RESUMO
A rare and autosomal recessive premature aging disorder, Werner syndrome (WS) is characterized by the early onset of aging-associated diseases, including shortening stature, alopecia, bilateral cataracts, skin ulcers, diabetes, osteoporosis, arteriosclerosis, and chromosomal instability, as well as cancer predisposition. WRN, the gene responsible for WS, encodes DNA helicase with a 3' to 5' exonuclease activity, and numerous studies have revealed that WRN helicase is involved in the maintenance of chromosome stability through actions in DNA, e.g., DNA replication, repair, recombination, and epigenetic regulation via interaction with DNA repair factors, telomere-binding proteins, histone modification enzymes, and other DNA metabolic factors. However, although these efforts have elucidated the cellular functions of the helicase in cell lines, they have not been linked to the treatment of the disease. Life expectancy has improved for WS patients over the past three decades, and it is hoped that a fundamental treatment for the disease will be developed. Disease-specific induced pluripotent stem (iPS) cells have been established, and these are expected to be used in drug discovery and regenerative medicine for WS patients. In this article, we review trends in research to date and present some perspectives on WS research with regard to the application of pluripotent stem cells. Furthermore, the elucidation of disease mechanisms and drug discovery utilizing the vast amount of scientific data accumulated to date will be discussed.
Assuntos
Síndrome de Werner , Humanos , Síndrome de Werner/genética , Síndrome de Werner/terapia , Helicase da Síndrome de Werner/genética , Helicase da Síndrome de Werner/metabolismo , RecQ Helicases/genética , Exodesoxirribonucleases/genética , Epigênese Genética , Fosfodiesterase I/genética , Fosfodiesterase I/metabolismo , DNA , Instabilidade Cromossômica , Proteínas de Ligação a Telômeros/genéticaRESUMO
Introdução: Síndrome de Werner, doença autossômica recessiva, tem como característica o envelhecimento precoce e acelerado. Objetivo: Descrever a evolução clínica favorável da síndrome de Werner em paciente acompanhada periodicamente no ambulatório de geriatria para promover atenção ao processo de envelhecimento por meio de abordagem preventiva e tratamento precoce das alterações que caracterizam a doença. Material e Método: Paciente de 31 anos de idade, sexo feminino, admitida no ambulatório de Aconselhamento Genético de um hospital-escola do noroeste paulista, apresentando baixa estatura, ulcerações, dor em região plantar e dificuldade para deambular, alterações cutâneas pigmentares com fissuras e ressecamento de toda a pele, além de cabelos grisalhos e quebradiços, catarata bilateral, hipotireoidismo e osteoporose. Tinha antecedentes familiares compatíveis com pais consanguíneos, um casal de irmãos hígidos e mãe com histórico de ocorrência de dois abortos espontâneos consecutivos. Apresentava, portanto, critérios diagnósticos para síndrome de Werner. Foi tratada nos ambulatórios de geriatria, endocrinologia, dermatologia, oftalmologia e ortopedia da mesma Instituição. Resultado: O tratamento consistiu na remoção cirúrgica de catarata, uso de levotiroxina 75 mcg/dia e de creme hidratante para pele (ácido salicílico 20% e vaselina sólida 30g), calçado ortopédico para pé neuropático com solado em EVA de média compressão, antiderrapante, confeccionado sob medida. Houve melhora na sintomatologia, especialmente quanto à deambulação com as medidas terapêuticas adotadas. Conclusão: A avaliação interdisciplinar inicial da paciente foi fundamental, pois possibilitou a elaboração precoce do diagnóstico e o acompanhamento no ambulatório de geriatria, promovendo maior atenção ao processo de envelhecimento preconizado por uma abordagem preventiva e tratamento subsequente das alterações que caracterizam a síndrome de Werner.(AU)
Introduction: Werner syndrome, an autosomal recessive disease, is characterized by premature and accelerated aging. Objective: To describe the favorable clinical evolution of Werner's syndrome in a patient periodically followed in the geriatric outpatient clinic to promote attention to the aging process through a preventive approach and early treatment of the changes that characterize the disease. Material and Method: A 31-year-old female patient, admitted to the Genetic Counseling outpatient clinic of a school hospital in northwestern pigmentary skin changes with cracks and dryness of the entire skin, as well as gray and brittle hair, bilateral cataract, hypothyroidism and osteoporosis. She had a family history compatible with consanguineous parents, a couple of healthy siblings and a mother with a history of two consecutive miscarriages. It therefore presented diagnostic criteria for Werner syndrome. She was treated in geriatric, endocrinology, dermatology, ophthalmology and orthopedics clinics of the same institution. Result: The treatment consisted of surgical removal of cataract, use of levothyroxine 75 mcg/day and moisturizing cream for skin (salicylic acid 20% and solid petroleum jelly 30g), orthopedic footwear for neuropathic foot anti-slip, made to measure. There was improvement in symptomatology, especially regarding ambulation with the therapeutic measures adopted. Conclusion: The initial interdisciplinary evaluation of the patient was fundamental, since it enabled the early preparation of the diagnosis and the follow-up in the geriatric outpatient clinic, promoting greater attention to the aging process recommended by a preventive approach and subsequent treatment of the changes that characterize Werner's syndrome.(AU)
Introducción: El síndrome de Werner, una enfermedad autosómica recesiva, se caracteriza por un envejecimiento prematuro y acelerado. Objetivo: Describir la evolución clínica favorable del síndrome de Werner en un paciente en seguimiento periódico en la consulta externa de geriatría para promover la atención al proceso de envejecimiento a través de un abordaje...(AU)
Assuntos
Humanos , Feminino , Adulto , Síndrome de Werner/diagnóstico , Síndrome de Werner/terapia , Envelhecimento , Senilidade Prematura/complicações , Evolução Clínica , Características da Família , Senilidade Prematura , Aconselhamento GenéticoRESUMO
Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the representative genetic progeroid syndromes and have been widely studied in the field of aging research. HGPS is a pediatric disease in which premature aging symptoms appear in early childhood, and death occurs at an average age of 14.5 years, mainly due to cardiovascular disease (CVD). Conversely, WS patients exhibit accelerated aging phenotypes after puberty and die in their 50s due to CVD and malignant tumors. Both diseases are models of human aging, leading to a better understanding of the aging-associated development of CVD. In this review, we discuss the pathogenesis and treatment of atherosclerotic diseases presented by both progeroid syndromes with the latest findings.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Progéria , Síndrome de Werner , Envelhecimento , Aterosclerose/genética , Doenças Cardiovasculares/genética , Pré-Escolar , Humanos , Progéria/genética , Progéria/terapia , Síndrome de Werner/complicações , Síndrome de Werner/genética , Síndrome de Werner/terapiaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndrome de Werner/terapia , Adolescente , Terapia Combinada , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/patologia , Prognóstico , Condicionamento Pré-Transplante , Síndrome de Werner/complicações , Síndrome de Werner/patologiaAssuntos
Absorciometria de Fóton/métodos , Difosfonatos/uso terapêutico , Fraturas do Fêmur , Osteoporose , Helicase da Síndrome de Werner/genética , Síndrome de Werner , Feminino , Fraturas do Fêmur/diagnóstico , Fraturas do Fêmur/etiologia , Fraturas do Fêmur/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese , Osteoporose/complicações , Osteoporose/diagnóstico , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Administração dos Cuidados ao Paciente/métodos , Polimorfismo de Nucleotídeo Único , Síndrome de Werner/complicações , Síndrome de Werner/genética , Síndrome de Werner/terapiaAssuntos
Administração dos Cuidados ao Paciente , Guias de Prática Clínica como Assunto , Pesquisa/organização & administração , Síndrome de Werner , Consenso , Prática Clínica Baseada em Evidências/métodos , Prática Clínica Baseada em Evidências/normas , Humanos , Incidência , Comunicação Interdisciplinar , Japão/epidemiologia , Mutação , Administração dos Cuidados ao Paciente/métodos , Administração dos Cuidados ao Paciente/normas , Síndrome de Werner/diagnóstico , Síndrome de Werner/epidemiologia , Síndrome de Werner/fisiopatologia , Síndrome de Werner/terapia , Helicase da Síndrome de Werner/genéticaRESUMO
Aging is a natural and unavoidable part of life. However, aging is also the primary driver of the dominant human diseases, such as cardiovascular disease, cancer, and neurodegenerative diseases, including Alzheimer's disease. Unraveling the sophisticated molecular mechanisms of the human aging process may provide novel strategies to extend 'healthy aging' and the cure of human aging-related diseases. Werner syndrome (WS), is a heritable human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. As a classical premature aging disease, etiological exploration of WS can shed light on the mechanisms of normal human aging and facilitate the development of interventional strategies to improve healthspan. Here, we summarize the latest progress of the molecular understandings of WRN protein, highlight the advantages of using different WS model systems, including Caenorhabditis elegans, Drosophila melanogaster and induced pluripotent stem cell (iPSC) systems. Further studies on WS will propel drug development for WS patients, and possibly also for normal age-related diseases.
Assuntos
Envelhecimento/patologia , Síndrome de Werner/patologia , Animais , Caenorhabditis elegans/fisiologia , Drosophila melanogaster/fisiologia , Humanos , Modelos Biológicos , Mutação , Síndrome de Werner/genética , Síndrome de Werner/terapiaRESUMO
INTRODUCTION: Werner syndrome is a rare autosomal recessive disorder caused by mutations in the Werner syndrome WRN gene, on chromosome 8. Those affected manifest early the features of ageing. DISCUSSION: Cataract surgery is prone to post-operative complications in those with Werner syndrome. The development of cystoid macular oedema (CMO) is likely multifactorial. Patients with WS have diabetes mellitus type 2 which can contribute to macular oedema. There is a deposition of abnormal WRN proteins in the macula which also predisposes to macular oedema. The trauma of cataract surgery appears to be the main stimulus for the development of CMO. CMO may, as a result, be difficult to manage in Werner syndrome patients. CONCLUSION: Further study is needed to elucidate the precise role of retinal WRN protein expression in the development of CMO in those with Werner syndrome. A tailored and more successful approach to the treatment of CMO in such patients may result.
Assuntos
Síndrome de Werner , Adulto , Extração de Catarata/métodos , Técnicas de Diagnóstico Oftalmológico , Feminino , Humanos , Edema Macular/terapia , Masculino , Irmãos , Resultado do Tratamento , Síndrome de Werner/diagnóstico , Síndrome de Werner/terapia , Helicase da Síndrome de Werner/metabolismoRESUMO
Werner syndrome (WS) confers a high risk of the development of neoplasias, including hematological malignancies, and curative treatment for these malignancies is difficult to achieve. A 44-year-old man with myelodysplastic syndrome was admitted to our hospital. He was diagnosed with mutation-proven WS. He underwent cord blood transplantation (CBT) following fludarabine, busulfan, and melphalan administration. A chimerism analysis of his marrow blood on day 62 showed a donor pattern >95%, which confirmed engraftment. The patient lived for 15 months while maintaining remission of MDS without treatment-related toxicity. Our case shows that CBT can be a treatment modality for WS patients with hematological malignancies.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Síndromes Mielodisplásicas/terapia , Síndrome de Werner/terapia , Adulto , Antineoplásicos/uso terapêutico , Humanos , Masculino , Síndromes Mielodisplásicas/etiologia , Transplante Homólogo , Resultado do Tratamento , Síndrome de Werner/complicaçõesAssuntos
Encefalopatias/induzido quimicamente , Diabetes Insípido Neurogênico/induzido quimicamente , Doxorrubicina/efeitos adversos , Ifosfamida/efeitos adversos , Neoplasias Retroperitoneais/tratamento farmacológico , Sarcoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Encefalopatias/diagnóstico por imagem , Diabetes Insípido Neurogênico/diagnóstico por imagem , Doxorrubicina/administração & dosagem , Seguimentos , Humanos , Ifosfamida/administração & dosagem , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Neoplasias Retroperitoneais/patologia , Medição de Risco , Sarcoma/patologia , Tomografia Computadorizada por Raios X/métodos , Síndrome de Werner/diagnóstico , Síndrome de Werner/terapiaRESUMO
Progeria is a devastating disorder in which patients exhibit signs of premature aging. The most well-known progeroid syndromes include Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner Syndrome (WS). While HGPS and WS are rare, they often result in severe age-associated complications starting in the early developmental period or after the pubertal growth spurt during adolescence, respectively. In addition, patients with HGPS ultimately die of diseases normally seen in the elderly population, with stroke and myocardial infarction as the leading causes of death. Many WS patients develop similar cardiovascular complications but also have an increased predisposition to developing multiple rare malignancies. These premature aging disorders, as well as animal and cell culture models that recapitulate these diseases, have provided insight into the genetics and cellular pathways that underlie these human conditions and have also uncovered possible mechanisms behind normal aging. Here we discuss the history, the types of progeria, and the various pathophysiological mechanisms that drive these diseases. We also address recent medical advances and treatment modalities for patients with progeria.
Assuntos
Desenvolvimento do Adolescente , Progéria , Puberdade , Síndrome de Werner , Adolescente , Animais , Feminino , Humanos , Masculino , Progéria/genética , Progéria/metabolismo , Progéria/fisiopatologia , Progéria/terapia , Síndrome de Werner/genética , Síndrome de Werner/metabolismo , Síndrome de Werner/fisiopatologia , Síndrome de Werner/terapiaRESUMO
Epidemiological studies have shown that age is the chief risk factor for atherosclerotic cardiovascular diseases, but the molecular mechanisms that underlie the increase in risk conferred by aging remain unclear. Evidence suggests that the cardiovascular repair system is impaired with advancing age, thereby inducing age-associated cardiovascular dysfunction. Such impairment could be attributable to senescence of cardiovascular tissues at the cellular level as a result of telomere shortening, DNA damage, and genomic instability. In fact, the replicative ability of cardiovascular cells, particularly stem cells and/or progenitor cells, has been shown to decline with age. Recently, considerable progress has been made in understanding the pathogenesis of human progeroid syndromes that feature cardiovascular aging. Most of the genes responsible have a role in DNA metabolism, and mutated forms of these genes result in alterations of the response to DNA damage and in decreased cell proliferation, which might be common features of a phenotype of aging. Here we review the cardiovascular research on cellular senescence, stem cell aging, and progeroid syndromes and discuss the potential role of cellular senescence in the mechanisms underlying both normal aging and premature aging syndromes.
Assuntos
Envelhecimento , Doenças Cardiovasculares/patologia , Senescência Celular , Endotélio Vascular/patologia , Progéria/patologia , Células-Tronco/patologia , Síndrome de Werner/patologia , Fatores Etários , Senilidade Prematura/patologia , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/terapia , Senescência Celular/genética , Endotélio Vascular/fisiopatologia , Humanos , Músculo Liso Vascular/patologia , Progéria/genética , Progéria/fisiopatologia , Progéria/terapia , Estresse Fisiológico , Telômero/metabolismo , Síndrome de Werner/genética , Síndrome de Werner/fisiopatologia , Síndrome de Werner/terapiaRESUMO
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.
Assuntos
Progéria/genética , Síndrome de Werner/genética , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Dano ao DNA/fisiologia , Modelos Animais de Doenças , Exodesoxirribonucleases , Humanos , Lamina Tipo A/metabolismo , Lamina Tipo A/fisiologia , Modelos Biológicos , Fenótipo , Progéria/terapia , Processamento de Proteína Pós-Traducional , RecQ Helicases/fisiologia , Síndrome de Werner/terapia , Helicase da Síndrome de WernerRESUMO
Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes. With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes.
Assuntos
Envelhecimento/genética , Epigênese Genética/genética , Transtornos do Crescimento/genética , Neoplasias/genética , Progéria/genética , Síndrome de Werner/genética , Exodesoxirribonucleases , Componentes do Gene , Humanos , Lamina Tipo A/genética , Lipoproteínas/genética , Proteínas de Membrana/genética , Metaloendopeptidases , Metaloproteases/genética , Progéria/terapia , RecQ Helicases/genética , Síndrome de Werner/terapia , Helicase da Síndrome de WernerAssuntos
Síndrome de Werner , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/terapia , Diagnóstico Diferencial , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Mutação , PPAR gama/agonistas , Pioglitazona , Prognóstico , RecQ Helicases/genética , Tiazolidinedionas/uso terapêutico , Síndrome de Werner/diagnóstico , Síndrome de Werner/genética , Síndrome de Werner/fisiopatologia , Síndrome de Werner/terapiaRESUMO
To clarify the effect of Werner's syndrome (WS) on beta-islet cell function, the oral glucose tolerance test (OGTT) was repeatedly performed over a period of 16 years in one patient with WS. The data obtained on insulin secretion were assessed in this study. The patient was a 50-yr-old woman of consanguineous parentage. She presented with gray hair, cataracts, a beak-shaped nose and high-pitched voice. She was diagnosed as WS on the basis of her characteristic appearance. OGTT was performed 14 times during 9 admissions to our hospital. After ingestion of glucose, plasma glucose (PG) levels and immuno-reactive insulin (IRI) at 0, 30, 60, 90, 120 and 180 min were determined. PG levels during OGTT gradually increased during dietary therapy and, at the age of 48, insulin treatment was started [PG level at 120 min during OGTT at 46 yr (before treatment) was 1.5 times that at 34 yr]. Insulin secretion had also gradually decreased during the follow-up period (sum of IRI at 34 yr during OGTT post-treatment; 550.8 IU/ml, sum of IRI at 50 yr during OGTT post-treatment; 244.5 IU/ml). However, the insulinogenic indices were maintained at almost the same level value. Our results indicate that insufficient insulin secretion, which could not overcome insulin resistance, might play a crucial role in the pathophysiology and progression of diabetes in WS along with insulin resistance due to a post-receptor defect.
Assuntos
Diabetes Mellitus/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/fisiopatologia , Síndrome de Werner/fisiopatologia , Adolescente , Adulto , Diabetes Mellitus/etiologia , Diabetes Mellitus/prevenção & controle , Feminino , Seguimentos , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Pessoa de Meia-Idade , Síndrome de Werner/complicações , Síndrome de Werner/terapiaRESUMO
We described a case of Werner's syndrome associated with osteosarcoma. A 37-year-old Japanese man was diagnosed as having Werner's syndrome by the presence of juvenile cataracts, skin sclerosis and hyperpigmentation of the feet, high-pitched voice, characteristic bird-like appearance of the face with beak-shaped nose, thinning of the entire skin and hyperkeratoses on soles, hyperlipemia, hyperuricemia, diabetes melitus, and the mutated responsible gene (WRN). He had a 3-month history of a tumor on his left forearm. Histologically, the tumor included four histological patterns; a malignant fibrous histiocytoma-like, a desmoid-like, a dermatofibrosarcoma protuberans-like, and a chondrosarcoma-like pattern. Tumoral osteoid formation was also found in the tumor. Therefore, the tumor was diagnosed as osteosarcoma.