DNA Damage in the Oligodendrocyte Lineage and Its Role in Brain Aging
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The Progeria Syndrome Fact Sheet
HUTCHINSON-GILFORD PROGERIA SYNDROME FREQUENTLY ASKED QUESTIONS WHAT IS PROGERIA? Hutchinson-Gilford Progeria Syndrome “Progeria” or “HGPS” is a rare, fatal genetic condition characterized by an appearance of accelerated aging in children. Its name is derived from the Greek and means "prematurely old." While there are different forms of Progeria*, the classic type is Hutchinson- Gilford Progeria Syndrome, which was named after the doctors who first described it in England: in 1886 by Dr. Jonathan Hutchinson, and in 1897 by Dr. Hastings Gilford. HOW COMMON IS PROGERIA? Progeria affects approximately 1 in 4 - 8 million newborns. It affects both sexes equally and all races. In the past 15 years, children with Progeria have been reported all over the world , including in: Algeria Cuba Ireland Peru Sweden Argentina Denmark Israel Philippines Switzerland Australia Dominican Italy Poland Turkey Austria Republic Japan Portugal United States Belgium Egypt Libya Puerto Rico Venezuela Brazil England Mexico Romania Vietnam Canada France Morocco South Africa Yugoslavia China Germany Netherlands South Korea Columbia India Pakistan Spain WHAT ARE THE FEATURES OF PROGERIA? Although they are born looking healthy, most children with Progeria begin to display many characteristics of Progeria within the first year of life. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease and stroke. The children have a remarkably similar appearance, despite differing ethnic backgrounds. Children with Progeria die of atherosclerosis (heart disease) at an average age of thirteen years (with a range of about 8 – 21 years). WHAT DOES PROGERIA HAVE TO DO WITH AGING? Children with Progeria are genetically predisposed to premature, progressive heart disease. -
Atypical Progeroid Syndrome ID: 20-0188; April 2021 (P.E262K LMNA) DOI: 10.1530/EDM-20-0188
ID: 20-0188 -20-0188 M Yukina and others Atypical progeroid syndrome ID: 20-0188; April 2021 (p.E262K LMNA) DOI: 10.1530/EDM-20-0188 Atypical progeroid syndrome (p.E262K LMNA mutation): a rare cause of short stature and osteoporosis Correspondence Marina Yukina, Nurana Nuralieva, Ekaterina Sorkina, Ekaterina Troshina, should be addressed Anatoly Tiulpakov, Zhanna Belaya and Galina Melnichenko to E Sorkina Email Endocrinology Research Centre, Moscow, Russia [email protected] Summary Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy- associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophyandmetaboliccomplicationsbutvarydifferentlydependingonaparticularmutationandevenpatients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS. Learning points: • Atypicalprogeroidsyndromes(APS)arerareandheterogenicwithdifferentageofonsetanddegreeofmetabolic -
Molecular Basis of Progeroid Syndromes–S–S– the Wwthe Erner Andanderner Hutchinson-Gilford Syndromes
Proc. Indian natn Sci Acad. B69 No. 4 pp 625-640 (2003) Molecular Basis of Progeroid Syndromes–s–s– the WWthe erner andanderner Hutchinson-Gilford Syndromes JUNKO OSHIMA*, NANCY B HANSON and GEORGE M MARTIN Department of Pathology, University of W ashington, Seattle, WA 98195, USA (Received on 17 July 2003; Accepted after r evision on 6 August 2003) Segmental progeroid syndromes are members of a group of disorders in which affected individuals present various featur es suggestive of accelerated aging. The two best-known examples are the Werner syndro m e (WS; “Progeria of the adult”) and the Hutchinson-Gilford Progeria syndrome (HGPS; “Progeria of child- hood”). The gene responsible for WS, WRN, was identified in 1996 and encodes a multifunctional nuclear protein with exonuclease and helicase domains. WS patients and cells isolated from the WS patients show various genomic instability phenotypes, including an incr eased incidence of cancer. The WRN protein is thought to play a crucial role in optimizing the regulation of DNA repair processes. Recently, a novel r ecurr ent mutation in the LMNA gene has been shown to be responsible for HGPS. LMNA encodes nuclear intermediate filaments, lamins A and C; mutant lamins are thought to result in nuclear fragility. Ther e ar e at least six other disor ders caused by LMNA mutations, most of which affect cells and tissues of mesenchymal origins, including atypical forms of WS. The pathophysiologies of these and certain other progeroid syndromes indicate an important role for DNA damage in the genesis of common age- related disorders. Key WWKey ords: WWords: erner syndrome, WRN, RecQ, Hutchinson-Gilford Progeria syndrome, LMNA, Lamin, Genomic instability, Aging, Human Introduction of WS, previously based upon clinical criteria, can Segmental progeroid syndromes encompass a now be confirmed by molecular biological methods. -
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2018, 65 (2), 227-238 Note Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent de novo mutation in the POLD1 gene Haruka Sasaki1), 2), Kumiko Yanagi3) *, Satoshi Ugi4), Kunihisa Kobayashi1), Kumiko Ohkubo5), Yuji Tajiri6), Hiroshi Maegawa4), Atsunori Kashiwagi7) and Tadashi Kaname3) * 1) Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka 818-8502, Japan 2) Division of Diabetic Medicine, Bunyukai Hara Hospital, Ohnojo, Fukuoka 816-0943, Japan 3) Department of Genome Medicine, National Research Institute for Child Health, Setagaya, Tokyo 157-8535, Japan 4) Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan 5) Department of Laboratory Medicine, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka 814-0180, Japan 6) Division of Endocrinology and Metabolism, Kurume University School of Medicine, Kurume, Fukuoka 830-0111, Japan 7) Diabetes Center, Seikokai Kusatsu General Hospital, Kusatsu, Shiga 525-8585, Japan Abstract. Segmental progeroid syndromes with lipodystrophy are extremely rare, heterogeneous, and complex multi-system disorders that are characterized by phenotypic features of premature aging affecting various tissues and organs. In this study, we present a “sporadic/isolated” Japanese woman who was ultimately diagnosed with mandibular hypoplasia, deafness, progeroid features, and progressive lipodystrophy (MDPL) syndrome (MIM #615381) using whole exome sequencing analysis. She had been suspected as having atypical Werner syndrome and/or progeroid syndrome based on observations spanning a 30-year period; however, repeated genetic testing by Sanger sequencing did not identify any causative mutation related to various subtypes of congenital partial lipodystrophy (CPLD) and/or mandibular dysplasia with lipodystrophy (MAD). -
1. Progeria 101: Frequently Asked Questions
1. PROGERIA 101: FREQUENTLY ASKED QUESTIONS 1. Progeria 101: Frequently Asked Questions What is Hutchinson-Gilford Progeria Syndrome? What is PRF’s history and mission? What causes Progeria? How is Progeria diagnosed? Are there different types of Progeria? Is Progeria contagious or inherited? What is Hutchinson-Gilford Progeria Syndrome (HGPS or Progeria)? Progeria is also known as Hutchinson-Gilford Progeria Syndrome (HGPS). Genetic testing for It was first described in 1886 by Dr. Jonathan Hutchinson and in 1897 by Progeria can be Dr. Hastings Gilford. Progeria is a rare, fatal, “premature aging” syndrome. It’s called a syndrome performed from a because all the children have very similar symptoms that “go together”. The small sample of blood children have a remarkably similar appearance, even though Progeria affects children of all different ethnic backgrounds. Although most babies with (1-2 tsp) or sometimes Progeria are born looking healthy, they begin to display many characteristics from a sample of saliva. of accelerated aging by 18-24 months of age, or even earlier. Progeria signs include growth failure, loss of body fat and hair, skin changes, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease, and stroke. Children with Progeria die of atherosclerosis (heart disease) or stroke at an average age of 13 years (with a range of about 8-21 years). Remarkably, the intellect of children with Progeria is unaffected, and despite the physical changes in their young bodies, these extraordinary children are intelligent, courageous, and full of life. 1.2 THE PROGERIA HANDBOOK What is PRF’s history and mission? The Progeria Research Foundation (PRF) was established in the United States in 1999 by the parents of a child with Progeria, Drs. -
Human Radiosensitivity and Radiosusceptibility: What Are the Differences?
International Journal of Molecular Sciences Review Human Radiosensitivity and Radiosusceptibility: What Are the Differences? Laura El-Nachef 1, Joelle Al-Choboq 1, Juliette Restier-Verlet 1, Adeline Granzotto 1, Elise Berthel 1,2, Laurène Sonzogni 1,Mélanie L. Ferlazzo 1, Audrey Bouchet 1 , Pierre Leblond 3, Patrick Combemale 3, Stéphane Pinson 4, Michel Bourguignon 1,5 and Nicolas Foray 1,* 1 Inserm, U1296 unit, Radiation: Defense, Health and Environment, Centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France; [email protected] (L.E.-N.); [email protected] (J.A.-C.); Juliette.Restier–[email protected] (J.R.-V.); [email protected] (A.G.); [email protected] (E.B.); [email protected] (L.S.); [email protected] (M.L.F.); [email protected] (A.B.); [email protected] (M.B.) 2 Neolys Diagnostics, 67960 Entzheim, France 3 Centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France; [email protected] (P.L.); [email protected] (P.C.) 4 Hospices Civils de Lyon, Quai des Célestins, 69002 Lyon, France; [email protected] 5 Université Paris Saclay Versailles St Quentin en Yvelines, 78035 Versailles, France * Correspondence: [email protected]; Tel.: +33-4-78-78-28-28 Abstract: The individual response to ionizing radiation (IR) raises a number of medical, scientific, and societal issues. While the term “radiosensitivity” was used by the pioneers at the beginning Citation: El-Nachef, L.; Al-Choboq, of the 20st century to describe only the radiation-induced adverse tissue reactions related to cell J.; Restier-Verlet, J.; Granzotto, A.; death, a confusion emerged in the literature from the 1930s, as “radiosensitivity” was indifferently Berthel, E.; Sonzogni, L.; Ferlazzo, used to describe the toxic, cancerous, or aging effect of IR. -
Early Onset Diabetes in Two Children Due to Progeria, a Monogenic Disease of DNA Repair
CASE REPORT DO I: 10.4274/jcrpe.galenos.2019.2019.0126 J Clin Res Pediatr Endocrinol 2020;12(3):315-318 Early Onset Diabetes in Two Children due to Progeria, a Monogenic Disease of DNA Repair Martin Holder¹, Valerie Schwitzgebel² ¹Klinikum Stuttgart, Olgahospital, Department of Pediatric Endocrinology and Diabetology, Stuttgart, Germany ²Hopital des Enfants, Endocrinologie et Diabetologie Pediatriques, Geneve, Switzerland What is already known on this topic? Less is known about type 2 like diabetes mellitus in children and adolescents with progeria-syndrome although they have a high risk of developing diabetes mellitus. What this study adds? Early and regular screening for diabetes mellitus are mandatory. Treatment with metformin at an early stage should be recommended to prevent early symptoms of diabetes and potentially delay the clinical course of progeria Abstract Progeria syndrome is a rare disorder in childhood which causes accelerated systemic aging. Due to the accelerated aging process, disorders which normally occur only in old age will appear in these children at a much younger age. We report two children with progeria syndrome, in whom fulminant diabetes mellitus manifested at a very early age. Keywords: Progeria syndrome, diabetes mellitus, metformin, prevention. Introduction cardiovascular disease can occur. Additionally, they may have audiologic, dental, and ophthalmologic issues Progeria syndrome is a group of very rare genetic disorders that impair their lives. Less is known about metabolic which are characterized by premature aging and classified complications in children with progeria syndrome. In by various names based on causative etiology: Hutchinson- WS, also known as adult progeroid syndrome, type 2 like Gilford progeria syndrome (HGPS), Néstor-Guillermo progeria diabetes mellitus is one of the clinical manifestations of syndrome, atypical progeria syndromes, restrictive dermopathy, the disease and attention must give to the differential mandibuloacral dysplasia, Werner syndrome (WS), Bloom diagnosis (1). -
Werner and Hutchinson–Gilford Progeria Syndromes: Mechanistic Basis of Human Progeroid Diseases
REVIEWS MECHANISMS OF DISEASE Werner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases Brian A. Kudlow*¶, Brian K. Kennedy* and Raymond J. Monnat Jr‡§ Abstract | Progeroid syndromes have been the focus of intense research in part because they might provide a window into the pathology of normal ageing. Werner syndrome and Hutchinson–Gilford progeria syndrome are two of the best characterized human progeroid diseases. Mutated genes that are associated with these syndromes have been identified, mouse models of disease have been developed, and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases. Progeroid syndromes are heritable human disorders with therefore termed segmental, as opposed to global, features that suggest premature ageing1. These syndromes progeroid syndromes. Among the segmental progeroid have been well characterized as clinical disease entities, syndromes, the syndromes that most closely recapitu- and in many instances the associated genes and causative late the features of human ageing are Werner syndrome mutations have been identified. The identification of (WS), Hutchinson–Gilford progeria syndrome (HGPS), genes that are associated with premature-ageing-like Cockayne syndrome, ataxia-telangiectasia, and the con- syndromes has increased our understanding of molecu- stitutional chromosomal disorders of Down, Klinefelter lar pathways that protect cell viability and function, and -
DNA Replication Timing Alterations Identify Common Markers Between Distinct Progeroid Diseases
DNA replication timing alterations identify common PNAS PLUS markers between distinct progeroid diseases Juan Carlos Rivera-Muliaa, Romain Despratb, Claudia Trevilla-Garciaa, Daniela Cornacchiac, Hélène Schwererd, Takayo Sasakia, Jiao Simaa, Tyler Fellsa, Lorenz Studerc, Jean-Marc Lemaitreb,d,1, and David M. Gilberta,e,1 aDepartment of Biological Science, Florida State University, Tallahassee, FL 32306; bPlateforme de Reprogrammation Cellulaire (SAFE-iPSC) Stem Cell Core Facility, Infrastructure Nationale d’Ingénierie des Cellules Souches Pluripotentes et Cellules Différenciées (INGESTEM), Centres Hospitaliers Universitaires de Montpellier, Hopital Saint Eloi, F3400 Montpellier, France; cThe Center for Stem Cell Biology, Memorial Sloan-Kettering Institute, New York, NY 10065; dInstitute of Regenerative Medicine and Biotherapies, U1183 INSERM, Université de Montpellier, F3400 Montpellier, France; and eCenter for Genomics and Personalized Medicine, Florida State University, Tallahassee, FL 32306 Edited by Terry L. Orr-Weaver, Whitehead Institute, Cambridge, MA, and approved November 8, 2017 (received for review June 30, 2017) Progeroid syndromes are rare genetic disorders that phenotypi- the mechanisms linking the cellular defects to pathophysiological cally resemble natural aging. Different causal mutations have been manifestations of the disease. identified, but no molecular alterations have been identified that Previously, we demonstrated that the temporal order of ge- are in common to these diseases. DNA replication timing (RT) is a -
Outcomes of 4 Years of Molecular Genetic Diagnosis on a Panel Of
Grelet et al. Orphanet Journal of Rare Diseases (2019) 14:288 https://doi.org/10.1186/s13023-019-1189-z RESEARCH Open Access Outcomes of 4 years of molecular genetic diagnosis on a panel of genes involved in premature aging syndromes, including laminopathies and related disorders Maude Grelet1,2, Véronique Blanck1, Sabine Sigaudy1,2, Nicole Philip1,2, Fabienne Giuliano3, Khaoula Khachnaoui3, Godelieve Morel4,5, Sarah Grotto6, Julia Sophie7, Céline Poirsier8, James Lespinasse9, Laurent Alric10, Patrick Calvas7, Gihane Chalhoub11, Valérie Layet12, Arnaud Molin13, Cindy Colson13, Luisa Marsili14, Patrick Edery4,5, Nicolas Lévy1,2,15 and Annachiara De Sandre-Giovannoli1,2,15* Abstract Background: Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated. Methods: Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad. Results: Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. -
Blueprint Genetics Progeria and Progeroid Syndromes Panel
Progeria and Progeroid Syndromes Panel Test code: DE0201 Is a 17 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of Hutchinson-Gilford progeria syndrome or a syndrome with progeroid features. About Progeria and Progeroid Syndromes Hutchinson-Gilford progeria syndrome (HGPS) is caused by LMNA mutations with autosomal dominant inheritance but almost all individuals with HGPS have a de novo mutation. All the major syndromes with proreroid features have autosomal recessive inheritance although the ALDH18A1 related cutis laxa is also inherited in dominant manner. HGPS manifest with features of accelerated aging observed in early childhood. Age of disease onset and progress rate varies but is remarkably consistent overall. Children with HGPS usually appear normal at birth. Profound failure to thrive occurs during the first year. Patients have a head disproportionately large for face, prominent eyes, partial alopecia progressing to total alopecia, loss of subcutaneous fat, progressive joint contractures, bone changes and nail dystrophy occur by age of three. Later symptoms include conductive hearing loss, dental crowding and partial lack of secondary tooth eruption. Motor and mental development is normal. Average life span is approximately 15 years. Premature death occurs as a result of atherosclerotic events, either myocardial infarct or stroke. Diagnosis is based on clinical features and detection of heterozygous LMNA variants either within exon 11 (termed classic HGPS) or at the intronic border of exon 11 (termed atypical HGPS). Although no other gene than LMNA associates with HGPS, premature aging occur in many other syndromes with so-called progeroid features, thus the panel also include genes causing the following syndromes: Cockayne syndrome, congenital generalized lipodystrophy, cutis laxa and progeroid type Ehlers-Danlos syndrome among some others. -
Functional Analysis of POLD1 P.Ser605del Variant: the Aging Phenotype of MDPL Syndrome Is Associated with an Impaired DNA Repair Capacity
www.aging-us.com AGING 2021, Vol. 13, No. 4 Research Paper Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity Michela Murdocca1, Paola Spitalieri1, Claudia De Masi1, Ion Udroiu2, Jessica Marinaccio2, Massimo Sanchez3, Rosa Valentina Talarico1, Chiara Fiorillo4, Monica D’Adamo5, Paolo Sbraccia5, Maria Rosaria D’Apice6, Giuseppe Novelli1,6, Antonella Sgura2, Federica Sangiuolo1,6 1Department of Biomedicine and Prevention, Tor Vergata University, Rome 00133, Italy 2Department of Science, “Roma Tre” University, Rome 00154, Italy 3Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome 00161, Italy 4Paediatric Neurology and Neuromuscular Disorders, University of Genoa and Istituto Gaslini, Genoa 16147, Italy 5Department of Systems Medicine, Tor Vergata University, Rome 00133, Italy 6Laboratory of Medical Genetics, Tor Vergata Hospital, Rome 00133, Italy Correspondence to: Maria Rosaria D’Apice, Antonella Sgura; email: [email protected], [email protected] Keywords: MDPL syndrome, POLD1 gene, age-related disease, DNA repair, telomere damage Received: October 29, 2020 Accepted: January 4, 2021 Published: February 22, 2021 Copyright: © 2021 Murdocca et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy define a rare systemic disorder, named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. We report a MDPL female heterozygote for the recurrent p.Ser605del variant.