1. Ahmed Z, Hao S, Williamson T, McMorris CA, Bousman CA. Psychotropic prescribing rates and pharmacogenomic testing implications for autism in the Canadian primary care sentinel surveillance network. Pharmacogenetics and genomics. 2022; 32(3): 94-100.

OBJECTIVE: To estimate prescribing rates of psychotropic drugs to individuals with autism and the proportion of these individuals who could benefit from pharmacogenetic testing. METHODS: Prescribing data for 92 psychotropic drugs, including 31 antidepressants, 22 antipsychotics, 14 mood stabilizer/antiepileptics, 17 anxiolytic/hypnotics and eight antiadrenergic/psychostimulant were retrieved from medical records of 787 (613 males) autistic individuals who sought treatment from a primary care office enrolled in the Canadian Primary Care Sentinel Surveillance Network between 2012 and 2014. Each prescribed drug was cross-referenced with pharmacogenomic-based prescribing guidelines published by the Clinical Pharmacogenetics Implementation Consortium, the Dutch Pharmacogenetics Working Group, and the Canadian Pharmacogenomics Network for Drug Safety. RESULTS: More than half (58%) of the participants were prescribed a psychotropic drug and 37% were prescribed two or more psychotropic drugs concurrently. Among the 83 psychotropic drugs examined, 54 (65%) were prescribed to one or more participants during the study’s observation period. The ten most frequently prescribed psychotropics were methylphenidate (16.3%), risperidone (12.8%), lorazepam (12.1%), fluoxetine (7.9%), sertraline (7.1%), quetiapine (6.9%), aripiprazole (6.1%), lisdexamfetamine (5.8%), citalopram (5.6%) and clonazepam (4.8%). Seventeen (32%) of the 54 psychotropic drugs prescribed were linked to a pharmacogenomic-based prescribing guideline, including risperidone, sertraline, aripiprazole and citalopram. CONCLUSIONS: Our findings suggest primary care providers in Canada prescribe a wide range of psychotropics to their patients with autism, some of which may benefit from the integration of pharmacogenomic information into their treatment planning.

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2. Bagattoni S, Lardani L, D’Alessandro G, Piana G. Oral health status of Italian children with Autism Spectrum Disorder. European journal of paediatric dentistry. 2021; 22(3): 243-7.

AIM: Autism Spectrum Disorder (ASD) is characterised by communication deficits and repetitive unusual behaviours. The behaviour guidance of these children represents a challenge for the dental team. The aim of the study was to evaluate the oral health status in a group of Italian children with ASD. MATERIALS AND METHODS: Study Design: Sixty-four Italian children with ASD and 64 controls were included. Data were collected by means of questionnaires and clinical examinations. RESULTS: Dental trauma (p=0.007), bruxism (p=0.001) and biting objects habit (p=0.021) were more frequent in the study group; fluoride exposure was lower (p=0.001) (chi-square test). The mean plaque index was 1.48 ±0.75 in the study group and 0.81±0.56 in the control group (p=0.001; Mann-Whitney U test); the mean dmft/DMFT was 3.00 ±1.2 and 2.3 ±1.8 in the study group and 1.8 ±1.1 and 1.0 ±1.1 in the control group (p<0.001; Mann-Whitney U test). Anterior open bite was more frequent in the study group (p=0.013; Chi-square test). No significant differences were found for enamel defects, molar relationship, posterior crossbite and deep bite. Significantly more children with ASD showed a negative behaviour (80% vs 35%: p =0.001; Chi-square test). CONCLUSION Children with ASD have a poorer oral health status than healthy children. The early establishment of a home dental hygiene should be encouraged.

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3. Bartlett E, Archibald AD, Francis D, Ling L, Thomas R, Chandler G, Ward L, O’Farrell G, Pandelache A, Delatycki MB, Bennetts BH, Ho G, Fisk K, Baker EK, Amor DJ, Godler DE. Paternal retraction of a fragile X allele to normal size, showing normal function over two generations. American journal of medical genetics Part A. 2022; 188(1): 304-9.

The FMR1 premutation (PM:55-199 CGG) is associated with fragile X-associated tremor/ataxia syndrome (FXTAS) and when maternally transmitted is at risk of expansion to a hypermethylated full mutation (FM: ≥ 200 CGG) that causes fragile X syndrome (FXS). We describe a maternally transmitted PM (77 CGG) that was passed to a son (103 CGG), and to a daughter (220-1822 CGG), who were affected with FXTAS and FXS, respectively. The male with the PM showed low-level mosaicism for normal size of 30 and 37 CGG. This male had two offspring: one female mosaic for PM and FM (56, 157, >200 CGG) and another with only a 37 CGG allele detected in multiple tissues, neither with a clinical phenotype. The female with the 37 CGG allele showed normal levels of FMR1 methylation and mRNA and passed this 37 CGG allele to one of her daughters, who was also unaffected. These findings show that post-zygotic paternal retraction can lead to low-level mosaicism for normal size alleles, with these normal alleles being functional when passed over two generations.

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4. Bolourian Y, Losh A, Hamsho N, Eisenhower A, Blacher J. General Education Teachers’ Perceptions of Autism, Inclusive Practices, and Relationship Building Strategies. Journal of autism and developmental disorders. 2021.

To identify target areas for professional development, this mixed-methods study examined general education teachers’ perceptions of autism and pedagogical practices in early elementary classrooms in the United States. In focus groups, teachers (N = 18) identified terms they associated with autism and strategies they used for inclusion and relationship building. Participants systematically free-listed and ranked their responses to three prompts. Using ranked responses, saliency scores were calculated to assess the perceived importance and frequency of responses. Teachers’ most salient perceptions of autism (e.g., social difficulties, focused/fixed interests) revealed an awareness of core symptoms. Salient inclusion practices included assigning special classroom responsibilities and showcasing student talents; salient relationship-building strategies included embracing students’ special interests and engaging in one-on-one time. Implications for teacher trainings are discussed.

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5. Boukhatem I, Fleury S, Welman M, Le Blanc J, Thys C, Freson K, Best MG, Würdinger T, Allen BG, Lordkipanidzé M. The brain-derived neurotrophic factor prompts platelet aggregation and secretion. Blood advances. 2021; 5(18): 3568-80.

Brain-derived neurotrophic factor (BDNF) has both autocrine and paracrine roles in neurons, and its release and signaling mechanisms have been extensively studied in the central nervous system. Large quantities of BDNF have been reported in circulation, essentially stored in platelets with concentrations reaching 100- to 1000-fold those of neurons. Despite this abundance, the function of BDNF in platelet biology has not been explored. At low concentrations, BDNF primed platelets, acting synergistically with classical agonists. At high concentrations, BDNF induced complete biphasic platelet aggregation that in part relied on amplification from secondary mediators. Neurotrophin-4, but not nerve growth factor, and an activating antibody against the canonical BDNF receptor tropomyosin-related kinase B (TrkB) induced similar platelet responses to BDNF, suggesting TrkB could be the mediator. Platelets expressed, both at their surface and in their intracellular compartment, a truncated form of TrkB lacking its tyrosine kinase domain. BDNF-induced platelet aggregation was prevented by inhibitors of Ras-related C3 botulinum toxin substrate 1 (Rac1), protein kinase C, and phosphoinositide 3-kinase. BDNF-stimulated platelets secreted a panel of angiogenic and inflammatory cytokines, which may play a role in maintaining vascular homeostasis. Two families with autism spectrum disorder were found to carry rare missense variants in the BDNF gene. Platelet studies revealed defects in platelet aggregation to low concentrations of collagen, as well as reduced adenosine triphosphate secretion in response to adenosine diphosphate. In summary, circulating BDNF levels appear to regulate platelet activation, aggregation, and secretion through activation of a truncated TrkB receptor and downstream kinase-dependent signaling.

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6. Faust TE, Gunner G, Schafer DP. Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS. Nature reviews Neuroscience. 2021; 22(11): 657-73.

Almost 60 years have passed since the initial discovery by Hubel and Wiesel that changes in neuronal activity can elicit developmental rewiring of the central nervous system (CNS). Over this period, we have gained a more comprehensive picture of how both spontaneous neural activity and sensory experience-induced changes in neuronal activity guide CNS circuit development. Here we review activity-dependent synaptic pruning in the mammalian CNS, which we define as the removal of a subset of synapses, while others are maintained, in response to changes in neural activity in the developing nervous system. We discuss the mounting evidence that immune and cell-death molecules are important mechanistic links by which changes in neural activity guide the pruning of specific synapses, emphasizing the role of glial cells in this process. Finally, we discuss how these developmental pruning programmes may go awry in neurodevelopmental disorders of the human CNS, focusing on autism spectrum disorder and schizophrenia. Together, our aim is to give an overview of how the field of activity-dependent pruning research has evolved, led to exciting new questions and guided the identification of new, therapeutically relevant mechanisms that result in aberrant circuit development in neurodevelopmental disorders.

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7. Hedley D, Hayward SM, Denney K, Uljarević M, Bury S, Sahin E, Brown CM, Clapperton A, Dissanayake C, Robinson J, Trollor J, Stokes MA. The association between COVID-19, personal wellbeing, depression, and suicide risk factors in Australian autistic adults. Autism research : official journal of the International Society for Autism Research. 2021; 14(12): 2663-76.

The COVID-19 pandemic has had a significant impact on the mental health and wellbeing of the world’s population, with particularly negative effects on vulnerable populations, including autistic people. Although some consensus regarding specific impact on aspects of wellbeing and mental health in autism is starting to emerge, it is unclear whether the pandemic has increased suicide risk. The goals of this study were to examine (a) potential associations between COVID-19 impact and depression, personal wellbeing, and suicide risk factors in Australian autistic adults and (b) age and gender effects. The COVID-19 Impact Scale (CIS), Personal Wellbeing Index, Patient Health Questionnaire, and the Suicide Behavior Questionnaire, Revised (SBQ-R), were administered to 111 autistic adults aged 20 to 71 years during the second wave of the COVID-19 pandemic in Australia. COVID-19 impact showed small associations with poorer personal wellbeing (r = -0.224, p = 0.023, [-0.409, -0.016]) and higher depressive symptoms (r = 0.268, p = 0.006, [0.056, 0.445]) and was not associated with the SBQ-R suicide risk score (r = 0.081, p = 0.418, [-0.118, 0.264). No significant effects were identified for age. Although model results were similar for women and men, the strength of the associations between personal wellbeing and depression (z = -2.16, p = 0.015), and depression and SBQ-R suicide risk (z = 1.961, p = 0.025), were stronger in women than in men. Qualitative analysis of an open response question from the CIS suggested that the pandemic had both positive and negative impacts on participants. The COVID-19 pandemic has had a large impact on the mental health and wellbeing of the world’s population, particularly vulnerable populations such as autistic people. It is not known if these impacts on mental health and wellbeing have increased suicide risk. Our findings suggest that the impact of the COVID-19 pandemic may be associated with poorer wellbeing and higher depression, but is not associated with suicide risk. Overall, autistic people reported both positive and negative impacts of the pandemic on their lives.

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8. Lee CH, Bartholomay KL, Marzelli MJ, Miller JG, Bruno JL, Lightbody AA, Reiss AL. Neuroanatomical Profile of Young Females with Fragile X Syndrome: A Voxel-Based Morphometry Analysis. Cerebral cortex (New York, NY : 1991). 2021.

Fragile X syndrome is a genetic condition associated with alterations in brain and subsequent cognitive development. However, due to a milder phenotype relative to males, females with fragile X syndrome are underrepresented in research studies. In the current study, we investigate neuroanatomical differences in young females (age range: 6.03-16.32 years) with fragile X syndrome (N = 46) as compared to age-, sex-, and verbal abilities-matched participants (comparison group; N = 35). Between-group analyses of whole-brain and regional brain volumes were assessed using voxel-based morphometry. Results demonstrate significantly larger total gray and white matter volumes in girls with fragile X syndrome compared to a matched comparison group (Ps < 0.001). In addition, the fragile X group showed significantly larger gray matter volume in a bilateral parieto-occipital cluster and a right parieto-occipital cluster (Ps < 0.001). Conversely, the fragile X group showed significantly smaller gray matter volume in the bilateral gyrus rectus (P < 0.03). Associations between these regional brain volumes and key socio-emotional variables provide insight into gene-brain-behavior relationships underlying the fragile X syndrome phenotype in females. These findings represent the first characterization of a neuroanatomical phenotype in a large sample of girls with fragile X syndrome and expand our knowledge about potential neurodevelopmental mechanisms underlying cognitive-behavioral outcomes in this condition.

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9. Schmidt J, Goergens J, Pochechueva T, Kotter A, Schwenzer N, Sitte M, Werner G, Altmüller J, Thiele H, Nürnberg P, Isensee J, Li Y, Müller C, Leube B, Reinhardt HC, Hucho T, Salinas G, Helm M, Jachimowicz RD, Wieczorek D, Kohl T, Lehnart SE, Yigit G, Wollnik B. Biallelic variants in YRDC cause a developmental disorder with progeroid features. Human genetics. 2021; 140(12): 1679-93.

The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. By trio whole-exome sequencing, we identified a novel homozygous missense mutation, c.662T > C, in YRDC affecting an evolutionary highly conserved amino acid (p.Ile221Thr). Functional characterization of patient-derived dermal fibroblasts revealed that this mutation impairs YRDC function and consequently results in reduced t(6)A modifications of tRNAs. Furthermore, we established and performed a novel and highly sensitive 3-D Q-FISH analysis based on single-telomere detection to investigate the impact of YRDC on telomere maintenance. This analysis revealed significant telomere shortening in YRDC-mutant cells. Moreover, single-cell RNA sequencing analysis of YRDC-mutant fibroblasts revealed significant transcriptome-wide changes in gene expression, specifically enriched for genes associated with processes involved in DNA repair. We next examined the DNA damage response of patient’s dermal fibroblasts and detected an increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect. Thus, our data suggest that YRDC may affect the maintenance of genomic stability. Together, our findings indicate that biallelic variants in YRDC result in a developmental disorder with progeroid features and might be linked to increased genomic instability and telomere shortening.

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10. Tokatly Latzer I, Grossman Z, Sachs N, Yahal O, Even-Zohar D, Carmon L, Flor-Hirsch H, Ringel A, Farah CF, Avni-Maskit M, Leitner Y. Failure of Israeli pediatric residency curricula to cover child development and special education issues: results of a national survey on levels of knowledge. Israel journal of health policy research. 2021; 10(1): 45.

BACKGROUND: There is an increasing prevalence of developmental difficulties among Israeli children. We aimed to assess whether pediatricians are equipped to diagnose and manage them. METHODS: We assessed the knowledge of basic child development issues and availability of services and content of special education systems among a randomly selected national sample of residents and senior Israeli pediatricians. This was done via an 70-itemed survey developed especially for this study which consisted of seven main subjects: developmental milestones, global developmental delay, autism spectrum disorder, attention deficit hyperactivity disorder, protocol for referring to a child development institute, availability and facilities of special education systems, and medical conditions associated with developmental delay. RESULTS: A total of 310 pediatricians (an 86 % usable response rate) participated. The total median knowledge score was 32.1 % (IQR 17.8-53.5 %). Knowledge was significantly better among senior pediatricians (p < .001), those working in an office-based setting (p < .001), and those who were parents (p < .001) or had a family history of a developmental condition (p = .003). Most responders (94 %) felt that their resident training in child development was inadequate, and that they do not have sufficient access to resources and guidelines about child development and special education systems (80 %). CONCLUSIONS: The gap in knowledge on topics of child development and special education systems among Israeli pediatricians stems from inadequacies in the current curricula of pediatric residencies. The alarmingly low scores of our survey on these issues call for prompt revamping of the syllabus to include them.

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