1. Biswas M, Vanwong N, Sukasem C. Pharmacogenomics and non-genetic factors affecting drug response in autism spectrum disorder in Thai and other populations: current evidence and future implications. Front Pharmacol;2023;14:1285967.

Autism spectrum disorder (ASD) may affect family and social life profoundly. Although there is no selective pharmacotherapy for ASD, the Food and Drug Administration (FDA) has recommended risperidone/aripiprazole to treat the associated symptoms of ASD, such as agitation/irritability. Strong associations of some pharmacokinetic/pharmacodynamic gene variants, e.g., CYP2D6 and DRD2, with risperidone-induced hyperprolactinemia have been found in children with ASD, but such strong genetic associations have not been found directly for aripiprazole in ASD. In addition to pharmacogenomic (PGx) factors, drug-drug interactions (DDIs) and possibly cumulative effects of DDIs and PGx may affect the safety or effectiveness of risperidone/aripiprazole, which should be assessed in future clinical studies in children with ASD. Reimbursement, knowledge, and education of healthcare professionals are the key obstacles preventing the successful implementation of ASD pharmacogenomics into routine clinical practice. The preparation of national and international PGx-based dosing guidelines for risperidone/aripiprazole based on robust evidence may advance precision medicine for ASD.

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2. Eygnor A, Angulo A, Cobian M, Wilson R, Coan E, Reynolds A, Friedman S, Boles RE. Assessing Community Needs for Autism Spectrum Disorder: A Review of Rural/Frontier Needs Through Community Outreach With Developmental Pediatrics. Clin Pediatr (Phila);2024 (Feb 20):99228241233803.

Early intervention is known to improve long-term outcomes for individuals with autism spectrum disorder (ASD). Access barriers to care limit timely engagement with supportive services. This report characterized the community needs and supportive services for children and families with suspected or diagnosed ASD. Families and providers participating in outreach clinics identified available services and their attitudes about support for ASD diagnosis. Chart reviews provided referral history, insurance, and current services. Children were nearly 6 years old, 95% of families relied on public health insurance, whereas 50% reported traveling 11 miles or greater for supportive services. Most providers (83%) were medically trained in primary care and placed 1-5 referrals per month to a tertiary referral hospital. Providers reported travel difficulty as the primary reason for referring patients for evaluation. Multiple barriers for supportive services were identified, highlighting the importance to increase the capacity and availability of local ASD supportive services.

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3. Faraji R, Ganji Z, Khandan Khadem Z, Akbari-Lalimi H, Eidy F, Zare H. Volume-based and Surface-Based Methods in Autism Compared with Healthy Controls Are Free surfer and CAT12 in Agreement?. Iran J Child Neurol;2024 (Winter);18(1):93-118.

OBJECTIVES: Autism Spectrum Disorder (ASD) encompasses a range of neurodevelopmental disorders, and early detection is crucial. This study aims to identify the Regions of Interest (ROIs) with significant differences between healthy controls and individuals with autism, as well as evaluate the agreement between FreeSurfer 6 (FS6) and Computational Anatomy Toolbox (CAT12) methods. MATERIALS & METHODS: Surface-based and volume-based features were extracted from FS software and CAT12 toolbox for Statistical Parametric Mapping (SPM) software to estimate ROI-wise biomarkers. These biomarkers were compared between 18 males Typically Developing Controls (TDCs) and 40 male subjects with ASD to assess group differences for each method. Finally, agreement and regression analyses were performed between the two methods for TDCs and ASD groups. RESULTS: Both methods revealed ROIs with significant differences for each parameter. The Analysis of Covariance (ANCOVA) showed that both TDCs and ASD groups indicated a significant relationship between the two methods (p<0.001). The R(2) values for TDCs and ASD groups were 0.692 and 0.680, respectively, demonstrating a moderate correlation between CAT12 and FS6. Bland-Altman graphs showed a moderate level of agreement between the two methods. CONCLUSION: The moderate correlation and agreement between CAT12 and FS6 suggest that while some consistency is observed in the results, CAT12 is not a superior substitute for FS6 software. Further research is needed to identify a potential replacement for this method.

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4. Gu J, Li T, Dong H. Maternal autistic traits and anxiety in children with typical development in Chinese families: a moderated mediation model of mothers’ negative emotional expressions and child gender. Front Psychol;2024;15:1264173.

BACKGROUND: Prior studies have focused on the effects of maternal autistic traits on children with autism, but little attention has been paid to the effects of maternal autistic traits on typically developing children, while the mechanisms of the effects are not clear. OBJECTIVE: Given that, a moderated mediation model was conducted to examine the association between maternal autistic traits and typically developing children’s anxiety and the underlying mechanisms. METHODS AND RESULTS: Participants were 648 mother-child dyads in which these children had no autistic siblings. Mothers reported their autistic traits and negative emotional expressions in the family and children’s anxiety. The results indicated that children’s anxiety was predicted by maternal autistic traits. Mediating analysis revealed that mothers’ negative emotional expressions partially mediated the association between their autistic traits and children’s anxiety. The findings also indicated that child gender moderated the relationship between maternal emotional expressions and children’s anxiety. Specifically, anxiety in girls was more strongly predicted by negative emotional expressions from their mothers than in boys. CONCLUSION: These results have important theoretical and practical implications for reducing the adverse effect of maternal autistic traits on children’s anxiety, especially for girls. The present study also reveals that maternal negative emotional expression is an important mechanism. Causal conclusions cannot be drawn based on cross-sectional research design, so it is necessary to conduct longitudinal studies in the future.

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5. Hou F, Mao A, Shan S, Li Y, Meng W, Zhan J, Nie W, Jin H. Evaluating the clinical utility of a long-read sequencing-based approach in genetic testing of fragile-X syndrome. Clin Chim Acta;2023 (Nov 1);551:117614.

BACKGROUND: Fragile X syndrome (FXS) arises from the FMR1 CGG expansion. Comprehensive genetic testing for FMR1 CGG expansions, AGG interruptions, and microdeletions is essential to provide genetic counseling for females carrying premutation alleles. However, conventional PCR-based FMR1 assays mainly focus on CGG repeats, and could detect AGG interruption only in males. METHODS: The clinical utility of a long-read sequencing-based assay termed comprehensive analysis of FXS (CAFXS) was evaluated in 238 high-risk samples by comparing to conventional PCR assays. RESULTS: PCR assays identified five premuation and three full mutation categories alleles in all the samples, and CAFXS successfully called all the FMR1 CGG expansion. CAFXS identified 24-bp microdeletions upstream to the trinucleotide region with 30 CGG repeats, which was miscalled by the length-based PCR methods. CAFXS also identified a 187-bp deletion in about 1/7 of the sequencing reads in a male patient with mosaic full mutation alleles. CAFXS allowed for precise constructing the FMR1 CGG repeat and AGG interruption pattern in all the samples, and identified a novel and alternative CGA interruption in one normal female sample. CONCLUSIONS: CAFXS represents a more comprehensive and accurate approach for FXS genetic testing that potentially enables more informed genetic counseling compared to PCR-based methods.

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6. Moore R, Poulsen J, Reardon L, Samples-Morris C, Simmons H, Ramsey KM, Whatley ML, Lane JB. Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives. Adv Ther;2024 (Feb 20)

Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder mainly affecting female individuals. Trofinetide was recently approved as the first treatment for RTT, largely on the basis of results from the phase 3 LAVENDER trial, in which trofinetide showed improvements in core symptoms of RTT compared with placebo. However, gastrointestinal (GI) symptoms such as diarrhea and vomiting were commonly reported side effects, and taste was also a reported issue. The objective of this article is to describe the perspectives of five caregivers of girls in trofinetide clinical trials as well as those of three nurse trial coordinators, with a focus on management of GI symptoms of trofinetide treatment.Audio Abstract available for this article. Audio Abstract: Jane Lane provides an overview and discusses key findings of the article titled « Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives. » (MP4 83274 KB).

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7. Ntoulas G, Brakatselos C, Nakas G, Asprogerakas MZ, Delis F, Leontiadis LJ, Trompoukis G, Papatheodoropoulos C, Gkikas D, Valakos D, Vatsellas G, Politis PK, Polissidis A, Antoniou K. Multi-level profiling of the Fmr1 KO rat unveils altered behavioral traits along with aberrant glutamatergic function. Transl Psychiatry;2024 (Feb 20);14(1):104.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disabilities and the most prevalent monogenic cause of autism. Although the knockout (KO) of the Fmr1 gene homolog in mice is primarily used for elucidating the neurobiological substrate of FXS, there is limited association of the experimental data with the pathophysiological condition in humans. The use of Fmr1 KO rats offers additional translational validity in this regard. Therefore, we employed a multi-level approach to study the behavioral profile and the glutamatergic and GABAergic neurotransmission status in pathophysiology-associated brain structures of Fmr1 KO rats, including the recordings of evoked and spontaneous field potentials from hippocampal slices, paralleled with next-generation RNA sequencing (RNA-seq). We found that these rats exhibit hyperactivity and cognitive deficits, along with characteristic bidirectional glutamatergic and GABAergic alterations in the prefrontal cortex and the hippocampus. These results are coupled to affected excitability and local inhibitory processes in the hippocampus, along with a specific transcriptional profile, highlighting dysregulated hippocampal network activity in KO rats. Overall, our data provide novel insights concerning the biobehavioral profile of FmR1 KO rats and translationally upscales our understanding on pathophysiology and symptomatology of FXS syndrome.

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8. Shahid Khan M, Alamgir Kabir M, Mohammad Tareq S. Socio-economic status and autism spectrum disorder: A case-control study in Bangladesh. Prev Med Rep;2024 (Feb);38:102614.

There are unexpectedly a few statistics about the socio-economic status (SES) and related socio-demographic factors (SDFs) of parents having child with ASD in Bangladesh. The prevalence of ASD might correlate with SES and related SDFs. A case-control study was conducted in 24 locations across 21 districts, encompassing all divisions, to assess the association between SES and the risk of developing ASD in Bangladesh. The structured questionnaire was administered through face-to-face interviews with 620 parents of the subject (310 ASD and 310 healthy controls) from January 2020 to June 2021. For univariate, bivariate and multivariate analyses, IBM SPSS version 23 was employed. The significance level was set at P ≤ 0.05, and the Odds Ratio (OR) within a 95 % CI was used to determine whether the variable poses a higher odd or not. After adjusting all significant covariates of binary logistic regression (including some dummy variables) in forward logistic regression model analysis, the higher level of SES, advanced level of father’s education (≥master), 22-35 years old age group of the father, and nuclear family were strongly associated with decreased odds of ASD compared to healthy controls. Only the male gender was strongly associated with an increased odds of ASD compared to the control. The results will aid policymakers in developing plans considering the SES and related SDFs that influence the risk of developing ASD in Bangladesh. Further research using population-based cohorts or nested case-control designs with matched control is necessary to observe and generalize the association.

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9. Shilbayeh SAR, Adeen IS, Ghanem EH, Aljurayb H, Aldilaijan KE, AlDosari F, Fadda A. Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism. Front Pharmacol;2024;15:1356763.

Background: Autism spectrum disorders (ASDs) encompass a broad range of phenotypes characterized by diverse neurological alterations. Genomic studies have revealed considerable overlap between the molecular mechanisms implicated in the etiology of ASD and genes involved in the pharmacokinetic (PK) and pharmacodynamic (PD) pathways of antipsychotic drugs employed in ASD management. Given the conflicting data originating from candidate PK or PD gene association studies in diverse ethnogeographic ASD populations, dosage individualization based on « actionable » pharmacogenetic (PGx) markers has limited application in clinical practice. Additionally, off-label use of different antipsychotics is an ongoing practice, which is justified given the shortage of approved cures, despite the lack of satisfactory evidence for its safety according to precision medicine. This exploratory study aimed to identify PGx markers predictive of risperidone (RIS) exposure in autistic Saudi children. Methods: This prospective cohort study enrolled 89 Saudi children with ASD treated with RIS-based antipsychotic therapy. Plasma levels of RIS and 9-OH-RIS were measured using a liquid chromatography-tandem mass spectrometry system. To enable focused exploratory testing, genotyping was performed with the Axiom PharmacoFocus Array, which included a collection of probe sets targeting PK/PD genes. A total of 720 PGx markers were included in the association analysis. Results: A total of 27 PGx variants were found to have a prominent impact on various RIS PK parameters; most were not located within the genes involved in the classical RIS PK pathway. Specifically, 8 markers in 7 genes were identified as the PGx markers with the strongest impact on RIS levels (p < 0.01). Four PGx variants in 3 genes were strongly associated with 9-OH-RIS levels, while 5 markers in 5 different genes explained the interindividual variability in the total active moiety. Notably, 6 CYP2D6 variants exhibited strong linkage disequilibrium; however, they significantly influenced only the metabolic ratio and had no considerable effects on the individual estimates of RIS, 9-OH-RIS, or the total active moiety. After correction for multiple testing, rs78998153 in UGT2B17 (which is highly expressed in the brain) remained the most significant PGx marker positively adjusting the metabolic ratio. For the first time, certain human leukocyte antigen (HLA) markers were found to enhance various RIS exposure parameters, which reinforces the gut-brain axis theory of ASD etiology and its suggested inflammatory impacts on drug bioavailability through modulation of the brain, gastrointestinal tract and/or hepatic expression of metabolizing enzymes and transporters. Conclusion: Our hypothesis-generating approach identified a broad spectrum of PGx markers that interactively influence RIS exposure in ASD children, which indicated the need for further validation in population PK modeling studies to define polygenic scores for antipsychotic efficacy and safety, which could facilitate personalized therapeutic decision-making in this complex neurodevelopmental condition.

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10. Sun K, Li Y, Zhai Z, Yin H, Liang S, Zhai F, Cui Y, Zhang G. Effects of transcutaneous auricular vagus nerve stimulation and exploration of brain network mechanisms in children with high-functioning autism spectrum disorder: study protocol for a randomized controlled trial. Front Psychiatry;2024;15:1337101.

BACKGROUND: Autism Spectrum Disorders (ASD) are a collection of neurodevelopmental diseases characterized by poor social interaction and communication, a limited range of interests, and stereotyped behavior. High-functioning autism (HFA) indicates a subgroup of individuals with autism who possess cognitive and/or language skills that are within the average to above-normal range for their age. Transcutaneous auricular vagus nerve stimulation (taVNS) holds promise in children with HFA. However, few studies have used randomized controlled trials to validate the effectiveness of taVNS. Therefore, in this study, we intend to provide a study protocol to examine the therapeutic effects of taVNS in individuals diagnosed with HFA and to investigate the process of brain network remodeling in individuals with ASD using functional imaging techniques to observe alterations in large-scale neural networks. METHODS AND DESIGN: We planned to employ a randomized, double-blind experimental design, including 40 children receiving sham stimulation and 40 children receiving real stimulation. We will assess clinical scales and perform functional imaging examinations before and after the stimulation. Additionally, we will include age- and gender-matched healthy children as controls and conduct functional imaging examinations. We plan first to observe the therapeutic effects of taVNS. Furthermore, we will observe the impact of taVNS stimulation on the brain network. DISCUSSION: taVNS was a low-risk, easy-to-administer, low-cost, and portable option to modulate the vagus system. taVNS may improve the social performance of HFA. Changes in the network properties of the large-scale brain network may be related to the efficacy of taVNS. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn, identifier ChiCTR2300074035.

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11. Tang X, Ma Z, SiuChing K, Xu L, Liu Q, Yang L, Wang Y, Cao Q, Li X, Liu J. Altered Intrinsic Brain Spontaneous Activities in Children With Autism Spectrum Disorder Comorbid ADHD. J Atten Disord;2024 (Feb 20):10870547241233207.

OBJECTIVE: The study involved 17 children with Autism Spectrum Disorder (ASD), 21 with ADHD, 30 with both (ASD + ADHD), and 28 typically developing children (TD). METHODS: The amplitude of low-frequency fluctuations (ALFF) was measured as a regional brain function index. Intrinsic functional connectivity (iFC) was also analyzed using the region of interest (ROI) identified in ALFF analysis. Statistical analysis was done via one-way ANCOVA, Gaussian random field (GRF) theory, and post-hoc pair-wise comparisons. RESULTS: The ASD + ADHD group showed increased ALFF in the left middle frontal gyrus (MFG.L) compared to the TD group. In terms of global brain function, the ASD group displayed underconnectivity in specific regions compared to the ASD + ADHD and TD groups. CONCLUSION: The findings contribute to understanding the neural mechanisms underlying ASD + ADHD.

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12. Tonti E, Lee YM, Gruenke N, Ferren J, Stutzman DL. Impact of Pharmacogenomics on Pediatric Psychotropic Medication Prescribing in an Ambulatory Care Setting. J Child Adolesc Psychopharmacol;2024 (Feb);34(1):52-60.

Objective: Evidence for pharmacogenomic (PGx) guided treatment in child and adolescent psychiatry is growing. This study evaluated the impact of PGx testing on psychotropic medication prescribing in an ambulatory child and adolescent psychiatry and a developmental pediatrics clinic. Methods: This was a single-center, retrospective, descriptive analysis of patients who underwent PGx testing between January 2015 and October 2022 at a child and adolescent psychiatry clinic or developmental pediatrics clinic. The primary outcome was the proportion of patients with at least one psychotropic medication modification made 6-month posttesting that could be attributed to CYP2C19, CYP2D6, HLA-B*15:02, or HLA-A*31:01. Secondary outcomes included reason for testing, types of therapeutic modifications made, and whether the therapeutic modifications concorded with PGx guidelines. Results: A total of 193 patients were analyzed. The average age was 10 ± 4 years old, 60% were male, 78% were Caucasian. Sixty-eight percent had a primary diagnosis of a neurodevelopmental disorder, namely autism spectrum disorder (51%), and attention-deficit/hyperactivity disorder (14%). The reasons for PGx testing included medication inefficacy (34%), medication intolerance (20%), and family request (19%). At the time of PGx testing, 37% of patients were taking ≥1 psychotropic medication with PGx annotation. Overall, 35 PGx-related therapeutic modifications were made in 32 (17%) patients. These included continuing current PGx medication (6.2%) and starting PGx medication (5.2%). These modifications mainly involved antidepressants. Out of these 35 PGx-related therapeutic modifications, 94% were concordant with PGx guidelines. Among 29 patients who were prescribed at least one CYP2D6 inhibitor, 25 (86%) underwent CYP2D6 phenoconversion. Conclusions: It is critical to apply pediatric age-specific considerations when utilizing PGx testing in child and adolescent psychiatry. PGx testing stewardship could provide a framework to guide the clinical utility of PGx in a pediatric population with mental health conditions, including neurodevelopmental disorders.

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13. Wan Y, Zhang L, Xu Z, Su Q, Leung TF, Chan D, Wong OWH, Chan S, Chan FKL, Tun HM, Ng SC. Alterations in fecal virome and bacteriome virome interplay in children with autism spectrum disorder. Cell Rep Med;2024 (Feb 20);5(2):101409.

Emerging evidence suggests autism spectrum disorder (ASD) is associated with altered gut bacteria. However, less is known about the gut viral community and its role in shaping microbiota in neurodevelopmental disorders. Herein, we perform a metagenomic analysis of gut-DNA viruses in 60 children with ASD and 64 age- and gender-matched typically developing children to investigate the effect of the gut virome on host bacteria in children with ASD. ASD is associated with altered gut virome composition accompanied by the enrichment of Clostridium phage, Bacillus phage, and Enterobacteria phage. These ASD-enriched phages are largely associated with disrupted viral ecology in ASD. Importantly, changes in the interplay between the gut bacteriome and virome seen in ASD may influence the encoding capacity of microbial pathways for neuroactive metabolite biosynthesis. These findings suggest an impaired bacteriome-virome ecology in ASD, which sheds light on the importance of bacteriophages in pathogenesis and the development of microbial therapeutics in ASD.

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