1. Aishworiya R, Hwang YH, Santos E, Hayward B, Usdin K, Durbin-Johnson B, Hagerman R, Tassone F. Clinical implications of somatic allele expansion in female FMR1 premutation carriers. Scientific reports. 2023; 13(1): 7050.

Carriers of a premutation allele (PM) in the FMR1 gene are at risk of developing a number of Fragile X premutation asssociated disorders (FXPAC), including Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-associated neuropsychiatric disorders (FXAND). We have recently reported somatic CGG allele expansion in female PM; however, its clinical significance remains unclear. The aim of this study was to examine the potential clinical association between somatic FMR1 allele instability and PM associated disorders. Participants comprised of 424 female PM carriers age 0.3- 90 years. FMR1 molecular measures and clinical information on the presence of medical conditions, were determined for all subjects for primary analysis. Two sub-groups of participants (age ≥ 25, N = 377 and age ≥ 50, N = 134) were used in the analysis related to presence of FXPOI and FXTAS, respectively. Among all participants (N = 424), the degree of instability (expansion) was significantly higher (median 2.5 vs 2.0, P = 0.026) in participants with a diagnosis of attention deficit hyperactivity disorder (ADHD) compared to those without. FMR1 mRNA expression was significantly higher in subjects with any psychiatric disorder diagnosis (P = 0.0017); specifically, in those with ADHD (P = 0.009), and with depression (P = 0.025). Somatic FMR1 expansion was associated with the presence of ADHD in female PM and FMR1 mRNA levels were associated with the presence of mental health disorders. The findings of our research are innovative as they suggest a potential role of the CGG expansion in the clinical phenotype of PM and may potentially guide clinical prognosis and management.

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2. Antezana L, Valdespino A, Wieckowski AT, Coffman MC, Carlton CN, Garcia KM, Gracanin D, White SW, Richey JA. Social Anxiety Symptoms Predict Poorer Facial Emotion Recognition in Autistic Male Adolescents and Young Adults Without Intellectual Disability. Journal of autism and developmental disorders. 2023.

Utilizing a novel computerized task, we aimed to examine whether social anxiety symptoms would be related to individual differences in facial emotion recognition (FER) in a sample of autistic male adolescents and young adults without intellectual disability. Results indicated that social anxiety and IQ predicted poorer FER, irrespective of specific emotion type. When probing specific effects within emotion and condition types, social anxiety impacted surprise and disgust FER during a truncated viewing condition and not full viewing condition. Collectively, results suggest that social anxiety in autism may play a larger role in FER than previously thought. Future work should consider the role of social anxiety within autism as a factor that may meaningfully relate to FER assessment and intervention.

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3. Du Y, Chen L, Yan MC, Wang YL, Zhong XL, Xv CX, Li YB, Cheng Y. Neurometabolite levels in the brains of patients with autism spectrum disorders: A meta-analysis of proton magnetic resonance spectroscopy studies (N = 1501). Molecular psychiatry. 2023.

Evidence suggests that neurometabolite alterations may be involved in the pathophysiology of autism spectrum disorders (ASDs). We performed a meta-analysis of proton magnetic resonance spectroscopy ((1)H-MRS) studies to examine the neurometabolite levels in the brains of patients with ASD. A systematic search of PubMed and Web of Science identified 54 studies for the meta-analysis. A random-effects meta-analysis demonstrated that compared with the healthy controls, patients with ASD had lower N-acetyl-aspartate-containing compound (NAA) and choline-containing compound (Cho) levels and NAA/(creatine-containing compound) Cr ratios in the gray matter and lower NAA and glutamate + glutamine (Glx) levels in the white matter. Furthermore, NAA and gamma-aminobutyric acid (GABA) levels, NAA/Cr ratios, and GABA/Cr ratios were significantly decreased in the frontal cortex of patients with ASD, whereas glutamate (Glu) levels were increased in the prefrontal cortex. Additionally, low NAA levels and GABA/Cr ratios in the temporal cortex, low NAA levels and NAA/Cr ratios in the parietal and dorsolateral prefrontal cortices, and low NAA levels in the cerebellum and occipital cortex were observed in patients with ASD. Meta-regression analysis revealed that age was positively associated with effect size in studies analyzing the levels of gray matter NAA and white matter Glx. Taken together, these results provide strong clinical evidence that neurometabolite alterations in specific brain regions are associated with ASD and age is a confounding factor for certain neurometabolite levels in patients with ASD.

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4. Glessner JT, Khan ME, Chang X, Liu Y, Otieno FG, Lemma M, Slaby I, Hain H, Mentch F, Li J, Kao C, Sleiman PMA, March ME, Connolly J, Hakonarson H. Rare recurrent copy number variations in metabotropic glutamate receptor interacting genes in children with neurodevelopmental disorders. Journal of neurodevelopmental disorders. 2023; 15(1): 14.

BACKGROUND: Neurodevelopmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are examples of complex and partially overlapping phenotypes that often lack definitive corroborating genetic information. ADHD and ASD have complex genetic associations implicated by rare recurrent copy number variations (CNVs). Both of these NDDs have been shown to share similar biological etiologies as well as genetic pleiotropy. METHODS: Platforms aimed at investigating genetic-based associations, such as high-density microarray technologies, have been groundbreaking techniques in the field of complex diseases, aimed at elucidating the underlying disease biology. Previous studies have uncovered CNVs associated with genes within shared candidate genomic networks, including glutamate receptor genes, across multiple different NDDs. To examine shared biological pathways across two of the most common NDDs, we investigated CNVs across 15,689 individuals with ADHD (n = 7920), ASD (n = 4318), or both (n = 3,416), as well as 19,993 controls. Cases and controls were matched by genotype array (i.e., Illumina array versions). Three case-control association studies each calculated and compared the observed vs. expected frequency of CNVs across individual genes, loci, pathways, and gene networks. Quality control measures of confidence in CNV-calling, prior to association analyses, included visual inspection of genotype and hybridization intensity. RESULTS: Here, we report results from CNV analysis in search for individual genes, loci, pathways, and gene networks. To extend our previous observations implicating a key role of the metabotropic glutamate receptor (mGluR) network in both ADHD and autism, we exhaustively queried patients with ASD and/or ADHD for CNVs associated with the 273 genomic regions of interest within the mGluR gene network (genes with one or two degrees protein-protein interaction with mGluR 1-8 genes). Among CNVs in mGluR network genes, we uncovered CNTN4 deletions enriched in NDD cases (P = 3.22E - 26, OR = 2.49). Additionally, we uncovered PRLHR deletions in 40 ADHD cases and 12 controls (P = 5.26E - 13, OR = 8.45) as well as clinically diagnostic relevant 22q11.2 duplications and 16p11.2 duplications in 23 ADHD + ASD cases and 9 controls (P = 4.08E - 13, OR = 15.05) and 22q11.2 duplications in 34 ADHD + ASD cases and 51 controls (P = 9.21E - 9, OR = 3.93); those control samples were not with previous 22qDS diagnosis in their EHR records. CONCLUSION: Together, these results suggest that disruption in neuronal cell-adhesion pathways confers significant risk to NDDs and showcase that rare recurrent CNVs in CNTN4, 22q11.2, and 16p11.2 are overrepresented in NDDs that constitute patients predominantly suffering from ADHD and ASD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02286817 First Posted: 10 November 14, ClinicalTrials.gov Identifier: NCT02777931 first posted: 19 May 2016, ClinicalTrials.gov Identifier: NCT03006367 first posted: 30 December 2016, ClinicalTrials.gov Identifier: NCT02895906 first posted: 12 September 2016.

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5. Levine MA, Chen H, Wodka EL, Caffo BS, Ewen JB. Autism and Hierarchical Models of Intelligence. Journal of autism and developmental disorders. 2023.

BACKGROUND: The Wechsler Intelligence Scale for Children (WISC) employs a hierarchical model of general intelligence in which index scores separate out different clinically-relevant aspects of intelligence; the test is designed such that index scores are statistically independent from one another within the normative sample. Whether or not the existing index scores meet the desired psychometric property of being statistically independent within autistic samples is unknown. METHOD: We conducted a factor analysis on WISC fifth edition (WISC-V) (N = 83) and WISC fourth edition (WISC-IV) (N = 131) subtest data in children with autism. We compared the data-driven exploratory factor analysis with the manual-derived index scores, including in a typically developing (TD) WISC-IV cohort (N = 209). RESULTS: The WISC-IV TD cohort showed the expected 1:1 relationship between empirically derived factors and manual-derived index scores. We observed less unique correlations between our data-driven factors and manualized IQ index scores in both ASD samples (WISC-IV and WISC-V). In particular, in both WISC-IV and -V, working memory (WM) influenced index scores in autistic individuals that do not load on WM in the normative sample. CONCLUSIONS: WISC index scores do not show the desired statistical independence within autistic samples, as judged against an empirically-derived exploratory factor analysis. In particular, within the currently used WISC-V version, WM influences multiple index scores.

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6. Michel L, Ricou C, Bonnet-Brilhault F, Houy-Durand E, Latinus M. Sounds Pleasantness Ratings in Autism: Interaction Between Social Information and Acoustical Noise Level. Journal of autism and developmental disorders. 2023.

A lack of response to voices, and a great interest for music are part of the behavioral expressions, commonly (self-)reported in Autism Spectrum Disorder (ASD). These atypical interests for vocal and musical sounds could be attributable to different levels of acoustical noise, quantified in the harmonic-to-noise ratio (HNR). No previous study has investigated explicit auditory pleasantness in ASD comparing vocal and non-vocal sounds, in relation to acoustic noise level. The aim of this study is to objectively evaluate auditory pleasantness. 16 adults on the autism spectrum and 16 neuro-typical (NT) matched adults rated the likeability of vocal and non-vocal sounds, with varying harmonic-to-noise ratio levels. A group by category interaction in pleasantness judgements revealed that participants on the autism spectrum judged vocal sounds as less pleasant than non-vocal sounds; an effect not found for NT participants. A category by HNR level interaction revealed that participants of both groups rated sounds with a high HNR as more pleasant for non-vocal sounds. A significant group by HNR interaction revealed that people on the autism spectrum tended to judge as less pleasant sounds with high HNR and more pleasant those with low HNR than NT participants. Acoustical noise level of sounds alone does not appear to explain atypical interest for voices and greater interest in music in ASD.

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7. Muller E, Shalev I, Bachmat E, Eran A. Data-driven dissection of the fever effect in autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2023.

Some individuals with autism spectrum disorder (ASD) demonstrate marked behavioral improvements during febrile episodes, in what is perhaps the only present-day means of modulating the core ASD phenotype. Understanding the nature of this so-called fever effect is therefore essential for leveraging this natural temporary relief of symptoms to a sustained efficacious intervention. Toward this goal, we used machine learning to analyze the rich clinical data of the Simons Simplex Collection, in which one out of every six children with ASD was reported to improve during febrile episodes, across multiple ASD domains. Reported behavioral improvements during febrile episodes were associated with maternal infection in pregnancy (OR = 1.7, 95% CI = [1.42, 2.03], P = 4.24 × 10(-4) ) and gastrointestinal (GI) dysfunction (OR = 1.46, 95% CI = [1.15, 1.81], P = 1.94 × 10(-3) ). Family members of children reported to improve when febrile have an increased prevalence of autoimmune disorders (OR = 1.43, 95% CI = [1.23, 1.67], P = 3.0 × 10(-6) ), language disorders (OR = 1.63, 95% CI = [1.29, 2.04], P = 2.5 × 10(-5) ), and neuropsychiatric disorders (OR = 1.59, 95% CI = [1.34, 1.89], P < 1 × 10(-6) ). Since both GI abnormalities and maternal immune activation have been linked to ASD via proinflammatory cytokines, these results might suggest a possible involvement of immune dysregulation in the fever effect, consistent with findings in mouse models. This work advances our understanding of the fever-responsive ASD subtype and motivates the future studies to directly test the link between proinflammatory cytokines and behavioral modifications in individuals with ASD.

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8. Rabot J, Rødgaard EM, Joober R, Dumas G, Bzdok D, Bernhardt B, Jacquemont S, Mottron L. Genesis, modelling and methodological remedies to autism heterogeneity. Neuroscience and biobehavioral reviews. 2023: 105201.

Diagnostic criteria used in autism research have undergone a shift towards the inclusion of a larger population, paralleled by increasing, but variable, estimates of autism prevalence across clinical settings and continents. A categorical diagnosis of autism spectrum disorder is now consistent with large variations in language, intelligence, comorbidity, and severity, leading to a heterogeneous sample of individuals, increasingly distant from the initial prototypical descriptions. We review the history of autism diagnosis and subtyping, and the evidence of heterogeneity in autism at the cognitive, neurological, and genetic levels. We describe two strategies to address the problem of heterogeneity: clustering, and truncated-compartmentalized enrollment strategy based on prototype recognition. The advances made using clustering methods have been modest. We present an alternative, new strategy for dissecting autism heterogeneity, emphasizing incorporation of prototypical samples in research cohorts, comparison of subgroups defined by specific ranges of values for the clinical specifiers, and retesting the generality of neurobiological results considered to be acquired from the entire autism spectrum on prototypical cohorts defined by narrow specifiers values.

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9. Yamada R, Fujii T, Hattori K, Hori H, Matsumura R, Kurashimo T, Ishihara N, Yoshida S, Sumiyoshi T, Kunugi H. Discrepancy between Clinician-rated and Self-reported Depression Severity is Associated with Adverse Childhood Experience, Autistic-like Traits, and Coping Styles in Mood Disorders. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology. 2023; 21(2): 296-303.

OBJECTIVE: This study aimed to determine if the discrepancy between depression severity rated by clinicians and that reported by patients depends on key behavioral/psychological features in patients with mood disorders. METHODS: Participants included 100 patients with mood disorders. First, we examined correlations and regressions between scores on the Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory (BDI). Second, we divided the participants into those who provided 1) greater ratings for the BDI compared with the HAMD (BDI relative- overrating, BO) group, 2) comparable ratings for the BDI and HAMD (BDI relatively concordant, BC) group, or 3) less ratings for the BDI (BDI relative-underrating, BU) group. Adverse childhood experiences, autistic-like traits, and coping styles were evaluated with a six-item short version of the Childhood Trauma Questionnaire (CTQ-6), the Social Responsiveness Scale for Adults (SRS-A), and the Ways of Coping Checklist (WCCL), respectively. RESULTS: A significant correlation was found between HAMD and BDI scores. Total and emotional abuse subscale scores from the CTQ-6, and the self-blame subscale scores from the WCCL were significantly higher for the BO group compared with the BU group. The BO group also elicited significantly higher SRS-A total scores than did the other groups. CONCLUSION: These findings suggest that patients with adverse emotional experiences, autistic-like traits, and self-blame coping styles perceive greater distress than that evaluated objectively by clinicians. The results indicate the need for inclusion of subjective assessments to effectively evaluate depressive symptoms in patients deemed to have these psycho- behavioral concerns.

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10. Zhang M, Wu Y, Lu Z, Song M, Huang X, Mi L, Yang J, Cui X. Effects of Vitamin D Supplementation on Children with Autism Spectrum Disorder: A Systematic Review and Meta-analysis. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology. 2023; 21(2): 240-51.

The effect of vitamin D supplementation on individuals with autism spectrum disorder (ASD) is inconclusive. We aimed to conduct a meta-analysis of the available randomized controlled trials (RCTs) to explore whether vitamin D supplementation can improve core symptoms and coexisting conditions in children with ASD. Data were obtained by searching the PubMed, Embase, Web of Science, CINAHL and Cochrane Library databases up to February 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using a random-effects model, mean differences with 95% confidence intervals (CIs) were calculated through a meta-analysis. There were eight RCTs with 266 children with ASD in the present review, among which six RCTs were included in the meta-analysis. Children who received vitamin D supplementation showed a significant improvement in stereotypical behavior scores (pooled mean difference (MD): -1.39; 95% CI: -2.7, -0.07; P = 0.04) with low heterogeneity (I(2) = 34%), and there was a trend toward decreased total scores on the Social Responsiveness Scale (SRS) and Childhood Autism Rating Scale (CARS, P = 0.05); however, there were no other significant differences in the core symptoms of ASD and coexisting conditions between groups as measured by the Aberrant Behavior Checklist (ABC). Vitamin D supplementation appears to improve stereotypical behaviors but does not improve other core symptoms and coexisting conditions. Further randomized controlled trials with large sample sizes and individualized doses are needed.

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