8 research outputs found
Recommended from our members
Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group.
Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10Â years
Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder
<div><p>DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.</p></div
Reproducibility and Complications in Gene Searches: Linkage on Chromosome 6, Heterogeneity, Association, and Maternal Inheritance in Juvenile Myoclonic Epilepsy
Genes associated with the DMRs identified by bump-hunting.
<p>CNV: copy number variant.</p
Massively-parallel bisulphite sequencing testing of candidate differentially methylated regions.
<p>Differences in DNA methylation between ASD and TD cohorts are shown for <b>(a)</b><i>FAM134B</i> and <b>(b)</b><i>OR2L13</i>. Absolute methylation values are displayed in the top panels, with the –log<sub>10</sub> p-values as determined by bump-hunting (<i>dmrFind</i>). Differences in microarray mean β value (ASD-TD) and massively-parallel bisulphite sequencing data (ASD-TD) show concordance for decreased DNA methylation in the ASD subjects at both loci (middle panels). The Illumina 450 K Probes track displays CGs tiled by probes on the microarray. While the trends of DNA methylation changes were confirmed by the sequencing-based approaches, statistical significance testing was positive (p<0.05) for the <i>OR2L13</i> locus, with a trend towards significance at the <i>FAM134B</i> locus (split violin plots, lower panels). Of all the subjects tested, a CNV was found in only one individual at <i>OR2L13</i>, otherwise neither locus had CNVs present that could potentially affect interpretation of results.</p
Biological and technical confounders contribute to methylation value variation.
<p>The heat map displays the –log<sub>10</sub> p-values of the linear regressions of the top ten principal components onto each known covariate. The color key shows corresponding numeric values, with red indicating increased significance. The majority of variation is accounted for by experimental influences, with age and ancestry also contributing significantly to variation.</p