Pubmed du 28/02/20

vendredi 28 février 2020

1. Aldosary M, Al-Bakheet A, Al-Dhalaan H, Almass R, Alsagob M, Al-Younes B, AlQuait L, Mustafa OM, Bulbul M, Rahbeeni Z, Alfadhel M, Chedrawi A, Al-Hassnan Z, AlDosari M, Al-Zaidan H, Al-Muhaizea MA, AlSayed MD, Salih MA, AlShammari M, Faizal-Ul-Haque M, Chishti MA, Al-Harazi O, Al-Odaib A, Kaya N, Colak D. Rett Syndrome, a Neurodevelopmental Disorder, Whole-Transcriptome, and Mitochondrial Genome Multiomics Analyses Identify Novel Variations and Disease Pathways. Omics ;2020 (Feb 27)

Rett syndrome (RTT) is a severe neurodevelopmental disorder reported worldwide in diverse populations. RTT is diagnosed primarily in females, with clinical findings manifesting early in life. Despite the variable rates across populations, RTT has an estimated prevalence of approximately 1 in 10,000 live female births. Among 215 Saudi Arabian patients with neurodevelopmental and autism spectrum disorders, we identified 33 patients with RTT who were subsequently examined by genome-wide transcriptome and mitochondrial genome variations. To the best of our knowledge, this is the first in-depth molecular and multiomics analyses of a large cohort of Saudi RTT cases with a view to informing the underlying mechanisms of this disease that impact many patients and families worldwide. The patients were unrelated, except for 2 affected sisters, and comprised of 25 classic and eight atypical RTT cases. The cases were screened for methyl-CpG binding protein 2 (MECP2), CDKL5, FOXG1, NTNG1, and mitochondrial DNA (mtDNA) variants, as well as copy number variations (CNVs) using a genome-wide experimental strategy. We found that 15 patients (13 classic and two atypical RTT) have MECP2 mutations, 2 of which were novel variants. Two patients had novel FOXG1 and CDKL5 variants (both atypical RTT). Whole mtDNA sequencing of the patients who were MECP2 negative revealed two novel mtDNA variants in two classic RTT patients. Importantly, the whole-transcriptome analysis of our RTT patients’ blood and further comparison with previous expression profiling of brain tissue from patients with RTT revealed 77 significantly dysregulated genes. The gene ontology and interaction network analysis indicated potentially critical roles of MAPK9, NDUFA5, ATR, SMARCA5, RPL23, SRSF3, and mitochondrial dysfunction, oxidative stress response and MAPK signaling pathways in the pathogenesis of RTT genes. This study expands our knowledge on RTT disease networks and pathways as well as presents novel mutations and mtDNA alterations in RTT in a population sample that was not previously studied.

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2. Bedford SA, Park MTM, Devenyi GA, Tullo S, Germann J, Patel R, Anagnostou E, Baron-Cohen S, Bullmore ET, Chura LR, Craig MC, Ecker C, Floris DL, Holt RJ, Lenroot R, Lerch JP, Lombardo MV, Murphy DGM, Raznahan A, Ruigrok ANV, Smith E, Spencer MD, Suckling J, Taylor MJ, Thurm A, Lai MC, Chakravarty MM. Greater cortical thickness in individuals with ASD. Mol Psychiatry ;2020 (Mar) ;25(3):507-508.

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3. Clarke KA, Williams DL. Instruction Using Augmentative and Alternative Communication Supports : Description of Current Practices by Speech-Language Pathologists Who Work With Children With Autism Spectrum Disorder. Am J Speech Lang Pathol ;2020 (Feb 26):1-11.

Purpose The aim of this research study was to examine common practices of speech-language pathologists (SLPs) who work with children with autism spectrum disorder (ASD) with respect to whether or not SLPs consider processing differences in ASD or the effects of input during their instruction. Method Following a qualitative research method, how SLPs instruct and present augmentative and alternative communication systems to individuals with ASD, their rationale for method selection, and their perception of the efficacy of selected interventions were probed. Semistructured interviews were conducted as part of an in-depth case report with content analysis. Results Based on completed interviews, 4 primary themes were identified : (a) instructional method, (b) input provided, (c) decision-making process, and (d) perceived efficacy of treatment. Additionally, one secondary theme, training and education received, was identified. Conclusions Clinicians reported making decisions based on the needs of the child ; however, they also reported making decisions based on the diagnostic category that characterized the child (i.e., ASD). The use of modeling when teaching augmentative and alternative communication to individuals with ASD emerged as a theme, but variations in the method of modeling were noted. SLPs did not report regularly considering processing differences in ASD, nor did they consider the effects of input during instruction.

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4. Kaur S, Silver G, Samuels S, Rosen AH, Weiss M, Mauer EA, Gerber LM, Greenwald BM, Traube C. Delirium and Developmental Disability : Improving Specificity of a Pediatric Delirium Screen. Pediatr Crit Care Med ;2020 (Feb 26)

OBJECTIVES : Children with developmental disabilities are at high risk for developing delirium when critically ill. However, existing pediatric delirium screening tools were designed for children with typical development. The objective of this study was to improve the specificity of the Cornell Assessment for Pediatric Delirium, to allow for accurate detection of delirium in developmentally delayed children admitted to the PICU. We hypothesized that the Cornell Assessment for Pediatric Delirium, when combined with fluctuation in level of awareness as measured by the Richmond Agitation-Sedation Scale, would be valid and reliable for the diagnosis of delirium in developmentally delayed children. DESIGN : Prospective observational double-blind cohort study. SETTING : Tertiary care academic PICU. PATIENTS : Children with moderate to severe developmental delay. INTERVENTIONS : Each child was evaluated by the bedside nurse with the Cornell Assessment for Pediatric Delirium once every 12 hours and the Richmond Agitation-Sedation Scale every 4 hours. Cornell Assessment for Pediatric Delirium (score >/= 9) + Richmond Agitation-Sedation Scale fluctuation (change in Richmond Agitation-Sedation Scale score of at least 2 points during a 24-hr period) was compared with the criterion standard psychiatric evaluation for diagnosis of delirium. MEASUREMENTS AND MAIN RESULTS : Forty children participated ; 94 independent paired assessments were completed. The psychiatrists’ diagnostic evaluations were compared with the detection of delirium by the Cornell Assessment for Pediatric Delirium and Richmond Agitation-Sedation Scale. Specificity of the Cornell Assessment for Pediatric Delirium + Richmond Agitation-Sedation Scale fluctuation was 97% (CI, 90-100%), positive predictive value of Cornell Assessment for Pediatric Delirium + Richmond Agitation-Sedation Scale fluctuation was 89% (CI, 65-99%) ; and negative predictive value remained acceptable at 87% (95% CI, 77-94%). In addition, to confirm interrater reliability of the criterion standard, 11 assessments were performed by two or more psychiatrists in a blinded fashion. There was perfect agreement (kappa = 1), indicating reliability in psychiatric diagnosis of delirium in developmentally delayed children. CONCLUSION : When used in conjunction with Richmond Agitation-Sedation Scale score fluctuation, the Cornell Assessment for Pediatric Delirium is a sensitive and specific tool for the detection of delirium in children with developmental delay. This allows for reliable delirium screening in this hard-to-assess population.

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5. Li G, Chen MH, Li G, Wu D, Lian C, Sun Q, Shen D, Wang L. A Longitudinal MRI Study of Amygdala and Hippocampal Subfields for Infants with Risk of Autism. Graph Learn Med Imaging (2019) ;2019 (Oct) ;11849:164-171.

Currently, there are still no early biomarkers to detect infants with risk of autism spectrum disorder (ASD), which is mainly diagnosed based on behavioral observations at three or four years of age. Since intervention efforts may miss a critical developmental window after 2 years old, it is clinically significant to identify imaging-based biomarkers at an early stage for better intervention, before behavioral diagnostic signs of ASD typically arising. Previous studies on older children and young adults with ASD demonstrate altered developmental trajectories of the amygdala and hippocampus. However, our knowledge on their developmental trajectories in early postnatal stages remains very limited. In this paper, for the first time, we propose a volume-based analysis of the amygdala and hippocampal subfields of the infant subjects with risk of ASD at 6, 12, and 24 months of age. To address the challenge of low tissue contrast and small structural size of infant amygdala and hippocampal subfields, we propose a novel deep-learning approach, dilated-dense U-Net, to digitally segment the amygdala and hippocampal subfields in a longitudinal dataset, the National Database for Autism Research (NDAR). A volume-based analysis is then performed based on the segmentation results. Our study shows that the overgrowth of amygdala and cornu ammonis sectors (CA) 1-3 May start from 6 months of age, which may be related to the emergence of autistic spectrum disorder.

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6. Matsumura K, Seiriki K, Okada S, Nagase M, Ayabe S, Yamada I, Furuse T, Shibuya H, Yasuda Y, Yamamori H, Fujimoto M, Nagayasu K, Yamamoto K, Kitagawa K, Miura H, Gotoda-Nishimura N, Igarashi H, Hayashida M, Baba M, Kondo M, Hasebe S, Ueshima K, Kasai A, Ago Y, Hayata-Takano A, Shintani N, Iguchi T, Sato M, Yamaguchi S, Tamura M, Wakana S, Yoshiki A, Watabe AM, Okano H, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T. Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes. Nat Commun ;2020 (Feb 26) ;11(1):859.

Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome ; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.

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7. Stanley IH, Day TN, Gallyer AJ, Shelef L, Kalla C, Gutierrez PM, Joiner TE. Autism-related traits and suicide risk among active duty U.S. military service members. Psychol Serv ;2020 (Feb 27)

Suicide rates within the U.S. military are elevated. The interpersonal theory of suicide, supported within military samples, suggests that social disconnectedness confers risk for suicide. Autism spectrum disorder (ASD) is characterized by symptoms-difficulties in social communication/interaction (SCI) and restricted and repetitive behaviors (RRBs)-that contribute to social disconnectedness. To our knowledge, no study has examined ASD-related traits and suicide risk among active duty U.S. military service members. Participants included 292 active duty U.S. military service members (M [SD] age = 28.67 [7.40] years, 68.5% male, 78.1% White). The Autism Spectrum Quotient, Repetitive Behaviours Questionnaire-2 for Adults, Self-Injurious Thoughts and Behaviors Interview-Short Form, and Interpersonal Needs Questionnaire assessed for SCI difficulties, RRBs, suicidal symptoms, and interpersonal theory of suicide constructs (i.e., perceived burdensomeness, thwarted belongingness), respectively. Elevated levels of SCI difficulties and RRBs were associated with increased odds of reporting suicidal thoughts and behaviors occurring since joining the military, controlling for the number of years of service and suicidal symptoms occurring prior to joining the military. Perceived burdensomeness and thwarted belongingness statistically accounted for the relationship between ASD-related traits and suicidal ideation occurring since joining the military ; a rival mediator, emotion dysregulation, was not a significant mediator. Among active duty U.S. military service members, greater ASD-related traits were associated with an increased likelihood of reporting suicidal thoughts and behaviors occurring since joining the military. Clinical efforts targeting perceived burdensomeness and thwarted belongingness might reduce suicide risk among military service members with elevated ASD-related traits. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

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