Internet Usage by Patients with Multiple Sclerosis: Implications to Participatory Medicine and Personalized Healthcare

Online health information and services for patients were suggested to improve symptom management and treatment adherence, thereby contributing to healthcare optimization. This paper aimed to characterize multiple sclerosis (MS) patients Internet usage. Information regarding browsing habits, Internet reliability, and the medical team's attitude to information collected online was obtained by questionnaires from MS patients. Data was compared between nonbrowsers, browsers on MS topics, and browsers on non-MS topics only. From the 96 patients recruited, 61 (63.5%) performed MS-related searches. The most viewed topics were “understanding the disease” and “treatments”. Patients reported that the information helped coping with MS and assured them of the appropriateness of their therapy. Shorter disease duration was correlated with higher Internet activity. Disabled patients were more interested in online interaction with specialists and support groups. This paper suggests that MS patients benefit from online information, and it emphasizes the importance of resources tailored to patients needs

Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder.

Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex

A: Internet Usage by Patients with Multiple Sclerosis

Online health information and services for patients were suggested to improve symptom management and treatment adherence, thereby contributing to healthcare optimization. This paper aimed to characterize multiple sclerosis (MS) patients Internet usage. Information regarding browsing habits, Internet reliability, and the medical team's attitude to information collected online was obtained by questionnaires from MS patients. Data was compared between nonbrowsers, browsers on MS topics, and browsers on non-MS topics only. From the 96 patients recruited, 61 (63.5%) performed MS-related searches. The most viewed topics were "understanding the disease" and "treatments". Patients reported that the information helped coping with MS and assured them of the appropriateness of their therapy. Shorter disease duration was correlated with higher Internet activity. Disabled patients were more interested in online interaction with specialists and support groups. This paper suggests that MS patients benefit from online information, and it emphasizes the importance of resources tailored to patients needs

A Physical Map, Including a BAC/PAC Clone Contig, of the Williams-Beuren Syndrome–Deletion Region at 7q11.23

Williams-Beuren syndrome (WBS) is a developmental disorder caused by haploinsufficiency for genes in a 2-cM region of chromosome band 7q11.23. With the exception of vascular stenoses due to deletion of the elastin gene, the various features of WBS have not yet been attributed to specific genes. Although ⩾16 genes have been identified within the WBS deletion, completion of a physical map of the region has been difficult because of the large duplicated regions flanking the deletion. We present a physical map of the WBS deletion and flanking regions, based on assembly of a bacterial artificial chromosome/P1-derived artificial chromosome contig, analysis of high-throughput genome-sequence data, and long-range restriction mapping of genomic and cloned DNA by pulsed-field gel electrophoresis. Our map encompasses 3 Mb, including 1.6 Mb within the deletion. Two large duplicons, flanking the deletion, of ⩾320 kb contain unique sequence elements from the internal border regions of the deletion, such as sequences from GTF2I (telomeric) and FKBP6 (centromeric). A third copy of this duplicon exists in inverted orientation distal to the telomeric flanking one. These duplicons show stronger sequence conservation with regard to each other than to the presumptive ancestral loci within the common deletion region. Sequence elements originating from beyond 7q11.23 are also present in these duplicons. Although the duplicons are not present in mice, the order of the single-copy genes in the conserved syntenic region of mouse chromosome 5 is inverted relative to the human map. A model is presented for a mechanism of WBS-deletion formation, based on the orientation of duplicons' components relative to each other and to the ancestral elements within the deletion region

Rare Disease Diagnostics: A Single-center Experience and Lessons Learnt

Objective: The growing availability of next-generation sequencing technologies has revolutionized medical genetics, facilitating discovery of causative genes in numerous Mendelian disorders. Nevertheless, there are still many undiagnosed cases. We report the experience of the Genetics Institute at Rambam Health Care Campus in rare disease diagnostics using whole-exome sequencing (WES). Methods: Phenotypic characterization of patients was done in close collaboration with referring physicians. We utilized WES analysis for diagnosing families suspected for rare genetic disorders. Bioinformatic analysis was performed in-house using the Genoox analysis platform. Results: Between the years 2014 and 2017, we studied 34 families. Neurological manifestations were the most common reason for referral (38%), and 55% of families were consanguineous. A definite diagnosis was reached in 21 cases (62%). Four cases (19%) were diagnosed with variants in novel genes. In addition, six families (18%) had strong candidate novel gene discoveries still under investigation. Therefore, the true diagnosis rate is probably even higher. Some of the diagnoses had a significant impact such as alerting the patient management and providing a tailored treatment. Conclusions: An accurate molecular diagnosis can set the stage for improved patient care and provides an opportunity to study disease mechanisms, which may lead to development of tailored treatments. Data from our genetic research program demonstrate high diagnostic and novel disease-associated or causative gene discovery rates. This is likely related to the unique genetic architecture of the population in Northern Israel as well as to our strategy for case selection and the close collaboration between analysts, geneticists, and clinicians, all working in the same hospital

Proportion of variance in gene expression is explained by a major IFN-β response component and donor-specific components.

<p>Variance component analysis was modeled with the following components: Donor - representing variance contributed by unspecified differences between donors; IFN-β exposure (<i>in vitro</i> IFN-β treated LCL sample versus the untreated sample); Age (stratified to under 40 years old or above); Gender; MS subtype (relapsing remitting, relapsing progressive, secondary progressive), Treatment status (IFN-β treatment naïve donors, or donors treated for at least 1 year at the time of sample collection); and Ethnicity (Jewish/Arab). The Residual component models all the variability that cannot be attributed to any of the explicit variance components.</p

Gene Expression Profiling of the Response to Interferon Beta in Epstein-Barr-Transformed and Primary B Cells of Patients with Multiple Sclerosis

<div><p>The effects of interferon-beta (IFN-β), one of the key immunotherapies used in multiple sclerosis (MS), on peripheral blood leukocytes and T cells have been extensively studied. B cells are a less abundant leukocyte type, and accordingly less is known about the B cell-specific response to IFN-β. To identify gene expression changes and pathways induced by IFN-β in B cells, we studied the <i>in vitro</i> response of human Epstein Barr-transformed B cells (lymphoblast cell lines-LCLs), and validated our results in primary B cells. LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-β exposure, with over 50 previously unrecognized as IFN-β response genes. Pathways analysis demonstrated that IFN-β affected LCLs in a similar manner to other cell types by activating known IFN-β canonical pathways. Additionally, IFN-β increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Novel response genes identified herein, <i>NEXN</i>, <i>DDX60L</i>, <i>IGFBP4</i>, and <i>HAPLN3</i>, B cell receptor pathway genes, <i>CD79B</i> and <i>SYK</i>, and lymphocyte activation genes, <i>LAG3</i> and <i>IL27RA</i>, were validated as IFN-β response genes in primary B cells. In this study new IFN-β response genes were identified in B cells, with possible implications to B cell-specific functions. The study's results emphasize the applicability of LCLs for studies of human B cell drug response. The usage of LCLs from patient-based repositories may facilitate future studies of drug response in MS and other immune-mediated disorders with a B cell component.</p></div

The LCL gene expression response to IFN-β.

<p>A: Volcano plot for the IFN-β gene expression response in LCLs. Log2(fold change) of expression levels following IFN-β exposure and P-values (one-way ANOVA) are depicted for each transcript probe. The horizontal dashed line represents the threshold for the adjusted P-value of 0.05. Vertical dashed line indicates threshold of log2(fold change)>1 and <−1. Differentially expressed genes (in black) are genes with log2(fold change) ≥1 and adjusted P-value ≤0.05, novel IFN-β response genes included in RTPCR validation analyses are marked. For pathways analyses a lower threshold was employed (dotted vertical line) with log2(fold change)≥0.4 (dark grey dots). B: Venn diagram describing the proportion of differentially expressed genes in response to IFN-β [log2(fold change)≥1, adjusted P-value<0.05, bold outlined ellipse] that are novel response genes (grey shade), and a comparison to the published differentially expressed genes up-regulated in LCLs in comparison to primary B cells, based on the data of Caliskan and colleagues [log2(fold change)≥1, adjusted P-value<0.05]<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102331#pone.0102331-Caliskan1" target="_blank">[26]</a>. Definition of novel IFN-β response genes is based on the Interferome V2.01 database (accessed 19.8.13) search for the 115 IFN-β response differentially expressed genes. Numbers indicate the number of genes within each subgroup.</p