Pubmed du 28/01/20

mardi 28 janvier 2020

1. Dizitzer Y, Meiri G, Flusser H, Michaelovski A, Dinstein I, Menashe I. Comorbidity and health services’ usage in children with autism spectrum disorder : a nested case-control study. Epidemiol Psychiatr Sci. 2020 ; 29 : e95.

AIMS : Children with autism spectrum disorder (ASD) tend to suffer from various medical comorbidities. We studied the comorbidity burden and health services’ utilisation of children with ASD to highlight potential aetiologies and to better understand the medical needs of these children. METHODS : In this nested case-control study, ASD cases and controls - matched by age, sex and ethnicity in a 1:5 ratio - were sampled from all children born between 2009 and 2016 at a tertiary medical centre. Data were obtained from the hospital’s electronic database. Comorbid diagnoses were classified according to pathophysiological aetiology and anatomical/systemic classification of disease. Standard univariate and multivariate statistics were used to demonstrate comorbidities and health services’ utilisation patterns that are significantly associated with ASD. RESULTS : ASD children had higher rates of comorbidities according to both pathophysiological and anatomical/systemic classifications (p < 0.001). The most marked significant differences were observed for : hearing impairments (OR = 4.728 ; 95% CI 2.207-10.127) and other auricular conditions (OR = 5.040 ; 95% CI 1.759-14.438) ; neurological (OR = 8.198 ; 95% CI 5.690-11.813) and ophthalmological (OR = 3.381 ; 95% CI 1.617-7.068) conditions ; and ADD/ADHD (OR = 3.246 ; 95% CI 1.811-5.818). A subgroup analysis revealed a more profound case-control difference in anaemia rates among girls than in boys (OR = 3.25 ; 95% CI 1.04-10.19 v. OR = 0.74 ; 95% CI 0.33-1.64 respectively) and an opposite trend (larger differences in males than in females in cardiovascular diseases (OR = 1.99 ; 95% CI 1.23-3.23 v. OR = 0.76 ; 95% CI 0.17-3.45, respectively)). In addition, larger case-control differences were seen among Bedouin children than in Jewish children in a number of medical comorbidities (Breslow-Day test for homogeneity of odds ratio p-value <0.05). Finally, we found that children with ASD tended to be referred to the emergency department and to be admitted to the hospital more frequently than children without ASD, even after adjusting for their comorbidity burden (aOR = 1.28 ; 95% CI 1.08-1.50 and aOR = 1.28 ; 95% CI 1.11-1.47 for >1 referrals and admissions per year, respectively). CONCLUSIONS : The findings of this study contribute to the overall understanding of comorbid conditions and health services’ utilisation for children with ASD. The higher prevalences of comorbidities and healthcare services’ utilisation for children with ASD highlight the additional medical burden associated with this condition.

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2. Elsabbagh M. Linking risk factors and outcomes in autism spectrum disorder : is there evidence for resilience ?. BMJ (Clinical research ed). 2020 ; 368 : l6880.

Autism spectrum disorder (referred to here as autism) is one of several overlapping neurodevelopmental conditions that have variable impacts on different individuals. This variability results from dynamic interactions between biological and non-biological risk factors, which result in increasing differentiation between individuals over time. Although this differentiation continues well into adulthood, the infancy period is when the brain and behavior develop rapidly, and when the first signs and symptoms of autism emerge. This review discusses advances in our understanding of the causal pathways leading to autism and overlapping neurodevelopmental conditions. Research is also mapping trajectories of brain and behavioral development for some risk groups, namely later born siblings of children with autism and/or infants referred because of developmental concerns. This knowledge has been useful in improving early identification and establishing the feasibility of targeted interventions for infant risk groups before symptoms arise. However, key knowledge gaps remain, such as the discovery of protective factors (biological or environmental) that may mitigate the impact of risk. Also, the dynamic mechanisms that underlie the associations between risk factors and outcomes need further research. These include the processes of resilience, which may explain why some individuals at risk for autism achieve better than expected outcomes. Bridging these knowledge gaps would help to provide tools for early identification and intervention that reflect dynamic developmental pathways from risk to outcomes.

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3. Gabis LV, Shefer S, Raas-Rothschild A. Ethical Dilemmas Linked to Fragile X Testing of Minors-a Preliminary Survey Among Professionals. Journal of molecular neuroscience : MN. 2020.

Asymptomatic female carriers of the FMR1 premutation at childbearing age have been mostly identified through prenatal genetic testing, which is routinely proposed in Israel. During the last few years, a premutation phenotype in males and females has been defined-FXAND, including neuropsychiatric disorder, learning difficulties, endocrine dysfunction, and premature ovarian failure. So when a family at risk is identified, should individuals be tested for premutation even if minors ? In order to understand what professionals’ views are with regard to testing FMR1 premutation in minors, we performed a questionnaire testing both ethical attitudes and knowledge. Eighty-two percent of professionals would positively consider fragile X testing in minors, and an additional 15.4% would consider it in boys only. The specific phenotype of full mutation is recognized well by health professionals, while the premutation phenotype is not well known. There is a need to expand awareness on the fragile X premutation phenotype through better information. Testing of fragile X premutation status in minors should be considered, when at risk due to family history.

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4. Happe F, Frith U. Annual Research Review : Looking back to look forward - changes in the concept of autism and implications for future research. J Child Psychol Psychiatry. 2020.

The concept of autism is a significant contribution from child psychiatry that has entered wider culture and public consciousness, and has evolved significantly over the last four decades. Taking a rather personal retrospective, reflecting on our own time in autism research, this review explores changes in the concept of autism and the implications of these for future research. We focus on seven major changes in how autism is thought of, operationalised, and recognised : (1) from a narrow definition to wide diagnostic criteria ; (2) from a rare to a relatively common condition, although probably still under-recognised in women ; (3) from something affecting children, to a lifelong condition ; (4) from something discreet and distinct, to a dimensional view ; (5) from one thing to many ’autisms’, and a compound or ’fractionable’ condition ; (6) from a focus on ’pure’ autism, to recognition that complexity and comorbidity is the norm ; and finally, (7) from conceptualising autism purely as a ’developmental disorder’, to recognising a neurodiversity perspective, operationalised in participatory research models. We conclude with some challenges for the field and suggestions for areas currently neglected in autism research.

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5. Kaufmann WE. Long QT interval in Rett syndrome : expanding the knowledge of a poorly understood phenomenon. Dev Med Child Neurol. 2020.

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6. Kengne Kamga K, Nguefack S, Minka K, Wonkam Tingang E, Esterhuizen A, Nchangwi Munung S, De Vries J, Wonkam A. Cascade Testing for Fragile X Syndrome in a Rural Setting in Cameroon (Sub-Saharan Africa). Genes. 2020 ; 11(2).

Fragile X Syndrome (FXS), an X-linked dominant monogenic condition, is the main genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD). FXS is associated with an expansion of CGG repeat sequence in the Fragile X Mental Retardation gene 1 (FMR1) on chromosome X. Following a neuropediatric assessment of two male siblings who presented with signs of FXS that was confirmed with molecular testing, we provided cascade counselling and testing to the extended family. A total of 46 individuals were tested for FXS ; among them, 58.70% (n = 27) were females. The mean age was 9.4 (+/-5) years for children and 45.9 (+/-15.9) years for adults. Pedigree analysis suggested that the founder of these families was likely a normal transmitting male. Four out of 19 males with clinical ID were confirmed to have a full mutation for FXS, while 14/27 females had a pathologic CGG expansion (>56 CGG repeats) on one of their X chromosomes. Two women with premature menopause were confirmed of being carriers of premutation (91 and 101 CGG repeats). We also identified maternal alleles (91 and 126 CGG repeats) which expanded to a full mutation in their offspring (>200 CGG repeats). This study is a rare report on FXS from Africa and illustrates the case scenario of implementing genetic medicine for a neurogenetic condition in a rural setting.

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7. Laczmanska I, Stembalska A, Zlocinska M, Kozlowska J, Skiba P, Pesz K, Slezak R, Smigiel R, Jakubiak A, Misiak B, Sasiadek MM. Multiplex ligation-dependent probe amplification as a screening test in children with autism spectrum disorders. Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2020.

BACKGROUND : Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders, characterized by the presence of various symptoms related to deficits in communication and social interactions as well as stereotyped and repetitive behavior. Increasing evidence indicates the contribution of genetic factors in the etiology of ASDs. Genetic diagnosis in ASDs is based on identifying chromosome aberrations, microaberrations and point mutations in specific genes. One of the diagnostic tools is multiplex ligase-dependent probe amplification (MLPA) with a set of probes dedicated to ASDs (SALSA MLPA P343 Autism-1 ; MRC-Holland BV, Amsterdam, the Netherlands) targeting the genes located in the regions 15q11-q13, 16p11 and the SHANK3 gene in the 22q13 region. OBJECTIVES : Our study included 240 patients referred to the clinical genetics unit because of ASDs and/or developmental delay and/or an intellectual disability. Before genetic testing, the patients underwent a comprehensive medical work-up. MATERIAL AND METHODS : Multiplex ligase-dependent probe amplification was performed in 256 DNA samples from 240 probands and 16 family members using the SALSA MLPA P343 Autism-1 probe mix (MRC-Holland BV) according to the manufacturer’s protocol. RESULTS : We obtained 234 normal results and 22 abnormal results (15 probands and 7 abnormal results for probands’ parents or siblings). We diagnosed 1 16p11 microdeletion syndrome and 1 16p11 microduplication syndrome. We also found 3 deletions and 1 duplication in 15q13 region including 2 or 3 genes and 9 single probe alterations in the regions examined (1 duplication and 7 deletions). CONCLUSIONS : Due to the low costs, MLPA test may be a good tool for the genetic screening of ASD patients.

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8. Lamash L, Josman N. Full-information factor analysis of the Daily Routine and Autonomy (DRA) questionnaire among adolescents with autism spectrum disorder. Journal of adolescence. 2020 ; 79 : 221-31.

INTRODUCTION : Adolescents with autism spectrum disorder (ASD) show poor independence in daily activities. Unlike existing instruments, the innovative self-report Daily Routine and Autonomy questionnaire (DRA) addresses their level of and desire for independence in activities throughout a full daily routine. This study describes the DRA development, explores its psychometric properties and internal consistency reliability using full-information factor analysis (FIFA), and identifies levels of and desire for independence among adolescents with ASD. METHODS : Seventy-two Israeli adolescents with ASD (58 boys and 14 girls) aged 11-19 years (M = 14.59, SD = 1.61) completed the DRA. Statistical analyses were performed using SPSS and R. Internal consistency reliability, FIFA, Spearman’s correlations, t-tests, and Wilcoxon signed-rank were conducted to assess relationships and differences between the DRA parts. RESULTS : The FIFA revealed three factors with high sum-of-squared loadings (4.09-5.13). Of the 31 DRA items, 28 had factor loadings higher than 0.35 and were retained in the study questionnaire. The DRA had moderate-to-high internal reliability for factors (alpha = 0.65-0.84) and total scores (alpha = 0.86-0.90). Participants showed partial independence in most daily activities, with high desire for independence in social and leisure activities. Significant gaps in half of the DRA items indicate the participants’ desire for independence was significantly higher than their independence level. CONCLUSION : The DRA provides crucial information about levels of and desire for autonomy that can be used to promote participation of adolescents with ASD in setting their own goals for independent living.

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9. LeClaire JP, Stille SO, Foster KD, Berg RG. Analyzing essays about treating adults with special health care needs and intellectual and developmental disabilities. Journal of dental education. 2020.

OBJECTIVE : Analyze reflection essays written by one graduating class of students after an initial experience in a clinic for adults with special health care needs (SHCN) and intellectual and developmental disabilities, to draw insights from the patterns of observations expressed. METHODS : Essays were written by students from the University of Colorado School of Dental Medicine during the 2016-2017 academic year after completing a 1-day clinical experience treating this patient population. Readers identified 18 primary themes (PTs) previously identified in essays written during 2012-2013. RESULTS : The PT Complex communicating through third party was identified in 79.4% of essays. Least common were Frustrated patient could not understand (1.9%) and Frustrated patient could not talk (1.9%). Nine PTs were grouped to represent 3 component themes (CTs) : CT1 Communication challenges, CT2 Behavioral challenge, and CT3 Altruistic responses. This grouping showed moderate internal reliability. A fourth, CT4 Emotional challenges, was rejected due to low internal reliability. CT1 was most frequently identified, followed by CT3 then CT2. Three PTs were chosen as indicative of desirable outcomes and were labeled outcome themes (OTs) : OT1 Willing to see patients with SHCNs after graduation, OT2 Would like more Special Care Clinic (SCC) experiences in the future, and OT3 Looking forward to next SCC experience. Associations between CTs and OTs were not statistically significant, but provided useful insights. CONCLUSION : Reflection essays indicate discussion of strategies to manage behavioral challenges and encouragement of altruistic feelings are both vital in orientation sessions. These topics may be critical to positive student perceptions of the experience.

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10. Niikura H, Burns M, Bae R, Sorajja P. Transcatheter Therapy for Residual MR and Iatrogenic ASD after MitraClip and ASD closure. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2020.

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11. Rajabioun M, Motie Nasrabadi A, Shamsollahi MB, Coben R. Effective brain connectivity estimation between active brain regions in autism using the dual Kalman-based method. Biomedizinische Technik Biomedical engineering. 2020 ; 65(1) : 23-32.

Brain connectivity estimation is a useful method to study brain functions and diagnose neuroscience disorders. Effective connectivity is a subdivision of brain connectivity which discusses the causal relationship between different parts of the brain. In this study, a dual Kalman-based method is used for effective connectivity estimation. Because of connectivity changes in autism, the method is applied to autistic signals for effective connectivity estimation. For method validation, the dual Kalman based method is compared with other connectivity estimation methods by estimation error and the dual Kalman-based method gives acceptable results with less estimation errors. Then, connectivities between active brain regions of autistic and normal children in the resting state are estimated and compared. In this simulation, the brain is divided into eight regions and the connectivity between regions and within them is calculated. It can be concluded from the results that in the resting state condition the effective connectivity of active regions is decreased between regions and is increased within each region in autistic children. In another result, by averaging the connectivity between the extracted active sources of each region, the connectivity between the left and right of the central part is more than that in other regions and the connectivity in the occipital part is less than that in others.

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12. Sala G, Hooley M, Stokes MA. Romantic Intimacy in Autism : A Qualitative Analysis. J Autism Dev Disord. 2020.

Although autistic people have difficulties with social-emotional reciprocity, most still desire intimate romantic relationships. This study sought to identify enablers and barriers to emotional and physical intimacy for Autistic (n = 31) and non-autistic (n = 26) individuals. All participants completed an online survey including demographic information, the Autism Spectrum Quotient and questions on intimacy which were subject to thematic analysis. Enablers of intimacy for both groups included communication, sharing and similarity, respect and safety for self and other, and working on the relationship. Barriers for both groups included intra- and interpersonal conflicts ; autistic people specifically highlighted uncertainty about relationships and communication. These findings suggest autistic and non-autistic people have similar notions of intimacy, yet have different challenges in experiencing it.

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13. Sihombing NRB, Cai S, Wong DPW, Guan M, Chong SS, Faradz SMH, Winarni TI. Repeat expansion and methylation-sensitive triplet-primed polymerase chain reaction for fragile X mental retardation 1 gene screening in institutionalised intellectually disabled individuals. Singapore medical journal. 2020.

INTRODUCTION : Fragile X syndrome (FXS) is the most prevalent X-linked intellectual disability (ID) and a leading genetic cause of autism, characterised by cognitive and behavioural impairments. The hyperexpansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene leads to abnormal hypermethylation, resulting in the lack or absence of its protein. Tools for establishing the diagnosis of FXS have been extensively developed, including assays based on triplet-primed polymerase chain reaction (TP-PCR) for detection and quantification of the CGG trinucleotide repeat expansion, as well as determination of the methylation status of the alleles. This study aimed to utilise a simple, quick and affordable method for high sensitivity and specificity screening and diagnosis of FXS in institutionalised individuals with ID. METHODS : A total of 109 institutionalised individuals at the Center for Social Rehabilitation of Intellectual Disability Kartini, Temanggung, Central Java, Indonesia, were screened in a three-step process using FastFrax Identification, Sizing and Methylation Status Kits. RESULTS : Two samples that were classified as indeterminate with respect to the 41-repeat control at the identification step were subsequently determined to be non-expanded by both sizing and methylation status analyses. Two samples classified as expanded at the identification step were determined to carry full mutation expansions > 200 repeats that were fully methylated using sizing and methylation status analyses, respectively, yielding a disease prevalence of 1.83%. CONCLUSION : Repeat expansion and methylation-specific TP-PCR is practical, effective and inexpensive for the diagnosis of FXS, especially in high-risk populations of individuals with ID of undetermined aetiology.

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14. Silleresi S, Prevost P, Zebib R, Bonnet-Brilhault F, Conte D, Tuller L. Identifying Language and Cognitive Profiles in Children With ASD via a Cluster Analysis Exploration : Implications for the New ICD-11. Autism Res. 2020.

The new version of the International Classification of Diseases (ICD-11) mentions the existence of four different profiles in the verbal part of the Autism Spectrum Disorder (ASD), describing them as combinations of either spared or impaired functional language and intellectual abilities. The aim of the present study was to put ASD heterogeneity to the forefront by exploring whether clear profiles related to language and intellectual abilities emerge when investigation is extended to the entire spectrum, focusing on verbal children. Our study proposed a systematic investigation of both language (specifically, structural language abilities) and intellectual abilities (specifically, nonverbal cognitive abilities) in 51 6- to 12-year-old verbal children with ASD based on explicitly motivated measures. For structural language abilities, sentence repetition and nonword repetition tasks were selected ; for nonverbal cognitive abilities, we chose Raven’s Progressive Matrices, as well as Matrix Reasoning and Block Design from the Wechsler Scales. An integrative approach based on cluster analyses revealed five distinct profiles. Among these five profiles, all four logically possible combinations of structural language and nonverbal abilities mentioned in the ICD-11 were detected. Three profiles emerged among children with normal language abilities and two emerged among language-impaired children. Crucially, the existence of discrepant profiles of abilities suggests that children with ASD can display impaired language in presence of spared nonverbal intelligence or spared language in the presence of impaired nonverbal intelligence, reinforcing the hypothesis of the existence of a separate language module in the brain. LAY SUMMARY : The present work put Autism Spectrum Disorder heterogeneity to the forefront by exploring whether clear profiles related to language and cognitive abilities emerge when investigation is extended to the entire spectrum (focusing on verbal children). The use of explicitly motivated measures of both language and cognitive abilities and of an unsupervised machine learning approach, the cluster analysis, (a) confirmed the existence of all four logically possible profiles evoked in the new ICD-11, (b) evoked the existence of (at least) a fifth profile of language/cognitive abilities, and (c) reinforced the hypothesis of a language module in the brain. (c) 2020 International Society for Autism Research, Wiley Periodicals, Inc.

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15. Su Z, Frost EL, Lammert CR, Przanowska RK, Lukens JR, Dutta A. tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model. RNA biology. 2020 : 1-13.

tRNA-derived small fragments (tRFs) and tRNA halves have emerging functions in different biological pathways, such as regulating gene expression, protein translation, retrotransposon activity, transgenerational epigenetic changes and response to environmental stress. However, small RNAs like tRFs and microRNAs in the maternal-fetal interface during gestation have not been studied extensively. Here we investigated the small RNA composition of mouse placenta/decidua, which represents the interface where the mother communicates with the foetus, to determine whether there are specific differences in tRFs and microRNAs during fetal development and in response to maternal immune activation (MIA). Global tRF expression pattern, just like microRNAs, can distinguish tissue types among placenta/decidua, fetal brain and fetal liver. In particular, 5’ tRNA halves from tRNA(Gly), tRNA(Glu), tRNA(Val) and tRNA(Lys) are abundantly expressed in the normal mouse placenta/decidua. Moreover, tRF and microRNA levels in the maternal-fetal interface change dynamically over the course of embryonic development. To see if stress alters non-coding RNA expression at the maternal-fetal interface, we treated pregnant mice with a viral infection mimetic, which has been shown to promote autism-related phenotypes in the offspring. Acute changes in the levels of specific tRFs and microRNAs were observed 3-6 h after MIA and are suppressed thereafter. A group of 5’ tRNA halves is down-regulated by MIA, whereas a group of 18-nucleotide tRF-3a is up-regulated. In conclusion, tRFs show tissue-specificity, developmental changes and acute response to environmental stress, opening the possibility of them having a role in the fetal response to MIA.

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16. VanOrmer Simpson J. Commentary : Parent Perspective on Familial Risk for Autism Spectrum Disorder. Journal of pediatric psychology. 2020.

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