1. Carmona-Serrano N, Moreno-Guerrero AJ, Marín-Marín JA, López-Belmonte J. Evolution of the Autism Literature and the Influence of Parents : A Scientific Mapping in Web of Science. Brain Sci ;2021 (Jan 8) ;11(1)

Parents interventions are relevant to address autism spectrum disorder (ASD). The objective of this study is to analyze the importance and evolution of ASD and its relationship with the parents (ASD-PAR) in the publications indexed in Web of Science. For this, a bibliometric methodology has been used, based on a scientific mapping of the reported documents. We have worked with an analysis unit of 1381 documents. The results show that the beginnings of scientific production date back to 1971. There are two clearly differentiated moments in scientific production. A first moment (1971-2004), where the production volume is low. A second moment (2005-2019), where the volume of production increases considerably. Therefore, it can be said that the subject began to be relevant for the scientific community from 2005 to the present. The keyword match rate between set periods marks a high level of match between periods. It is concluded that the main focus of the research on ASD-PAR is on the stress that is generated in families with children with ASD, in addition to the family problems that the fact that these children also have behavior problems can cause.

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2. Chen L, Shi XJ, Liu H, Mao X, Gui LN, Wang H, Cheng Y. Oxidative stress marker aberrations in children with autism spectrum disorder : a systematic review and meta-analysis of 87 studies (N = 9109). Transl Psychiatry ;2021 (Jan 5) ;11(1):15.

There is increasing awareness that oxidative stress may be implicated in the pathophysiology of autism spectrum disorder (ASD). Here we aimed to investigate blood oxidative stress marker profile in ASD children by a meta-analysis. Two independent investigators systematically searched Web of Science, PubMed, and Cochrane Library and extracted data from 87 studies with 4928 ASD children and 4181 healthy control (HC) children. The meta-analysis showed that blood concentrations of oxidative glutathione (GSSG), malondialdehyde, homocysteine, S-adenosylhomocysteine, nitric oxide, and copper were higher in children with ASD than that of HC children. In contrast, blood reduced glutathione (GSH), total glutathione (tGSH), GSH/GSSG, tGSH/GSSG, methionine, cysteine, vitamin B9, vitamin D, vitamin B12, vitamin E, S-adenosylmethionine/S-adenosylhomocysteine, and calcium concentrations were significantly reduced in children with ASD relative to HC children. However, there were no significance differences between ASD children and HC children for the other 17 potential markers. Heterogeneities among studies were found for most markers, and meta-regressions indicated that age and publication year may influence the meta-analysis results. These results therefore clarified blood oxidative stress profile in children with ASD, strengthening clinical evidence of increased oxidative stress implicating in pathogenesis of ASD. Additionally, given the consistent and large effective size, glutathione metabolism biomarkers have the potential to inform early diagnosis of ASD.

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3. Choi B, Shah P, Rowe ML, Nelson CA, Tager-Flusberg H. A Longitudinal Study of Parent Gestures, Infant Responsiveness, and Vocabulary Development in Infants at Risk for Autism Spectrum Disorder. J Autism Dev Disord ;2021 (Jan 8)

We investigated gestures that parents used with 12-, 18-, and 24-month-old infants at high or low risk for autism spectrum disorder (ASD ; high-risk diagnosed with ASD : n = 21 ; high-risk classified as no ASD : n = 34 ; low-risk classified as no ASD : n = 34). We also examined infant responses to parent gestures and assessed the extent to which parent gesture relates to vocabulary development. Parents of three groups gestured in similar frequencies and proportions. Infants, in turn, responded similarly to parent gestures regardless of the infant’s ASD risk and later diagnosis. Finally, parents who gestured more at 12 months had children with better vocabulary at 36 months than parents who gestured less. These findings highlight the importance of examining parent gestures when predicting language development.

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4. Corona LL, Wagner L, Wade J, Weitlauf AS, Hine J, Nicholson A, Stone C, Vehorn A, Warren Z. Toward Novel Tools for Autism Identification : Fusing Computational and Clinical Expertise. J Autism Dev Disord ;2021 (Jan 8):1-10.

Barriers to identifying autism spectrum disorder (ASD) in young children in a timely manner have led to calls for novel screening and assessment strategies. Combining computational methods with clinical expertise presents an opportunity for identifying patterns within large clinical datasets that can inform new assessment paradigms. The present study describes an analytic approach used to identify key features predictive of ASD in young children, drawn from large amounts of data from comprehensive diagnostic evaluations. A team of expert clinicians used these predictive features to design a set of assessment activities allowing for observation of these core behaviors. The resulting brief assessment underlies several novel approaches to the identification of ASD that are the focus of ongoing research.

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5. Dahiya AV, DeLucia E, McDonnell CG, Scarpa A. A systematic review of technological approaches for autism spectrum disorder assessment in children : Implications for the COVID-19 pandemic. Res Dev Disabil ;2021 (Jan 8) ;109:103852.

BACKGROUND : Screening and diagnostic assessments tools for autism spectrum disorder (ASD) are important to administer during childhood to facilitate timely entry into intervention services that can promote developmental outcomes across the lifespan. However, assessment services are not always readily available to families, as they require significant time and resources. Currently, in-person screening and diagnostic assessments for ASD are limited due to the COVID-19 pandemic and will continue to be a concern for situations that limit in-person contact. Thus, it is important to expand the modalities in which child assessments are provided, including the use of technology. AIMS : This systematic review aims to identify technologies that screen or assess for ASD in 0-12 year-old children, summarizing the current state of the field and suggesting future directions. METHODS : An electronic database search was conducted to gather relevant articles to synthesize for this review. OUTCOMES AND RESULTS : 16 studies reported use of novel technology to assess children suspected of ASD. CONCLUSIONS AND IMPLICATIONS : Results strongly supported live-video evaluations, video observations, and online or phone methods, but there is a need for research targeting the feasibility of these methods as it applies to the stay-at-home orders required by the pandemic, and other situations that limit clients from seeing providers in-person.

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6. Del Giudice T, Dose C, Görtz-Dorten A, Steiner J, Bruning N, Bell H, Roland P, Walter D, Junghänel M, Döpfner M. Dimensions of Autistic Traits Rated by Parents of Children and Adolescents with Suspected Autism Spectrum Disorders. J Autism Dev Disord ;2021 (Jan 8)

To examine the factor structure of autism spectrum disorder (ASD) and the psychometric properties of the German Symptom Checklist for Autism Spectrum Disorders (SCL-ASD). Data were collected from 312 clinical referrals with suspected ASD (2-18 years). Confirmatory factor analyses and analyses of reliability, convergent and divergent validity were performed. A bifactor model with one general ASD factor and two specific factors (interaction-communication ; restricted, repetitive behaviors) provided an adequate data fit. Internal consistencies of the SCL-ASD subscales and the total scale were > .70. Correlations with measures of ASD traits were higher than correlations with measures of externalizing and internalizing symptoms. The results support a factor structure consistent with DSM-5/ICD-11 criteria. The SCL-ASD has sound psychometric properties.

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7. Di Lorenzo G, Riccioni A, Ribolsi M, Siracusano M, Curatolo P, Mazzone L. Auditory Mismatch Negativity in Youth Affected by Autism Spectrum Disorder With and Without Attenuated Psychosis Syndrome. Front Psychiatry ;2020 ;11:555340.

The present study investigates the differences in auditory mismatch negativity (MMN) parameters given in a sample of young subjects with autism spectrum disorder (ASD, n = 37) with or without co-occurrent attenuated psychosis syndrome (APS). Our results show that ASD individuals present an MMN decreased amplitude and prolonged latency, without being influenced by concurrent APS. Additionally, when correlating the MMN indexes to clinical features, in the ASD + APS group, we found a negative correlation between the severity of autistic symptoms and the MMN latency in both frequency (f-MMN r = -0.810 ; p < 0.0001) and duration (d-MMN r = -0.650 ; p = 0.006) deviants. Thus, our results may provide a more informative characterization of the ASD sub-phenotype when associated with APS, highlighting the need for further longitudinal investigations.

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8. Garrido N, Cruz F, Egea RR, Simon C, Sadler-Riggleman I, Beck D, Nilsson E, Ben Maamar M, Skinner MK. Sperm DNA methylation epimutation biomarker for paternal offspring autism susceptibility. Clin Epigenetics ;2021 (Jan 7) ;13(1):6.

BACKGROUND : Autism spectrum disorder (ASD) has increased over tenfold over the past several decades and appears predominantly associated with paternal transmission. Although genetics is anticipated to be a component of ASD etiology, environmental epigenetics is now also thought to be an important factor. Epigenetic alterations, such as DNA methylation, have been correlated with ASD. The current study was designed to identify a DNA methylation signature in sperm as a potential biomarker to identify paternal offspring autism susceptibility. METHODS AND RESULTS : Sperm samples were obtained from fathers that have children with or without autism, and the sperm then assessed for alterations in DNA methylation. A genome-wide analysis (> 90%) for differential DNA methylation regions (DMRs) was used to identify DMRs in the sperm of fathers (n = 13) with autistic children in comparison with those (n = 13) without ASD children. The 805 DMR genomic features such as chromosomal location, CpG density and length of the DMRs were characterized. Genes associated with the DMRs were identified and found to be linked to previously known ASD genes, as well as other neurobiology-related genes. The potential sperm DMR biomarkers/diagnostic was validated with blinded test sets (n = 8-10) of individuals with an approximately 90% accuracy. CONCLUSIONS : Observations demonstrate a highly significant set of 805 DMRs in sperm that can potentially act as a biomarker for paternal offspring autism susceptibility. Ancestral or early-life paternal exposures that alter germline epigenetics are anticipated to be a molecular component of ASD etiology.

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9. Haggerty DK, Strakovsky RS, Talge NM, Carignan CC, Glazier-Essalmi AN, Ingersoll BR, Karthikraj R, Kannan K, Paneth NS, Ruden DM. Prenatal phthalate exposures and autism spectrum disorder symptoms in low-risk children. Neurotoxicol Teratol ;2021 (Jan-Feb) ;83:106947.

BACKGROUND : Prenatal exposure to environmental chemicals has been associated with Autism Spectrum Disorder (ASD) symptoms in some, but not all, studies, but most research has not accounted for other childhood behavior problems. OBJECTIVES : To evaluate the specific associations of prenatal phthalate exposures with ASD symptoms in children (ages 3-6) accounting for other behavior problems, and to assess sex differences in these associations. METHODS : We measured phthalate metabolites in prenatal urine samples. Mothers completed the Social Responsiveness Scale-2nd edition (SRS-2) to assess child ASD symptoms and the Child Behavior Checklist (CBCL) to assess general behavior problems. We assessed associations of the sum of di-(2-ethylhexyl) phthalate metabolites, monobutyl phthalate, mono-isobutyl phthalate, and monoethyl phthalate (mEP) with ASD symptoms, adjusting for other behavior problems, using linear regression models (n=77). RESULTS : Most associations were null, and the sample size limited power to detect associations, particularly in the stratified analyses. After adjusting for internalizing and externalizing problems from the CBCL, ASD symptoms increased for each doubling of prenatal mEP concentration among boys only. CONCLUSIONS : Further investigation of maternal prenatal urinary phthalate metabolite concentrations and ASD symptoms while adjusting for other behavioral problems is warranted.

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10. Im DS. Treatment of Aggression in Adults with Autism Spectrum Disorder : A Review. Harv Rev Psychiatry ;2021 (Jan-Feb 01) ;29(1):35-80.

BACKGROUND : Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by markedly impaired social interaction, impaired communication, and restricted/repetitive patterns of behavior, interests, and activities. In addition to challenges caused by core symptoms, maladaptive behaviors such as aggression can be associated with ASD and can further disrupt functioning and quality of life. For adults with ASD, these behaviors can portend adverse outcomes (e.g., harm to others or to the individual with ASD, hindering of employment opportunities, criminal justice system involvement). This article reviews the scientific literature to provide an update on evidence-based interventions for aggression in adults with ASD. METHOD : A search of the electronic databases CINAHL, EMBASE, and PsycINFO was conducted using relevant search terms. After reviewing titles, abstracts, full-length articles, and reference lists, 70 articles were identified and reviewed. RESULTS : The strongest (controlled trial) evidence suggests beneficial effects of risperidone, propranolol, fluvoxamine, vigorous aerobic exercise, and dextromethorphan/quinidine for treating aggression in adults with ASD, with lower levels of evidence supporting behavioral interventions, multisensory environments, yokukansan, and other treatments. CONCLUSIONS : Additional randomized, controlled trials using consistent methodology that adequately addresses sources of bias are needed to determine which treatments are reliably effective in addressing aggression in adults with ASD. In the meantime, considering efficacy and adverse effect/long-term risk profiles, a practical approach could start with functional assessment-informed behavioral interventions along with encouragement of regular, vigorous aerobic exercise to target aggression in adults with ASD, with pharmacotherapy employed if these interventions are unavailable or inadequate based on symptom acuity.

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11. Kovarski K, Charpentier J, Roux S, Batty M, Houy-Durand E, Gomot M. Emotional visual mismatch negativity : a joint investigation of social and non-social dimensions in adults with autism. Transl Psychiatry ;2021 (Jan 5) ;11(1):10.

Unusual behaviors and brain activity to socio-emotional stimuli have been reported in Autism Spectrum Disorder (ASD). Atypical reactivity to change and intolerance of uncertainty are also present, but little is known on their possible impact on facial expression processing in autism. The visual mismatch negativity (vMMN) is an electrophysiological response automatically elicited by changing events such as deviant emotional faces presented among regular neutral faces. While vMMN has been found altered in ASD in response to low-level changes in simple stimuli, no study has investigated this response to visual social stimuli. Here two deviant expressions were presented, neutral and angry, embedded in a sequence of repetitive neutral stimuli. vMMN peak analyses were performed for latency and amplitude in early and late time windows. The ASD group presented smaller amplitude of the late vMMN to both neutral and emotional deviants compared to the typically developed adults (TD) group, and only the TD group presented a sustained activity related to emotional change (i.e., angry deviant). Source reconstruction of the vMMNs further revealed that any change processing elicited a reduced activity in ASD group compared to TD in the saliency network, while the specific processing emotional change elicited activity in the temporal region and in the insula. This study confirms atypical change processing in ASD and points to a specific difficulty in the processing of emotional changes, potentially playing a crucial role in social interaction deficits. Nevertheless, these results require to be further replicated with a greater sample size and generalized to other emotional expressions.

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12. Linehan C, Araten-Bergam T, Baumbusch J, Beadle-Brown J, Bigby C, Birkbeck G, Bradley V, Brown M, Bredewold F, Chirwa M, Cui J, Godoy Gimenez M, Gomiero T, Kanova S, Kroll T, MacLachlan M, Mirfin-Veitch B, Narayan J, Nearchou F, Nolan A, O’Donovan MA, Santos FH, Siska J, Stainton T, Tideman M, Tossebro J. COVID-19 IDD : A global survey exploring family members’ and paid staff’s perceptions of the impact of COVID-19 on individuals with intellectual and developmental disabilities and their caregivers. HRB Open Res ;2020 ;3:39.

Background : This protocol outlines research to explore family members’ and paid staff’s perceptions of the impact of COVID-19 on individuals with intellectual and developmental disabilities and their caregivers. Evidence suggests that people with intellectual and developmental disabilities experience disparities in healthcare access and utilisation. This disparity was evident early in the pandemic when discussions arose regarding the potential exclusion of this population to critical care. Methods : An anonymous online survey will be conducted with caregivers, both family members and paid staff, to explore their perceptions of the impact of COVID-19 in terms of demographics, living arrangements, access to services, social distancing, and carer wellbeing. The survey will be developed by the research team, many of whom are experts in intellectual disability within their own jurisdictions. Using back-translation our team will translate the survey for distribution in 18 countries worldwide for international comparison. The survey team have extensive personal and professional networks and will promote the survey widely on social media with the support of local disability and advocacy agencies. Statistical descriptive and comparative analyses will be conducted. Ethical approval has been obtained for this study from University College Dublin’s Human Research Ethics Committee (HS-20-28-Linehan). Dissemination : Study findings will be prepared in a number of formats in order to meet the needs of different audiences. Outputs will include academic papers, lessons learned paper, practice guidelines, reports, infographics and video content. These outputs will be directed to families, frontline and management delivering disability services, national-level policy makers, healthcare quality and delivery authorities, national pandemic organisations and international bodies.

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13. Liu SH, Shi XJ, Fan FC, Cheng Y. Peripheral blood neurotrophic factor levels in children with autism spectrum disorder : a meta-analysis. Sci Rep ;2021 (Jan 8) ;11(1):15.

Increasing evidence suggests that abnormal regulation of neurotrophic factors is involved in the etiology and pathogenesis of Autism Spectrum Disorder (ASD). However, clinical data on neurotrophic factor levels in children with ASD were inconsistent. Therefore, we performed a systematic review of peripheral blood neurotrophic factors levels in children with ASD, and quantitatively summarized the clinical data of peripheral blood neurotrophic factors in ASD children and healthy controls. A systematic search of PubMed and Web of Science identified 31 studies with 2627 ASD children and 4418 healthy controls to be included in the meta-analysis. The results of random effect meta-analysis showed that the peripheral blood levels of brain-derived neurotrophic factor (Hedges’ g = 0.302 ; 95% CI = 0.014 to 0.591 ; P = 0.040) , nerve growth factor (Hedges’ g = 0.395 ; 95% CI = 0.104 to 0.686 ; P = 0.008) and vascular endothelial growth factor (VEGF) (Hedges’ g = 0.097 ; 95% CI = 0.018 to 0.175 ; P = 0.016) in children with ASD were significantly higher than that of healthy controls, whereas blood neurotrophin-3 (Hedges’ g = – 0.795 ; 95% CI = – 1.723 to 0.134 ; P = 0.093) and neurotrophin-4 (Hedges’ g = 0.182 ; 95% CI = – 0.285 to 0.650 ; P = 0.445) levels did not show significant differences between cases and controls. Taken together, these results clarified circulating neurotrophic factor profile in children with ASD, strengthening clinical evidence of neurotrophic factor aberrations in children with ASD.

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14. Liu Z, Mao X, Dan Z, Pei Y, Xu R, Guo M, Liu K, Zhang F, Chen J, Su C, Zhuang Y, Tang J, Xia Y, Qin L, Hu Z, Liu X. Gene variations in autism spectrum disorder are associated with alteration of gut microbiota, metabolites and cytokines. Gut Microbes ;2021 (Jan-Dec) ;13(1):1-16.

The genetic variations and dysbiosis of gut microbiota are associated with ASD. However, the role of the microbiota in the etiology of ASD in terms of host genetic susceptibility remains unclear. This study aims to systematically explore the interplay between host genetic variation and gut microbiota in ASD children. Whole-exon sequencing was applied to 26 ASD children and 26 matched controls to identify the single nucleotide variations (SNVs) in ASD. Our previous study revealed alteration in gut microbiota and disorder of metabolism activity in ASD for this cohort. Systematic bioinformatic analyses were further performed to identify associations between SNVs and gut microbiota, as well as their metabolites. The ASD SNVs were significantly enriched in genes associated with innate immune response, protein glycosylation process, and retrograde axonal transport. These SNVs were also correlated with the microbiome composition and a broad aspect of microbial functions, especially metabolism. Additionally, the abundance of metabolites involved in the metabolic network of neurotransmitters was inferred to be causally related to specific SNVs and microbes. Furthermore, our data suggested that the interaction of host genetics and gut microbes may play a crucial role in the immune and metabolism homeostasis of ASD. This study may provide valuable clues to investigate the interaction of host genetic variations and gut microbiota in the pathogenesis of ASD.

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15. Longevity O. Expression of Concern on « Ubiquinol Improves Symptoms in Children with Autism ». Oxid Med Cell Longev ;2020 ;2020:3803527.

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16. Madison JM, Duong K, Vieux EF, Udeshi ND, Iqbal S, Requadt E, Fereshetian S, Lewis MC, Gomes AS, Pierce KA, Platt RJ, Zhang F, Campbell AJ, Lal D, Wagner FF, Clish CB, Carr SA, Sheng M, Scolnick EM, Cottrell JR. Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features. iScience ;2021 (Jan 22) ;24(1):101935.

Genetic variation of the 16p11.2 deletion locus containing the KCTD13 gene and of CUL3 is linked with autism. This genetic connection suggested that substrates of a CUL3-KCTD13 ubiquitin ligase may be involved in disease pathogenesis. Comparison of Kctd13 mutant (Kctd13 (-/-) ) and wild-type neuronal ubiquitylomes identified adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in adenosine monophosphate (AMP) synthesis, as a KCTD13 ligase substrate. In Kctd13 (-/-) neurons, there were increased levels of succinyl-adenosine (S-Ado), a metabolite downstream of ADSS. Notably, S-Ado levels are elevated in adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. The increased S-Ado levels in Kctd13 (-/-) neurons were decreased by treatment with an ADSS inhibitor. Lastly, functional analysis of human KCTD13 variants suggests that KCTD13 variation may alter ubiquitination of ADSS. These data suggest that succinyl-AMP metabolites accumulate in Kctd13 (-/-) neurons, and this observation may have implications for our understanding of 16p11.2 deletion syndrome.

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17. Marshall E, Nomi JS, Dirks B, Romero C, Kupis L, Chang C, Uddin LQ. Coactivation pattern analysis reveals altered salience network dynamics in children with autism spectrum disorder. Netw Neurosci ;2020 ;4(4):1219-1234.

Brain connectivity studies of autism spectrum disorder (ASD) have historically relied on static measures of functional connectivity. Recent work has focused on identifying transient configurations of brain activity, yet several open questions remain regarding the nature of specific brain network dynamics in ASD. We used a dynamic coactivation pattern (CAP) approach to investigate the salience/midcingulo-insular (M-CIN) network, a locus of dysfunction in ASD, in a large multisite resting-state fMRI dataset collected from 172 children (ages 6-13 years ; n = 75 ASD ; n = 138 male). Following brain parcellation by using independent component analysis, dynamic CAP analyses were conducted and k-means clustering was used to determine transient activation patterns of the M-CIN. The frequency of occurrence of different dynamic CAP brain states was then compared between children with ASD and typically developing (TD) children. Dynamic brain configurations characterized by coactivation of the M-CIN with central executive/lateral fronto-parietal and default mode/medial fronto-parietal networks appeared less frequently in children with ASD compared with TD children. This study highlights the utility of time-varying approaches for studying altered M-CIN function in prevalent neurodevelopmental disorders. We speculate that altered M-CIN dynamics in ASD may underlie the inflexible behaviors commonly observed in children with the disorder.

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18. McDonald TAM. The broader autism phenotype constellations-disability matrix paradigm : Theoretical model for autism and the broader autism phenotype. Med Hypotheses ;2021 (Jan) ;146:110456.

The prevalence of autism has increased dramatically over the last 60 years, and the cause of this increase is unclear. In this paradigm-shift paper, I propose an explanatory paradigm for the cause of autism and its increased prevalence in the general population. I also discuss how social and historical contexts may have influenced the evolution and manifestation of specific traits in the autism population. These traits expand the characterization of the broader autism phenotype to include a constellation of socially valued traits, termed Broader Autism Phenotype Constellations (BAPCO). The frequency of these traits may have increased due to assortative mating opportunities that occurred alongside social changes in education and occupational opportunities over the last 100 years. I propose that assortative mating can lead to both positive and negative developmental consequences affecting social and language development. I also propose that BAPCO traits, which are not intrinsically disabilities, could interact with co-occurring conditions in a new model called the BAPCO-Disability Matrix Paradigm (BAPCO-DMAP). In this paradigm, autism is located at the intersection of BAPCO traits and at least one co-occurring condition. These proposed models support the need to create a more comprehensive definition of autism that includes constellations of BAPCO traits. The BAPCO-DMAP paves the way to testable predictions of autism prevalence and provides a framework to better understand the foundational traits of autism. Finally, this paradigm radically redefines the broader autism phenotype with characteristics that can inform therapy and child development.

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19. Pagan C, Benabou M, Leblond C, Cliquet F, Mathieu A, Lemière N, Goubran-Botros H, Delorme R, Leboyer M, Callebert J, Bourgeron T, Launay JM. Decreased phenol sulfotransferase activities associated with hyperserotonemia in autism spectrum disorders. Transl Psychiatry ;2021 (Jan 7) ;11(1):23.

Hyperserotonemia is the most replicated biochemical abnormality associated with autism spectrum disorders (ASD). However, previous studies of serotonin synthesis, catabolism, and transport have not elucidated the mechanisms underlying this hyperserotonemia. Here we investigated serotonin sulfation by phenol sulfotransferases (PST) in blood samples from 97 individuals with ASD and their first-degree relatives (138 parents and 56 siblings), compared with 106 controls. We report a deficient activity of both PST isoforms (M and P) in platelets from individuals with ASD (35% and 78% of patients, respectively), confirmed in autoptic tissues (9 pineal gland samples from individuals with ASD-an important source of serotonin). Platelet PST-M deficiency was strongly associated with hyperserotonemia in individuals with ASD. We then explore genetic or pharmacologic modulation of PST activities in mice : variations of PST activities were associated with marked variations of blood serotonin, demonstrating the influence of the sulfation pathway on serotonemia. We also conducted in 1645 individuals an extensive study of SULT1A genes, encoding PST and mapping at highly polymorphic 16p11.2 locus, which did not reveal an association between copy number or single nucleotide variations and PST activity, blood serotonin or the risk of ASD. In contrast, our broader assessment of sulfation metabolism in ASD showed impairments of other sulfation-related markers, including inorganic sulfate, heparan-sulfate, and heparin sulfate-sulfotransferase. Our study proposes for the first time a compelling mechanism for hyperserotonemia, in a context of global impairment of sulfation metabolism in ASD.

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20. Pejhan S, Rastegar M. Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease. Biomolecules ;2021 (Jan 8) ;11(1)

Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry de novo mutation(s) in the Methyl-CpG-Binding Protein 2 (MECP2) gene. While the majority of RTT patients have MECP2 mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (miR132) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the MECP2 gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and miR132.

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21. Scott AJW, Wang Y, Abdel-Jaber H, Thabtah F, Ray S. Improving screening systems of autism by machine learning with data sampling. Technol Health Care ;2021 (Jan 8)

OBJECTIVES : Autism Spectrum Disorder (ASD) is a complex range of neurodegenerative conditions that impact individuals’ social behaviour and communication skills. However, ASD data often contains far more controls than cases. This poses a serious challenge when creating classification models due to deriving models that favour controls during the classification of individuals. This problem is known as class imbalance, and it may reduce the performance in classification models derived by machine learning (ML) techniques due to individuals may remain undetected. METHODS : ML appears to help in the distressing disorder by improving outcome quality besides speeding up the access to early diagnosis and consequential treatment. A screening dataset that consists of over 1100 instances was used to perform extensive quantitative analysis using different data resampling techniques and according to specific evaluation metrics. We measure the effect of class imbalance on autism screening performance using different data resampling techniques with a ML classifier and with respect to sensitivity, specificity, and F1-measure. We would like to know which resampling methods work well in balancing autism screening data. RESULTS : The results reveal that data resampling, and especially oversampling, improve results derived by the considered ML classifier. More importantly, there was superiority in terms of sensitivity and specificity for models derived by Naive Bayes classifier when oversampling methods have been used for data pre-processing on the autism data considered. CONCLUSION : The results reported encourages further improvement of the design and implementation of ASD screening systems using intelligent technology.

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22. Sotelo-Orozco J, Abbeduto L, Hertz-Picciotto I, Slupsky CM. Association Between Plasma Metabolites and Psychometric Scores Among Children With Developmental Disabilities : Investigating Sex-Differences. Front Psychiatry ;2020 ;11:579538.

Background : Developmental disabilities are defined by delays in learning, language, and behavior, yet growing evidence has revealed disturbances in metabolic systems that may also be present. Little is known about whether these metabolic issues contribute to the symptoms or severity of these disabilities, or whether sex plays a role in these associations, given that boys are disproportionately affected by some developmental disabilities. Here we sought to investigate the correlation between psychometric scores, sex, and the plasma metabolome. Methods : The plasma metabolomes of children with autism spectrum disorder (ASD ; n = 167), idiopathic developmental delay (i-DD ; n = 51), Down syndrome (DS ; n = 31), and typically developing controls (TD ; n = 193) were investigated using NMR spectroscopy. Spearman rank correlations and multiple linear regression models (adjusted for child’s neurodevelopmental diagnosis, child’s sex, child’s age, child’s race/ethnicity, maternal age at child’s birth, and parental homeownership) were used to examine the association between plasma metabolites and sex in relation to psychometric measures of cognitive skills, adaptive behavior, and maladaptive behavior in our study population. Results : Higher levels of metabolites involved in cellular energy and mitochondrial function among children with ASD (fumarate and cis-aconitate), DS (lactate), and TD (pyruvate) are associated with poorer cognitive and adaptive subscales. Similarly, higher o-acetylcarnitine associated with deficits in cognitive subscales among all DS cases and TD boys, and carnitine correlated with increased maladaptive behavior among girls with ASD and girls with DS. Among children with DS, elevated myo-inositol, ornithine, and creatine correlated with poorer scores across several subscales. Even among TD cases, elevated 3-hydroxybutyrate correlated with decreased receptive language. In contrast, higher levels of glutamate were associated with better socialization skills among ASD cases. Even after adjusting for the child’s neurodevelopmental diagnosis, sex, and other possible confounders, key metabolites including glycolysis metabolites (lactate and pyruvate), ketone bodies (3-hydroxybutyrate and acetoacetate), TCA cycle metabolites (cis-aconitate and fumarate), as well as ornithine were associated with deficits in multiple domains of cognitive function, adaptive skills, and aberrant behaviors. Conclusions : Our results highlight that some plasma metabolites may relate to specific functional subdomains within cognitive, adaptive, and behavioral development with some variation by diagnosis and sex.

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23. Stewart SL, Celebre A, Head MJ, James ML, Martin L, Fries BE. A Case-Mix System for Children and Youth With Developmental Disabilities. Health services insights ;2020 ;13:1178632920977899.

Limited funding across health and social service programs presents a challenge regarding how to best match resources to the needs of the population. There is increasing consensus that differences in individual characteristics and care needs should be reflected in variations in service costs, which has led to the development of case-mix systems. The present study sought to develop a new approach to allocate resources among children and youth with intellectual and developmental disabilities (IDD) as part of a system-wide Medicaid payment reform initiative in Arkansas. To develop the system, assessment data collected using the interRAI Child and Youth Mental Health-Developmental Disability instrument was matched to paid service claims. The sample consisted of 346 children and youth with developmental disabilities in the home setting. Using automatic interactions detection, individuals were sorted into unique, clinically relevant groups (ie, based on similar resource use) and a standardized relative measure of the cost of services provided to each group was calculated. The resulting case-mix system has 8 distinct, final groups and explains 30% of the variance in per diem costs. Our analyses indicate that this case-mix classification system could provide the foundation for a future prospective payment system that is centered around stability and equitability in the allocation of limited resources within this vulnerable population.

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24. Yue F, Deng S, Xi Q, Jiang Y, He J, Zhang H, Liu R. Prenatal detection of a 3q29 microdeletion in a fetus with ventricular septum defect : A case report and literature review. Medicine (Baltimore) ;2021 (Jan 8) ;100(1):e24224.

RATIONALE : Chromosomal 3q deletion is a recurrent genomic alternation, which is rarely reported in clinic. PATIENT CONCERNS : A 27-year-old woman underwent amniocentesis for cytogenetic analysis and single nucleotide polymorphism (SNP) array analysis at 27 weeks of gestation, due to ventricular septum defect in prenatal ultrasound findings. DIAGNOSES : G-banding analysis showed the karyotype of the fetus was normal and the couple also had normal karyotypes. However, SNP array detected a 1.71 Mb microdelection in 3q29, which was described as arr[hg19]3q29(194184392-195887205) × 1. There are 12 genes located in this locus. INTERVENTIONS : The couple refused SNP array to testify the 3q29 microdeletion was inherited or de novo and they chose termination of pregnancy. OUTCOMES : The deleted region in the fetus overlapped with part 3q29 microdeletion syndrome, which was characterized by learning disability, speech delay, mental deficiency, ocular abnormalities and craniofacial features. In addition, no similar/overlapping 3q29 microdeletion cases were reported according to the published literature and database. LESSONS : For the chromosomal microscopic imbalances partially overlapping with the defined pathogenic syndrome, deleted/duplicated size, genetic materials and phenotypic diversity should be taken into consideration when genetic counseling is offered by the clinicians.

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25. Zhang Y, Tian Y, Wu P, Chen D. Application of Skeleton Data and Long Short-Term Memory in Action Recognition of Children with Autism Spectrum Disorder. Sensors (Basel) ;2021 (Jan 8) ;21(2)

The recognition of stereotyped action is one of the core diagnostic criteria of Autism Spectrum Disorder (ASD). However, it mainly relies on parent interviews and clinical observations, which lead to a long diagnosis cycle and prevents the ASD children from timely treatment. To speed up the recognition process of stereotyped actions, a method based on skeleton data and Long Short-Term Memory (LSTM) is proposed in this paper. In the first stage of our method, the OpenPose algorithm is used to obtain the initial skeleton data from the video of ASD children. Furthermore, four denoising methods are proposed to eliminate the noise of the initial skeleton data. In the second stage, we track multiple ASD children in the same scene by matching distance between current skeletons and previous skeletons. In the last stage, the neural network based on LSTM is proposed to classify the ASD children’s actions. The performed experiments show that our proposed method is effective for ASD children’s action recognition. Compared to the previous traditional schemes, our scheme has higher accuracy and is almost non-invasive for ASD children.

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26. Zhao T, Lyu S, Lu G, Juan L, Zeng X, Wei Z, Hao J, Peng J. SC2disease : a manually curated database of single-cell transcriptome for human diseases. Nucleic Acids Res ;2021 (Jan 8) ;49(D1):D1413-D1419.

SC2disease (http://easybioai.com/sc2disease/) is a manually curated database that aims to provide a comprehensive and accurate resource of gene expression profiles in various cell types for different diseases. With the development of single-cell RNA sequencing (scRNA-seq) technologies, uncovering cellular heterogeneity of different tissues for different diseases has become feasible by profiling transcriptomes across cell types at the cellular level. In particular, comparing gene expression profiles between different cell types and identifying cell-type-specific genes in various diseases offers new possibilities to address biological and medical questions. However, systematic, hierarchical and vast databases of gene expression profiles in human diseases at the cellular level are lacking. Thus, we reviewed the literature prior to March 2020 for studies which used scRNA-seq to study diseases with human samples, and developed the SC2disease database to summarize all the data by different diseases, tissues and cell types. SC2disease documents 946 481 entries, corresponding to 341 cell types, 29 tissues and 25 diseases. Each entry in the SC2disease database contains comparisons of differentially expressed genes between different cell types, tissues and disease-related health status. Furthermore, we reanalyzed gene expression matrix by unified pipeline to improve the comparability between different studies. For each disease, we also compare cell-type-specific genes with the corresponding genes of lead single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) to implicate cell type specificity of the traits.

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