1. Agusti I, Alvarez-Mora MI, Wijngaard R, Borras A, Barcos T, Peralta S, Guimera M, Goday A, Manau D, Rodriguez-Revenga L. Correlation of FMR4 expression levels to ovarian reserve markers in FMR1 premutation carriers. J Ovarian Res;2024 (May 17);17(1):103.

BACKGROUND: Fragile X-associated primary ovarian insufficiency (FXPOI), characterized by amenorrhea before age 40 years, occurs in 20% of female FMR1 premutation carriers. Presently, there are no molecular or biomarkers that can help predicting which FMR1 premutation women will develop FXPOI. We previously demonstrated that high FMR4 levels can discriminate between FMR1 premutation carriers with and without FXPOI. In the present study the relationship between the expression levels of FMR4 and the ovarian reserve markers was assessed in female FMR1 premutation carriers under age of 35 years. METHODS: We examined the association between FMR4 transcript levels and the measures of total antral follicle count (AFC) and serum anti-müllerian hormone (AMH) levels as markers of ovarian follicle reserve. RESULTS: Results revealed a negative association between FMR4 levels and AMH (r = 0.45) and AFC (r = 0.64). Statistically significant higher FMR4 transcript levels were found among those FMR1 premutation women with both, low AFCs and AMH levels. CONCLUSIONS: These findings reinforce previous studies supporting the association between high levels of FMR4 and the risk of developing FXPOI in FMR1 premutation carriers.

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2. Augé P, Maruani A, Humeau E, Ellul P, Cartigny A, Lefebvre A, Dellapiazza F, Delorme R, Peyre H. Global Sensory Features are Linked to Executive and Attentional Impairments in Autism Spectrum Disorders. J Autism Dev Disord;2024 (May 18)

Sensory features, executive and attentional impairments are frequently reported in individuals with autism spectrum disorders (ASD). However, little is known about their complex relationships. In this study, we aim to examine the executive and attentional difficulties related to distinct sensory profiles. We identified sensory profiles with a Latent Profile Analysis (LPA) based on scores on the Short Sensory Profile (SSP) questionnaire in 95 children with ASD aged 6 to 17 years. Executive and attention functions were assessed using the Behavior Rating Inventory of Executive Functions (BRIEF) questionnaire and Attention-Deficit Hyperactivity Disorder Rating Scale (ADHD-RS). A three-cluster solution based on raw SSP scores identified a « high », a « medium » and a « low » SSP profile. We found a significant relationship between executive functions, attentional skills and the global severity of sensory features, reinforcing findings of previous studies in the literature. A two-cluster solution based on normalized SSP (i.e. equalized for the global severity) identified distinct sensory profiles, mainly discriminated by the score of underresponsive/seeks sensation. We found no significant difference between these two clusters for the BRIEF and ADHD-RS related scores. Our study suggests that the heterogeneity of sensory features in ASD may not be explained by differences in executive and attention functions. Future studies are needed to refine the link between sensory features and executive functions in autism.

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3. Laue HE, Bonham KS, Coker MO, Moroishi Y, Pathmasiri W, McRitchie S, Sumner S, Hoen AG, Karagas MR, Klepac-Ceraj V, Madan JC. Prospective association of the infant gut microbiome with social behaviors in the ECHO consortium. Mol Autism;2024 (May 17);15(1):21.

BACKGROUND: Identifying modifiable risk factors of autism spectrum disorders (ASDs) may inform interventions to reduce financial burden. The infant/toddler gut microbiome is one such feature that has been associated with social behaviors, but results vary between cohorts. We aimed to identify consistent overall and sex-specific associations between the early-life gut microbiome and autism-related behaviors. METHODS: Utilizing the Environmental influences on Children Health Outcomes (ECHO) consortium of United States (U.S.) pediatric cohorts, we gathered data on 304 participants with fecal metagenomic sequencing between 6-weeks to 2-years postpartum (481 samples). ASD-related social development was assessed with the Social Responsiveness Scale (SRS-2). Linear regression, PERMANOVA, and Microbiome Multivariable Association with Linear Models (MaAsLin2) were adjusted for sociodemographic factors. Stratified models estimated sex-specific effects. RESULTS: Genes encoding pathways for synthesis of short-chain fatty acids were associated with higher SRS-2 scores, indicative of ASDs. Fecal concentrations of butyrate were also positively associated with ASD-related SRS-2 scores, some of which may be explained by formula use. LIMITATIONS: The distribution of age at outcome assessment differed in the cohorts included, potentially limiting comparability between cohorts. Stool sample collection methods also differed between cohorts. Our study population reflects the general U.S. population, and thus includes few participants who met the criteria for being at high risk of developing ASD. CONCLUSIONS: Our study is among the first multicenter studies in the U.S. to describe prospective microbiome development from infancy in relation to neurodevelopment associated with ASDs. Our work contributes to clarifying which microbial features associate with subsequent diagnosis of neuropsychiatric outcomes. This will allow for future interventional research targeting the microbiome to change neurodevelopmental trajectories.

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4. Marchal I. A genetic rescue strategy for Timothy syndrome. Nat Biotechnol;2024 (May);42(5):699.

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5. Pauly R, Johnson L, Feltus FA, Casanova EL. Enrichment of a subset of Neanderthal polymorphisms in autistic probands and siblings. Mol Psychiatry;2024 (May 17)

Homo sapiens and Neanderthals underwent hybridization during the Middle/Upper Paleolithic age, culminating in retention of small amounts of Neanderthal-derived DNA in the modern human genome. In the current study, we address the potential roles Neanderthal single nucleotide polymorphisms (SNP) may be playing in autism susceptibility in samples of black non-Hispanic, white Hispanic, and white non-Hispanic people using data from the Simons Foundation Powering Autism Research (SPARK), Genotype-Tissue Expression (GTEx), and 1000 Genomes (1000G) databases. We have discovered that rare variants are significantly enriched in autistic probands compared to race-matched controls. In addition, we have identified 25 rare and common SNPs that are significantly enriched in autism on different ethnic backgrounds, some of which show significant clinical associations. We have also identified other SNPs that share more specific genotype-phenotype correlations but which are not necessarily enriched in autism and yet may nevertheless play roles in comorbid phenotype expression (e.g., intellectual disability, epilepsy, and language regression). These results strongly suggest Neanderthal-derived DNA is playing a significant role in autism susceptibility across major populations in the United States.

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6. Smith M, Ferguson HJ. Indistinguishable behavioural and neural correlates of perceptual self-other distinction in autistic and neurotypical adults. Cortex;2024 (Apr 24)

Previous research has suggested that self-bias (i.e., enhanced cognitive processing of self-versus other-relevant information) may be atypical in autism spectrum conditions (ASC), perhaps due to difficulties with self-other distinction. However, empirical evidence for this is inconsistent, and the neural basis of processing differences remains unknown. We present two experiments that aimed to test perceptual self-bias and familiarity effects in ASC using a perceptual-association task. Participants were asked to distinguish face/label associations of the self from those of other people of differing levels of familiarity (i.e., friend vs stranger). Experiment 1 took an individual differences approach by testing whether behavioural self-bias is associated with the number of autistic traits in a neurotypical adult sample (N = 59). Experiment 2 took a case-control approach by testing whether behavioural self-bias and associated ERP responses differ between neurotypical (N = 27) and autistic (N = 30) adults. Across both experiments, behavioural results showed that participants experienced a self-bias (self > friend and stranger) and a familiarity effect (e.g., friend > stranger); neither effect was affected by the number of autistic traits or autism diagnosis. In Experiment 2, analysis of N1, N2, and P3 ERP components revealed a typical self-bias in both groups (self distinct from friend and stranger), and only the autistic group showed evidence of a familiarity effect (N2 more negative-going for stranger than friend). The findings are discussed in relation to self-other distinction ability, and the relevance of other neuropsychological and psychiatric conditions such as anxiety and alexithymia are also considered.

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7. Yang F, You H, Mizui T, Ishikawa Y, Takao K, Miyakawa T, Li X, Bai T, Xia K, Zhang L, Pang D, Xu Y, Zhu C, Kojima M, Lu B. Inhibiting proBDNF to mature BDNF conversion leads to ASD-like phenotypes in vivo. Mol Psychiatry;2024 (May 18)

Autism Spectrum Disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is regulated by mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF in a diametrically opposite manner: proBDNF inhibits while mBDNF potentiates synapses. Here we generated a knock-in mouse line (BDNF(met/leu)) in which the conversion of proBDNF to mBDNF is attenuated. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNF(met/leu) mice showed reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity in the hippocampus. They also exhibited ASD-like phenotypes, including stereotypical behaviors and deficits in social interaction. Moreover, the plasma proBDNF/mBDNF ratio was significantly increased in ASD patients compared to normal children in a case-control study. Thus, deficits in proBDNF to mBDNF conversion in the brain may contribute to ASD-like behaviors, and plasma proBDNF/mBDNF ratio may be a potential biomarker for ASD.

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8. Zhao M, Hou M, Herold F, Chen Y, Werneck AO, Block ME, Kramer AF, Taylor A, Cunha PM, Chaput JP, Falck RS, Owen N, Zou L. Associations of meeting 24-hour movement behavior guidelines with social and emotional function in youth with ASD/ADHD. J Affect Disord;2024 (May 18)

BACKGROUND: The 24-hour movement behavior (24-HMB) guidelines recommend that children and adolescents should limit screen time (ST), get an adequate amount of sleep (SL), and engage in sufficient physical activity (PA) to ensure health and healthy development. Meeting 24-HMB guidelines is associated with positive mental health outcomes (e.g., social and emotional function) in the general population. However, it is unclear whether such findings extend to children and adolescents with comorbid Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). Thus, we examined associations of meeting 24-HMB guidelines with social and emotional function in children and adolescents with comorbid ASD/ADHD. METHODS: Data from the 2020-2021 National Survey of Children’s Health – a U.S. national, population-based, cross-sectional study – were used. We extracted and analyzed data on children and adolescents (aged between 6 and 17 years) diagnosed with comorbidity of ASD/ADHD. Data on movement behaviors (PA, ST, and SL) and specific outcome variables (social function and emotional function) were collected through caregiver-proxy reports. Logistic regressions were performed to examine the associations between meeting 24-HMB guidelines and social and emotional outcomes adjusting for covariates (e.g., age, sex, ethnicity, weight status, birth status, socio-economic status, and receiving medication/behavioral treatment). RESULTS: Among 979 children and adolescents with comorbid ASD/ADHD, only 3.8 % met all three 24-HMB guidelines. In total, 45.0 % of participants met at least one guideline, and 25.5 % of those met at least two guidelines. Compared to those who did not meet any 24-HMB guidelines, meeting SL + ST guidelines was significantly associated with lower odds of poorer social function (being bullied: OR = 0.3, 95%CI [0.1-0.7]; arguing: OR = 0.2, 95%CI[0.1-0.4]). Furthermore, meeting PA + ST + SL guidelines was associated with lower odds of poorer emotional function (depression: OR = 0.5, 95%CI[0.3-0.7]). CONCLUSION: Meeting 24-HMB guidelines was associated with better social and emotional function in U.S. children and adolescents with comorbid ASD/ADHD; however, currently very few with comorbid ASD/ADHD meet all 24-HMB guidelines. These results emphasize the importance of promoting adherence to the 24-HMB guidelines among children and adolescents facing the challenges of comorbid ASD/ADHD. These cross-sectional findings point to the need for further empirical evidence from longitudinal studies to support our conclusions.

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