1. Boban S, Leonard H, Wong K, Wilson A, Downs J. {{Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices}}. {Am J Med Genet A};2018 (Apr 28)
Sleep disturbances are debilitating for individuals with Rett syndrome (RTT) and their families yet the evidence base for management is poor. We investigated management strategies and their relationships with sleep problems. Data were provided by 364/461 (79%) families with a child with RTT and registered with the International RTT Phenotype Database. Logistic regression models were used to investigate relationships between impacts of sleep problems on the child and family with age group, mutation type, medication type, and sleep hygiene score. Linear regression models were used to estimate the association of disorders of initiating and maintaining sleep (DIMS) with age group, mutation type, medication type, and sleep hygiene. Among those who ever had difficulty falling asleep or night waking, use of any medication was associated with higher odds of moderate/major impact sleep problems (relative to minor/no impact) for the affected child and the family, as well as higher DIMS scores, when compared with the no treatment/nonmedication group accounting for the effects of age, mutation type, and sleep hygiene score. Better use of sleep hygiene practices was associated with lower odds of moderate/major impact on the family (odds ratio 0.60, 95% confidence intervals [CIs] 0.37, 0.98) and lower DIMS scores (geometric mean ratio 0.86, 95%CI 0.80, 0.92) compared with poorer use after adjusting for covariates. Attention to sleep hygiene remains an important management strategy for sleep problems in RTT. Further prospective research is required to investigate efficacy of pharmaceutical treatments.
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2. Dickie EW, Ameis SH, Shahab S, Calarco N, Smith DE, Miranda D, Viviano JD, Voineskos AN. {{Personalized Intrinsic Network Topography Mapping and Functional Connectivity Deficits in Autism Spectrum Disorder}}. {Biol Psychiatry};2018 (Mar 17)
BACKGROUND: Recent advances in techniques using functional magnetic resonance imaging data demonstrate individually specific variation in brain architecture in healthy individuals. To our knowledge, the effects of individually specific variation in complex brain disorders have not been previously reported. METHODS: We developed a novel approach (Personalized Intrinsic Network Topography, PINT) for localizing individually specific resting-state networks using conventional resting-state functional magnetic resonance imaging scans. Using cross-sectional data from participants with autism spectrum disorder (ASD; n = 393) and typically developing (TD) control participants (n = 496) across 15 sites, we tested: 1) effect of diagnosis and age on the variability of intrinsic network locations and 2) whether prior findings of functional connectivity differences in persons with ASD compared with TD persons remain after PINT application. RESULTS: We found greater variability in the spatial locations of resting-state networks within individuals with ASD compared with those in TD individuals. For TD persons, variability decreased from childhood into adulthood and increased in late life, following a U-shaped pattern that was not present in those with ASD. Comparison of intrinsic connectivity between groups revealed that the application of PINT decreased the number of hypoconnected regions in ASD. CONCLUSIONS: Our results provide a new framework for measuring altered brain functioning in neurodevelopmental disorders that may have implications for tracking developmental course, phenotypic heterogeneity, and ultimately treatment response. We underscore the importance of accounting for individual variation in the study of complex brain disorders.
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3. Duffney LJ, Valdez P, Tremblay MW, Cao X, Montgomery S, McConkie-Rosell A, Jiang YH. {{Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1e and literature review}}. {Am J Med Genet B Neuropsychiatr Genet};2018 (Apr 27)
Genetic mutations in genes encoding proteins involved in epigenetic machinery have been reported in individuals with autism spectrum disorder (ASD), intellectual disability, congenital heart disease, and other disorders. H1 histone linker protein, the basic component in nucleosome packaging and chromatin organization, has not been implicated in human disease until recently. We report a de novo deleterious mutation of histone cluster 1 H1 family member e (HIST1H1E; c.435dupC; p.Thr146Hisfs*50), encoding H1 histone linker protein H1.4, in a 10-year-old boy with autism and intellectual disability diagnosed through clinical whole exome sequencing. The c.435dupC at the 3′ end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy-terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain. Taken together with other recent cases with mutations of HIST1H1E in intellectual disability, the evidence supporting the link to causality in disease is strong. Our finding implicates the deficiency of H1 linker histone protein in autism. The systematic review of candidate genes implicated in ASD revealed that 42 of 215 (19.5%) genes are directly involved in epigenetic regulations and the majority of these genes belong to histone writers, readers, and erasers. While the mechanism of how haploinsufficiency of HIST1H1E causes autism is entirely unknown, our report underscores the importance of further study of the function of this protein and other histone linker proteins in brain development.
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4. He Q, Arroyo ED, Smukowski SN, Xu J, Piochon C, Savas JN, Portera-Cailliau C, Contractor A. {{Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice}}. {Mol Psychiatry};2018 (Apr 27)
Sensory perturbations in visual, auditory and tactile perception are core problems in fragile X syndrome (FXS). In the Fmr1 knockout mouse model of FXS, the maturation of synapses and circuits during critical period (CP) development in the somatosensory cortex is delayed, but it is unclear how this contributes to altered tactile sensory processing in the mature CNS. Here we demonstrate that inhibiting the juvenile chloride co-transporter NKCC1, which contributes to altered chloride homeostasis in developing cortical neurons of FXS mice, rectifies the chloride imbalance in layer IV somatosensory cortex neurons and corrects the development of thalamocortical excitatory synapses during the CP. Comparison of protein abundances demonstrated that NKCC1 inhibition during early development caused a broad remodeling of the proteome in the barrel cortex. In addition, the abnormally large size of whisker-evoked cortical maps in adult Fmr1 knockout mice was corrected by rectifying the chloride imbalance during the early CP. These data demonstrate that correcting the disrupted driving force through GABAA receptors during the CP in cortical neurons restores their synaptic development, has an unexpectedly large effect on differentially expressed proteins, and produces a long-lasting correction of somatosensory circuit function in FXS mice.
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5. Melancia F, Trezza V. {{Modelling Fragile X syndrome in the laboratory setting: a behavioral perspective}}. {Behav Brain Res};2018 (Apr 25)
Fragile X syndrome is the most common form of inherited mental retardation and the most frequent monogenic cause of syndromic autism spectrum disorders. The syndrome is caused by the loss of the Fragile X Mental Retardation Protein (FMRP), a key RNA-binding protein involved in synaptic plasticity and neuronal morphology. Patients show intellectual disability, social deficits, repetitive behaviors and impairments in social communication. The aim of this review is to outline the importance of behavioral phenotyping of animal models of FXS from a developmental perspective, by showing how the behavioral characteristics of FXS at the clinical level can be translated into effective, developmentally-specific and clinically meaningful behavioral readouts in the laboratory setting. After introducing the behavioral features, diagnostic criteria and off-label pharmacotherapy of FXS, we outline how FXS-relevant behavioral features can be modelled in laboratory animals in the course of development: we review the progress to date, discuss how behavioral phenotyping in animal models of FXS is essential to identify potential treatments, and discuss caveats and future directions in this research field.
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6. Townend GS, Ehrhart F, van Kranen HJ, Wilkinson M, Jacobsen A, Roos M, Willighagen EL, van Enckevort D, Evelo CT, Curfs LMG. {{MECP2 variation in Rett syndrome – an overview of current coverage of genetic and phenotype data within existing databases}}. {Hum Mutat};2018 (Apr 27)
Rett syndrome (RTT) is a monogenic rare disorder that causes severe neurological problems. In most cases it results from a loss of function mutation in the gene encoding methyl-CPG-binding protein 2 (MECP2). Currently, about 900 unique MECP2 variations (benign and pathogenic) have been identified and it is suspected that the different mutations contribute to different levels of disease severity. For researchers and clinicians, it is important that genotype-phenotype information is available to identify disease-causing mutations for diagnosis, to aid in clinical management of the disorder, and to provide counselling for parents. In this study, 13 genotype-phenotype databases were surveyed for their general functionality and availability of RTT-specific MECP2 variation data. For each database we investigated findability and interoperability alongside practical user functionality, and type and amount of genetic and phenotype data. The main conclusions are that, as well as being challenging to find these databases and specific MECP2 variants held within, interoperability is as yet poorly developed and requires effort to search across databases. Nevertheless, we found several thousand online database entries for MECP2 variations and their associated phenotypes, diagnosis or predicted variant effects, which is a good starting point for researchers and clinicians who want to provide, annotate, and use the data. This article is protected by copyright. All rights reserved.
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7. Williams SM, An JY, Edson J, Watts M, Murigneux V, Whitehouse AJO, Jackson CJ, Bellgrove MA, Cristino AS, Claudianos C. {{An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder}}. {Mol Psychiatry};2018 (Apr 27)
A number of genetic studies have identified rare protein-coding DNA variations associated with autism spectrum disorder (ASD), a neurodevelopmental disorder with significant genetic etiology and heterogeneity. In contrast, the contributions of functional, regulatory genetic variations that occur in the extensive non-protein-coding regions of the genome remain poorly understood. Here we developed a genome-wide analysis to identify the rare single nucleotide variants (SNVs) that occur in non-coding regions and determined the regulatory function and evolutionary conservation of these variants. Using publicly available datasets and computational predictions, we identified SNVs within putative regulatory regions in promoters, transcription factor binding sites, and microRNA genes and their target sites. Overall, we found that the regulatory variants in ASD cases were enriched in ASD-risk genes and genes involved in fetal neurodevelopment. As with previously reported coding mutations, we found an enrichment of the regulatory variants associated with dysregulation of neurodevelopmental and synaptic signaling pathways. Among these were several rare inherited SNVs found in the mature sequence of microRNAs predicted to affect the regulation of ASD-risk genes. We show a paternally inherited miR-873-5p variant with altered binding affinity for several risk-genes including NRXN2 and CNTNAP2 putatively overlay maternally inherited loss-of-function coding variations in NRXN1 and CNTNAP2 to likely increase the genetic liability in an idiopathic ASD case. Our analysis pipeline provides a new resource for identifying loss-of-function regulatory DNA variations that may contribute to the genetic etiology of complex disorders.
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8. Vessoyan K, Steckle G, Easton B, Nichols M, Mok Siu V, McDougall J. {{Using eye-tracking technology for communication in Rett syndrome: perceptions of impact}}. {Augment Altern Commun};2018 (Apr 27):1-12.
Studies have investigated the use of eye-tracking technology to assess cognition in individuals with Rett syndrome, but few have looked at this access method for communication for this group. Loss of speech, decreased hand use, and severe motor apraxia significantly impact functional communication for this population. Eye gaze is one modality that may be used successfully by individuals with Rett syndrome. This multiple case study explored whether using eye-tracking technology, with ongoing support from a team of augmentative and alternative communication (AAC) therapists, could help four participants with Rett syndrome meet individualized communication goals. Two secondary objectives were to examine parents’ perspectives on (a) the psychosocial impact of their child’s use of the technology, and (b) satisfaction with using the technology. All four participants were rated by the treating therapists to have made improvement on their goals. According to both quantitative findings and descriptive information, eye-tracking technology was viewed by parents as contributing to participants’ improved psychosocial functioning. Parents reported being highly satisfied with both the device and the clinical services received. This study provides initial evidence that eye-tracking may be perceived as a worthwhile and potentially satisfactory technology to support individuals with Rett syndrome in communicating. Future, more rigorous research that addresses the limitations of a case study design is required to substantiate study findings.
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9. Lochman I, Svachova V, Milkova Pavlikova K, Medricka H, Novak V, Trilecova L, Pavliska L, Prochazka V. {{Serum Cytokine and Growth Factor Levels in Children with Autism Spectrum Disorder}}. {Med Sci Monit};2018 (Apr 29);24:2639-2646.
BACKGROUND The immune system may have a role in the pathogenesis of autism spectrum disorder (ASD), including typical and atypical autism. The aim of this study was to determine whether a cytokine and growth factor panel could be identified for the diagnosis and prognosis in children with ASD, including typical and atypical autism. MATERIAL AND METHODS This study included 26 children with ASD (typical or atypical) and 11 of their siblings who did not have ASD. A panel of ten serum cytokines and growth factors were investigated using addressable laser bead assay (ALBIA) and enzyme-linked immunosorbent assay (ELISA) kits. Results were correlated with scores using the Childhood Autism Rating Scale (CARS) and Autism Diagnostic Observation Schedule (ADOS) for the children with ASD and compared with the findings from their siblings without ASD. RESULTS There were no statistically significant differences in serum cytokine and growth factor levels between children with ASD and their siblings. The scores using CARS and ADOS were significantly greater in children with typical autism compared with children with atypical autism as part of the ASD spectrum. Serum levels of cytokines and growth factors showed a positive correlation with CARS and ADOS scores but differed between children with typical and atypical autism and their siblings. CONCLUSIONS The findings of this study showed that serum measurement of appropriately selected panels of cytokines and growth factors might have a role in the diagnosis of ASD.
