Pubmed du 19/01/20

dimanche 19 janvier 2020

1. Barbaro J, Yaari M. Study protocol for an evaluation of ASDetect - a Mobile application for the early detection of autism. BMC Pediatr ;2020 (Jan 18) ;20(1):21.

BACKGROUND : Autism Spectrum Conditions (ASC) can be reliably diagnosed by 24 months of age. However, despite the well-known benefits of early intervention, there is still a research-practice gap in the timely identification of ASC, particularly in low-resourced settings. The Social Attention and Communication Surveillance (SACS) tool, which assesses behavioural markers of autism between 12 to 24 months of age, has been implemented in Maternal and Child Health (MCH) settings, with excellent psychometric properties. ASDetect is a free mobile application based on the SACS, which is designed to meet the need for an effective, evidence-based tool for parents, to learn about children’s early social-communication development and assess their child’s ’likelihood’ for ASC. STUDY AIMS : The primary aim of this study is to evaluate the psychometric properties of ASDetect in the early detection of children with ASC. A secondary aim is to assess ASDetect’s acceptability and parental user experience with the application. METHODS : Families are recruited to download the application and participate in the study via social media, health professionals (e.g., MCH nurses, paediatricians) and word of mouth. All participating caregivers complete a demographic questionnaire, survey regarding their user experience, and the Social Responsiveness Scale-2 (SRS-2), an autism screening questionnaire ; they are also invited to participate in focus groups. Children identified at ’high likelihood’ for ASC based on the ASDetect results, the SRS-2 or parental and/or professional concerns undergo a formal, gold-standard, diagnostic assessment. Receiver Operating Characteristic analyses will be used to assess psychometric properties of ASDetect. Thematic analyses will be used to explore themes arising in the focus groups to provide insights regarding user experiences with the app. Multiple regression analyses will be carried out to determine the extent to which demographic factors, parental stress and beliefs on health surveillance and child results on ASDetect are associated with the parental user-experience of the application. DISCUSSION : With a strong evidence-base and global access, ASDetect has the potential to empower parents by providing them with knowledge of their child’s social-communication development, validating and reassuring any parental concerns, and supporting them in communicating with other health professionals, ultimately enhancing child and family outcomes and well-being.

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2. Chen TC, Hsieh MH, Lin YT, Chan PS, Cheng CH. Mismatch negativity to different deviant changes in autism spectrum disorders : A meta-analysis. Clin Neurophysiol ;2020 (Jan 1)

OBJECTIVE : Mismatch negativity (MMN) has been continuously used to evaluate the functional integrity of central auditory processing. However, it still remains inconclusive whether patients with autism spectrum disorder (ASD) demonstrate reduced MMN responses in all deviant types. METHODS : To reconcile the previous controversial findings, we performed a meta-analysis of peer-reviewed MMN articles concerning ASD. The potential moderators regarding different deviant types, diagnosis, and age on the effect sizes (Hedges’ g) were also assessed. RESULTS : Compared to the controls, ASD patients showed reduced MMN amplitudes (g = -0.37, p = 0.001) and prolonged latencies (g = -0.33, p = 0.041) in response to speech-sound deviants. Children/adolescents with ASD manifested reduced MMN amplitudes in response to tone-duration deviants (g = -0.46, p = 0.014). Furthermore, the results showed significantly shortened MMN latencies to tone-frequency deviants in patients with autism (g = 0.29, p = 0.038) and, in contrast, prolonged MMN latencies (g = -0.74, p = 0.001) in patients with Asperger syndrome. CONCLUSION : MMN deficits are robust in ASD patients, suggesting an altered central ability in auditory discrimination. SIGNIFICANCE : MMN alterations were displayed in different profiles with respect to frequency, duration and phoneme changes.

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3. Geurts HM, Pol SE, Lobbestael J, Simons CJP. Executive Functioning in 60+ Autistic Males : The Discrepancy Between Experienced Challenges and Cognitive Performance. J Autism Dev Disord ;2020 (Jan 17)

As executive functioning (EF) is especially sensitive to age-related cognitive decline, EF was evaluated by using a multi-method assessment. Fifty males (60-85 years) with a late adulthood autism spectrum condition (ASC) diagnosis and 51 non-ASC males (60-83 years) were compared on cognitive tests across EF domains (cognitive flexibility, planning, processing speed, and working memory) and a self- and proxy report of the Behavior Rating Inventory of Executive Function-Adult Version. While no objective performance differences emerged, autistic males and their proxies did report more EF challenges than non-ASC males on the subjective measure. In order to know how to support the older autistic men who received their ASC diagnosis in late adulthood with their daily life EF challenges, it is important to understand what underlies these subjective EF problems.

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4. Hiraide T, Watanabe S, Matsubayashi T, Yanagi K, Nakashima M, Ogata T, Saitsu H. A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder. Mol Genet Genomic Med ;2020 (Jan 17):e1145.

BACKGROUND : TOP2B encodes type II topoisomerase beta, which controls topological changes during DNA transcription. TOP2B is expressed in the developing nervous system and is involved in brain development and neural differentiation. Recently, a de novo missense TOP2B variant (c.187C>T) has been identified in an individual with neurodevelopmental disorder (NDD). However, the association between TOP2B variants and NDDs remains uncertain. METHODS : Trio-based whole-exome sequencing was performed on a 7-year-old girl, presenting muscle hypotonia, stereotypic hand movements, epilepsy, global developmental delay, and autism spectrum disorder. Brain magnetic resonance images were normal. She was unable to walk independently and spoke no meaningful words. RESULTS : We found a de novo variant in TOP2B (NM_001330700.1:c.187C>T, p.(His63Tyr)), which is identical to the previous case. The clinical features of the two individuals with the c.187C>T variant overlapped. CONCLUSION : Our study supports the finding that TOP2B variants may cause NDDs.

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5. Labonne JDJ, Driessen TM, Harris ME, Kong IK, Brakta S, Theisen J, Sangare M, Layman LC, Kim CH, Lim J, Kim HG. Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31. J Clin Med ;2020 (Jan 19) ;9(1)

We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative CNVs, narrowed down the candidate chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in the whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our microdeletion patient DGDP289A compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect protein-protein interactions between LRRK2 and its binding partners, of which eight have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development, and, thus, we propose that intellectual disability and autism, displayed in the 12q12 microdeletions, are likely caused by LRRK2. Using another affected member, DGDP289B, with a microdeletion at Xp22.31, in this family, we performed the genomic and clinical delineation with six published and nine unreported cases. We propose HDHD1 and PNPLA4 for X-linked intellectual disability in this region, since their high transcript levels in the human brain substantiate their role in intellectual functioning.

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6. Liu Y, Zhang Y, Zarrei M, Dong R, Yang X, Zhao D, Scherer SW, Gai Z. Refining critical regions in 15q24 microdeletion syndrome pertaining to autism. Am J Med Genet B Neuropsychiatr Genet ;2020 (Jan 18)

Chromosome 15q24 microdeletion syndrome is characterized by developmental delay, facial dysmorphism, hearing loss, hypotonia, recurrent infection, and other congenital malformations including microcephaly, scoliosis, joint laxity, digital anomalies, as well as sometimes having autism spectrum disorder (ASD) and attention deficit hyperactivity disorder. Here, we report a boy with a 2.58-Mb de novo deletion at chromosome 15q24. He is diagnosed with ASD and having multiple phenotypes similar to those reported in cases having 15q24 microdeletion syndrome. To delineate the critical genes and region that might be responsible for these phenotypes, we reviewed all previously published cases. We observe a potential minimum critical region of 650 kb (LCR15q24A-B) affecting NEO1 among other genes that might pertinent to individuals with ASD carrying this deletion. In contrast, a previously defined minimum critical region downstream of the 650-kb interval (LCR15q24B-D) is more likely associated with the developmental delay, facial dysmorphism, recurrent infection, and other congenital malformations. As a result, the ASD phenotype in this individual is potentially attributed by genes particularly NEO1 within the newly proposed critical region.

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7. McCullagh EA, Poleg S, Greene NT, Huntsman MM, Tollin DJ, Klug A. Characterization of auditory and binaural spatial hearing in a Fragile X Syndrome mouse model. eNeuro ;2020 (Jan 15)

The auditory brainstem compares sound-evoked excitation and inhibition from both ears to compute sound source location and determine spatial acuity. Although alterations to the anatomy and physiology of the auditory brainstem have been demonstrated in Fragile X Syndrome (FXS) it is not known whether these changes cause spatial acuity deficits in FXS. To test the hypothesis that FXS-related alterations to brainstem circuits impair spatial hearing abilities, a reflexive prepulse inhibition (PPI) task, with variations in sound (gap, location, masking) as the prepulse stimulus, was used on Fmr1 knockout mice and B6 controls. Specifically, Fmr1 mice show decreased PPI compared to wildtype during gap detection, changes in sound source location, and spatial release from masking with no alteration to their overall startle thresholds compared to wildtype. Lastly, Fmr1 mice have increased latency to respond in these tasks suggesting additional impairments in the pathway responsible for reacting to a startling sound. This study further supports data in humans with FXS that show similar deficits in PPI.Significance Statement : This is the first study to characterize auditory spatial acuity in a mouse model of FXS. We saw minor differences in Fmr1 mice compared to B6 mice in several measures of auditory acuity as measured by inhibition of the startle response. Fmr1 mice had increased latency to startle for almost all conditions compared to B6 mice suggesting altered timing to acoustic cues. These experiments further show that, consistent with patient report and anatomical/physiological data, the auditory system is altered in a mouse model of FXS, though with some potential compensation leading to a subtle behavioral impact.

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8. Mills W, Kondakis N, Orr R, Warburton M, Milne N. Does Hydrotherapy Impact Behaviours Related to Mental Health and Well-Being for Children with Autism Spectrum Disorder ? A Randomised Crossover-Controlled Pilot Trial. Int J Environ Res Public Health ;2020 (Jan 15) ;17(2)

BACKGROUND : Children diagnosed with Autism Spectrum Disorder (ASD) are less physically active than typically developing children due to reduced socialisation and delayed gross-motor skills, negatively impacting social, emotional and physical well-being. This study aimed to determine whether hydrotherapy influences behaviours which impact mental health and well-being in children with ASD. METHODS : A within-subjects, randomised crossover-controlled pilot trial was used over 8 weeks. Children aged 6-12 years and diagnosed with ASD (n = 8) were randomly allocated to Group 1 (n = 4) or Group 2 (n = 4). All children participated in hydrotherapy intervention from either weeks 1 to 4 or weeks 5 to 8. The Child Behaviour Checklist (CBCL) measured behaviour changes impacting mental health and well-being, administered at weeks 0, 4 and 8. RESULTS : No observable differences were found in CBCL subscales between Group 1 or 2 at baseline (week 0). Paired-samples t-tests revealed significant improvements post-intervention : Anxious/Depressed subdomain (p = 0.02) and the Internalising Problems Domain Summary (p = 0.026), with large effect size (d = 1.03 and d = 1.06 respectively). Thought Problems (p = 0.03) and Attention Problems (p = 0.01) both significantly improved post-intervention. The Total Problems score significantly improved post-intervention (p = 0.018) with a large effect size (d = 1.04). CONCLUSION : Hydrotherapy may enhance behaviours impacting mental health and well-being of children with ASD and could be considered a beneficial therapy option.

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9. Pickles A, McCauley JB, Pepa LA, Huerta M, Lord C. The adult outcome of children referred for autism : typology and prediction from childhood. J Child Psychol Psychiatry ;2020 (Jan 19)

BACKGROUND : Autism Spectrum Disorder is highly heterogeneous, no more so than in the complex world of adult life. Being able to summarize that complexity and have some notion of the confidence with which we could predict outcome from childhood would be helpful for clinical practice and planning. METHODS : Latent class profile analysis is applied to data from 123 participants from the Early Diagnosis Study (Lord et al., Archives of General Psychiatry, 2006, 63, 694) to summarize in a typology the multifacetted early adult outcome of children referred for autism around age 2. The form of the classes and their predictability from childhood is described. RESULTS : Defined over 15 measures, the adult outcomes were reduced to four latent classes, accounting for much of the variation in cognitive and functional measures but little in the affective measures. The classes could be well and progressively more accurately predicted from childhood IQ and symptom severity measurement taken at age 2 years to age 9 years. Removing verbal and nonverbal IQ and autism symptom severity measurement from the profile of adult measures did not change the number of the latent classes ; however, there was some change in the class composition and they were more difficult to predict. CONCLUSIONS : While an empirical summary of adult outcome is possible, careful consideration needs to be given to the aspects that should be given priority. An outcome typology that gives weight to cognitive outcomes is well predicted from corresponding measures taken in childhood, even after account for prediction bias from fitting a complex model to a small sample. However, subjective well-being and affective aspects of adult outcome were weakly related to functional outcomes and poorly predicted from childhood.

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10. Yu KH, Palmer N, Fox K, Prock L, Mandl KD, Kohane IS, Prilutsky D. The phenotypical implications of immune dysregulation in fragile X syndrome. Eur J Neurol ;2019 (Dec 26)

BACKGROUND AND PURPOSE : Immune system dysfunction and inflammatory dysregulation have been shown in several animal models of fragile X syndrome (FXS). However, the phenotypical implications of this dysregulation have not been systematically evaluated in a large patient cohort. METHODS : Five thousand seven hundred thirty-six FXS patients from a nationwide health insurance database were identified and compared to 573 600 age- and sex-matched controls. The phenome-wide association studies codes of FXS patients and those without FXS were compared and the false discovery rate was controlled at 0.05 using the Benjamini-Hochberg procedure. RESULTS : In addition to the commonly reported comorbidities of FXS, an over-representation of infectious diseases, including otitis media, cellulitis and abscess of fingers or toes, viral enteritis, candidiasis and pneumonia, was discovered. In addition, there was an under-representation of autoimmune disorders in FXS patients. CONCLUSIONS : Our systematic comorbidity analyses identified immunologically-based phenotypes associated with FXS. Our findings align with previous observations of compromised immunity and phagocytic defects in animal models of FXS. These results suggest the importance of immune-related pathways in FXS patients and their relevance to the FMR1 gene.

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