1. Castro CP, Diehl AG, Boyle AP. Challenges in screening for de novo noncoding variants contributing to genetically complex phenotypes. HGG Adv;2023 (Jul 13);4(3):100210.

Understanding the genetic basis for complex, heterogeneous disorders, such as autism spectrum disorder (ASD), is a persistent challenge in human medicine. Owing to their phenotypic complexity, the genetic mechanisms underlying these disorders may be highly variable across individual patients. Furthermore, much of their heritability is unexplained by known regulatory or coding variants. Indeed, there is evidence that much of the causal genetic variation stems from rare and de novo variants arising from ongoing mutation. These variants occur mostly in noncoding regions, likely affecting regulatory processes for genes linked to the phenotype of interest. However, because there is no uniform code for assessing regulatory function, it is difficult to separate these mutations into likely functional and nonfunctional subsets. This makes finding associations between complex diseases and potentially causal de novo single-nucleotide variants (dnSNVs) a difficult task. To date, most published studies have struggled to find any significant associations between dnSNVs from ASD patients and any class of known regulatory elements. We sought to identify the underlying reasons for this and present strategies for overcoming these challenges. We show that, contrary to previous claims, the main reason for failure to find robust statistical enrichments is not only the number of families sampled, but also the quality and relevance to ASD of the annotations used to prioritize dnSNVs, and the reliability of the set of dnSNVs itself. We present a list of recommendations for designing future studies of this sort that will help researchers avoid common pitfalls.

Lien vers le texte intégral (Open Access ou abonnement)

2. Claussen AH, Dimitrov LV, Bhupalam S, Wheaton AG, Danielson ML. Short Sleep Duration: Children’s Mental, Behavioral, and Developmental Disorders and Demographic, Neighborhood, and Family Context in a Nationally Representative Sample, 2016-2019. Prev Chronic Dis;2023 (Jul 13);20:E58.

INTRODUCTION: Many children and adolescents experience insufficient sleep, which poses risks for their short- and long-term health and development. This study examined the concurrent associations of contextual factors, including child, demographic, neighborhood, and family factors, with short sleep duration. METHODS: We combined data on children aged 3 to 17 years from the 2016-2019 National Survey of Children’s Health (N = 112,925) to examine the association of parent-reported child short sleep duration (ages 3-5 y, <10 h; 6-12 y, <9 h; 13-17 y, <8 h) with mental, behavioral, and developmental disorders (MBDDs); selected physical health conditions; and demographic, neighborhood, and family factors. RESULTS: Overall, 34.7% of children experienced short sleep duration. The prevalence was highest among children aged 6 to 12 years (37.5%); children from racial and ethnic minority groups, especially non-Hispanic Black children (50.0%); children from low-income households (44.9%); children with an MBDD (39.6%); children experiencing negative neighborhood factors (poor conditions and lack of safety, support, and amenities, 36.5%); and family factors such as inconsistent bedtime (57.3%), poor parental mental (47.5%) and physical health (46.0%), and adverse childhood experiences (44.1%). The associations between sleep and demographic, neighborhood, and family factors, and MBDD remained significant after controlling for all other factors. CONCLUSION: This study identified several individual, family, and community factors that may contribute to children's short sleep duration and can be targeted to improve healthy development, particularly among children with an MBDD, from households with low socioeconomic status, or from racial and ethnic minority groups who are at increased risk for short sleep duration.

Lien vers le texte intégral (Open Access ou abonnement)

3. Curnow E, Rutherford M, Maciver D, Johnston L, Prior S, Boilson M, Shah P, Jenkins N, Meff T. Mental health in autistic adults: A rapid review of prevalence of psychiatric disorders and umbrella review of the effectiveness of interventions within a neurodiversity informed perspective. PLoS One;2023;18(7):e0288275.

BACKGROUND: Autistic adults have high risk of mental ill-health and some available interventions have been associated with increased psychiatric diagnoses. Understanding prevalence of psychiatric diagnoses is important to inform the development of individualised treatment and support for autistic adults which have been identified as a research priority by the autistic community. Interventions require to be evaluated both in terms of effectiveness and regarding their acceptability to the autistic community. OBJECTIVE: This rapid review identified the prevalence of psychiatric disorders in autistic adults, then systematic reviews of interventions aimed at supporting autistic adults were examined. A rapid review of prevalence studies was completed concurrently with an umbrella review of interventions. Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed, including protocol registration (PROSPERO#CRD42021283570). DATA SOURCES: MEDLINE, CINAHL, PsycINFO, and Cochrane Database of Systematic Reviews. STUDY ELIGIBILITY CRITERIA: English language; published 2011-2022; primary studies describing prevalence of psychiatric conditions in autistic adults; or systematic reviews evaluating interventions for autistic adults. APPRAISAL AND SYNTHESIS: Bias was assessed using the Prevalence Critical Appraisal Instrument and AMSTAR2. Prevalence was grouped according to psychiatric diagnosis. Interventions were grouped into pharmacological, employment, psychological or mixed therapies. Strength of evidence for interventions was assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluation). Autistic researchers within the team supported interpretation. RESULTS: Twenty prevalence studies were identified. Many included small sample sizes or failed to compare their sample group with the general population reducing validity. Prevalence of psychiatric diagnoses was variable with prevalence of any psychiatric diagnosis ranging from 15.4% to 79%. Heterogeneity was associated with age, diagnosis method, sampling methods, and country. Thirty-two systematic reviews of interventions were identified. Four reviews were high quality, four were moderate, five were low and nineteen critically low, indicating bias. Following synthesis, no intervention was rated as ‘evidence based.’ Acceptability of interventions to autistic adults and priorities of autistic adults were often not considered. CONCLUSIONS: There is some understanding of the scope of mental ill-health in autism, but interventions are not tailored to the needs of autistic adults, not evidence based, and may focus on promoting neurotypical behaviours rather than the priorities of autistic people.

Lien vers le texte intégral (Open Access ou abonnement)

4. Dimian AF, Estes AM, Dager S, Piven J, Wolff JJ. Predicting self-injurious behavior at age three among infant siblings of children with autism. Autism Res;2023 (Jul 13)

Existing research suggests that self-injurious behavior (SIB) is a relatively common interfering behavior that can occur across the lifespan of individuals with autism spectrum disorder (ASD). We previously reported that SIB or proto-injurious SIB at 12 months was related to increased risk of SIB at 24 months among a preschool sample of children with a high familial likelihood for ASD (Dimian et al., 2017). In the present study, we extend these findings, examine SIB occurrence, and associated potential risk factors at 36 months. The present sample included 149 infants with an older sibling with ASD (65.8% male) who completed assessments at ages 12, 24, and 36 months. Descriptive analyses and binary logistic regression models were utilized. SIB was more prevalent among those children who received a diagnosis of ASD. Logistic regression indicated that presence of SIB, stereotypy, hyper- and hypo- sensory responsivity, and lower intellectual functioning at age 12 months significantly predicted the occurrence of SIB at 36 months. These findings have implications for understanding developmental processes culminating in persistent SIB and may inform prevention programming.

Lien vers le texte intégral (Open Access ou abonnement)

5. Golse B. The polyfactorial model of autism and the question of causality. Front Psychiatry;2023;14:1117807.

After recalling the different pediatric, psychopathological and child psychiatric models of mental disorders in children and adolescents, the author presents in detail the so-called polyfactorial model, which includes primary, secondary, and mixed factors. This model is the epistemological heir of the Freudian concept of « complementary series. » The example of autism is then explored as a paradigm of the usefulness of this polyfactorial model. Finally, we reflect on the notion of causality, from Aristotelian causality to epigenetic causality, which could 1 day re-legitimize psychoanalysis and the impact of the relationship on genome expression.

Lien vers le texte intégral (Open Access ou abonnement)

6. Green J. Debate: Neurodiversity, autism and healthcare. Child Adolesc Ment Health;2023 (Jul 12)

We are at a time of unparalleled flux in our understanding of what autism is and now to respond to it, including our understanding of the role of clinical services. For any clinician working in the context of child development and child mental health services, the majority experience is probably of overwhelming demand, and then perhaps confusion. Referrals for neurodevelopmental conditions, and particularly autism, have become an increasing proportion of UK CAMHS referrals in recent years-with the consequent lengthening of wait times extending to years, sometimes equivalent to the whole length of a child’s life up until that point. Services are struggling to develop response strategies to meet user frustration, a task not helped by the fact that most interventions in current use have no good evidence of effectiveness. Consequently, a plethora of local approaches and initiatives have developed. In this article I address these clinical and related issues. I discuss current different uses of the term autism, the relation to intellectual disability, and introduce a conceptualisation of autism as emergent and transactional, which is consistent with current developmental and intervention science. This could bridge between neurodiversity and clinical perspectives and implies a framing of early intervention support that has strong clinical trials evidence and provides the basis for a rational and pre-emptive evidenced care pathway, which I describe.

Lien vers le texte intégral (Open Access ou abonnement)

7. Lax E, Do Carmo S, Enuka Y, Sapozhnikov DM, Welikovitch LA, Mahmood N, Rabbani SA, Wang L, Britt JP, Hancock WW, Yarden Y, Szyf M. Methyl-CpG binding domain 2 (Mbd2) is an epigenetic regulator of autism-risk genes and cognition. Transl Psychiatry;2023 (Jul 13);13(1):259.

The Methyl-CpG-Binding Domain Protein family has been implicated in neurodevelopmental disorders. The Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity. Some evidence linked this protein to neurodevelopment. However, its exact role in neurodevelopment and brain function is mostly unknown. Here we show that Mbd2-deficiency in mice (Mbd2-/-) results in deficits in cognitive, social and emotional functions. Mbd2 binds regulatory DNA regions of neuronal genes in the hippocampus and loss of Mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal genes in Mbd2-/- mice. Differentially expressed genes significantly overlap with gene-expression changes observed in brains of Autism Spectrum Disorder (ASD) individuals. Notably, downregulated genes are significantly enriched for human ortholog ASD risk genes. Observed hippocampal morphological abnormalities were similar to those found in individuals with ASD and ASD rodent models. Hippocampal Mbd2 knockdown partially recapitulates the behavioral phenotypes observed in Mbd2-/- mice. These findings suggest that Mbd2 is a novel epigenetic regulator of genes that are associated with ASD in humans. Mbd2 loss causes behavioral alterations that resemble those found in ASD individuals.

Lien vers le texte intégral (Open Access ou abonnement)

8. Luo Y, Lv K, Du Z, Zhang D, Chen M, Luo J, Wang L, Liu T, Gong H, Fan X. Minocycline improves autism-related behaviors by modulating microglia polarization in a mouse model of autism. Int Immunopharmacol;2023 (Jul 11);122:110594.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with few pharmacological treatments. Minocycline, a tetracycline derivative that inhibits microglial activation, has been well-identified with anti-inflammatory properties and neuroprotective effects. A growing body of research suggests that ASD is associated with neuroinflammation, abnormal neurotransmitter levels, and neurogenesis. Thus, we hypothesized that minocycline could improve autism-related behaviors by inhibiting microglia activation and altering neuroinflammation. To verify our hypothesis, we used a mouse model of autism, BTBR T + Itpr3tf/J (BTBR). As expected, minocycline administration rescued the sociability and repetitive, stereotyped behaviors of BTBR mice while having no effect in C57BL/6J mice. We also found that minocycline improved neurogenesis and inhibited microglia activation in the hippocampus of BTBR mice. In addition, minocycline treatment inhibited Erk1/2 phosphorylation in the hippocampus of BTBR mice. Our findings show that minocycline administration alleviates ASD-like behaviors in BTBR mice and improves neurogenesis, suggesting that minocycline supplementation might be a potential strategy for improving ASD symptoms.

Lien vers le texte intégral (Open Access ou abonnement)

9. Madigand J, Rio M, Vandevelde A. Equine assisted services impact on social skills in autism spectrum disorder: A meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry;2023 (Jul 13);125:110765.

Many studies focus on the impact of equine assisted services (EAS) on social skills in autism spectrum disorder (ASD) but existing data are not consensual and the only available meta-analysis included only three studies and did not consider the social responsiveness scale (SRS). This meta-analysis aims to measure the impact of EAS on social skills in ASD. Using Pubmed, Embase, Web of Science and the Cochrane Library, the means and standard deviations of every available SRS post-intervention scores in each participant group were collected from the five selected randomised controlled trials with 240 participants. An EAS significant beneficial impact was found for the total SRS score, social communication and social cognition. A tendency to a significant impact was found for social awareness and social motivation. No significant difference was shown for autistic mannerisms. This meta-analysis shows a significant beneficial impact of EAS for several social skills in ASD. Further randomised controlled trials are required to complement these results and expand the knowledge on the field of possibilities of this care in ASD.

Lien vers le texte intégral (Open Access ou abonnement)

10. Marek S, Forbes G, Avery RA, Zanganeh T, Davidson S, DeCarlo E, Kumar P, Hammersmith K. Potential blindness from nutritional xerophthalmia in autistic patients. J aapos;2023 (Jul 13)

BACKGROUND: Vitamin A is vital to retinal rod function and epithelial cell differentiation. Although uncommon in the developed world, vitamin A deficiency (VAD) secondary to poor diets or gastrointestinal disease has been reported and can lead to xerophthalmia, which is characterized by night blindness and a spectrum of ocular surface changes. Patients with autism spectrum disorder have been shown to have restrictive diets secondary to sensory issues leading to rejection of foods except for those of certain color or texture. METHODS: We present a case series of 6 pediatric patients with autism who developed varying degrees of xerophthalmia due to VAD, which resulted from restrictive eating. RESULTS: All patients presented with a history of eye irritation that was not relieved by antibiotic or allergy eye drops. Further questioning revealed they had restrictive diets consisting of only or mostly white and tan foods, and serum vitamin A testing confirmed severe VAD. Most stages of xerophthalmia were completely reversed with vitamin A supplementation, but in 2 patients more advanced xerophthalmia resulted in irreversible blindness and ocular damage. CONCLUSIONS: Both pediatricians and pediatric eye care providers must be vigilant for VAD as an etiology of eye irritation, photophobia, or new-onset visual impairment in autistic children. A review of the child’s diet must be implemented as a standard part of routine history taken in this vulnerable population. Early identification and vitamin A supplementation can prevent irreversible ocular compromise and vision loss.

Lien vers le texte intégral (Open Access ou abonnement)

11. Molloy CJ, Cooke J, Gatford NJF, Rivera-Olvera A, Avazzadeh S, Homberg JR, Grandjean J, Fernandes C, Shen S, Loth E, Srivastava DP, Gallagher L. Bridging the translational gap: what can synaptopathies tell us about autism?. Front Mol Neurosci;2023;16:1191323.

Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved in synaptic biology. Synaptopathies are commonly associated with autism and developmental delay and may be associated with a range of other neuropsychiatric outcomes. Altered synaptic biology is suggested by both preclinical and clinical studies in autism based on evidence of differences in early brain structural development and altered glutamatergic and GABAergic neurotransmission potentially perturbing excitatory and inhibitory balance. This review focusses on the NRXN-NLGN-SHANK pathway, which is implicated in the synaptic assembly, trans-synaptic signalling, and synaptic functioning. We provide an overview of the insights from preclinical molecular studies of the pathway. Concentrating on NRXN1 deletion and SHANK3 mutations, we discuss emerging understanding of cellular processes and electrophysiology from induced pluripotent stem cells (iPSC) models derived from individuals with synaptopathies, neuroimaging and behavioural findings in animal models of Nrxn1 and Shank3 synaptic gene conditions, and key findings regarding autism features, brain and behavioural phenotypes from human clinical studies of synaptopathies. The identification of molecular-based biomarkers from preclinical models aims to advance the development of targeted therapeutic treatments. However, it remains challenging to translate preclinical animal models and iPSC studies to interpret human brain development and autism features. We discuss the existing challenges in preclinical and clinical synaptopathy research, and potential solutions to align methodologies across preclinical and clinical research. Bridging the translational gap between preclinical and clinical studies will be necessary to understand biological mechanisms, to identify targeted therapies, and ultimately to progress towards personalised approaches for complex neurodevelopmental conditions such as autism.

Lien vers le texte intégral (Open Access ou abonnement)

12. Moshe S, Oppenheim D, Slonim M, Hamburger L, Maccabi Y, Yirmiya N. Positive and challenging themes in parents’ perceptions of their relationships with their child with autism: Comparison between mothers and fathers. Autism;2023 (Jul 13):13623613231182513.

Most studies of how parents of children with autism see the parent-child relationship used questionnaires completed by the parents and focused on challenges. This study broadened the lens by interviewing parents using open-ended questions that provide an opportunity to raise challenging but also positive experiences. Seventy-five mother-father dyads were interviewed individually about their own and their spouses’ relationships with their preschooler, and we found nine relationship themes. In descending order, the themes mentioned most frequently by mothers were « Security and Closeness, » « Love, » and « Tenderness and Sensitivity, » and by fathers were « Pleasure in Joint Activities, » « Security and Closeness, » and « Guidance. » Positive themes were more common than challenging themes. Finally, more mothers mentioned the themes « Love, » « Tenderness and Sensitivity, » « High Involvement and Care, » and « Difficulties » than did fathers, whereas more fathers mentioned the themes « Guidance » and « Pleasure in Joint Activities » than did mothers. The findings portray a nuanced view of the parenting experience of mothers and fathers of preschoolers with autism.

Lien vers le texte intégral (Open Access ou abonnement)

13. Radhoe TA, Agelink van Rentergem JA, Torenvliet C, Groenman AP, van der Putten WJ, Geurts HM. Finding Similarities in Differences Between Autistic Adults: Two Replicated Subgroups. J Autism Dev Disord;2023 (Jul 12)

Autism is heterogeneous, which complicates providing tailored support and future prospects. We aim to identify subgroups in autistic adults with average to high intelligence, to clarify if certain subgroups might need support. We included 14 questionnaire variables related to aging and/or autism (e.g., demographic, psychological, and lifestyle). Community detection analysis was used for subgroup identification in an original sample of 114 autistic adults with an adulthood diagnosis (autism) and 58 non-autistic adults as comparison group (COMP), and a replication sample (N(Autism) = 261; N(COMP) = 287), both aged 30-89 years. Next, we identified subgroups and assessed external validity (for cognitive and psychological difficulties, and quality of life [QoL]) in the autism samples. To test specificity, we repeated the analysis after adding 123 adults with ADHD, aged 30-80 years. As expected, the autism and COMP groups formed distinct subgroups. Among autistic adults, we identified three subgroups of which two were replicated. One of these subgroups seemed most vulnerable on the cluster variables; this subgroup also reported the most cognitive and psychological difficulties, and lowest QoL. Adding the ADHD group did not alter results. Within autistic adults, one subgroup could especially benefit from support and specialized care, although this must be tested in future studies.

Lien vers le texte intégral (Open Access ou abonnement)

14. Ross MM, Aizenman E. GluA1-Shank3 interaction decreases in response to chronic neuronal depolarization. Neurosci Lett;2023 (Jul 13);809:137305.

Interactions between AMPA receptors and synaptic scaffolding proteins are key regulators of synaptic receptor density and, thereby, synapse strength. Shank3 is one such scaffolding protein with high clinical relevance, as genetic variants and deletions of this protein have been linked to autism spectrum disorder. Shank3 acts as a master regulator of the postsynaptic density of glutamatergic synapses, interacting with ionotropic and metabotropic glutamate receptors and cytoskeletal elements to modulate synaptic structure. Notably, Shank3 has been shown to interact directly with the AMPAR subunit GluA1, and Shank3 knockout animals show deficits in AMPAR-mediated synaptic transmission. In this study, we sought to characterize the stability of GluA1-Shank3 interaction in response to chronic stimuli using a highly sensitive and specific proximity ligation assay. We found that GluA1-Shank3 interactions decrease in response to prolonged neuronal depolarization induced by elevated extracellular potassium, and that this reduced interaction is blocked by NMDA receptor antagonism. These results firmly establish the close interaction of GluA1 and Shank3 in cortical neurons in vitro, and that this select interaction is subject to modulation by depolarization.

Lien vers le texte intégral (Open Access ou abonnement)

15. Sacrey LR, Zwaigenbaum L, Elshamy Y, Smith IM, Brian JA, Wass S. Comparative strengths and challenges on face-to-face and computer-based attention tasks in autistic and neurotypical toddlers. Autism Res;2023 (Jul 13)

The objectives were to compare patterns of visual attention in toddlers diagnosed with autism spectrum disorder (ASD) as compared to their sex- and age-matched neurotypical (NT) peers. Participants included 23 toddlers with ASD and 19 NT toddlers (mean age: 25.52 versus 25.21 months, respectively) assessed using computerized tasks to measure sustained attention, disengaging attention, and cognitive control, as well as an in-person task to assess joint attention. Toddlers in the ASD group showed increased looking durations on the sustained attention task, as well as reduced frequencies of responding to and initiating joint attention compared to NT peers, but showed no differences on tasks of disengaging attention and cognitive control. The results suggest that toddlers with ASD have attentional strengths that may provide a foundation for building attention, communicative, and ultimately, academic skills.

Lien vers le texte intégral (Open Access ou abonnement)

16. Schenkelberg MA, Clarke EC, Wasser H, Ward DS, Essenmacher MM, Thompson KL, Willis EA. A call for obesity prevention interventions for young children with intellectual and developmental disabilities. Transl Behav Med;2023 (Jul 13)

Health disparities among children with intellectual and developmental disabilities (IDD) are present in early childhood. Yet, this population is underrepresented in health behavior research. In this commentary the authors highlight the need for multi-level physical activity and nutrition research for obesity prevention with a specific focus on young children with Down syndrome, a population at greater risk of developing overweight and obesity compared to typically developing peers. This commentary describes the comorbidities and developmental challenges faced by many children with Down syndrome which may influence weight-related physical activity and nutrition behaviors. Additionally, the authors advocate for involving a multidisciplinary team of experts to inform the adaptation or development of multi-level, theory-driven behavioral interventions to prevent obesity among children with Down syndrome. eng

Lien vers le texte intégral (Open Access ou abonnement)

17. Sener EF, Dana H, Tahtasakal R, Hamurcu Z, Taheri S, Delibasi N, Mehmetbeyoglu E, Sukranli ZY, Dal F, Tufan E, Oflamaz AO, Doganyigit Z, Ozkul Y, Rassoulzadegan M. Heterozygous Cc2d1a mice show sex-dependent changes in the Beclin-1/p62 ratio with impaired prefrontal cortex and hippocampal autophagy. Prog Neuropsychopharmacol Biol Psychiatry;2023 (Jul 13);125:110764.

Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders characterized by repetitive behaviors, lack of social interaction and communication. CC2D1A is identified in patients as an autism risk gene. Recently, we suggested that heterozygous Cc2d1a mice exhibit impaired autophagy in the hippocampus. We now report the analysis of autophagy markers (Lc3, Beclin and p62) in different regions hippocampus, prefrontal cortex, hypothalamus and cerebellum, with an overall decrease in autophagy and changes in Beclin-1/p62 ratio in the hippocampus. We observed sex-dependent variations in transcripts and protein expression levels. Moreover, our analyses suggest that alterations in autophagy initiated in Cc2d1a heterozygous parents are variably transmitted to offspring, even when the offspring’s genotype is wild type. Aberration in the autophagy mechanism may indirectly contribute to induce synapse alteration in the ASD brain.

Lien vers le texte intégral (Open Access ou abonnement)

18. Shankar VG, Klann E. Size matters: Fighting repeat expansion size in fragile X syndrome using antisense oligonucleotides. Proc Natl Acad Sci U S A;2023 (Jul 25);120(30):e2309678120.

Lien vers le texte intégral (Open Access ou abonnement)

19. Tataru C, Peras M, Rutherford E, Dunlap K, Yin X, Chrisman BS, DeSantis TZ, Wall DP, Iwai S, David MM. Topic modeling for multi-omic integration in the human gut microbiome and implications for Autism. Sci Rep;2023 (Jul 13);13(1):11353.

While healthy gut microbiomes are critical to human health, pertinent microbial processes remain largely undefined, partially due to differential bias among profiling techniques. By simultaneously integrating multiple profiling methods, multi-omic analysis can define generalizable microbial processes, and is especially useful in understanding complex conditions such as Autism. Challenges with integrating heterogeneous data produced by multiple profiling methods can be overcome using Latent Dirichlet Allocation (LDA), a promising natural language processing technique that identifies topics in heterogeneous documents. In this study, we apply LDA to multi-omic microbial data (16S rRNA amplicon, shotgun metagenomic, shotgun metatranscriptomic, and untargeted metabolomic profiling) from the stool of 81 children with and without Autism. We identify topics, or microbial processes, that summarize complex phenomena occurring within gut microbial communities. We then subset stool samples by topic distribution, and identify metabolites, specifically neurotransmitter precursors and fatty acid derivatives, that differ significantly between children with and without Autism. We identify clusters of topics, deemed « cross-omic topics », which we hypothesize are representative of generalizable microbial processes observable regardless of profiling method. Interpreting topics, we find each represents a particular diet, and we heuristically label each cross-omic topic as: healthy/general function, age-associated function, transcriptional regulation, and opportunistic pathogenesis.

Lien vers le texte intégral (Open Access ou abonnement)

20. Tsompanidis A, Blanken L, Broere-Brown ZA, van Rijn BB, Baron-Cohen S, Tiemeier H. Sex differences in placenta-derived markers and later autistic traits in children. Transl Psychiatry;2023 (Jul 13);13(1):256.

Autism is more prevalent in males and males on average score higher on measures of autistic traits. Placental function is affected significantly by the sex of the fetus. It is unclear if sex differences in placental function are associated with sex differences in the occurrence of autistic traits postnatally. To assess this, concentrations of angiogenesis-related markers, placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) were assessed in maternal plasma of expectant women in the late 1(st) (mean= 13.5 [SD = 2.0] weeks gestation) and 2(nd) trimesters (mean=20.6 [SD = 1.2] weeks gestation), as part of the Generation R Study, Rotterdam, the Netherlands. Subsequent assessment of autistic traits in the offspring at age 6 was performed with the 18-item version of the Social Responsiveness Scale (SRS). Associations of placental protein concentrations with autistic traits were tested in sex-stratified and cohort-wide regression models. Cases with pregnancy complications or a later autism diagnosis (n = 64) were also assessed for differences in placenta-derived markers. sFlt-1 levels were significantly lower in males in both trimesters but showed no association with autistic traits. PlGF was significantly lower in male pregnancies in the 1(st) trimester, and significantly higher in the 2(nd) trimester, compared to female pregnancies. Higher PlGF levels in the 2(nd) trimester and the rate of PlGF increase were both associated with the occurrence of higher autistic traits (PlGF-2(nd): n = 3469,b = 0.24 [SE = 0.11], p = 0.03) in both unadjusted and adjusted linear regression models that controlled for age, sex, placental weight and maternal characteristics. Mediation analyses showed that higher autistic traits in males compared to females were partly explained by higher PlGF or a faster rate of PlGF increase in the second trimester (PlGF-2(nd): n = 3469, ACME: b = 0.005, [SE = 0.002], p = 0.004). In conclusion, higher PlGF levels in the 2(nd) trimester and a higher rate of PlGF increase are associated with both being male, and with a higher number of autistic traits in the general population.

Lien vers le texte intégral (Open Access ou abonnement)

21. Watanabe D, Watanabe T. Distinct Frontoparietal Brain Dynamics Underlying the Co-Occurrence of Autism and ADHD. eNeuro;2023 (Jul);10(7)

Previous diagnostic systems precluded the co-existence of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in one person; but, after many clinical reports, the diagnostic criteria were updated to allow their co-occurrence. Despite such a clinical change, the neurobiological bases underpinning the comorbidity remain poorly understood, and whether the ASD+ADHD condition is a simple overlap of the two disorders is unknown. Here, to answer this question, we compared the brain dynamics of high-functioning ASD+ADHD children with age-/sex-/IQ-matched pure ASD, pure ADHD, and typically developing (TD) children. Regarding autistic traits, the socio-communicational symptom of the ASD+ADHD children was explained by the same overstable brain dynamics as seen in pure ASD. In contrast, their ADHD-like traits were grounded on a unique neural mechanism that was unseen in pure ADHD: the core symptoms of pure ADHD were associated with the overly flexible whole-brain dynamics that were triggered by the unstable activity of the dorsal-attention network and the left parietal cortex; by contrast, the ADHD-like cognitive instability of the ASD+ADHD condition was correlated with the atypically frequent neural transition along a specific brain state pathway, which was induced by the atypically unstable activity of the frontoparietal control network and the left prefrontal cortex. These observations need to be validated in future studies using more direct and comprehensive behavioral indices, but the current findings suggest that the ASD+ADHD comorbidity is not a mere overlap of the two disorders. Particularly, its ADHD-like traits could represent a unique condition that would need a specific diagnosis and bespoke treatments.

Lien vers le texte intégral (Open Access ou abonnement)

22. Wei R, Yehia L, Ni Y, Eng C. The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome. HGG Adv;2023 (Jul 13);4(3):100199.

Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS). Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus cancer in PHTS. Recently, we showed copy number variations to be associated with ASD/DD versus cancer in these PHTS individuals. We also found that mitochondrial complex II variants occurring in 10% of PHTS individuals modify breast cancer risk and thyroid cancer histology. These studies suggest that mitochondrial pathways could act as important factors in PHTS phenotype development. However, the mitochondrial genome (mtDNA) has never been systematically studied in PHTS. We therefore investigated the mtDNA landscape extracted from whole-genome sequencing data from 498 PHTS individuals, including 164 with ASD/DD (PHTS-onlyASD/DD), 184 with cancer (PHTS-onlyCancer), 132 with neither ASD/DD nor cancer (PHTS-neither), and 18 with both ASD/DD and cancer (PHTS-ASDCancer). We demonstrate that PHTS-onlyASD/DD has significantly higher mtDNA copy number than PHTS-onlyCancer group (p = 9.2 × 10(-3) in all samples; p = 4.2 × 10(-3) in the H haplogroup). PHTS-neither group has significantly higher mtDNA variant burden than PHTS-ASDCancer group (p = 4.6 × 10(-2)); the PHTS-noCancer group (PHTS-onlyASD/DD and PHTS-neither groups) also shows higher variant burden than the PHTS-Cancer group (PHTS-onlyCancer and PHTS-ASD/Cancer groups; p = 3.3 × 10(-2)). Our study implicates the mtDNA as a modifier of ASD/DD versus cancer phenotype development in PHTS.

Lien vers le texte intégral (Open Access ou abonnement)

23. Yuan B, Luo L, Hu C, Lin F, Yang T, Chen J, Li T. Retinoic acid supplementation ameliorates motor incoordination via RARα-CBLN2 in the cerebellum of a prenatal valproic acid-exposed rat autism model. Neurosci Lett;2023 (Jul 13);809:137316.

In addition to their core symptoms, most individuals with autism spectrum disorder (ASD) also experience motor impairments. These impairments are often linked to the cerebellum, which is the focus of the current study. Herein, we utilized a prenatal valproic acid (VPA)-induced rat model of autism and performed RNA sequencing in the cerebellum. Relative to control animals, the VPA-treated offspring demonstrated both abnormal motor coordination and impaired dendritic arborization of Purkinje cells (PCs). Concurrently, we observed a decrease in the cerebellar expression of retinoic acid (RA) synthesis enzymes (RDH10, ALDH1A1), metabolic enzyme (CYP26A2), and lower levels of RA, retinoic acid receptor α (RARα), and Cerebellin2 (CBLN2) in the VPA-treated offspring. However, RA supplementation ameliorated these deficits, restoring motor coordination, normalizing PCs dendritic arborization, and increasing the expression of RA, RARα, and CBLN2. Further, ChIP assays confirmed that RA supplementation enhanced RARα’s binding capacity to CBLN2 promoters. Collectively, these findings highlight the therapeutic potential of RA for treating motor incoordination in VPA-induced autism, acting through the RARα-CBLN2 pathway.

Lien vers le texte intégral (Open Access ou abonnement)

24. Zablotsky B, Ng AE, Black LI, Blumberg SJ. Diagnosed Developmental Disabilities in Children Aged 3-17 Years: United States, 2019-2021. NCHS Data Brief;2023 (Jul)(473):1-8.

Developmental disabilities are common in children in the United States, and the prevalence has increased in recent years (1). Timely estimates are necessary to assess the adequacy of services and interventions that children with developmental disabilities typically need (2). This report provides updated prevalence estimates for diagnosed autism spectrum disorder, intellectual disability, and other developmental delay among children aged 3-17 years from the 2019-2021 National Health Interview Survey (NHIS), with differences in prevalence examined between years and by sex, age group, and race and Hispanic origin. Estimates are also presented for any developmental disability, defined as having had one or more of these three diagnoses.

Lien vers le texte intégral (Open Access ou abonnement)

25. Zuffa S, Schimmel P, Gonzalez-Santana A, Belzer C, Knol J, Bölte S, Falck-Ytter T, Forssberg H, Swann J, Diaz Heijtz R. Early-life differences in the gut microbiota composition and functionality of infants at elevated likelihood of developing autism spectrum disorder. Transl Psychiatry;2023 (Jul 13);13(1):257.

Evidence from cross-sectional human studies, and preliminary microbial-based intervention studies, have implicated the microbiota-gut-brain axis in the neurobiology of autism spectrum disorder (ASD). Using a prospective longitudinal study design, we investigated the developmental profile of the fecal microbiota and metabolome in infants with (n = 16) and without (n = 19) a family history of ASD across the first 36 months of life. In addition, the general developmental levels of infants were evaluated using the Mullen Scales of Early Learning (MSEL) test at 5 and 36 months of age, and with ADOS-2 at 36 months of age. At 5 months of age, infants at elevated-likelihood of ASD (EL) harbored less Bifidobacterium and more Clostridium and Klebsiella species compared to the low-likelihood infants (LL). Untargeted metabolic profiling highlighted that LL infants excreted a greater amount of fecal γ-aminobutyric acid (GABA) at 5 months, which progressively declined with age. Similar age-dependent patterns were not observed in the EL group, with GABA being consistently low across all timepoints. Integrated microbiome-metabolome analysis showed a positive correlation between GABA and Bifidobacterium species and negative associations with Clostridium species. In vitro experiments supported these observations demonstrating that bifidobacteria can produce GABA while clostridia can consume it. At the behavioral level, there were no significant differences between the EL and LL groups at 5 months. However, at 36 months of age, the EL group had significantly lower MSEL and ADOS-2 scores compared to the LL group. Taken together, the present results reveal early life alterations in gut microbiota composition and functionality in infants at elevated-likelihood of ASD. These changes occur before any behavioral impairments can be detected, supporting a possible role for the gut microbiota in emerging behavioral variability later in life.

Lien vers le texte intégral (Open Access ou abonnement)