Pubmed du 14/11/19

jeudi 14 novembre 2019

1. Bavykina IA, Popov VI, Zvyagin AA, Bavykin DV. [Frequency of determining markers of casein’s inhability and gluten in children with disorders of autistic spectrum]. Vopr Pitan ;2019 ;88(4):41-47.

The most optimal approach to the problem of managing children with autism spectrum disorders (ASD) is a complex one that involves a pediatric gastroenterologist, a nutritionist, a neurologist, a psychiatrist. Currently, there are studies that confirm the effectiveness of diet in the correction of neuropsychiatric status and gastroenterological disorders in ASD. Evidence supporting the therapeutic value of diets is limited and inconclusive. Diet therapy should be used only if food allergy or gluten or casein intolerance is diagnosed. Aim. To study the frequency of detection of markers of gluten and casein intolerance in children with ASD. Material and methods. The study involved 51 children (39 boys and 12 girls) aged 3 to 15 years with a diagnosis of ASD. Among the study participants, 20 children used gluten-free diet and casein-free diet for more than 6 months. The material for the study was venous blood taken from the elbow vein in the morning on an empty stomach. Determination of specific IgG-antibodies to casein and gliadin, IgA-antibodies to deamidized gliadin peptides was carried out by enzyme immunoassay. The level of total IgA to exclude selective deficiency was also determined. Results and discussion. Most children with ASD (79.5%) had increased levels of specific IgG antibodies to casein. The increase in IgG antigliadin antibodies was determined in 19.3% of children who do not follow a gluten-free diet, and antibodies to deamidized gliadin Ig peptides were not detected in any patient. Gluten intolerance in children with ASD is characterized by sensitivity to it and occurs in 40-50%. Conclusion. According to the literature and the results of own studies, some children with ASD have gluten and casein intolerance. Before the appointment of diet therapy for children with ASD, it is necessary to conduct a survey to clarify the nature of intolerance and the choice of optimal tactics of diet therapy.

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2. Ben-Mahmoud A, Al-Shamsi AM, Ali BR, Al-Gazali L. Evaluating the Role of MAST1 as an Intellectual Disability Disease Gene : Identification of a Novel De Novo Variant in a Patient with Developmental Disabilities. J Mol Neurosci ;2019 (Nov 12)

Intellectual disability (ID) is one of the most common developmental disorders characterized by a congenital limitation in intellectual functioning and adaptive behavior. More than 800 genes have been implicated so far in the pathogenesis of syndromic and non-syndromic ID conditions with the actual number is expected to be over two thousand. The advent of next-generation sequencing resulted in the identification of many novel ID genes with new genes are being reported on weekly basis. The level of evidence on ID genes varies with some of them being preliminary. MAST1 have been hinted at as being causative of ID but the evidence has been very sketchy. Extensive search of the literature identified three heterozygous de novo missense variants in MAST1 as possible causes of syndromic ID in three individuals where intellectual disability has been a major feature. Using exome sequencing, we identified a novel missense variant c.3539T>G, p.(Leu1180Arg) in MAST1 in an Emirati patient with intellectual disability, microcephaly, and dysmorphic features. In silico pathogenicity prediction analyses predict that all the four missense variants reported in this study are likely to be damaging. Immunostaining of cells expressing human MAST1 showed that majority large proportion of the expressed protein is colocalized the microtubule filaments in the cytoplasm. However, the identified variant c.3539T>G, p.(Leu1180Arg) as well as the other three variants seem to localize in a similar pattern to wild-type indicating a disease mechanism not involving mis-targeting. We, therefore, suggest that mutations in MAST1 should be considered as strong candidates for intellectual disability in humans.

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3. Cucchiara F, Frumento P, Banfi T, Sesso G, Di Galante M, D’Ascanio P, Valvo G, Sicca F, Faraguna U. Electrophysiological features of sleep in children with Kir4.1 channel mutations and Autism-Epilepsy phenotype : a preliminary study. Sleep ;2019 (Nov 13)

STUDY OBJECTIVES : Recently, a role for gain-of-function (GoF) mutations of the astrocytic potassium channel Kir4.1 (KCNJ10 gene) has been proposed in subjects with Autism-Epilepsy phenotype (AEP). Epilepsy and autism spectrum disorder (ASD) are common and complexly related to sleep disorders. We tested whether well characterized mutations in KCNJ10 could result in specific sleep electrophysiological features, paving the way to the discovery of a potentially relevant biomarker for Kir4.1-related disorders. METHODS : For this case-control study, we recruited seven children with ASD either comorbid or not with epilepsy and/or EEG paroxysmal abnormalities (AEP) carrying GoF mutations of KCNJ10 and seven children with similar phenotypes but wild-type for the same gene, comparing period-amplitude features of slow waves detected by fronto-central bipolar EEG derivations (F3-C3, F4-C4, and Fz-Cz) during daytime naps. RESULTS : Children with Kir4.1 mutations displayed longer slow waves periods than controls, in Fz-Cz (mean period = 112,617 ms +/- SE = 0.465 in mutated versus mean period = 105,249 ms +/- SE = 0.375 in controls, p < 0.001). An analog result was found in F3-C3 (mean period = 125,706 ms +/- SE = 0.397 in mutated versus mean period = 120,872 ms +/- SE = 0.472 in controls, p < 0.001) and F4-C4 (mean period = 127,914 ms +/- SE = 0.557 in mutated versus mean period = 118,174 ms +/- SE = 0.442 in controls, p < 0.001). CONCLUSION : This preliminary finding suggests that period-amplitude slow wave features are modified in subjects carrying Kir4.1 GoF mutations. Potential clinical applications of this finding are discussed.

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4. Dana H, Bayramov KK, Delibasi N, Tahtasakal R, Bayramov R, Hamurcu Z, Sener EF. Disregulation of Autophagy in the Transgenerational Cc2d1a Mouse Model of Autism. Neuromolecular Med ;2019 (Nov 13)

Autism spectrum disorder (ASD) is a heterogeneously childhood neurodevelopmental disorder, believed to be under development of various genetic and environmental factors. Autophagy and related pathways have also been implicated in the etiology of ASD. We aimed to investigate autophagic markers by generating the transgenerational inheritance of ASD-like behaviors in the Cc2d1a animal model of ASD. Cc2d1a (+/-) mouse model of ASD was built in two different groups by following three generations. After behavior test, bilateral hippocampus was sliced. Western Blot assay and quantitative real-time polymerase chain reaction (QRT-PCR) were used for measurement of LC3 and Beclin-1 as key regulators of autophagy. All of the animal and laboratory studies were conducted in the Erciyes University Genome and Stem Cell Center (GENKOK). Significant LC3 and Beclin-1 mRNA expression levels were observed in mouse hippocampus between groups and generations. Western blot confirmed the changes of the proteins in the hippocampus. LC3 expressions were increased for females and decreased for males compared to the control group. Beclin-1 expression levels were found to be significantly decreased in males and females compared to controls. This study could help explain a new pathway of autophagy in ASD mouse models. Future animal studies need to investigate sex differences in mouse modeling autism-relevant genes like CC2D1A. We anticipate our results to be a starting point for more comprehensive autophagy studies in this mouse model of ASD.

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5. Fahmi M, Yasui G, Seki K, Katayama S, Kaneko-Kawano T, Inazu T, Kubota Y, Ito M. In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment. Int J Mol Sci ;2019 (Nov 8) ;20(22)

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which has multiple functions such as binding to methylated DNA or interacting with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We investigated the evolution and molecular features of MeCP2, CDKL5, and FOXG1 and their binding partners using phylogenetic profiling to gain a better understanding of their similarities. We also predicted the structural order-disorder propensity and assessed the evolutionary rates per site of MeCP2, CDKL5, and FOXG1 to investigate the relationships between disordered structure and other related properties with RTT. Here, we provide insight to the structural characteristics, evolution and interaction landscapes of those three proteins. We also uncovered the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT.

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6. Ferretti LA, McCallion P. Translating the Chronic Disease Self-Management Program for Community-Dwelling Adults With Developmental Disabilities. J Aging Health ;2019 (Dec) ;31(10_suppl):22s-38s.

Objective : The study was to test the feasibility of supplementary materials (DD-CDSMP) supporting people with developmental disabilities who are aging to participate in the Chronic Disease Self-Management Program (CDSMP). CDSMP is a six-session group intervention designed to increase self-management of chronic health conditions. Method : Supplementary materials were utilized within two CDSMP workshops. Each workshop involved seven to nine persons with developmental disabilities and five to seven staff. Supplementary materials to the existing intervention manual were reviewed using a framework for modifications and adaptions for evidence-based interventions. Process interviews with leaders and participants, pre- and posttests on self-management activity and satisfaction surveys assessed outcomes and feasibility. Results : Classes were successfully held with a 70% completer rate, and all materials proved useful. Discussion : People with developmental disabilities as they age tend to have more comorbid conditions than the general population. Developing and implementing materials and strategies to making self-management more accessible to people with developmental disabilities in mainstream rather than segregated settings will improve the quality of people’s lives.

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7. Ghanouni P, Jarus T, Zwicker JG, Lucyshyn J, Fenn B, Stokley E. Design Elements During Development of Videogame Programs for Children with Autism Spectrum Disorder : Stakeholders’ Viewpoints. Games Health J ;2019 (Nov 13)

Introduction : Research has demonstrated that videogame programs can be an effective intervention targeting social challenges among children with autism spectrum disorder (ASD). Despite the rapid growth in developing videogame programs, incorporation of stakeholders’ views has been limited. Objective : This project aimed to identify the design elements that should be considered during development of videogame programs for children with ASD, from the perspectives of stakeholders. Materials and Methods : We involved 26 stakeholders, including parents of children with ASD, youth with ASD, and clinicians working with individuals with ASD in focus groups and interviews. Results : Thematic analysis yielded three themes : (1) addressing heterogeneity and diverse needs ; (2) mirroring real world ; and (3) teaching strategies. Conclusion : Incorporating these elements during development of videogame programs can help enhance the outcomes for children with ASD. By including stakeholders’ voices, it is assumed that the developed videogame programs may serve as user-friendly and engaging tools to potentially complement traditional interventions when overcoming social difficulties in individuals with ASD.

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8. Kardani A, Soltani A, Sewell RDE, Shahrani M, Rafieian-Kopaei M. Neurotransmitter, antioxidant and anti-neuroinflammatory mechanistic potentials of herbal medicines in ameliorating autism spectrum disorder. Curr Pharm Des ;2019 (Nov 12)

BACKGROUND : Autism spectrum disorder (ASD) is a neurodevelopmental issue that disrupts behavior, nonverbal communication, and social interaction, impacting all aspects of an individual’s social development. The underlying origin of autism is unclear, however, oxidative stress as well as serotonergic, adrenergic and dopaminergic systems are thought to be implicated in ASD. Despite the fact that there is no effective medication for autism, current pharmacological treatments are utilized to ameliorate some of the symptoms such as self-mutilation, aggression, repetitive and stereotyped behaviors, inattention, hyperactivity, and sleep disorders. METHODS : In accord with the literature regarding the activity of herbal medicines on neurotransmitter function, we aimed to review the most worthy medicinal herbs possessing neuroprotective effects. RESULTS : Based on the outcome, medicinal herbs such as Zingiber officinale, Astragalus membranaceu, Ginkgo biloba, Centella asiatica and Acorus calamus, have antioxidant activity, can influence neurotransmitter systems and are potentially neuroprotective. CONCLUSIONS : Consequently, these herbs, in theory at least, appear to be suitable candidates within an overall management strategy for those on the autism spectrum.

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9. Lovell B, Wetherell MA. Exploring the Moderating Role of Benefit Finding on the Relationship Between Child Problematic Behaviours and Psychological Distress in Caregivers of Children with ASD. J Autism Dev Disord ;2019 (Nov 14)

Caregivers of children with ASD often find benefits associated with their caregiving role, and benefit finding predicts lower distress. Child problematic behaviours (CPB), which positively predict caregivers’ distress, are perceived to be being less problematic, or more manageable, by caregivers who find benefits. Benefit finding therefore might mitigate the negative psychological impact of CPB. A sample of n = 158 caregivers of children with ASD completed an online survey assessing benefit finding, CPB, and psychological distress. CPB positively, and benefit finding negatively, predicted caregivers’ distress. Moderation effects however were not observed. Findings implicate increased CPB and lower benefit finding as risk factors for caregivers’ psychological distress. Findings provide clearly definable targets for intervention.

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10. Mirzaa GM, Chong JX, Piton A, Popp B, Foss K, Guo H, Harripaul R, Xia K, Scheck J, Aldinger KA, Sajan SA, Tang S, Bonneau D, Beck A, White J, Mahida S, Harris J, Smith-Hicks C, Hoyer J, Zweier C, Reis A, Thiel CT, Jamra RA, Zeid N, Yang A, Farach LS, Walsh L, Payne K, Rohena L, Velinov M, Ziegler A, Schaefer E, Gatinois V, Genevieve D, Simon MEH, Kohler J, Rotenberg J, Wheeler P, Larson A, Ernst ME, Akman CI, Westman R, Blanchet P, Schillaci LA, Vincent-Delorme C, Gripp KW, Mattioli F, Guyader GL, Gerard B, Mathieu-Dramard M, Morin G, Sasanfar R, Ayub M, Vasli N, Yang S, Person R, Monaghan KG, Nickerson DA, van Binsbergen E, Enns GM, Dries AM, Rowe LJ, Tsai ACH, Svihovec S, Friedman J, Agha Z, Qamar R, Rodan LH, Martinez-Agosto J, Ockeloen CW, Vincent M, Sunderland WJ, Bernstein JA, Eichler EE, Vincent JB, Bamshad MJ. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder. Genet Med ;2019 (Nov 14)

PURPOSE : Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS : We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS : Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION : De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

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11. Saffari A, Arno M, Nasser E, Ronald A, Wong CCY, Schalkwyk LC, Mill J, Dudbridge F, Meaburn EL. RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation. Mol Autism ;2019 ;10:38.

Background : A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods : Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results : In the discordant twin analysis, three genes showed evidence for DE at FDR < 10% : IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations : Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions : Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals.

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12. Shorey S, Ng ED, Haugan G, Law E. The parenting experiences and needs of Asian primary caregivers of children with autism : A meta-synthesis. Autism ;2019 (Nov 13):1362361319886513.

Parents of children with autism are faced with higher risks of unemployment, divorce, and poorer mental health than parents of children with other disorders. Such parenting stress can be further exacerbated by cultural and environmental factors such as the more conservative and collectivistic Asian values. Therefore, this review identifies and synthesizes literature on the parenting experiences and needs of Asian primary caregivers of children with autism using a critical interpretive method. A qualitative meta-summary was conducted. Seven electronic databases (CINAHL, Embase, ProQuest, PsycINFO, PubMed, Scopus, and Web of Science) were searched from each database’s date of inception to November 2018. In total, 44 studies were included in this review. Thirteen studies examined Asian immigrant parents’ experiences, and 31 studies were done among Asia-based parents. Six domains were identified : "personal parenting journey" ; "adaptation and coping strategies" ; "family, community, and social support" ; "experiences with healthcare, education, and social services" ; "future hopes and recommendations" ; and "unique experiences of immigrants." The distinctive influence of religious beliefs, cultural values, and environmental factors on Asian parenting experiences were discussed, and recommendations were proposed to better meet the needs of parents with autistic children.

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