DOCSLIB.ORG

Review Article

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Review Article REVIEW ARTICLE Neurological Manifestations of Primary Immunodeficiencies How to Cite This Article: Chavoshzadeh Z, Hashemitari A, Darougar S. Neurological Manifestations of Primary Immunodeficiencies. Iran J Child Neurol. 2018; 12(3): 7-23 Zahra CHAVOSHZADEH MD1, Abstract Amir HASHEMITARI MD2, Objective: Primary immunodeficiencies (PID) are a heterogeneous Sepideh DAROUGAR MD3 group of disorders with a variable clinical spectrum of manifestations. The central nervous system may be involved in PID with symptoms which may present initially or develop at later stages. The purpose of this study was to review the neurological manifestations of different PID syndromes. Materials & Methods: We focused on 104 selected studies on PID with certain neurological abnormalities which may accompany these disorders or may later signify a PID in their course. Results: Diverse neurological deficits accompanying certain PIDs may be mild or they may greatly influence the course of the disease with major impacts on the quality of life of these patients. 1. Department of Immunology and Conclusion: Early recognition and treatment is important to prevent or Allergy, Mofid’s Children Hospital, Shahid Beheshti University of Medical Sciences, reduce future irreversible neurological sequelae. Therefore physicians Tehran, Iran 2. East London NHS Foundation should be aware of the neurological features accompanying PID. Trust,London,United Kingdom Keywords: Neurological; Primary immunodeficiencies; Neurologic 3. Pediatric Respiratory Diseases Research Center, National Research Institute signs and symptoms of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran Introduction Corresponding author: Primary immunodeficiencies (PID) are a heterogeneous group of 354 Darougar S. MD distinct disorders with 344 different gene defects (1) with a variable clinical Email: [email protected] Address: Dr.Masih Daneshvari Hospital, spectrum of manifestations. A diagnosis of PID will often be considered Daar-Abad, Niavaran,Tehran, Iran. Phone Number:+989122881975 with a predisposition to frequent, severe or unusual infections, autoimmune disorders and malignancies or allergic disorders (2). Received: 29- May -2018 Last Revised: 30- May -2018 PIDs have been classified practically according to the affected immune Accepted: 11- June -2018 function to the following groups: immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies with associated Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 7 Neurological Manifestations of Primary Immunodeficiencies or syndromic features, antibody deficiencies, sequelae. The categorization of the inborn errors diseases of immune dysregulation, congenital of immunity is based on the International Union defects of phagocytes, defects in intrinsic and of Immunological Societies: 2017 Primary innate immunity, autoinflammatory disorders, Immunodeficiency Diseases Committee Report on complement deficiencies and phenocopies of PIDs Inborn Errors of Immunity (1). (3). The central nervous system may be involved in Materials & Methods PIDs with symptoms which may present initially or develop at later stages. The neurological The last version of IUIS Primary Immunodeficiencies symptoms may vary from mild cognitive defects Committee Report (1) on Inborn Errors of to severe disabilities (4). Physical examination Immunity was reviewed first to select certain PIDs may give the clinician valuable clues to the cause with neurological manifestations. Then a review of PIDs that underlie the neurological signs. of literature was started according to specific PID Certain neurological abnormalities may later associated with neurological manifestations with a signify a PID. Therefore physicians should be focus on 104 selected studies. aware of the neurological features accompanying Discussion immunodeficiencies. Neuromascular abnormality presenting with ataxia may be the first indicator of Immunodeficiencies affecting cellular and humoral ataxia-telengiectasia. Flaccid paralysis after live immunity poliovirus immunization may suggest combined Severe combined immunodeficiencies defined by immunodeficiency or antibody defects. Pernicious CD3 T cell lymphopenia anaemia may later result in neurological deficits in untreated CVID patients. Cognitive impairment, Adenosine Deaminase deficiency (ADA) nystagmus and cerebellar, spinal and peripheral ADA is a ubiquitous enzyme in purine salvage neuropathies are neurologic features seen in pathway which is also expressed in both the Chediac-Higashi Syndrome. Patients with Griscelli peripheral and central nervous systems (6). ADA syndrome may present with seizures, ataxia and deficiency is caused by mutations in the ADA gene occulomotor and reflex abnormalities. DiGeorge and is known as one of the most prevalent forms anomaly may present with subtle developmental of severe combined immunodeficiencies (6). The delays later manifesting as problem with school most common manifestations include recurrent and performances (5). Early recognition and treatment opportunistic fungal, viral and bacterial infections, may prevent or reduce future irreversible lymphopenia and failure to thrive (7). The main neurological sequelae (4). neurologic manifestations of these diseases result Neurological manifestations will be discussed from accumulation of adenosine metabolites in basal in detail according to the specific classification ganglia and thalamus which are rich in adenosine of primary immunodeficiencies to assist the receptors. These neurologic abnormalities include treating physicians’ timely diagnosis and prompt motor delay, hypotonia, mental retardation, treatment in order to avoid irreversible neurologic learning disability, hyperactivity, attention deficit, behavioural abnormalities, reduced verbal 8 Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 Neurological Manifestations of Primary Immunodeficiencies expression, seizure and sensorineural deafness (4, of one or more classes of immunoglobulin, failure 8). One infant has been reported with nystagmus to make antibodies in response to vaccines and and difficulty in focusing gaze was found to have lymphopenia (19). The ataxia telengiectasia brain atrophy on MRI (9). mutated (ATM) gene is involved in the response to DNA damage in the nervous system which leads to DNA Ligase IV deficiency impaired apoptosis and elimination of the damaged This autosomal recessive form of SCID is caused by neurons and neurodegeneration (4). Progressive an impairment of the DNA damage repair process neurodegeneration which mainly occurs with a with a pronounced radiosensitivity (10). DNA widespread loss of Purkinje cells in cerebellum is double-strand break repair via non-homologous the hallmark of ataxia-telengiectasia, manifesting end-joining (NHEJ) is involved in recombination as head and trunk swaying and gait abnormalities of immunoglobulin and T-cell receptor genes. (8, 13). It is followed by basal ganglia dysfunction Mutations in NHEJ components may lead to later in the course of the disease characterised microcephaly and immunodeficiency (11).The by hypotonia, tremor and choreoathetosis. These neurological manifestations of this disease include patients are usually confined to a wheelchair by microcephaly and developmental delay (12). the age of 10-12 years. In physical examination, further evaluation reveals diminished or absent Cernunnos deficiency tendon reflexes, positive Babinski sign, loss This is another rare autosomal recessive form of vibration sense, abnormal ocular motility, of SCID with severe T and B lymphopenia reduction in sensory conduction velocity and and dysgammaglobulinemia in addition to axonal degeneration of peripheral nerves (8). radiosensitivity caused by mutations in the CERNUNNOS or XRCC4-like factor (XLF). There are also Ataxia Telengiectasia-Like Disorders Microcephaly and developmental delay are the (ATLD) which are clinically similar to ataxia prominent neurological features (4, 8). telengiectasia although without telangiectasia and a slower progression of neurologic manifestations. CID with associated or syndromic features These patients remain ambulatory until their third Ataxia-Telengiectasia decades of lives (8, 20). This autosomal recessive complex disorder with Nijmegan Breakage Syndrome substantial severity in affected individuals (13) This is a rare autosomal recessive, multisystemic is characterized by ataxia, ocular and cutaneous disease of chromosomal instability presenting at telengiectasia, radiosensitivity, immunodeficiency, birth with microcephaly but no additional neurologic increased predisposition to malignancies (14) manifestation (21). The mutated gene (NBS) has and elevated serum alpha fetoprotein level. a critical role in responding to DNA damage. The Sinopulmonary infections (15-17) are common defect leads to neuronal loss and microcephaly. in these patients with development of chronic “Other manifestations include combined cellular lung disease in 25% (18). The most common and humoral immunodeficiency with recurrent immunologic abnormalities are low serum levels Iran J Child Neurol. Summer 2018 Vol. 12 No. 3 9 Neurological Manifestations of Primary Immunodeficiencies sinopulmonary infections, a strong predisposition and increased radiosensitivity accompanied by to develop malignancies and radiosensitivity” neurologic symptoms and growth delay due to (21). Due to the radiation hypersensitivity in these an increased apoptosis and reduced proliferative patients,
Load more

Recommended publications
  • IDF Patient & Family Handbook
    Immune Deficiency Foundation Patient & Family Handbook for Primary Immunodeficiency Diseases This book contains general medical information which cannot be applied safely to any individual case. Medical knowledge and practice can change rapidly. Therefore, this book should not be used as a substitute for professional medical advice. FIFTH EDITION COPYRIGHT 1987, 1993, 2001, 2007, 2013 IMMUNE DEFICIENCY FOUNDATION Copyright 2013 by Immune Deficiency Foundation, USA. REPRINT 2015 Readers may redistribute this article to other individuals for non-commercial use, provided that the text, html codes, and this notice remain intact and unaltered in any way. The Immune Deficiency Foundation Patient & Family Handbook may not be resold, reprinted or redistributed for compensation of any kind without prior written permission from the Immune Deficiency Foundation. If you have any questions about permission, please contact: Immune Deficiency Foundation, 110 West Road, Suite 300, Towson, MD 21204, USA; or by telephone at 800-296-4433. Immune Deficiency Foundation Patient & Family Handbook for Primary Immunodeficency Diseases 5th Edition This publication has been made possible through a generous grant from Baxalta Incorporated Immune Deficiency Foundation 110 West Road, Suite 300 Towson, MD 21204 800-296-4433 www.primaryimmune.org [email protected] EDITORS R. Michael Blaese, MD, Executive Editor Francisco A. Bonilla, MD, PhD Immune Deficiency Foundation Boston Children’s Hospital Towson, MD Boston, MA E. Richard Stiehm, MD M. Elizabeth Younger, CPNP, PhD University of California Los Angeles Johns Hopkins Los Angeles, CA Baltimore, MD CONTRIBUTORS Mark Ballow, MD Joseph Bellanti, MD R. Michael Blaese, MD William Blouin, MSN, ARNP, CPNP State University of New York Georgetown University Hospital Immune Deficiency Foundation Miami Children’s Hospital Buffalo, NY Washington, DC Towson, MD Miami, FL Francisco A.
    [Show full text]
  • Repercussions of Inborn Errors of Immunity on Growth☆ Jornal De Pediatria, Vol
    Jornal de Pediatria ISSN: 0021-7557 ISSN: 1678-4782 Sociedade Brasileira de Pediatria Goudouris, Ekaterini Simões; Segundo, Gesmar Rodrigues Silva; Poli, Cecilia Repercussions of inborn errors of immunity on growth☆ Jornal de Pediatria, vol. 95, no. 1, Suppl., 2019, pp. S49-S58 Sociedade Brasileira de Pediatria DOI: https://doi.org/10.1016/j.jped.2018.11.006 Available in: https://www.redalyc.org/articulo.oa?id=399759353007 How to cite Complete issue Scientific Information System Redalyc More information about this article Network of Scientific Journals from Latin America and the Caribbean, Spain and Journal's webpage in redalyc.org Portugal Project academic non-profit, developed under the open access initiative J Pediatr (Rio J). 2019;95(S1):S49---S58 www.jped.com.br REVIEW ARTICLE ଝ Repercussions of inborn errors of immunity on growth a,b,∗ c,d e Ekaterini Simões Goudouris , Gesmar Rodrigues Silva Segundo , Cecilia Poli a Universidade Federal do Rio de Janeiro (UFRJ), Faculdade de Medicina, Departamento de Pediatria, Rio de Janeiro, RJ, Brazil b Universidade Federal do Rio de Janeiro (UFRJ), Instituto de Puericultura e Pediatria Martagão Gesteira (IPPMG), Curso de Especializac¸ão em Alergia e Imunologia Clínica, Rio de Janeiro, RJ, Brazil c Universidade Federal de Uberlândia (UFU), Faculdade de Medicina, Departamento de Pediatria, Uberlândia, MG, Brazil d Universidade Federal de Uberlândia (UFU), Hospital das Clínicas, Programa de Residência Médica em Alergia e Imunologia Pediátrica, Uberlândia, MG, Brazil e Universidad del Desarrollo,
    [Show full text]
  • Orphanet Report Series Rare Diseases Collection
    Marche des Maladies Rares – Alliance Maladies Rares Orphanet Report Series Rare Diseases collection DecemberOctober 2013 2009 List of rare diseases and synonyms Listed in alphabetical order www.orpha.net 20102206 Rare diseases listed in alphabetical order ORPHA ORPHA ORPHA Disease name Disease name Disease name Number Number Number 289157 1-alpha-hydroxylase deficiency 309127 3-hydroxyacyl-CoA dehydrogenase 228384 5q14.3 microdeletion syndrome deficiency 293948 1p21.3 microdeletion syndrome 314655 5q31.3 microdeletion syndrome 939 3-hydroxyisobutyric aciduria 1606 1p36 deletion syndrome 228415 5q35 microduplication syndrome 2616 3M syndrome 250989 1q21.1 microdeletion syndrome 96125 6p subtelomeric deletion syndrome 2616 3-M syndrome 250994 1q21.1 microduplication syndrome 251046 6p22 microdeletion syndrome 293843 3MC syndrome 250999 1q41q42 microdeletion syndrome 96125 6p25 microdeletion syndrome 6 3-methylcrotonylglycinuria 250999 1q41-q42 microdeletion syndrome 99135 6-phosphogluconate dehydrogenase 67046 3-methylglutaconic aciduria type 1 deficiency 238769 1q44 microdeletion syndrome 111 3-methylglutaconic aciduria type 2 13 6-pyruvoyl-tetrahydropterin synthase 976 2,8 dihydroxyadenine urolithiasis deficiency 67047 3-methylglutaconic aciduria type 3 869 2A syndrome 75857 6q terminal deletion 67048 3-methylglutaconic aciduria type 4 79154 2-aminoadipic 2-oxoadipic aciduria 171829 6q16 deletion syndrome 66634 3-methylglutaconic aciduria type 5 19 2-hydroxyglutaric acidemia 251056 6q25 microdeletion syndrome 352328 3-methylglutaconic
    [Show full text]
  • NIH Public Access Author Manuscript J Allergy Clin Immunol
    NIH Public Access Author Manuscript J Allergy Clin Immunol. Author manuscript; available in PMC 2008 December 12. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: J Allergy Clin Immunol. 2007 October ; 120(4): 776±794. doi:10.1016/j.jaci.2007.08.053. The International Union of Immunological Societies (IUIS) Primary Immunodeficiency Diseases (PID) Classification Committee Raif. S. Geha, M.D., Luigi. D. Notarangelo, M.D. [Co-chairs], Jean-Laurent Casanova, M.D., Helen Chapel, M.D., Mary Ellen Conley, M.D., Alain Fischer, M.D., Lennart Hammarström, M.D., Shigeaki Nonoyama, M.D., Hans D. Ochs, M.D., Jennifer Puck, M.D., Chaim Roifman, M.D., Reinhard Seger, M.D., and Josiah Wedgwood, M.D. Abstract Primary immune deficiency diseases (PID) comprise a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, NK cells, as well as T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. Over 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic, immunological, and clinical features of PID has prompted the need for their classification, with the ultimate goal of facilitating diagnosis and treatment. To serve this goal, an international Committee of experts has met every two years since 1970. In its last meeting in Jackson Hole, Wyoming, United States, following three days of intense scientific presentations and discussions, the Committee has updated the classification of PID as reported in this article.
    [Show full text]
  • Mackenzie's Mission Gene & Condition List
    Mackenzie’s Mission Gene & Condition List What conditions are being screened for in Mackenzie’s Mission? Genetic carrier screening offered through this research study has been carefully developed. It is focused on providing people with information about their chance of having children with a severe genetic condition occurring in childhood. The screening is designed to provide genetic information that is relevant and useful, and to minimise uncertain and unclear information. How the conditions and genes are selected The Mackenzie’s Mission reproductive genetic carrier screen currently includes approximately 1300 genes which are associated with about 750 conditions. The reason there are fewer conditions than genes is that some genetic conditions can be caused by changes in more than one gene. The gene list is reviewed regularly. To select the conditions and genes to be screened, a committee comprised of experts in genetics and screening was established including: clinical geneticists, genetic scientists, a genetic pathologist, genetic counsellors, an ethicist and a parent of a child with a genetic condition. The following criteria were developed and are used to select the genes to be included: • Screening the gene is technically possible using currently available technology • The gene is known to cause a genetic condition • The condition affects people in childhood • The condition has a serious impact on a person’s quality of life and/or is life-limiting o For many of the conditions there is no treatment or the treatment is very burdensome for the child and their family. For some conditions very early diagnosis and treatment can make a difference for the child.
    [Show full text]
  • Mackenzie's Mission Gene & Condition List
    Mackenzie’s Mission Gene & Condition List What conditions are being screened for in Mackenzie’s Mission? Genetic carrier screening offered through this research study has been carefully developed. It is focused on providing people with information about their chance of having children with a severe genetic condition occurring in childhood. The screening is designed to provide genetic information that is relevant and useful, and to minimise uncertain and unclear information. How the conditions and genes are selected The Mackenzie’s Mission reproductive genetic carrier screen currently includes approximately 1300 genes which are associated with about 750 conditions. The reason there are fewer conditions than genes is that some genetic conditions can be caused by changes in more than one gene. The gene list is reviewed regularly. To select the conditions and genes to be screened, a committee comprised of experts in genetics and screening was established including: clinical geneticists, genetic scientists, a genetic pathologist, genetic counsellors, an ethicist and a parent of a child with a genetic condition. The following criteria were developed and are used to select the genes to be included: • Screening the gene is technically possible using currently available technology • The gene is known to cause a genetic condition • The condition affects people in childhood • The condition has a serious impact on a person’s quality of life and/or is life-limiting o For many of the conditions there is no treatment or the treatment is very burdensome for the child and their family. For some conditions very early diagnosis and treatment can make a difference for the child.
    [Show full text]
  • Whole Exome Sequencing Gene Package Intellectual Disability, Version 9.1, 31-1-2020
    Whole Exome Sequencing Gene package Intellectual disability, version 9.1, 31-1-2020 Technical information DNA was enriched using Agilent SureSelect DNA + SureSelect OneSeq 300kb CNV Backbone + Human All Exon V7 capture and paired-end sequenced on the Illumina platform (outsourced). The aim is to obtain 10 Giga base pairs per exome with a mapped fraction of 0.99. The average coverage of the exome is ~50x. Duplicate and non-unique reads are excluded. Data are demultiplexed with bcl2fastq Conversion Software from Illumina. Reads are mapped to the genome using the BWA-MEM algorithm (reference: http://bio-bwa.sourceforge.net/). Variant detection is performed by the Genome Analysis Toolkit HaplotypeCaller (reference: http://www.broadinstitute.org/gatk/). The detected variants are filtered and annotated with Cartagenia software and classified with Alamut Visual. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved Phenotype description including OMIM phenotype ID(s) OMIM median depth % covered % covered % covered gene symbol gene ID >10x >20x >30x A2ML1 {Otitis media, susceptibility to}, 166760 610627 66 100 100 96 AARS1 Charcot-Marie-Tooth disease, axonal, type 2N, 613287 601065 63 100 97 90 Epileptic encephalopathy, early infantile, 29, 616339 AASS Hyperlysinemia,
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0281166 A1 BHATTACHARJEE Et Al
    US 20160281 166A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0281166 A1 BHATTACHARJEE et al. (43) Pub. Date: Sep. 29, 2016 (54) METHODS AND SYSTEMIS FOR SCREENING Publication Classification DISEASES IN SUBJECTS (51) Int. Cl. (71) Applicant: PARABASE GENOMICS, INC., CI2O I/68 (2006.01) Boston, MA (US) C40B 30/02 (2006.01) (72) Inventors: Arindam BHATTACHARJEE, G06F 9/22 (2006.01) Andover, MA (US); Tanya (52) U.S. Cl. SOKOLSKY, Cambridge, MA (US); CPC ............. CI2O 1/6883 (2013.01); G06F 19/22 Edwin NAYLOR, Mt. Pleasant, SC (2013.01); C40B 30/02 (2013.01); C12O (US); Richard B. PARAD, Newton, 2600/156 (2013.01); C12O 2600/158 MA (US); Evan MAUCELI, (2013.01) Roslindale, MA (US) (21) Appl. No.: 15/078,579 (57) ABSTRACT (22) Filed: Mar. 23, 2016 Related U.S. Application Data The present disclosure provides systems, devices, and meth (60) Provisional application No. 62/136,836, filed on Mar. ods for a fast-turnaround, minimally invasive, and/or cost 23, 2015, provisional application No. 62/137,745, effective assay for Screening diseases, such as genetic dis filed on Mar. 24, 2015. orders and/or pathogens, in Subjects. Patent Application Publication Sep. 29, 2016 Sheet 1 of 23 US 2016/0281166 A1 SSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS S{}}\\93? sau36 Patent Application Publication Sep. 29, 2016 Sheet 2 of 23 US 2016/0281166 A1 &**** ? ???zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz??º & %&&zzzzzzzzzzzzzzzzzzzzzzz &Sssssssssssssssssssssssssssssssssssssssssssssssssssssssss & s s sS ------------------------------ Patent Application Publication Sep. 29, 2016 Sheet 3 of 23 US 2016/0281166 A1 23 25 20 FG, 2. Patent Application Publication Sep. 29, 2016 Sheet 4 of 23 US 2016/0281166 A1 : S Patent Application Publication Sep.
    [Show full text]
  • Access to Orphan Drugs in South Korea : Blind Spot of the Korean Health System
    Interim Report Access to Orphan Drugs in South Korea : Blind Spot of the Korean Health System UAEM Korea - 1 - Table of Contents Introduction I. Background A. Epidemiology of rare diseases in Korea B. Characteristics of Orphan Drug Industry in Korea C. Characteristics of Orphan Drug Supply in Korea D. Cases of Supply Failure by Multinational Pharmaceutical Companies E. Case Study: Gleevec F. Case Study: Lipiodol II. Stimulating the production of domestic pharmaceutical companies A. Current Policies that Support the Development of Orphan Drugs in Korea B. Policies that Support the Development of Orphan Drugs in Other Countries C. SWOT Analysis on Domestic Orphan Drug Industry D. Policy Suggestions III. Establishing State-Owned Pharmaceutical Companies A. Rationale B. Public Pharmacy in Foreign Countries C. Discussion on Public Pharmacy in Korea D. Blueprints on Public Pharmacy E. Alternatives Conclusion Appendix I. List of designated rare diseases in Korea II. List of designated orphan drugs in Korea - 2 - Introduction The South Korean government introduced social health insurance in 1977, achieving Universal Health Coverage in 1989. (Kwon, Lee, & Kim, 2015) With 97% of the population under the coverage of national health insurance, the Korean health system meets the health need of the majority of the population. (IQVIA, 2018) Yet, the Korean health system shows weakness in delivering healthcare for minority groups including rare disease patients. Rare disease patients in South Korea have difficulty in accessing orphan drugs - treatments for rare diseases - primarily due to the unstable supply. As pharmaceutical prices in Korea are used as reference prices in other countries, including China, if transnational pharmaceutical companies receive prices lower than what they demand, they often decide not to launch drugs or withdraw from supplying drugs in Korea.
    [Show full text]
  • J Recombination and Nonhomologous DNA End Joining
    Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining Valentyn Oksenycha,b,c, Vipul Kumara,b,c, Xiangyu Liud, Chunguang Guoa,b,c, Bjoern Schwera,b,c, Shan Zhad, and Frederick W. Alta,b,c,1 aHoward Hughes Medical Institute, bProgram in Cellular and Molecular Medicine, Boston Children’s Hospital, and cDepartment of Genetics, Harvard Medical School, Boston, MA 02115; and dInstitute for Cancer Genetics, Department of Pathology and Cell Biology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032 Contributed by Frederick W. Alt, December 26, 2012 (sent for review December 18, 2012) Classical nonhomologous end joining (C-NHEJ) is a major mamma- J coding segments are each flanked by RSs that target RAG. RAG lian DNA double-strand break (DSB) repair pathway that is required cleaves between the borders of two appropriately paired coding for assembly of antigen receptor variable region gene segments by segments and their flanking recombination signal sequences (RSs) V(D)J recombination. Recombination activating gene endonuclease to generate two hairpin-sealed coding ends (CEs) and two blunt 5′- initiates V(D)J recombination by generating DSBs between two V phosphorylated RS ends (SEs). The SEs are ligated back together (D)J coding gene segments and flanking recombination signal without further processing, whereas the coding ends must be sequences (RS), with the two coding ends and two RS ends joined opened and processed before they can be joined. Both CE and SE by C-NHEJ to form coding joins and signal joins, respectively.
    [Show full text]
  • Neurological Syndromes
    Neurological Syndromes J. Gordon Millichap Neurological Syndromes A Clinical Guide to Symptoms and Diagnosis J. Gordon Millichap, MD., FRCP Professor Emeritus of Pediatrics and Neurology Northwestern University Feinberg School of Medicine Chicago, IL, USA Pediatric Neurologist Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago , IL , USA ISBN 978-1-4614-7785-3 ISBN 978-1-4614-7786-0 (eBook) DOI 10.1007/978-1-4614-7786-0 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2013943276 © Springer Science+Business Media New York 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc.
    [Show full text]
  • Primary Immunodeficiency Precision Panel Overview Indications
    Primary Immunodeficiency Precision Panel Overview Primary Immunodeficiencies are a growing group of over 400 inborn errors of immunity that range in severity from life-threatening disorders presenting in infancy to less severe disorders diagnosed in adulthood. Most patients with primary immunodeficiencies present with recurrent or chronic infections. Some disorders impact essential immunologic pathways and result in susceptibility to opportunistic organisms, whereas other disorders may cause susceptibility to a very narrow number of pathogens with a broad age of presentation. The clinical presentation is variable and includes severe or unusual infections, autoimmune diseases and malignanciesPatients with many forms of primary immunodeficiencies are at increased risk for malignancies secondary to a number of different factors, including immune dysregulation, genetic predisposition, radiation sensitivity and impaired viral clearance. The Igenomix Primary Immunodeficiency Precision Panel can be used for an accurate and directed diagnosis as well as differential diagnosis of recurrent infections ultimately leading to a better management and prognosis of the disease. It provides a comprehensive analysis of the genes involved in this disease using next-generation sequencing (NGS) to fully understand the spectrum of relevant genes involved. Indications The Igenomix Primary Immunodeficiency Precision Panel is used for patients with a clinical diagnosis or suspicion with or without the following symptoms: ‐ Frequent and recurrent pneumonia, bronchitis, sinus infections, ear infections, meningitis or skin infections ‐ Inflammation and infection of internal organs ‐ Blood disorders ‐ Digestive problems such as cramping, loss of appetite, nausea and diarrhea ‐ Delayed growth and development ‐ Autoimmune disorders ‐ Family history of primary immunodeficiency Clinical Utility The clinical utility of this panel is: 1 ‐ The genetic and molecular confirmation for an accurate clinical diagnosis of a symptomatic patient.
    [Show full text]