Analysis of Clinical Trials. Nutrients;2023 (Mar 15);15(6)

Many studies have explored the efficacy of probiotics on autism spectrum disorder (ASD) in children, but there is no consensus on the curative effect. This systematic review and meta-analysis aimed to comprehensively investigate whether probiotics could improve behavioral symptoms in children with ASD. A systematic database search was conducted and a total of seven studies were included in the meta-analysis. We found a nonsignificant overall effect size of probiotics on behavioral symptoms in children with ASD (SMD = -0.24, 95% CI: -0.60 to 0.11, p = 0.18). However, a significant overall effect size was found in the subgroup of the probiotic blend (SMD = -0.42, 95% CI: -0.83 to -0.02, p = 0.04). Additionally, these studies provided limited evidence for the efficacy of probiotics due to their small sample sizes, a shorter intervention duration, different probiotics used, different scales used, and poor research quality. Thus, randomized, double-blind, and placebo-controlled studies following strict trial guidelines are needed to precisely demonstrate the therapeutic effects of probiotics on ASD in children.

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23. Hoshi M, Ishiyama M, Wada T, Hase K, Itoh M, Kikuiri T, Shirakawa T. Alteration of monoaminergic systems in the caudal medulla and its possible link to diurnal increase of apnea in a mouse model of Rett syndrome. J Oral Sci;2023;65(2):96-101.

PURPOSE: Methyl-CpG binding protein 2 (MeCP2)-deficient (Mecp2(-/y)) mice exhibit apneas that resemble respiratory abnormalities observed in Rett syndrome (RTT) patients. The present study aimed to clarify whether Mecp2(-/y) mice show diurnal variations in apnea as seen in RTT and how the MeCP2 deficiency affects monoaminergic systems that control breathing. METHODS: In 7-week-old Mecp2(-/y) mice, 24 h variation of apnea and effects of milnacipran, a serotonin/noradrenaline reuptake inhibitor, on the apnea were evaluated. The number of vesicular monoamine transporter 2 (VMAT2)-immunoreactive puncta in the caudal medulla was counted. Further, the effects of valproate (VPA) on the expression of tyrosine hydroxylase (TH) mRNA in the ventrolateral medulla of mice were assessed by RT-qPCR. RESULTS: Apnea occurred more frequently during the light phase under a 12:12 h light/dark environment in Mecp2(-/y) mice and milnacipran reduced apnea during the light phase but not during the dark phase. The number of VMAT2-immunoreactive puncta was reduced in Mecp2(-/y) mice. VPA treatment significantly increased TH mRNA expression in Mecp2(-/y) mice. CONCLUSION: Alteration of monoaminergic systems in the caudal medulla of Mecp2(-/y) mice is potentially relevant to the light-sensitive diurnal increase of apnea, and an improvement in monoaminergic neurotransmission can ameliorate the diurnal increase of apnea in Mecp2(-/y) mice.

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24. Juan CY. The Mealtime Behavior Problems of Children with Developmental Disabilities and the Teacher’s Stress in Inclusive Preschools. Children (Basel);2023 (Feb 24);10(3)

With an increasing number of children with developmental disabilities entering inclusive preschools, preschool teachers face more behavioral problems in class. Preschool teachers typically attempt to address mealtime behavior problems of children with and without developmental disabilities simultaneously in class. This study used qualitative research to identify the stress triggers of preschool teachers addressing the mealtime behavior problems of children with developmental disabilities. Five preschool teachers attended semi-structured interviews. The results indicated that most children with developmental disabilities had problems with eating only preferred foods, using eating utensils appropriately during mealtime, becoming distracted from eating, and becoming frustrated with the classroom routine. Although solving these problems triggered stress in the preschool teachers, their stress was mainly in response to the children’s parents, other children’s imitation of inappropriate mealtime behaviors, and classroom schedule time management. Most of the preschool teachers stated that they had insufficient support. Preschool teachers require specialized information and strategies for improving the mealtime behaviors of children with developmental disabilities.

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25. Kawai H, Kishimoto M, Okahisa Y, Sakamoto S, Terada S, Takaki M. Initial Outcomes of the Safe and Sound Protocol on Patients with Adult Autism Spectrum Disorder: Exploratory Pilot Study. Int J Environ Res Public Health;2023 (Mar 9);20(6)

Sensory impairments are common features of autism spectrum disorder (ASD) and are associated with its social impairments. However, there is no established treatment for these impairments in adults with ASD. The Safe & Sound Protocol (SSP) is a listening program designed to improve social communication skills by reducing auditory hypersensitivity. We investigated the effectiveness of the SSP for adults with ASD. We administered the SSP to six participants with ASD aged 21-44 years old, and the effects were assessed using the Social Responsiveness Scale, Second Edition (SRS-2). Secondary outcomes were assessed using the Center for Epidemiological Studies Depression Scale (CES-D), State-Trait Anxiety Inventory (STAI), WHO Quality of Life 26 (WHOQOL-BREF), and Adolescent/Adult Sensory Profile (A/ASP). In this study, only the Social Awareness scale of the SRS-2 Family-Report showed a significant improvement after the intervention. In addition, it was significantly correlated with physical health of WHOQOL-BREF (r = -0.577, p = 0.012), state and trait anxiety of STAI (r = 0.576, p = 0.012; r = 0.708, p = 0.00009, respectively), and CES-D (r = 0.465, p = 0.05). In conclusion, the SSP has a partial effect on social impairments in adults with ASD, specifically on the Social Awareness subscale of the SRS-2.

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26. Kochav-Lev M, Bennett-Back O, Lotan M, Stein-Zamir C. The Use of the Alberta Infant Motor Scale (AIMS) as a Diagnostic Scale for Infants with Autism. Diagnostics (Basel);2023 (Mar 9);13(6)

Autism spectrum disorder (ASD) is a group of developmental disabilities presenting difficulties in social interaction and language and an increased occurrence of cognitive, sensory, and motor gaps. Early intervention has been reported to improve the function of children with ASD. However, motor screening for children with ASD is difficult, as there are no specific tools for identifying this specific population. This study reports the results of using the Alberta Infant Motor Scale (AIMS), which assesses gross infant motor skills from ages 0 to 18 months, as a screening tool for detecting motor developmental delay (MDD) in small children with ASD. METHODS: This retrospective cohort study included all children registered at one health care organization in Israel born between 2011 and 2017 (N = 240,299). Early childhood MDD was defined as having at least one recorded developmental physiotherapy (DPT) visit before the age of 2 years. Reasons for referral to DPT and the results of using AIMS as an appropriate tool for revealing developmental delays in infants with ASD are presented. RESULTS: ASD diagnosis was reported in 1821 children (prevalence rate 0.75%). Of those, 388 (odds ratio 4.1, 95% CI 3.6-4.6) children were referred to DPT. Children with ASD mostly received DPT for motor delays (46.19%), torticollis (19.52%), developmental delay (15.48%), and preterm birth (7.38%). The use of AIMS as an early detection tool suggests that more than 87% of children with ASD and MDD present with a developmental delay or risk for one when using this scale. CONCLUSIONS: The prevalence of ASD among children referred to DPT for MDD is higher than its prevalence within the general population. The most common reasons for a child with ASD to be referred for DPT services are MMDs. AIMS was found to be a sensitive tool to pinpoint relevant candidates for ASD screening among children treated in DPT. Possible effects of the study: The use of AIMS as a relevant assessment scale for this group of clients is recommended. Training DPTs in identifying initial ASD signs and developing their clinical reasoning abilities will increase the chance of implementing early intervention with this group of clients.

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27. Levy-Dayan H, Josman N, Rosenblum S. Basic Activity of Daily Living Evaluation of Children with Autism Spectrum Disorder: Do-Eat Washy Adaption Preliminary Psychometric Characteristics. Children (Basel);2023 (Mar 5);10(3)

This preliminary study aims to demonstrate the reliability and validity of the adapted Do-Eat Basic activities of daily living (BADL) assessment for children with autism spectrum disorder (ASD). Participants were 53 children ages 6-10 years: 17 diagnosed with high-severity ASD (HS-ASD) and 16 with low-severity ASD according to the DSM-5 and based on the CARS-2, and 20 controls with typical development. Measurement tools were the adapted Do-Eat Washy (Washy), Participation in Childhood Occupations Questionnaire (PICO-Q), and Pediatric Evaluation of Disability Inventory (PEDI). The Washy domains exhibited high internal consistency (α = 0.841-0.856). Significant differences were found between the HS-ASD and other groups in the Washy domains, exhibiting discriminant validity. The Washy convergent and concurrent validity indicated good results. A highly substantial negative correlation was shown between the Washy and three PICO-Q ADL difficulty-in-performance items (p < 0.001): bathing (-0.550), hygiene (-0.571), and handwashing (-0.733). The Washy performance scores and the PEDI total score demonstrated a strong correlation. (r = 0.799, p < 0.001). Primary results indicate that, following further research on larger representative samples, the Washy may be a reliable and valid tool for assessing BADL among children with ASD.

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28. Li X, Li Q, Xu L, Ma Z, Shi Y, Zhang X, Yang Y, Wang J, Fan L, Wu L. Involvement of Kir4.1 in pain insensitivity of the BTBR mouse model of autism spectrum disorder. Biochim Biophys Acta Mol Basis Dis;2023 (Mar 28);1869(5):166700.

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder. Abnormal pain sensation is a common clinical symptom of ASD that seriously affects the quality of life of patients with ASD and their families. However, the underlying mechanism is unclear. It is believed to be related to the excitability of neurons and the expression of ion channels. Herein, we confirmed that baseline pain and Complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain were impaired in the BTBR T+ Itpr3tf/J (BTBR) mouse model of ASD. RNA sequencing (RNA-seq) analyses of the dorsal root ganglia (DRG), which are closely related to pain in ASD model mice, revealed that high expression of KCNJ10 (encoding Kir4.1) might be an important factor in ASD pain sensation abnormalities. The levels of Kir4.1 were further verified by western blotting, RT-qPCR, and immunofluorescence. By inhibiting Kir4.1, the pain insensitivity of BTBR mice improved, confirming that a high expression level of Kir4.1 was highly correlated with decreased pain sensitivity in ASD. Meanwhile, we found that the anxiety behaviours and the social novelty recognition were changed after CFA induced inflammatory pain. And after inhibiting Kir4.1, the stereotyped behaviours and social novelty recognition of BTBR mice were also improved. Further, we found that the expression levels of glutamate transporters, excitatory amino acid transporter 1 (EAAT1), and excitatory amino acid transporter 2 (EAAT2) were increased in the DRG of BTBR mice but decreased after inhibiting Kir4.1. This suggests that Kir4.1 may play a key role in the improvement of pain insensitivity in ASD by regulating glutamate transporters. In conclusion, our findings revealed the possible mechanism and role of Kir4.1 in the pain insensitivity in ASD, using bioinformatics analyses and animal experiments, and provided a theoretical basis for clinically targeted intervention in ASD.

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29. Loi M, Bastianini S, Candini G, Rizzardi N, Medici G, Papa V, Gennaccaro L, Mottolese N, Tassinari M, Uguagliati B, Berteotti C, Martire VL, Zoccoli G, Cenacchi G, Trazzi S, Bergamini C, Ciani E. Cardiac Functional and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder. Int J Mol Sci;2023 (Mar 14);24(6)

CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD) is a severe neurodevelopmental disease that mostly affects girls, who are heterozygous for mutations in the X-linked CDKL5 gene. Mutations in the CDKL5 gene lead to a lack of CDKL5 protein expression or function and cause numerous clinical features, including early-onset seizures, marked hypotonia, autistic features, gastrointestinal problems, and severe neurodevelopmental impairment. Mouse models of CDD recapitulate several aspects of CDD symptomology, including cognitive impairments, motor deficits, and autistic-like features, and have been useful to dissect the role of CDKL5 in brain development and function. However, our current knowledge of the function of CDKL5 in other organs/tissues besides the brain is still quite limited, reducing the possibility of broad-spectrum interventions. Here, for the first time, we report the presence of cardiac function/structure alterations in heterozygous Cdkl5 +/- female mice. We found a prolonged QT interval (corrected for the heart rate, QTc) and increased heart rate in Cdkl5 +/- mice. These changes correlate with a marked decrease in parasympathetic activity to the heart and in the expression of the Scn5a and Hcn4 voltage-gated channels. Interestingly, Cdkl5 +/- hearts showed increased fibrosis, altered gap junction organization and connexin-43 expression, mitochondrial dysfunction, and increased ROS production. Together, these findings not only contribute to our understanding of the role of CDKL5 in heart structure/function but also document a novel preclinical phenotype for future therapeutic investigation.

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30. López B, Gregory NJ, Freeth M. Social attention patterns of autistic and non-autistic adults when viewing real versus reel people. Autism;2023 (Mar 30):13623613231162156.

Early research shows that autistic adults do not attend to faces as much as non-autistic adults. However, some recent studies where autistic people are placed in scenarios with real people reveal that they attend to faces as much as non-autistic people. This study compares attention to faces in two situations. In one, autistic and non-autistic adults watched a pre-recorded video. In the other, they watched what they thought were two people in a room in the same building, via a life webcam, when in fact exactly the same video in two situations. We report the results of 32 autistic adults and 33 non-autistic adults. The results showed that autistic adults do not differ in any way from non-autistic adults when they watched what they believed was people interacting in real time. However, when they thought they were watching a video, non-autistic participants showed higher levels of attention to faces than non-autistic participants. We conclude that attention to social stimuli is the result of a combination of two processes. One innate, which seems to be different in autism, and one that is influenced by social norms, which works in the same way in autistic adults without learning disabilities. The results suggest that social attention is not as different in autism as first thought. Specifically, the study contributes to dispel long-standing deficit models regarding social attention in autism as it points to subtle differences in the use of social norms rather than impairments.

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31. Manikantan K, Jaganathan S. A Model for Diagnosing Autism Patients Using Spatial and Statistical Measures Using rs-fMRI and sMRI by Adopting Graphical Neural Networks. Diagnostics (Basel);2023 (Mar 16);13(6)

This article proposes a model to diagnose autism patients using graphical neural networks. A graphical neural network relates the subjects (nodes) using the features (edges). In our model, radiomic features obtained from sMRI are used as edges, and spatial-temporal data obtained through rs-fMRI are used as nodes. The similarity between first-order and texture features from the sMRI data of subjects are derived using radiomics to construct the edges of a graph. The features from brain summaries are assembled and learned using 3DCNN to represent the features of each node of the graph. Using the structural similarities of the brain rather than phenotypic data or graph kernel functions provides better accuracy. The proposed model was applied to a standard dataset, ABIDE, and it was shown that the classification results improved with the use of both spatial (sMRI) and statistical measures (brain summaries of rs-fMRI) instead of using only medical images.

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32. Mayes SD, Calhoun SL, Waschbusch DA. Agreement between mother, father, and teacher ratings of cognitive disengagement syndrome (sluggish cognitive tempo) in children with autism and children with ADHD. Psychol Assess;2023 (Mar 30)

No studies have analyzed differences between mother, father, and teacher ratings of cognitive disengagement syndrome (CDS; formerly sluggish cognitive tempo). The sample included 1,115 children with autism and/or attention-deficit/hyperactivity disorder (ADHD) 4-16 years of age who were rated by mothers on the Pediatric Behavior Scale. Subsets of these children were also rated by fathers and/or teachers, resulting in 896 mother/father, 964 mother/teacher, and 745 father/teacher dyads. The CDS factor comprised four items assessing the core features of CDS: cognitive disengagement (in a fog/confused and stares/preoccupied/in own world) and hypoactivity (sluggish/slow moving/low energy and drowsy/sleepy/not alert). Overall, 37% of teachers, 22% of mothers, and 16% of fathers rated the children as significantly elevated on CDS symptoms. Teacher scores were significantly higher than mother scores, whose scores exceeded those of fathers. Agreement on whether a child had CDS was fair-moderate for mothers and fathers but poor for parents and teachers. Findings of more severe CDS teacher than parent ratings are in marked contrast to the opposite pattern found in studies of anxiety, depression, ADHD, oppositional behavior, conduct problems, autism, bullying, and victimization. Children may display fewer behavior problems at school than at home, and parents may be more aware of their child’s internal state than teachers. However, teachers may be more aware of the cognitive component of CDS that might interfere with functioning in the classroom more so than at home. Cognitive demands in school may reveal and intensify CDS symptoms. Findings highlight the importance of multi-informant ratings in research and clinical practice. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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33. Mueller S, Decker L, Menge S, Ludolph AC, Freischmidt A. The Fragile X Protein Family in Amyotrophic Lateral Sclerosis. Mol Neurobiol;2023 (Mar 29)

The fragile X protein (FXP) family comprises the multifunctional RNA-binding proteins FMR1, FXR1, and FXR2 that play an important role in RNA metabolism and regulation of translation, but also in DNA damage and cellular stress responses, mitochondrial organization, and more. FMR1 is well known for its implication in neurodevelopmental diseases. Recent evidence suggests substantial contribution of this protein family to amyotrophic lateral sclerosis (ALS) pathogenesis. ALS is a highly heterogeneous neurodegenerative disease with multiple genetic and unclear environmental causes and very limited treatment options. The loss of motoneurons in ALS is still poorly understood, especially because pathogenic mechanisms are often restricted to patients with mutations in specific causative genes. Identification of converging disease mechanisms evident in most patients and suitable for therapeutic intervention is therefore of high importance. Recently, deregulation of the FXPs has been linked to pathogenic processes in different types of ALS. Strikingly, in many cases, available data points towards loss of expression and/or function of the FXPs early in the disease, or even at the presymptomatic state. In this review, we briefly introduce the FXPs and summarize available data about these proteins in ALS. This includes their relation to TDP-43, FUS, and ALS-related miRNAs, as well as their possible contribution to pathogenic protein aggregation and defective RNA editing. Furthermore, open questions that need to be addressed before definitively judging suitability of these proteins as novel therapeutic targets are discussed.

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34. Nakai N, Sato M, Yamashita O, Sekine Y, Fu X, Nakai J, Zalesky A, Takumi T. Virtual reality-based real-time imaging reveals abnormal cortical dynamics during behavioral transitions in a mouse model of autism. Cell Rep;2023 (Mar 24):112258.

Functional connectivity (FC) can provide insight into cortical circuit dysfunction in neuropsychiatric disorders. However, dynamic changes in FC related to locomotion with sensory feedback remain to be elucidated. To investigate FC dynamics in locomoting mice, we develop mesoscopic Ca(2+) imaging with a virtual reality (VR) environment. We find rapid reorganization of cortical FC in response to changing behavioral states. By using machine learning classification, behavioral states are accurately decoded. We then use our VR-based imaging system to study cortical FC in a mouse model of autism and find that locomotion states are associated with altered FC dynamics. Furthermore, we identify FC patterns involving the motor area as the most distinguishing features of the autism mice from wild-type mice during behavioral transitions, which might correlate with motor clumsiness in individuals with autism. Our VR-based real-time imaging system provides crucial information to understand FC dynamics linked to behavioral abnormality of neuropsychiatric disorders.

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35. Nanda H, Frye RE. Synchrony 2022: Catalyzing Research and Treatments to Benefit Individuals with Neurodevelopmental Disorders including Autism Spectrum Disorders. J Pers Med;2023 (Mar 9);13(3)

A unique translational medicine conference for research into treatments that can benefit individuals with neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD), has been developed and hosted by The BRAIN Foundation (Pleasanton, CA, USA) since 2019 […].

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36. Narzisi A, Alonso-Esteban Y, Alcantud-Marín F. Autism and Children: Diagnosis, Functional Profiles and Intervention. Children (Basel);2023 (Mar 8);10(3)

In the last forty years, approaches to and the social perception of autism have changed significantly […].

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37. Pagni BA, Hill E, Walsh MJM, Delaney S, Ogbeama D, Monahan L, Cook JR, Guerithault N, Dixon MV, Ballard L, Braden BB. Distinct and shared therapeutic neural mechanisms of mindfulness-based and social support stress reduction groups in adults with autism spectrum disorder. J Psychiatry Neurosci;2023 (Mar-Apr);48(2):E102-E114.

BACKGROUND: Mindfulness-based stress reduction (MBSR) alleviates depression and anxiety in adults with autism spectrum disorder (ASD); however, underlying therapeutic neural mechanisms and mindfulness-specific effects have yet to be elucidated. METHODS: We randomly assigned adults with ASD to MBSR or social support/education (SE). They completed questionnaires that assessed depression, anxiety, mindfulness traits, autistic traits and executive functioning abilities as well as a self-reflection functional MRI task. We used repeated-measures analysis of covariance (ANCOVA) to evaluate behavioural changes. To identify task-specific connectivity changes, we performed a generalized psychophysiological interactions (gPPI) functional connectivity (FC) analysis on regions of interest (ROIs; insula, amygdala, cingulum and prefrontal cortex [PFC]). We used Pearson correlations to explore brain-behaviour relationships. RESULTS: Our final sample included 78 adults with ASD – 39 who received MBSR and 39 who received SE. Mindfulness-based stress reduction uniquely improved executive functioning abilities and increased mindfulness traits, whereas both MBSR and SE groups showed reductions in depression, anxiety and autistic traits. Decreases specific to MBSR in insula-thalamus FC were associated with anxiety reduction and increased mindfulness traits, including the trait « nonjudgment; » MBSR-specific decreases in PFC-posterior cingulate connectivity correlated with improved working memory. Both groups showed decreased amygdala-sensorimotor and medial-lateral PFC connectivity, which corresponded with reduced depression. LIMITATIONS: Larger sample sizes and neuropsychological evaluations are needed to replicate and extend these findings. CONCLUSION: Together, our findings suggest that MBSR and SE are similarly efficacious for depression, anxiety and autistic traits, whereas MBSR produced additional salutary effects related to executive functioning and mindfulness traits. Findings from gPPI identified shared and distinct therapeutic neural mechanisms, implicating the default mode and salience networks. Our results mark an early step toward the development of personalized medicine for psychiatric symptoms in ASD and offer novel neural targets for future neurostimulation research. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04017793.

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38. Pan H, Mao Y, Liu P, Li Y, Wei G, Qiao X, Ren Y, Zhao F. Extracting transition features among brain states based on coarse-grained similarity measurement for autism spectrum disorder analysis. Med Phys;2023 (Mar 30)

BACKGROUND: The abnormal brain functional connectivity (FC) of patients with mental diseases is closely linked to the transition features among brain states. However, the current research on state transition will produce certain division deviations in the measurement method of state division, and also ignore the transition features among multiple states that contain more abundant information for analyzing brain diseases. PURPOSE: To investigate the potential of the proposed method based on coarse-grained similarity measurement to solve the problem of state division, and consider the transition features among multiple states to analyze the FC abnormalities of autism spectrum disorder (ASD) patients. METHODS: We used resting-state functional magnetic resonance imaging to examine 45 autism spectrum disorders (ASD) and 47 healthy controls (HC). The FC between brain regions was calculated by the sliding window and correlation algorithm, and a novel coarse-grained similarity measure method was used to cluster the FC networks into five states, and then extract the features both of the state itself and the transition features among multiple states for analysis and diagnosis. RESULTS: (1) The state as divided by the coarse-grained measurement method improves the diagnostic performance of individuals with ASD compared with previous methods. (2) The transition features among multiple states can provide complementary information to the features of the state itself in the ASD analysis and diagnosis. (3) ASD individuals have different brain state transitions than HC. Specifically, the abnormalities in intra- and inter-network connectivity of ASD patients mainly occur in the default mode network, the visual network and the cerebellum. CONCLUSIONS: Such results demonstrate that our approach with new measurements and new features is effective and promising in brain state analysis and ASD diagnosis. This article is protected by copyright. All rights reserved.

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39. Porokhovnik LN, Pisarev VM, Chumachenko AG, Chudakova JM, Ershova ES, Veiko NN, Gorbachevskaya NL, Mamokhina UA, Sorokin AB, Basova AY, Lapshin MS, V LI, Kostyuk SV. Association of NEF2L2 Rs35652124 Polymorphism with Nrf2 Induction and Genotoxic Stress Biomarkers in Autism. Genes (Basel);2023 (Mar 15);14(3)

Increased oxidative/genotoxic stress is known to impact the pathophysiology of ASD (autism spectrum disorder). Clinical studies, however, reported limited, heterogeneous but promising responses to treatment with antioxidant remedies. We determined whether the functional polymorphism of the Nrf2 gene, master regulator of anti-oxidant adaptive reactions to genotoxic stress, links to the genotoxic stress responses and to an in vitro effect of a NRF2 inductor in ASD children. Oxidative stress biomarkers, adaptive responses to genotoxic/oxidative stress, levels of master antioxidant regulator Nrf2 and its active form pNrf2 before and after inducing by dimethyl fumarate (DMF), and promotor rs35652124 polymorphism of NFE2L2 gene encoding Nrf2 were studied in children with ASD (n = 179). Controls included healthy adults (n = 101). Adaptive responses to genotoxicity as indicated by H2AX and cytoprotection by NRF2 contents positively correlated in ASD children with a Spearman coefficient of R = 0.479 in T+, but not CC genotypes. ASD children with NRF2 rs35652124 CC genotype demonstrated significantly higher H2AX content (0.652 vs. 0.499 in T+) and pNrf2 induction by DMF, lowered 8-oxo-dG concentration in plasma and higher cfDNA/plasma nuclease activity ratio. Our pilot findings suggest that in ASD children the NEF2L2 rs35652124 polymorphism impacts adaptive responses that may potentially link to ASD severity. Our data warrant further studies to reveal the potential for NEF2L2 genotype-specific and age-dependent repurposing of DMF and/or other NRF2-inducing drugs.

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40. Pretzsch CM, Floris DL, Schäfer T, Bletsch A, Gurr C, Lombardo MV, Chatham CH, Tillmann J, Charman T, Arenella M, Jones E, Ambrosino S, Bourgeron T, Dumas G, Cliquet F, Leblond CS, Loth E, Oakley B, Buitelaar JK, Baron-Cohen S, Beckmann CF, Persico AM, Banaschewski T, Durston S, Freitag CM, Murphy DGM, Ecker C. Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism. Mol Psychiatry;2023 (Mar 29)

Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals’ adaptive skills naturally improve or remain stable, while others’ decrease. To pave the way for ‘precision-medicine’ approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6-30 years), with two assessment time points separated by ~12-24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful « Increasers », « No-changers », and « Decreasers » in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup’s neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences’ potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.

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41. Rooney J, Hodge R, Smith J, Vanstone K, Laugharne R, Shankar R. Survey of parents of children with intellectual disabilities and/or autism who experience chronic constipation. J Appl Res Intellect Disabil;2023 (Mar 30)

BACKGROUND: Constipation is common in children with intellectual disabilities and/or autism, but poorly researched. This study looks to understand parental knowledge, attitudes and management practices towards constipation in children with intellectual disabilities and/or autism. METHODS: A cross-sectional online survey developed with patient facing organisations was circulated to parents of children with intellectual disabilities and/or autism using an exponential and non-discriminatory snowballing method for recruitment. A smaller sample were purposively sampled for their in-depth experiences. RESULTS: Of 68 responses, people were open to discussing constipation and knowledgeable about risk factors. In the qualitative interviews, of 15 parents, they wanted to be treated as an expert in their child’s care. They desired a service that was more responsive when in difficulty. While wanting more information about medication options, parents want a more holistic approach. CONCLUSIONS: Services need more emphasis on holistic management. Listening to parents and treating them as experts is important.

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42. Roufael M, Bitar T, Sacre Y, Andres C, Hleihel W. Folate-Methionine Cycle Disruptions in ASD Patients and Possible Interventions: A Systematic Review. Genes (Basel);2023 (Mar 13);14(3)

Autism Spectrum Disorder (ASD) has become a major public health concern due to its rapidly rising incidence over the past few years. Disturbances in folate or methionine metabolism have been identified in many individuals with ASD, suggesting that the folate-methionine cycle may play an essential role in the pathogenesis of autism. Thus, changes in metabolite concentrations associated with this cycle could be used as potential biomarkers and therapeutic targets for ASD. The aim of this systematic review is to elucidate the perturbations of this cycle and the possible interventions that may be proposed in this context. Several studies have shown that high levels of homocysteine and low levels of vitamins B12 and folate are associated with ASD. These changes in serum metabolites are influenced by poor diet. In fact, children with ASD tend to eat selectively, which could compromise the quality of their diet and result in nutrient deficiencies. Moreover, these disturbances may also be caused by genetic predispositions such as polymorphisms of the MTHFR gene. Few studies have demonstrated the beneficial effects of the use of nutritional supplements in treating ASD children. Therefore, larger, well-structured studies are recommended to examine the impact of vitamin B12 and folate supplementation on homocysteine levels.

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43. Schlosser RW, Koul R. Advances in augmentative and alternative communication research for individuals with Autism spectrum disorder: moving research and practice forward. Augment Altern Commun;2023 (Mar 30):1-5.

Augmentative and alternative communication (AAC) approaches offer expressive and receptive supports for the segment of the population of individuals with autism spectrum disorder (ASD) who have little or no functional speech. The National Center for Autism Evidence and Practice (NCAEP) declared augmentative and alternative communication (AAC) interventions for individuals with autism an « evidence-based practice. » Following a brief analysis of the breakdown of studies included in NCAEP by dependent variable, we introduce each of the four papers published as part of this special issue on Advances in Augmentative and Alternative Communication Research for Individuals with Autism Spectrum Disorder. In addition to elucidating the contributions and advances of each paper to the research base, including the NCAEP report, we provide a critical commentary as applicable in the hopes of stimulating and guiding further research.

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44. Schmitt LM, Smith EG, Pedapati EV, Horn PS, Will M, Lamy M, Barber L, Trebley J, Meyer K, Heiman M, West KHJ, Hughes P, Ahuja S, Erickson CA. Results of a phase Ib study of SB-121, an investigational probiotic formulation, a randomized controlled trial in participants with autism spectrum disorder. Sci Rep;2023 (Mar 30);13(1):5192.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by core impairments in social communication as well as restricted, repetitive patterns of behavior and/or interests. Individuals with ASD, which includes about 2% of the US population, have challenges with activities of daily living and suffer from comorbid medical and mental health concerns. There are no drugs indicated for the core impairments of ASD. As such, there is a significant need for the development of new medication strategies for individuals with ASD. This first-in-human placebo-controlled, double-blind, crossover study investigated the safety (primary objective) and efficacy of oral SB-121, a combination of L. reuteri, Sephadex® (dextran microparticles), and maltose administered once daily for 28 days in 15 autistic participants. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted. These results provide support for further clinical evaluation of SB-121 as a treatment in autistic patients. To evaluate the safety and tolerability of multiple doses of SB-121 in subjects with autism spectrum disorder. Single-center, randomized, placebo-controlled, double-blind, crossover trial. 15 patients with autism spectrum disorder were randomized and analyzed. Daily dosing of SB-121 or placebo for 28 days, followed by approximately a 14 day washout, then 28 days of dosing with other treatment. Incidence and severity of adverse events, presence of Limosilactobacillus reuteri and Sephadex® in stool, and incidence of bacteremia with positive L. reuteri identification. Additional outcomes include changes from baseline on cognitive and behavior tests as well as biomarker levels. Adverse event rates were similar between SB-121 and placebo, with most reported as mild. There were no severe or serious adverse events. No participants had features of suspected bacteremia or notable changes in vital signs, safety laboratory, or ECG parameters from baseline. There was a statistically significant increase from baseline in the Vineland-3 Adaptive Behavior Composite score (p = 0.03) during SB-121 treatment. There was a trend for increased social/geometric viewing ratio following SB-121 treatment compared to placebo. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted.Trial registration: clinicaltrials.gov Identifier: NCT04944901.

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45. Segal O, Kowal T, Banet-Levi Y, Gabis LV. Executive Function and Working Memory Deficits in Females with Fragile X Premutation. Life (Basel);2023 (Mar 17);13(3)

The Fragile X premutation is a genetic instability of the FMR1 gene caused by 55-199 recurrences of the CGG sequence, whereas there are only 7-54 repeats of the CGG sequence in the normal condition. While males with the premutation of Fragile X were found to have difficulties in executive functions and working memory, little data have been collected on females. This study is among the first to address executive functions and phonological memory in females with the Fragile X premutation. Twenty-three female carriers aged 20-55 years and twelve non carrier females matched in age and levels of education (in years) participated in this study. Executive functions and phonological memory were assessed using the self-report questionnaire The Behavior Rating Inventory of Executive Function (BRIEF) and behavioral measures (nonword repetitions, forward and backward digit span). Females who were carriers of the premutation of the FMR1 gene reported less efficient executive functions in the BRIEF questionnaire compared to the control group. In addition, a relationship was found between the number of repetitions on the CGG sequence of nucleotides, nonword repetitions, and forward digit span. The findings suggest that the premutation of Fragile X in females affects their performance of executive functions and may have impact on everyday functioning.

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46. Seo H, Kim J, Yu C, Lim H. Intra-Rater and Inter-Rater Reliability Analysis of Muscle-Tone Evaluation Using a Myotonometer for Children with Developmental Disabilities. Healthcare (Basel);2023 (Mar 7);11(6)

Assessing muscle tone is an essential component of the diagnosis, prognosis, and treatment planning of developmental disabilities (DD) in children and is of great help in developing clinical diagnosis patterns. The purpose of this study was to investigate intra-rater and inter-rater reliability using the myotonometer, which is an assessment tool to measure muscle tone in children with DD. This study included 26 children diagnosed with DD. Two physical therapists measured the children’s muscle tone using a myotonometer. For all the muscles measured, reliability was determined using the intra-class correlation coefficient (ICC), the standard measurement error (SEM), and the minimal detectable change (MDC). The intra-rater reliability for all muscles was excellent (ICC = 0.75~0.78), except for the biceps brachii (ICC = 0.68). The inter-rater reliability was also excellent for all muscles (ICC = 0.75~0.95), and the SEM and MDC showed small measurement errors. Therefore, the intra-rater and inter-rater reliability of measurements by the myotonometer was found to be good or excellent. This suggests that the myotonometer is a tool that can objectively assess muscle tone, and it can be utilized in clinical practice to quickly and conveniently measure muscle tone in children with DD.

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47. Soccorso C, Milliken A, Hojlo M, Pawlowski K, Weas S, Sideridis G, Baumer N. Quality of Life and Family Impact in Down Syndrome, Autism Spectrum Disorder, and Co-occurring Down Syndrome and Autism Spectrum Disorder. J Dev Behav Pediatr;2023 (Apr 1);44(3):e185-e195.

OBJECTIVE: Families of children with neurodevelopmental disorders have developmental, behavioral, and social-emotional needs that affect quality of life (QoL). This study assesses the validity and utility of a caregiver QoL measure; characterizes QoL in families with children with Down syndrome (DS), autism spectrum disorder (ASD), and a dual diagnosis of DS and ASD (DS + ASD); and compares and explores differences in QoL based on diagnosis. METHODS: Caregivers of children and adolescents with ASD (n = 610) and DS (n = 177) completed the Pediatric Quality of Life Inventory Family Impact Module 2.0, yielding overall, parent functioning, family functioning, and subscale scores, and a Parent Global Impression (PGI) rating. An ASD cohort (n = 177) was sex matched to the DS cohort (n = 177) to mitigate potential sex bias. Additional analyses compared these groups with children and adolescents with DS + ASD (n = 37). RESULTS: Analyses showed that the Pediatric Quality of Life Inventory was valid and reliable in DS, ASD, and DS + ASD populations. No differences were reported in PGI ratings among groups. Caregivers in the DS group demonstrated higher QoL and family functioning compared with the ASD and DS + ASD groups. The DS group reported significantly better Emotional Functioning and Communication and less Worry than the ASD group. Compared with the ASD group, caregivers of the DS + ASD group indicated more concerns with Physical Functioning. Notably, the DS + ASD group had significantly lower levels of QoL than the DS group in nearly all caregiver functioning domains. CONCLUSION: This study highlights differences in QoL within and between neurodevelopmental disorder groups, which may help identify families requiring additional support, advocacy, and community engagement.

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48. Sohl K, Levinstein L, James A, Greer S, Boles K, Curran AB, Mahurin M, Mazurek MO, Nanclares V. ECHO (Extension for Community Healthcare Outcomes) Autism STAT: A Diagnostic Accuracy Study of Community-Based Primary Care Diagnosis of Autism Spectrum Disorder. J Dev Behav Pediatr;2023 (Apr 1);44(3):e177-e184.

OBJECTIVE: Children can be reliably diagnosed with autism spectrum disorder (ASD) by a highly trained clinician as early as 12 to 24 months of age, but recent estimates indicate that the average age of diagnosis is 4.4 years. We hypothesized that trained primary care physicians and practitioners can reliably and accurately diagnose children 14 to 48 months with unambiguous symptoms of ASD. METHODS: Through this diagnostic accuracy study, 20 patients diagnosed with ASD by clinicians trained through the ECHO (Extension for Community Healthcare Outcomes) Autism STAT program participated in an independent gold-standard evaluation at a regional autism center. Caregiver perceptions of the diagnostic process were also assessed. RESULTS: Of the 20 patients who received a diagnosis of ASD by a trained clinician and completed the study, 19 diagnoses were confirmed by a gold-standard evaluation. Caregivers indicated that undergoing diagnosis in their local community rather than an autism specialty center was helpful (4.8/5 on a 5-point Likert scale, n = 19). Results of this study demonstrate that primary care clinicians can be trained to reliably diagnose ASD in children 14 to 48 months with unambiguous symptoms. CONCLUSION: Diagnosis in the primary care setting may lead to earlier diagnosis and quicker connection to evidence-based therapies and interventions. Given the potential impact of increasing access to high-quality diagnostic services, the role of primary care clinicians in the diagnosis of ASD should be further evaluated.

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49. Spataro N, Trujillo-Quintero JP, Manso C, Gabau E, Capdevila N, Martinez-Glez V, Berenguer-Llergo A, Reyes S, Brunet A, Baena N, Guitart M, Ruiz A. High Performance of a Dominant/X-Linked Gene Panel in Patients with Neurodevelopmental Disorders. Genes (Basel);2023 (Mar 13);14(3)

Neurodevelopmental disorders (NDDs) affect 2-5% of the population and approximately 50% of cases are due to genetic factors. Since de novo pathogenic variants account for the majority of cases, a gene panel including 460 dominant and X-linked genes was designed and applied to 398 patients affected by intellectual disability (ID)/global developmental delay (GDD) and/or autism (ASD). Pathogenic variants were identified in 83 different genes showing the high genetic heterogeneity of NDDs. A molecular diagnosis was established in 28.6% of patients after high-depth sequencing and stringent variant filtering. Compared to other available gene panel solutions for NDD molecular diagnosis, our panel has a higher diagnostic yield for both ID/GDD and ASD. As reported previously, a significantly higher diagnostic yield was observed: (i) in patients affected by ID/GDD compared to those affected only by ASD, and (ii) in females despite the higher proportion of males among our patients. No differences in diagnostic rates were found between patients affected by different levels of ID severity. Interestingly, patients harboring pathogenic variants presented different phenotypic features, suggesting that deep phenotypic profiling may help in predicting the presence of a pathogenic variant. Despite the high performance of our panel, whole exome-sequencing (WES) approaches may represent a more robust solution. For this reason, we propose the list of genes included in our customized gene panel and the variant filtering procedure presented here as a first-tier approach for the molecular diagnosis of NDDs in WES studies.

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50. Talantseva OI, Portnova GV, Romanova RS, Martynova DA, Sysoeva OV, Grigorenko EL. Does the Potocki-Lupski Syndrome Convey the Autism Spectrum Disorder Phenotype? Case Report and Scoping Review. J Pers Med;2023 (Feb 28);13(3)

Potocki-Lupski Syndrome (PTLS) is a rare condition associated with a duplication of 17p11.2 that may underlie a wide range of congenital abnormalities and heterogeneous behavioral phenotypes. Along with developmental delay and intellectual disability, autism-specific traits are often reported to be the most common among patients with PTLS. To contribute to the discussion of the role of autism spectrum disorder (ASD) in the PTLS phenotype, we present a case of a female adolescent with a de novo dup(17) (p11.2p11.2) without ASD features, focusing on in-depth clinical, behavioral, and electrophysiological (EEG) evaluations. Among EEG features, we found the atypical peak-slow wave patterns and a unique saw-like sharp wave of 13 Hz that was not previously described in any other patient. The power spectral density of the resting state EEG was typical in our patient with only the values of non-linear EEG dynamics: Hjorth complexity and fractal dimension were drastically attenuated compared with the patient’s neurotypical peers. Here we also summarize results from previously published reports of PTLS that point to the approximately 21% occurrence of ASD in PTLS that might be biased, taking into account methodological limitations. More consistent among PTLS patients were intellectual disability and speech and language disorders.

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51. Tordjman S, Charrier A, Kazatchkine M, Roubertoux P, Botbol M, Bronsard G, Avrameas S. Natural IgG Anti-F (ab’)(2) Autoantibody Activity in Children with Autism. Biomedicines;2023 (Feb 27);11(3)

Background: Many and diverse autoimmune abnormalities have been reported in children with autism. Natural autoantibodies (NAAbs) play important immunoregulatory roles in recognition of the immune self. The objective of this study was to examine the presence of NAAbs in the sera of children with autism and across severity subgroups of autistic behavioral impairments. Methods: NAAbs were titrated in sera through an ELISA procedure in 60 low-functioning children with autism and 112 typically developing controls matched for age, sex and puberty. Results: Serum titers of IgG anti-F(ab’)(2) autoantibodies were significantly lower in children with autism compared to typically developing controls (p < 0.0001), and were significantly negatively associated with autism severity (p = 0.0001). This data appears to be related more specifically to autism than to intellectual disability, given that IgG anti-F(ab')(2) levels were significantly negatively correlated with IQ scores in the autism group (p = 0.01). Conclusions: This is the first report in autism of abnormally low natural anti-F(ab')(2) autoantibody activity. The findings suggest a dysfunction of self-recognition mechanisms which may play a role in the pathogenesis of autism, especially for the severely affected children. These findings strengthen the hypothesis of an autoimmune process in autism and open the prospect of alternative medical treatment. Further neuroimmunological research is warranted to understand the exact mechanisms underlying this reduced natural IgG anti-F (ab')(2) autoantibody activity, and to assess its impact on the pathophysiology and behavioral expression of autism.

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52. Trostle AJ, Li L, Kim SY, Wang J, Al-Ouran R, Yalamanchili HK, Liu Z, Wan YW. A Comprehensive and Integrative Approach to MeCP2 Disease Transcriptomics. Int J Mol Sci;2023 (Mar 7);24(6)

Mutations in MeCP2 result in a crippling neurological disease, but we lack a lucid picture of MeCP2’s molecular role. Individual transcriptomic studies yield inconsistent differentially expressed genes. To overcome these issues, we demonstrate a methodology to analyze all modern public data. We obtained relevant raw public transcriptomic data from GEO and ENA, then homogeneously processed it (QC, alignment to reference, differential expression analysis). We present a web portal to interactively access the mouse data, and we discovered a commonly perturbed core set of genes that transcends the limitations of any individual study. We then found functionally distinct, consistently up- and downregulated subsets within these genes and some bias to their location. We present this common core of genes as well as focused cores for up, down, cell fraction models, and some tissues. We observed enrichment for this mouse core in other species MeCP2 models and observed overlap with ASD models. By integrating and examining transcriptomic data at scale, we have uncovered the true picture of this dysregulation. The vast scale of these data enables us to analyze signal-to-noise, evaluate a molecular signature in an unbiased manner, and demonstrate a framework for future disease focused informatics work.

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53. Uscătescu LC, Kronbichler M, Said-Yürekli S, Kronbichler L, Calhoun V, Corbera S, Bell M, Pelphrey K, Pearlson G, Assaf M. Intrinsic neural timescales in autism spectrum disorder and schizophrenia. A replication and direct comparison study. Schizophrenia (Heidelb);2023 (Mar 30);9(1):18.

Intrinsic neural timescales (INT) reflect the duration for which brain areas store information. A posterior-anterior hierarchy of increasingly longer INT has been revealed in both typically developed individuals (TD), as well as persons diagnosed with autism spectrum disorder (ASD) and schizophrenia (SZ), though INT are, overall, shorter in both patient groups. In the present study, we aimed to replicate previously reported group differences by comparing INT of TD to ASD and SZ. We partially replicated the previously reported result, showing reduced INT in the left lateral occipital gyrus and the right post-central gyrus in SZ compared to TD. We also directly compared the INT of the two patient groups and found that these same two areas show significantly reduced INT in SZ compared to ASD. Previously reported correlations between INT and symptom severity were not replicated in the current project. Our findings serve to circumscribe the brain areas that can potentially play a determinant role in observed sensory peculiarities in ASD and SZ.

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54. Usui N, Kobayashi H, Shimada S. Neuroinflammation and Oxidative Stress in the Pathogenesis of Autism Spectrum Disorder. Int J Mol Sci;2023 (Mar 13);24(6)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by impairments in social communication, repetitive behaviors, restricted interests, and hyperesthesia/hypesthesia caused by genetic and/or environmental factors. In recent years, inflammation and oxidative stress have been implicated in the pathogenesis of ASD. In this review, we discuss the inflammation and oxidative stress in the pathophysiology of ASD, particularly focusing on maternal immune activation (MIA). MIA is a one of the common environmental risk factors for the onset of ASD during pregnancy. It induces an immune reaction in the pregnant mother’s body, resulting in further inflammation and oxidative stress in the placenta and fetal brain. These negative factors cause neurodevelopmental impairments in the developing fetal brain and subsequently cause behavioral symptoms in the offspring. In addition, we also discuss the effects of anti-inflammatory drugs and antioxidants in basic studies on animals and clinical studies of ASD. Our review provides the latest findings and new insights into the involvements of inflammation and oxidative stress in the pathogenesis of ASD.

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55. Vu M, Duhig AM, Tibrewal A, Campbell CM, Gaur A, Salomon C, Gupta A, Kruse M, Taraman S. Increased delay from initial concern to diagnosis of autism spectrum disorder and associated health care resource utilization and cost among children aged younger than 6 years in the United States. J Manag Care Spec Pharm;2023 (Apr);29(4):378-390.

BACKGROUND: Prolonged delays between first caregiver concern and autism spectrum disorder (ASD) diagnosis have been reported, but associations between length of time to diagnosis (TTD) and health care resource utilization (HCRU) and costs have not been studied in a large sample of children with ASD. OBJECTIVE: To address these informational gaps in the ASD diagnostic pathway. METHODS: This retrospective, observational, single cohort analysis of Optum’s administrative claims data from January 1, 2011, to December 31, 2020, included commercially insured children who had 2 or more claims for an ASD diagnosis (earliest diagnosis designated as the index date), were between the ages of older than 1.5 years and 6 years or younger at index date, and were continuously enrolled for up to 48 months before and for 12 months after the index date. Two cohorts (between the ages of older than 1.5 years and 3 years or younger and between the ages of older than 3 years and 6 years or younger at ASD diagnosis) were divided into shorter (less than median) and longer (greater than or equal to median) TTD around each cohort median TTD calculated from the first documented ASD-related concern to the earliest ASD diagnosis, because TTD may vary by age at diagnosis. This exploratory analysis compared all-cause and ASD-related HCRU and costs during a 12-month period preceding ASD diagnosis among children with shorter vs longer TTD. RESULTS: 8,954 children met selection criteria: 4,205 aged 3 years or younger and 4,749 aged older than 3 years at diagnosis, with median TTD of 9.5 and 22.1 months, respectively. In the year preceding ASD diagnosis, children with longer TTD in both age cohorts experienced a greater number of all-cause and ASD-related health care visits compared with those with shorter TTD (mean and median number of office or home visits were approximately 1.5- and 2-fold greater in longer vs shorter TTD groups; P < 0.0001). The mean all-cause medical cost per child in the year preceding ASD diagnosis was approximately 2-fold higher for those with longer vs shorter TTD ($5,268 vs $2,525 in the younger and $5,570 vs $2,265 in the older cohort; P < 0.0001 for both). Mean ASD-related costs were also higher across age cohorts for those with longer vs shorter TTD ($2,355 vs $859 in the younger and $2,351 vs $1,144 in the older cohort; P < 0.0001 for both). CONCLUSIONS: In the year prior to diagnosis, children with longer TTD experienced more frequent health care visits and greater cost burden in their diagnostic journey compared with children with shorter TTD. Novel diagnostic approaches that could accelerate TTD may reduce costs and HCRU for commercially insured children. DISCLOSURES: This study was funded by Cognoa, Inc. Optum received funding from Cognoa to conduct this study. Dr Salomon is an employee and holds stock options of Cognoa, Inc. Dr Campbell was an employee of Cognoa, Inc., at the time this study was conducted. Dr Duhig was an employee of Cognoa, Inc., at the time the study was conducted and holds stock options. Dr Vu, Ms Kruse, Mr Gaur, and Ms Gupta are employees and/or stockholders of Optum. Dr Tibrewal was an employee of Optum at the time the research for this study was conducted. Dr Taraman is an employee and holds stock options of Cognoa, Inc., receives consulting fees from Cognito Therapeutics, volunteers as a board member of the American Academy of Pediatrics California and Orange County Chapter, is a paid advisor for MI10 LLC, and owns stock options of NTX, Inc., and HandzIn.

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