1. Aarabi M, Kessler E, Madan-Khetarpal S, Surti U, Bellissimo D, Rajkovic A, Yatsenko SA. {{Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation}}. {European journal of medical genetics}. 2018.
Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelopmental abnormalities. In females, a spectrum of mild to moderate phenotype has been detected. We report two unrelated females with autism and mild intellectual disability. High resolution X-chromosome microarray analysis revealed de novo intragenic deletions in ARHGEF9 of 24kb and 56kb involving exons 5-8 and exons 3-8 and leading to truncated forms of collybistin. Peripheral blood samples revealed random X-chromosome inactivation in both patients. To explain phenotypic variability in female patients, we propose a model for disruption of collybistin and various irregular interactions in post-synaptic neurons based on X inactivation patterns. Our findings highlight the importance of ARHGEF9 integrity and suggest further research on its correlation with autism and neurobehavioral problems.
Lien vers le texte intégral (Open Access ou abonnement)
2. Akinsolu FT, Balczar E, Kovacs N, Gall T, Harangi M, Varga O. {{Developing a database for Rett syndrome research performed in the European Union: A resource for researchers and stakeholders}}. {Child Care Health Dev}. 2018.
BACKGROUND: For most rare diseases, which are often significantly under-resourced, sufficient information on funding landscape is missing, which may prevent effective use of research resources and be an obstacle to making effective decisions on research. The objective of this research was to create a database of Rett syndrome research projects carried out in the European Union (EU) and to provide a research landscape analysis. METHOD: Websites of organizations funding research projects were identified and systematically checked. Projects were analysed by date, place, funder types, and research topics. RESULTS: The analysis revealed that the total expenditure on Rett syndrome research was almost euro70 million, allocated among 247 projects mostly performed in Italy and the United Kingdom. The main research sponsor was the European Commission. Highlighting research trends and gaps, this work facilitates changes in rare disease research data management. CONCLUSION: This work demonstrates the feasibility of creating an EU-based research database on Rett syndrome projects. It provides a source of information on research development which is useful for individuals, organizations and key players in the private and public sector to make progressive decisions on Rett syndrome research.
Lien vers le texte intégral (Open Access ou abonnement)
3. Bhaskaran S, Lawrence L, Flora J, Perumalsamy V. {{Functional and cognitive vision assessment in children with autism spectrum disorder}}. {Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus}. 2018.
PURPOSE: To assess functional vision in children with autism spectrum disorder (ASD) with a cognitive visual function battery in addition to standard ophthalmic examinations. METHODS: Subjects were recruited from a school for children with ASD. In addition to a comprehensive ophthalmic examination, all children underwent cognitive vision assessment at a tertiary ophthalmological care center in India. RESULTS: A total of 30 children were included. The distribution of the number of children with mild to moderate versus severe ASD was nearly equal based on CARS autism scores. The majority of subjects had normal color vision (16/18), contrast (24), shape discrimination (26), and perception of directionality (28). Most were not able to identify optical illusions or differentiate tests of emotions. Ocular pursuits, saccades, and recognition of size differences were often abnormal. Poor visual closure was noted in (11) subjects. The duration of fixation to Heidi face target was inversely proportional to the severity of ASD. The study further established that cognitive visual impairment was present in children with ASD irrespective of their severity of ASD. CONCLUSIONS: All subjects had some form of cognitive visual impairment independent of ASD severity.
Lien vers le texte intégral (Open Access ou abonnement)
4. Carrette LLG, Blum R, Ma W, Kelleher RJ, 3rd, Lee JT. {{Tsix-Mecp2 female mouse model for Rett syndrome reveals that low-level MECP2 expression extends life and improves neuromotor function}}. {Proceedings of the National Academy of Sciences of the United States of America}. 2018.
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by a mutation in the X-linked methyl-CpG-binding protein 2 (MECP2). There is currently no disease-specific treatment, but MECP2 restoration through reactivation of the inactive X (Xi) has been of considerable interest. Progress toward an Xi-reactivation therapy has been hampered by a lack of suitable female mouse models. Because of cellular mosaicism due to random X-chromosome inactivation (XCI), Mecp2(+/-) heterozygous females develop only mild RTT. Here, we create an improved female mouse model by introducing a mutation in Tsix, the antisense regulator of XCI allelic choice. Tsix-Mecp2 mice show reduced MECP2 mosaicism and closely phenocopy the severely affected Mecp2-null males. Tsix-Mecp2 females demonstrate shortened lifespan, motor weakness, tremors, and gait disturbance. Intriguingly, they also exhibit repetitive behaviors, as is often seen in human RTT, including excessive grooming and biting that result in self-injury. With a Tsix allelic series, we vary MECP2 levels in brain and demonstrate a direct, but nonlinear correlation between MECP2 levels and phenotypic improvement. As little as 5-10% MECP2 restoration improves neuromotor function and extends lifespan five- to eightfold. Our study thus guides future pharmacological strategies and suggests that partial MECP2 restoration could have disproportionate therapeutic benefit.
Lien vers le texte intégral (Open Access ou abonnement)
5. Dekker V, Nauta MH, Timmerman ME, Mulder EJ, van der Veen-Mulders L, van den Hoofdakker BJ, van Warners S, Vet LJJ, Hoekstra PJ, de Bildt A. {{Social skills group training in children with autism spectrum disorder: a randomized controlled trial}}. {Eur Child Adolesc Psychiatry}. 2018.
In 122 high-functioning children with autism spectrum disorder (ASD; 9-13 years; 19 girls), we investigated the effectiveness of a 15-session social skills group training (SST) with and without parent and teacher involvement (PTI) in a randomized controlled trial with three conditions: SST (n = 47), SST-PTI (n = 51), and care-as-usual (CAU, n = 24). Hierarchical linear modeling was used for immediate and 6-month follow-up analyses. Measures were administered before randomization (blind), post-treatment and at follow-up (not blind). TRIAL REGISTRATION: Dutch Trial Register; http://www.trialregister.nl ; NTR2405. At post-treatment, children in both SSTs had improved significantly more than CAU on the primary outcome, Vineland Socialization (SST: Cohen’s d = 0.39; 95% CI – 2.23 to 3.11 and SST-PTI: d = 0.43; 95% CI – 2.19 to 3.15) and on the secondary outcome parent-SSRS « Cooperation » (SST: d = 0.43; 95% CI – 0.23 to 1.15 and SST-PTI: d = 0.45; 95% CI – 0.21 to 1.17), with no difference between post-treatment and follow-up. Additionally, children in SST-PTI improved significantly more on the teacher-SSRS than in CAU [« Cooperation » d =0.42 (95% CI – 0.33 to 1.13); « Assertion » d =0.34 (95% CI – 0.39 to 1.11); « Self-Control » d =0.61 (95% CI – 0.08 to 1.34)] and in SST [« Cooperation » d =0.34 (95% CI – 0.37 to 1.05); « Self-Control » d =0.59 (95% CI – 0.13 to 1.32)]. The current study corroborates earlier findings in smaller samples and wider age ranges, with small but statistically significant effects of SST for high-functioning pre-adolescent children with ASD. Parental and teacher involvement intensified treatment, yet did not yield an additional effect relative to SST for children only, as reported by parents. 6 months after training, no further improvement or decline was found.
Lien vers le texte intégral (Open Access ou abonnement)
6. Gallagher S, Pilch M, Hannigan A. {{Prior depressive symptoms and persistent child problem behaviours predict future depression in parents of children with developmental disabilities: The growing up in Ireland cohort study}}. {Res Dev Disabil}. 2018; 80: 170-9.
Predictors of depression over time were examined in parental carers of children with developmental disabilities (DD) and parents of typically developing children (controls) who participated in the Growing up in Ireland Study. Parents completed measures of depression, the Centre for Epidemiological Depression Scale (CES-D) and child problem behaviours, the Strength and Difficulties Questionnaire when the children were aged 9 (Wave 1) and 13 (Wave 2). Using CES-D cut-off scores to indicate probable depression, caregivers were more likely to be depressed at both waves compared to controls with a Wave 1 rate of depression of 14.6% vs. 7.9% (p<0.001, Cramer`s V=0.059) and Wave 2 (14.8% vs. 10%, p=0.003, Cramer`s V=0.038). While overall rates of depression were stable for caregivers, a shifting pattern emerged; 59.6% of those who were depressed at Wave 1, were not at Wave 2; similarly, 10.9% who were not depressed at Wave 1, were at Wave 2. Parents of children with DD were also more likely to report greater problem behaviours in their children compared to controls at both waves. Depression in caregivers at Wave 1 and persistent child problem behaviours were significant predictors of depression at Wave 2. In conclusion, while overall rates of depression remain stable in caregivers, there are shifting patterns evident with prior depression and persistent behaviour problems predictive of ongoing depression. Lien vers le texte intégral (Open Access ou abonnement)
7. Rose S, Niyazov DM, Rossignol DA, Goldenthal M, Kahler SG, Frye RE. {{Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder}}. {Molecular diagnosis & therapy}. 2018.
Autism spectrum disorder (ASD) affects ~ 2% of children in the United States. The etiology of ASD likely involves environmental factors triggering physiological abnormalities in genetically sensitive individuals. One of these major physiological abnormalities is mitochondrial dysfunction, which may affect a significant subset of children with ASD. Here we systematically review the literature on human studies of mitochondrial dysfunction related to ASD. Clinical aspects of mitochondrial dysfunction in ASD include unusual neurodevelopmental regression, especially if triggered by an inflammatory event, gastrointestinal symptoms, seizures, motor delays, fatigue and lethargy. Traditional biomarkers of mitochondrial disease are widely reported to be abnormal in ASD, but appear non-specific. Newer biomarkers include buccal cell enzymology, biomarkers of fatty acid metabolism, non-mitochondrial enzyme function, apoptosis markers and mitochondrial antibodies. Many genetic abnormalities are associated with mitochondrial dysfunction in ASD, including chromosomal abnormalities, mitochondrial DNA mutations and large-scale deletions, and mutations in both mitochondrial and non-mitochondrial nuclear genes. Mitochondrial dysfunction has been described in immune and buccal cells, fibroblasts, muscle and gastrointestinal tissue and the brains of individuals with ASD. Several environmental factors, including toxicants, microbiome metabolites and an oxidized microenvironment are shown to modulate mitochondrial function in ASD tissues. Investigations of treatments for mitochondrial dysfunction in ASD are promising but preliminary. The etiology of mitochondrial dysfunction and how to define it in ASD is currently unclear. However, preliminary evidence suggests that the mitochondria may be a fruitful target for treatment and prevention of ASD. Further research is needed to better understand the role of mitochondrial dysfunction in the pathophysiology of ASD.
Lien vers le texte intégral (Open Access ou abonnement)
8. Tangsuwansri C, Saeliw T, Thongkorn S, Chonchaiya W, Suphapeetiporn K, Mutirangura A, Tencomnao T, Hu VW, Sarachana T. {{Investigation of epigenetic regulatory networks associated with autism spectrum disorder (ASD) by integrated global LINE-1 methylation and gene expression profiling analyses}}. {PLoS One}. 2018; 13(7): e0201071.
BACKGROUND: The exact cause and mechanisms underlying the pathobiology of autism spectrum disorder (ASD) remain unclear. Dysregulation of long interspersed element-1 (LINE-1) has been reported in the brains of ASD-like mutant mice and ASD brain tissues. However, the role and methylation of LINE-1 in individuals with ASD remain unclear. In this study, we aimed to investigate whether LINE-1 insertion is associated with differentially expressed genes (DEGs) and to assess LINE-1 methylation in ASD. METHODS: To identify DEGs associated with LINE-1 in ASD, we reanalyzed previously published transcriptome profiles and overlapped them with the list of LINE-1-containing genes from the TranspoGene database. An Ingenuity Pathway Analysis (IPA) of DEGs associated with LINE-1 insertion was conducted. DNA methylation of LINE-1 was assessed via combined bisulfite restriction analysis (COBRA) of lymphoblastoid cell lines from ASD individuals and unaffected individuals, and the methylation levels were correlated with the expression levels of LINE-1 and two LINE-1-inserted DEGs, C1orf27 and ARMC8. RESULTS: We found that LINE-1 insertion was significantly associated with DEGs in ASD. The IPA showed that LINE-1-inserted DEGs were associated with ASD-related mechanisms, including sex hormone receptor signaling and axon guidance signaling. Moreover, we observed that the LINE-1 methylation level was significantly reduced in lymphoblastoid cell lines from ASD individuals with severe language impairment and was inversely correlated with the transcript level. The methylation level of LINE-1 was also correlated with the expression of the LINE-1-inserted DEG C1orf27 but not ARMC8. CONCLUSIONS: In ASD individuals with severe language impairment, LINE-1 methylation was reduced and correlated with the expression levels of LINE-1 and the LINE-1-inserted DEG C1orf27. Our findings highlight the association of LINE-1 with DEGs in ASD blood samples and warrant further investigation. The molecular mechanisms of LINE-1 and the effects of its methylation in ASD pathobiology deserve further study.
