Towards Mechanism- Based Treatments for Fragile X Syndrome

Total Page:16

File Type:pdf, Size:1020Kb

Towards Mechanism- Based Treatments for Fragile X Syndrome brain sciences Towards Mechanism- based Treatments for Fragile X Syndrome Edited by Daman Kumari and Inbal Gazy Printed Edition of the Special Issue Published in Brain Sciences www.mdpi.com/journal/brainsci Towards Mechanism-based Treatments for Fragile X Syndrome Towards Mechanism-based Treatments for Fragile X Syndrome Special Issue Editors Daman Kumari Inbal Gazy MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editors Daman Kumari Inbal Gazy National Institute of Diabetes National Institute of Diabetes USA USA Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Brain Sciences (ISSN 2076-3425) from 2018 to 2019 (available at: https://www.mdpi.com/journal/ brainsci/special issues/Fragile X Syndrome) For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03921-505-8 (Pbk) ISBN 978-3-03921-506-5 (PDF) Cover image courtesy of Elisa A. Waxman, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editors ..................................... vii Daman Kumari and Inbal Gazy Towards Mechanism-Based Treatments for Fragile X Syndrome Reprinted from: Brain Sci. 2019, 9, 202, doi:10.3390/brainsci9080202 ................. 1 Daman Kumari, Inbal Gazy and Karen Usdin Pharmacological Reactivation of the Silenced FMR1 Gene as a Targeted Therapeutic Approach for Fragile X Syndrome Reprinted from: Brain Sci. 2019, 9, 39, doi:10.3390/brainsci9020039 .................. 6 Manar Abu Diab and Rachel Eiges The Contribution of Pluripotent Stem Cell (PSC)-Based Models to the Study of Fragile X Syndrome (FXS) Reprinted from: Brain Sci. 2019, 9, 42, doi:10.3390/brainsci9020042 .................. 24 David R. Hampson, Alexander W. M. Hooper and Yosuke Niibori The Application of Adeno-Associated Viral Vector Gene Therapy to the Treatment of Fragile X Syndrome Reprinted from: Brain Sci. 2019, 9, 32, doi:10.3390/brainsci9020032 .................. 43 Carolyn M. Yrigollen and Beverly L. Davidson CRISPR to the Rescue: Advances in Gene Editing for the FMR1 Gene Reprinted from: Brain Sci. 2019, 9, 17, doi:10.3390/brainsci9010017 .................. 58 Xiaonan Zhao, Inbal Gazy, Bruce Hayward, Elizabeth Pintado, Ye Hyun Hwang, Flora Tassone and Karen Usdin Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model Reprinted from: Brain Sci. 2019, 9, 52, doi:10.3390/brainsci9030052 .................. 72 Rachel Michelle Sar´e, Christopher Figueroa, Abigail Lemons, Inna Loutaev and Carolyn Beebe Smith Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice Reprinted from: Brain Sci. 2019, 9, 13, doi:10.3390/brainsci9010013 .................. 87 Marwa Zafarullah and Flora Tassone Molecular Biomarkers in Fragile X Syndrome Reprinted from: Brain Sci. 2019, 9, 96, doi:10.3390/brainsci9050096 ..................101 Rakhi Pal and Aditi Bhattacharya Modelling Protein Synthesis as A Biomarker in Fragile X Syndrome Patient-Derived Cells Reprinted from: Brain Sci. 2019, 9, 59, doi:10.3390/brainsci9030059 ..................124 Craig A. Erickson, Walter E. Kaufmann, Dejan B. Budimirovic, Ave Lachiewicz, Barbara Haas-Givler, Robert M. Miller, Jayne Dixon Weber, Leonard Abbeduto, David Hessl, Randi J. Hagerman and Elizabeth Berry-Kravis Best Practices in Fragile X Syndrome Treatment Development Reprinted from: Brain Sci. 2018, 8, 224, doi:10.3390/brainsci8120224 .................136 v Jayne Dixon Weber, Elizabeth Smith, Elizabeth Berry-Kravis, Diego Cadavid, David Hessl and Craig Erickson Voice of People with Fragile X Syndrome and Their Families: Reports from a Survey on Treatment Priorities Reprinted from: Brain Sci. 2019, 9, 18, doi:10.3390/brainsci9020018 ..................145 Kristi L. Bartholomay, Cindy H. Lee, Jennifer L. Bruno, Amy A. Lightbody and Allan L. Reiss Closing the Gender Gap in Fragile X Syndrome: Review of Females with Fragile X Syndrome and Preliminary Research Findings Reprinted from: Brain Sci. 2019, 9, 11, doi:10.3390/brainsci9010011 ..................158 Debra L. Reisinger, Rebecca C. Shaffer, Ernest V. Pedapati, Kelli C. Dominick and Craig A. Erickson A Pilot Quantitative Evaluation of Early Life Language Development in Fragile X Syndrome Reprinted from: Brain Sci. 2019, 9, 27, doi:10.3390/brainsci9020027 ..................172 Lauren M. Schmitt, Rebecca C. Shaffer, David Hessl and Craig Erickson Executive Function in Fragile X Syndrome: A Systematic Review Reprinted from: Brain Sci. 2019, 9, 15, doi:10.3390/brainsci9010015 ..................184 Katherine C. Okoniewski, Anne C. Wheeler, Stacey Lee, Beth Boyea, Melissa Raspa, Jennifer L. Taylor and Donald B. Bailey Jr. Early Identification of Fragile X Syndrome through Expanded Newborn Screening Reprinted from: Brain Sci. 2019, 9, 4, doi:10.3390/brainsci9010004 ..................213 Anna W. Lee, Pamela Ventola, Dejan Budimirovic, Elizabeth Berry-Kravis and Jeannie Visootsak Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective Reprinted from: Brain Sci. 2018, 8, 214, doi:10.3390/brainsci8120214 .................225 vi About the Special Issue Editors Daman Kumari is a Staff Scientist in the Laboratory of Cell and Molecular Biology at the National Institutes of Health. Dr. Kumari has made several important contributions to the understanding of repeat-mediated FMR1 gene silencing in FXS. Her current research is focused on developing treatment strategies for FXS that are based on FMR1 gene reactivation. Dr. Kumari serves on the Editorial Board of Genetic Testing and Molecular Biomarkers, Brain Sciences, and Journal of Autism and Developmental Research and is an ad hoc peer reviewer for many scientific journals. Inbal Gazy received her Ph.D. in Human Genetics from the Hebrew University of Jerusalem, Israel. She is currently a Postdoctoral Fellow in the Laboratory of Cell and Molecular Biology at the National Institutes of Health. Dr. Gazy has contributed to the understanding of molecular mechanisms that are responsible for several genetic diseases. Her recent work focuses on the molecular mechanisms and consequences of the unusual repeat expansion mutation responsible for fragile X-related disorders. vii brain sciences Editorial Towards Mechanism-Based Treatments for Fragile X Syndrome Daman Kumari * and Inbal Gazy Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA * Correspondence: [email protected] Received: 13 August 2019; Accepted: 14 August 2019; Published: 16 August 2019 Fragile X syndrome (FXS) is the most common heritable form of intellectual disability, as well as the most common known monogenic cause of autism spectrum disorder (ASD), affecting 1 in 4000–8000 people worldwide. Almost 30 years ago, in 1991, the causative mutation for FXS was identified to be a CGG-repeat expansion in a gene named Fragile X Mental Retardation-1 (FMR1) located on the X chromosome [1,2]. At that time, it also became clear that methylation of a CpG island proximal to the repeats results in loss of gene expression and disease pathology [3–7]. While many decades have elapsed since these early discoveries, the underlying mechanisms involved in the expansion mutation, as well as the resulting gene silencing, still remain elusive. Soon after the identification of FMR1, a knockout mouse model was developed to better understand the role of FMR1 and its protein product, FMRP, in FXS [8]. Work from this mouse model, as well as other models, implicated FMRP activity in brain development, synaptic plasticity and neuronal transmission circuits [9,10]. This body of work led to clinical trials attempting to correct the deficient pathways in the brain of FXS patients [11]. However, all these clinical trials, although based on successful preclinical studies, did not show beneficial effects in FXS patients. Thus, currently there is no cure or effective treatment for FXS, and all the available interventions are focused on managing patient symptoms. Confronted with the gaps in knowledge and lack of treatments for FXS patients, the scientific community decided to revisit the approaches and practices used, implementing changes both in the preclinical and the clinical arenas. This special issue addresses some of the changes that are being made in the field towards finding effective treatments for FXS. As reviewed by Kumari et al. [12], there are two major avenues currently being pursued for development of effective treatments: (1) Targeting pathways altered in the absence of FMRP in the brain, and (2) Restoring FMRP expression. The fact that clinical trials focused on the restoration of altered pathways have not shown much promise to date, together with the development of new techniques and approaches in the biomedical field, has
Recommended publications
  • Abstract Book – Oral Sessions
    Sunday, June 21, 2015 12:00 p.m. - 1:15 p.m. Latin American Psychopharmacology Update: INNOVATIVE TREATMENTS IN PSYCHIATRY INNOVATIVE TREATMENTS IN PSYCHIATRY Flavio Kapczinski, The University of Texas Health Science Center at Houston Overall Abstract In this panel, we will propose innovative treatments in psychiatry and recent literature findings will be summarized. The effective pharmacological treatment of psychiatric diseases and development of new therapeutic entities has been a long-standing challenge. Despite the complexity and heterogeneity of psychiatric disorders, basic and clinical research studies and technological advancements in genomics, biomarkers, and imaging have begun to elucidate the pathophysiology of etiological complexity of psychiatric diseases and to identify efficacious new agents (Tcheremissine et al. 2014). Many psychiatric illnesses are associated with neuronal atrophy, characterized by loss of synaptic connections, increase of inflammatory markers like TNF-α and DAMPS (damage-associate molecular patterns,- cell free (ccf) DNA, heat shock proteins HSP70, HSP90, and HSP60, and cytochrome C), decrease of neurotrophic factors, increase of oxidative stress, mitochondrial dysfunction and apoptosis (Fries et al., 2012; Pfaffenseller et al., 2014). Also, neurocognitive impairment and poor psychosocial functioning has been related to a psychiatric disease. Therefore, trying to discover new therapeutic targets that act in these pathways can help to develop new treatment or improve the treatment of these serious diseases.
    [Show full text]
  • Childhood Cerebral X-Linked Adrenoleukodystrophy with Atypical Neuroimaging Abnormalities and a No…
    9/28/2018 Journal of Postgraduate Medicine: Childhood cerebral X-linked adrenoleukodystrophy with atypical neuroimaging abnormalities and a no… Open access journal indexed with Index Medicus & EMBASE Home | Subscribe | Feedback [Download PDF] CASE REPORT Year : 2018 | Volume : 64 | Issue : 1 | Page : 59-63 Childhood cerebral X-linked adrenoleukodystrophy with atypical neuroimaging abnormalities and a novel mutation M Muranjan1, S Karande1, S Sankhe2, S Eichler3, 1 Department of Pediatrics, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India 2 Department of Radiology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India 3 Centogene AG, Schillingallee 68, Rostock, Germany Correspondence Address: Dr. M Muranjan Department of Pediatrics, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra India Abstract Childhood cerebral X-linked adrenoleukodystrophy (XALD) typically manifests with symptoms of adrenocortical insufficiency and a variety of neurocognitive and behavioral abnormalities. A major diagnostic clue is the characteristic neuroinflammatory parieto-occipital white matter lesions on magnetic resonance imaging. This study reports a 5-year 10-month old boy presenting with generalized skin hyperpigmentation since 3 years of age. Over the past 9 months, he had developed right-sided hemiparesis and speech and behavioral abnormalities, which had progressed over 5 months to bilateral hemiparesis. Retrospective analyses of serial brain magnetic resonance images revealed an unusual pattern of lesions involving the internal capsules, corticospinal tracts in the midbrain and brainstem, and cerebellar white matter. The clinical diagnosis of childhood cerebral adrenoleukodystrophy was confirmed by elevated basal levels of adrenocorticotropin hormone and plasma very long chain fatty acid levels. Additionally, sequencing of the ABCD1 gene revealed a novel mutation.
    [Show full text]
  • The Effects and Feasibility of Using Tiered Instruction to Increase Conversational Turn Taking for Preschoolers with and Without Disabilities
    THE EFFECTS AND FEASIBILITY OF USING TIERED INSTRUCTION TO INCREASE CONVERSATIONAL TURN TAKING FOR PRESCHOOLERS WITH AND WITHOUT DISABILITIES A dissertation submitted to the Kent State University College and Graduate School of Education, Health, and Human Services in partial fulfillment of the requirements for the degree of Doctor of Philosophy By Sandra Hess Robbins May 2013 © Copyright, 2013 by Sandra Hess Robbins All Rights Reserved ii A dissertation written by Sandra Hess Robbins B.S.Ed., University of Wisconsin, Oshkosh, 2002 M.Ed., Kent State University, 2006 Ph.D., Kent State University, 2013 Approved by ____________________, Co-director, Doctoral Dissertation Committee Kristie Pretti-Frontcak ____________________, Co-director, Doctoral Dissertation Committee Sanna Harjusola-Webb ____________________, Member, Doctoral Dissertation Committee Christine Balan ____________________, Member, Doctoral Dissertation Committee Richard Cowan Accepted by ____________________, Director, School of Lifespan Development and Educational Mary Dellman-Jenkins Sciences ____________________, Dean, College of Education, Health, and Human Services Daniel F. Mahony iii ROBBINS, SANDRA HESS, Ph.D., May 2013 Lifespan Development and Educational Sciences THE EFFECTS AND FEASIBILITY OF USING TIERED INSTRUCTION TO INCREASE CONVERSATIONAL TURN TAKING FOR PRESCHOOLERS WITH AND WITHOUT DISABILITIES (282 pp.) Co-Directors of Dissertation: Kristie Pretti-Frontczak, Ph.D. Sanna Harjusola-Webb, Ph.D. The purpose of the study was to examine the effectiveness and feasibility of using tiered instruction to increase the frequency of conversational turn taking (CTT) among preschoolers with and without disabilities in an inclusive setting. Three CTT interventions (Universal Design for Learning, Peer Mediated Instruction, and Milieu Teaching) were organized on a hierarchy of intensity and implemented in an additive manner.
    [Show full text]
  • Ryerson University Spring Graduates
    Ryerson University Spring Graduates June 2020 Faculty of Arts 2 Faculty of Communication & Design 11 Faculty of Community Services 21 Faculty of Engineering and Architectural Science 35 Faculty of Science 46 Ted Rogers School of Management 54 Yeates School of Graduate Studies 71 The G. Raymond Chang School of Continuing Education 73 Faculty of Arts Pamela Sugiman Dean Faculty of Arts Janice Fukakusa Chancellor Mohamed Lachemi President and Vice-Chancellor Charmaine Hack Registrar Ryerson Gold Medal Presented to Mayah Obadia Geographic Analysis 2 Faculty of Arts Undergraduate Degree Programs Arts and Contemporary Studies Bachelor of Arts (Honours) *Diana Abo Harmouch Carmen Jajjo *Megumi Noteboom *Sima Rebecca Abrams Leya Jasat Valentina Padure Qeyam Amiri Sophie Johnson *Naiomi Marcia Perera Brodie Barrick Babina Kamalanathan Charlotte Jane Prokopec Rebecca Claire Chen Caroline Susan Kewley Regan Reynolds Erin Tanya Clarke Jessica Laurenza Joshua Ricci *Megan Lisa Devoe Claire Lowenstein Kaitlin Anganie Seepersaud *Manpreet Kaur Dhaliwal *Avigayil Margolis Gabriela Skwarko Tatum Lynn Donovan Sara McArthur Julia Macey Sullivan Faith Raha Giahi *Nadia Celeste McNairn *Helen Gillian Webb Meagan Gove *Mahbod Mehrvarz *Michael Worbanski Salem Habtom Andrew Moon Smyrna Wright *William Hanchar *Liana Gabriella Mortin Calum Jacques Potoula Mozas Criminology Bachelor of Arts (Honours) *Annabelle Adjei *Jenna Anne Giannini Veronica Hiu Lam Lee Stanislav Babinets Albina Glatman Karishma Catherine Lutchman Hela Bakhtari Farah Khaled Gregni Simbiat
    [Show full text]
  • Nicole Trask, Pharmd, Planning for the 2019 Specialty Drug Spend
    Planning for the 2019 Specialty Drug Spend August 24, 2018 Nicole Trask, PharmD Clinical Consultant Pharmacist University of Massachusetts – Clinical Pharmacy Services Disclosure for Nicole Trask I have no actual or potential conflict of interest in relation to this presentation. Budget Impact Modeling for 2 ||August 24, 2018 the Specialty Drug Spend Objectives • Identify high-impact specialty pipeline drugs expected to reach the market in 2019-2020 • Summarize efficacy data for high-impact specialty pipeline drugs and indicate their anticipated place in therapy • Compare specialty pipeline drugs to currently available therapeutic options • Predict the budgetary impact of specialty pipeline drugs and discuss strategies to mitigate costs Budget Impact Modeling for 3 ||August 24, 2018 the Specialty Drug Spend Identifying High-Impact Drugs Two key drivers • Clinical impact • Efficacy/effectiveness • Therapeutic alternatives • Economic impact • Cost • Volume Budget Impact Modeling for 4 ||August 24, 2018 the Specialty Drug Spend Assessing Clinical Impact Clinical trial data Therapeutic alternatives • Placebo-controlled, • Me-too drug vs. head-to-head studies first-in-class • Adverse events • Market competition • Potential drug-drug • Consensus interactions guidelines • Target population • Patient willingness to use medication Budget Impact Modeling for 5 ||August 24, 2018 the Specialty Drug Spend Assessing Economic Impact Cost Volume • NADAC, AWP, WAC • Prevalence/incidence of • Supplemental rebate disease • Outcomes-based • Frequency of contracts administration • Value assessments • Duration of therapy (e.g., AHRQ, ICER, PCORI) AHRQ=Agency for Healthcare Research and Quality, AWP=average wholesale price, ICER=Institute for Clinical and Economic Review, NADAC=national average drug acquisition cost, PCORI=Patient-centered Outcomes Research Institute, WAC=wholesale acquisition cost Budget Impact Modeling for 6 ||August 24, 2018 the Specialty Drug Spend Other Factors Affecting Budget Impact Disease-specific Prescriber-specific • Chronic vs.
    [Show full text]
  • Women with High Functioning ASD: Relationships and Sexual Health
    Claremont Colleges Scholarship @ Claremont CMC Senior Theses CMC Student Scholarship 2020 Women with High Functioning ASD: Relationships and Sexual Health Isabelle Taylor Follow this and additional works at: https://scholarship.claremont.edu/cmc_theses Part of the Developmental Psychology Commons Recommended Citation Taylor, Isabelle, "Women with High Functioning ASD: Relationships and Sexual Health" (2020). CMC Senior Theses. 2553. https://scholarship.claremont.edu/cmc_theses/2553 This Open Access Senior Thesis is brought to you by Scholarship@Claremont. It has been accepted for inclusion in this collection by an authorized administrator. For more information, please contact [email protected]. Claremont McKenna College Women with High Functioning ASD: Relationships and Sexual Health A Literature Review and Proposed Workshop Manual Submitted to Professor Caitlyn Gumaer By Isabelle Taylor for Senior Thesis 2020 November 30 Table of Contents Author’s Note.................................................................................................................................. 1 Abstract........................................................................................................................................... 2 Literature Review.................................................................................................................... 3 - 38 Symptoms and Diagnosis.............................................................................................. 3 - 7 Gender Differences.....................................................................................................
    [Show full text]
  • Rett Syndrome: Coming to Terms with Treatment
    Hindawi Publishing Corporation Advances in Neuroscience Volume 2014, Article ID 345270, 20 pages http://dx.doi.org/10.1155/2014/345270 Review Article Rett Syndrome: Coming to Terms with Treatment Alan Percy Civitan International Research Center, University of Alabama at Birmingham, 1720 2nd Avenue South, CIRC 320E, Birmingham, AL 35294-0021, USA Correspondence should be addressed to Alan Percy; [email protected] Received 5 January 2014; Accepted 26 February 2014; Published 10 April 2014 Academic Editor: Ronald L. Klein Copyright © 2014 Alan Percy. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rett syndrome (RTT) has experienced remarkable progress over the past three decades since emerging as a disorder of worldwide proportions, particularly with discovery of the linkage of RTT to MECP2 mutations. The advances in clinical research and the increasing pace of basic science investigations have accelerated the pattern of discovery and understanding. Clinical trials are ongoing and others are planned. A review of these events and the prospects for continued success are highlighted below. The girls and women encountered today with RTT are, overall, in better general, neurologic, and behavioral health than those encountered earlier. This represents important progress worldwide from the concerted efforts of a broadly based and diverse clinical and basic research consortium as well
    [Show full text]
  • FY19 Annual Report View Report
    Annual Report 2018–19 3 Introduction 5 Metropolitan Opera Board of Directors 6 Season Repertory and Events 14 Artist Roster 16 The Financial Results 20 Our Patrons On the cover: Yannick Nézet-Séguin takes a bow after his first official performance as Jeanette Lerman-Neubauer Music Director PHOTO: JONATHAN TICHLER / MET OPERA 2 Introduction The 2018–19 season was a historic one for the Metropolitan Opera. Not only did the company present more than 200 exiting performances, but we also welcomed Yannick Nézet-Séguin as the Met’s new Jeanette Lerman- Neubauer Music Director. Maestro Nézet-Séguin is only the third conductor to hold the title of Music Director since the company’s founding in 1883. I am also happy to report that the 2018–19 season marked the fifth year running in which the company’s finances were balanced or very nearly so, as we recorded a very small deficit of less than 1% of expenses. The season opened with the premiere of a new staging of Saint-Saëns’s epic Samson et Dalila and also included three other new productions, as well as three exhilarating full cycles of Wagner’s Ring and a full slate of 18 revivals. The Live in HD series of cinema transmissions brought opera to audiences around the world for the 13th season, with ten broadcasts reaching more than two million people. Combined earned revenue for the Met (box office, media, and presentations) totaled $121 million. As in past seasons, total paid attendance for the season in the opera house was 75%. The new productions in the 2018–19 season were the work of three distinguished directors, two having had previous successes at the Met and one making his company debut.
    [Show full text]
  • Pelizaeus-Merzbacher Disease (Pmd)
    PELIZAEUS‐MERZBACHER DISEASE (PMD) is a X‐linked disease that is transmitted from normal appearing carrier mothers to their sons. Each male born to these mothers has a 50/50 chance of being affected with PMD. Each female child born to them has a 50/50 chance of being a carrier herself. Having more than one affected child, with a disease that there is only 50/50 of, I know sounds impossible, but I did the same thing! You have to realize it's a 50/50 chance with every pregnancy. One way to possibly describe this is to take a deck of cards, remove all 4 aces. Let the 2 red ones represent females, the ace of hearts could represent a non‐carrier female, the ace of diamonds could represent a carrier female. Let the 2 black ones represent males, the ace of clubs could represent a non‐affected male, the ace of spades could represent an affected male. With each pregnancy you have a 1 in 4 chance of having an affected son. Turn the 4 cards face down and draw one, if it should be the ace of spades (affected male), you can't say, "I have already had my affected one", and exclude it from the next pregnancy. With each pregnancy you have to "draw" from all 4 "cards". This disease affects the myelin sheath, that insulates the nerves of the central nervous system. These nerve fibers, called axons, carry impulses from the brain to other parts of the body. The axons are similar to an electrical wire, the myelin is like insulation that covers them.
    [Show full text]
  • X-Linked Diseases: Susceptible Females
    REVIEW ARTICLE X-linked diseases: susceptible females Barbara R. Migeon, MD 1 The role of X-inactivation is often ignored as a prime cause of sex data include reasons why women are often protected from the differences in disease. Yet, the way males and females express their deleterious variants carried on their X chromosome, and the factors X-linked genes has a major role in the dissimilar phenotypes that that render women susceptible in some instances. underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the Genetics in Medicine (2020) 22:1156–1174; https://doi.org/10.1038/s41436- heart, blood, skin, muscle, and bones. Summarized here are many 020-0779-4 examples of the different presentations in males and females. Other INTRODUCTION SEX DIFFERENCES ARE DUE TO X-INACTIVATION Sex differences in human disease are usually attributed to The sex differences in the effect of X-linked pathologic variants sex specific life experiences, and sex hormones that is due to our method of X chromosome dosage compensation, influence the function of susceptible genes throughout the called X-inactivation;9 humans and most placental mammals – genome.1 5 Such factors do account for some dissimilarities. compensate for the sex difference in number of X chromosomes However, a major cause of sex-determined expression of (that is, XX females versus XY males) by transcribing only one disease has to do with differences in how males and females of the two female X chromosomes. X-inactivation silences all X transcribe their gene-rich human X chromosomes, which is chromosomes but one; therefore, both males and females have a often underappreciated as a cause of sex differences in single active X.10,11 disease.6 Males are the usual ones affected by X-linked For 46 XY males, that X is the only one they have; it always pathogenic variants.6 Females are biologically superior; a comes from their mother, as fathers contribute their Y female usually has no disease, or much less severe disease chromosome.
    [Show full text]
  • Brain Metabolic Profile After Intranasal Vs. Intraperitoneal Clomipramine
    International Journal of Molecular Sciences Article Brain Metabolic Profile after Intranasal vs. Intraperitoneal Clomipramine Treatment in Rats with Ultrasound Model of Depression Olga Abramova 1,2, Yana Zorkina 1,2,* , Timur Syunyakov 2,3 , Eugene Zubkov 1, Valeria Ushakova 1,2, Artemiy Silantyev 1, Kristina Soloveva 2, Olga Gurina 1, Alexander Majouga 4, Anna Morozova 1,2 and Vladimir Chekhonin 1,5 1 V. Serbsky National Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia; [email protected] (O.A.); [email protected] (E.Z.); [email protected] (V.U.); [email protected] (A.S.); [email protected] (O.G.); [email protected] (A.M.); [email protected] (V.C.) 2 Mental-Health Clinic No. 1 Named after N.A. Alekseev, 117152 Moscow, Russia; [email protected] (T.S.); [email protected] (K.S.) 3 Federal State Budgetary Institution Research Zakusov Institute of Pharmacology, 125315 Moscow, Russia 4 Drug Delivery Systems Laboratory, D. Mendeleev University of Chemical Technology of Russia, Miusskaya pl. 9, 125047 Moscow, Russia; [email protected] 5 Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia * Correspondence: [email protected]; Tel.: +7-916-588-4851 Citation: Abramova, O.; Zorkina, Y.; Abstract: Background: Molecular mechanisms of depression remain unclear. The brain metabolome Syunyakov, T.; Zubkov, E.; Ushakova, after antidepressant therapy is poorly understood and had not been performed for different routes V.; Silantyev, A.; Soloveva, K.; Gurina, of drug administration before the present study. Rats were exposed to chronic ultrasound stress O.; Majouga, A.; Morozova, A.; et al. and treated with intranasal and intraperitoneal clomipramine.
    [Show full text]
  • IMFAR 2010 Disclosure Report *Indicates Presenting Author
    IMFAR 2010 Disclosure Report *indicates presenting author Final Name Title Relationships Number 104.005 * R. B. Beaumont The Secret Agent Society: A Multimedia The Social Skills Training Institute: Curriculum for Enhancing the Social Skills of Employment (full or part-time) Children with Asperger's Disorder The Social Skills Training Institute: Receipt of royalties 104.007 R. L. Koegel Type, Function, and Complexity of Koegel Autism Consultants: Ownership or Language Gains in Young Children with partnership Autism Spectrum Disorder Following Behavioral Intervention 104.007 L. K. Koegel Type, Function, and Complexity of Koegel Autism Consultants: Ownership or Language Gains in Young Children with partnership Autism Spectrum Disorder Following Behavioral Intervention 104.008 R. L. Koegel Using the Tools of the Trade: The ADOS as a Koegel Autism Consultants: Ownership or Measure of Treatment Change partnership 104.008 L. K. Koegel Using the Tools of the Trade: The ADOS as a Koegel Autism Consultants: Ownership or Measure of Treatment Change partnership 105.002 A. S. Carter Relationship Between Sensory Over- Alice S. Carter: Receipt of royalties Responsivity and Anxiety in Young Children with Autism Spectrum Disorders: 105.007 A. S. Carter Early Sensory Over-Responsivity and Alice S. Carter: Receipt of royalties Affective Symptoms of Children with ASD and Later Family Impairment 105.01 A. M. Wetherby Early Red Flags for Autism Spectrum Author: Other: AW is an author of the Disorders in Toddlers in the Home Early Screening for Autism and Environment Communication Disorders (ESAC) Author: Non-remunerative Brookes Publishing: Other: AW is an author of the Communication and Symbolic Behavior Scales (CSBS) Brookes Publishing: Receipt of royalties 105.011 W.
    [Show full text]