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. 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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4. Stania M, Emich-Widera E, Kazek B, Kamieniarz A, Swatowska-Wenglarczyk M, Juras G. Modulation of center-of-pressure signal in children on the autism spectrum: A case-control study. Gait & posture. 2023; 103: 67-72.

BACKGROUND: Proper postural and motor control plays a fundamental role in the child’s ontogenetic development. So far, the postural control in children on the autism spectrum has mainly been assessed with standard posturographic measurements of center of pressure (COP) displacements. RESEARCH QUESTION: What are the differences in postural control between autistic and typically developing children? METHODS: The study group comprised 16 autistic children aged 6-10 years, identified by a psychiatrist. The control group consisted of 16 typically developing children aged 6-10 years with no posture deformities, no pervasive developmental disorder and no history of postural control or movement deficits. The data were collected during quiet standing with eyes open using a force plate. To gain a better insight into the postural control processes, the rambling-trembling and sample entropy analyses were used in COP data processing. RESULTS: Compared to typically developing children, those with autism spectrum had significantly higher values of COP and rambling trajectory parameters in the antero-posterior direction during quiet standing. The variables of the trembling trajectory did not differ significantly between the groups. The autistic children had significantly lower values of sample entropy in the antero-posterior direction compared to typically developing children. SIGNIFICANCE: More advanced measures of COP displacements including the rambling-trembling method and sample entropy revealed differences in postural control between autistic and typically developing children. These methods may therefore contribute to functional assessment of postural control deficits in children on the autism spectrum.

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5. Tarzi G, Mendoza O, Lunsky Y, St John L. The experiences and attitudes of family caregivers of adults with intellectual and developmental disabilities at different timepoints in the COVID-19 pandemic. Disability and health journal. 2023: 101472.

BACKGROUND: The COVID-19 pandemic has resulted in increased pressures for family caregivers of adults with intellectual and developmental disabilities (IDD). However, little is known about how their attitudes and perceptions have changed over the course of the pandemic. OBJECTIVE: To compare the COVID-19 experiences and attitudes of two groups of family caregivers, reported at different timepoints in the pandemic: prior to vaccine availability and after. METHODS: As part of a larger research study, family caregivers of adults with IDD from across Canada completed surveys on their COVID-19 experiences. Survey questions included responses about access to supports, stressors, self-efficacy, mental wellbeing, and pandemic impacts on their family member with IDD. Respondents were assigned to either of two groups based on the time of questionnaire completion: late 2020/early 2021 for Group 1 and mid 2022 for Group 2. Descriptive statistics and analysis between groups were reported. RESULTS: Despite being surveyed at different timepoints in the pandemic, both groups indicated concerns regarding lack of professional support and resources, lack of programming, and experiences of loneliness for their family members. However, Group 2 reported greater self-efficacy dealing with COVID-19 related challenges and greater overall mental wellbeing, compared to Group 1. Group 2 caregivers, after which vaccines were widely available in Canada, were largely vaccinated (96.4%). CONCLUSIONS: Despite the COVID-19 pandemic persisting for over two years, family caregivers of adults with IDD reported facing the same challenges as families who reported on their experiences a year prior. Notwithstanding, family caregivers surveyed later in the pandemic described a greater sense of self-efficacy and mental wellbeing.

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6. Zhang H, Tang X, Feng C, Gao Y, Hong Q, Zhang J, Zhang X, Zheng Q, Lin J, Liu X, Shen L. The use of data independent acquisition based proteomic analysis and machine learning to reveal potential biomarkers for autism spectrum disorder. Journal of proteomics. 2023; 278: 104872.

Autism spectrum disorder (ASD) is a complex neurological developmental disorder in children, and is associated with social isolation and restricted interests. The etiology of this disorder is still unknown. There is neither any confirmed laboratory test nor any effective therapeutic strategy to diagnose or cure it. We performed data independent acquisition (DIA) and multiple reaction monitoring (MRM) analysis of plasma from children with ASD and controls. The result showed that 45 differentially expressed proteins (DEPs) were identified between autistic subjects and controls. Among these, only one DEP was down-regulated in ASD; other DEPs were up-regulated in ASD children’s plasma. These proteins are found associated with complement and coagulation cascades, vitamin digestion and absorption, cholesterol metabolism, platelet degranulation, selenium micronutrient network, extracellular matrix organization and inflammatory pathway, which have been reported to be related to ASD. After MRM verification, five key proteins in complement pathway (PLG, SERPINC1, and A2M) and inflammatory pathway (CD5L, ATRN, SERPINC1, and A2M) were confirmed to be significantly up-regulated in ASD group. Through the screening of machine learning model and MRM verification, we found that two proteins (biotinidase and carbonic anhydrase 1) can be used as early diagnostic markers of ASD (AUC = 0.8, p = 0.0001). SIGNIFICANCE: ASD is the fastest growing neurodevelopmental disorder in the world and has become a major public health problem worldwide. Its prevalence has been steadily increasing, with a global prevalence rate of 1%. Early diagnosis and intervention can achieve better prognosis. In this study, data independent acquisition (DIA) and multiple reaction monitoring (MRM) analysis was applied to analyze the plasma proteome of ASD patients (31 (±5) months old), and 378 proteins were quantified. 45 differentially expressed proteins (DEPs) were identified between the ASD group and the control group. They mainly were associated with platelet degranulation, ECM proteoglycar, complement and coagulation cascades, selenium micronutrient network, regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor binding proteins (IGFBPs), cholesterol metabolism, vitamin metabolism, and inflammatory pathway. Through the integrated machine learning methods and the MRM verification of independent samples, it is considered that biotinidase and carbon anhydrase 1 have the potential to become biomarkers for the early diagnosis of ASD. These results complement proteomics database of the ASD patients, broaden our understanding of ASD, and provide a panel of biomarkers for the early diagnosis of ASD.

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