RESUMEN
INTRODUCTION: Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare premature aging genetic disorder caused by a point mutation in the lamin A gene, LMNA. Children with HGPS display short lifespans and typically die due to myocardial infarction or ischemic stroke, both acute cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the classic HGPS LMNA gene mutation on arterial thrombosis remains unknown. METHODS: Heterozygous LmnaG609G knock-in (LmnaG609G/+) mice, yielding an equivalent classic mutation observed in HGPS patients (c.1824C>T; pG608G mutation in the human LMNA gene) and corresponding wild-type (WT) control littermates underwent photochemically laser-induced carotid injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured. Furthermore, platelet activation and reactivity were investigated. RESULTS: LmnaG609G/+ mice displayed accelerated arterial thrombus formation, as underlined by shortened time to occlusion compared to WT littermates. Levels of factors involved in the coagulation and fibrinolytic system were comparable between groups, while LmnaG609G/+ animals showed higher plasma levels of thrombin-antithrombin complex and lower levels of antithrombin. Bone marrow analysis showed larger megakaryocytes in progeric mice. Lastly, enhanced platelet activation upon adenosine diphosphate, collagen-related peptide, and thrombin stimulation was observed in LmnaG609G/+ animals compared to the WT group, indicating a higher platelet reactivity in progeric animals. CONCLUSIONS: LMNA mutation in HGPS mice accelerates arterial thrombus formation, which is mediated, at least in part, by enhanced platelet reactivity, which consequently augments thrombin generation. Given the wide spectrum of antiplatelet agents available clinically, further investigation is warranted to consider the most suitable antiplatelet regimen for children with HGPS to mitigate disease mortality and morbidity.
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Plaquetas , Progeria , Trombosis , Animales , Progeria/genética , Progeria/sangre , Progeria/complicaciones , Ratones , Trombosis/sangre , Trombosis/genética , Plaquetas/metabolismo , Activación Plaquetaria , Lamina Tipo A/genética , Modelos Animales de Enfermedad , Masculino , HumanosRESUMEN
Background: Mandibuloacral dysplasia (MAD) syndrome is a rare genetic disease. Several progeroid syndromes including mandibuloacral dysplasia type A (MADA), mandibuloacral dysplasia type B(MADB), Hutchinson-Gilford progeria (HGPS) and mandibular hypoplasia, deafness, and lipodystrophy syndrome (MDPL) have been reported previously. A novel MAD progeroid syndrome (MADaM) has recently been reported. So far, 7 cases of MADaM diagnosed with molecular diagnostics have been reported in worldwide. In the Chinese population, cases of MAD associated with the MTX2 variant have never been reported. Methods: The clinical symptoms and the genetic analysis were identified and investigated in patients presented with the disease. In addition, we analyzed and compared 7 MADaM cases reported worldwide and summarized the progeroid syndromes reported in the Chinese population to date. Results: The present study reports a case of a novel homozygous mutation c.378 + 1G > A in the MTX2 gene, which has not been previously reported in the literature. Patients present with early onset and severe symptoms and soon after birth are found to have growth retardation. In addition to the progeroid features, skeletal deformities, generalized lipodystrophy reported previously, and other multisystem involvement, e.g. hepatosplenic, renal, and cardiovascular system, this case was also reported to have combined hypogammaglobulinemia. She has since been admitted to the hospital several times for infections. Among 22 previously reported progeroid syndromes, 16/22 were MADA or HGPS caused by LMNA gene mutations, and the homozygous c.1579C > T (p.R527C) mutation may be a hot spot mutation for MAD in the Chinese population. MAD and HGPS mostly present in infancy with skin abnormalities or alopecia, MDPL mostly presents in school age with growth retardation as the first manifestation, and is often combined with an endocrine metabolism disorder after several decades. Conclusion: This is the first case of MAD syndrome caused by mutations in MTX2 gene reported in the Chinese population. MTX2 gene c.378 + 1G > A homozygous mutation has not been previously reported and the report of this patient expands the spectrum of MTX2 mutations. In addition, we summarized the genotypes and clinical characteristics of patients with progeroid syndromes in China.
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Lipodistrofia , Progeria , Femenino , Humanos , Progeria/genética , Progeria/complicaciones , Progeria/diagnóstico , Lipodistrofia/genética , Síndrome , Mutación , Enfermedades Raras , Trastornos del Crecimiento/complicacionesRESUMEN
The term laminopathies refers to a group of congenital diseases characterized by accelerated degeneration of human tissues. Mutations in LMNA, LMNB, ZMPSTE24, and other genes lead to structural and functional abnormalities associated with lamins. One subtype of laminopathy is the generalized lipodystrophy-associated progeroid syndrome (GLPS), which occurs in patients with heterozygous mutations of the LMNA gene c.29C>T(p.T10I). This paper reports the first case of GLPS in China and compares the clinical features of other GLPS patients with literature reports. A 16-year-old male patient was treated for diabetic ketoacidosis, presenting with premature aging appearance, systemic lipodystrophy, severe fatty liver, and decreased bone density. After peripheral blood DNA extraction and second-generation sequencing, a heterozygous mutation of exon 1 of the LMNA gene c.29C>T(p.T10I) was detected. This case of GLPS may provide a diagnostic and therapeutic basis for potential patients.
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Laminopatías , Lipodistrofia Generalizada Congénita , Lipodistrofia , Progeria , Masculino , Humanos , Adolescente , Lipodistrofia Generalizada Congénita/complicaciones , Lipodistrofia Generalizada Congénita/diagnóstico , Lipodistrofia Generalizada Congénita/genética , Progeria/complicaciones , Progeria/genética , Mutación , Lipodistrofia/genética , Lipodistrofia/complicaciones , Laminopatías/complicaciones , Lamina Tipo A/genéticaRESUMEN
With the exception of HIV-associated lipodystrophy, lipodystrophy syndromes are rare conditions characterized by a lack of adipose tissue, which is not generally recovered. As a consequence, an ectopic deposition of lipids frequently occurs, which usually leads to insulin resistance, atherogenic dyslipidemia, and hepatic steatosis. These disorders include certain accelerated aging syndromes or progeroid syndromes. Even though each of them has unique clinical features, most show common clinical characteristics that affect growth, skin and appendages, adipose tissue, muscle, and bone and, in some of them, life expectancy is reduced. Although the molecular bases of these Mendelian disorders are very diverse and not well known, genomic instability is frequent as a consequence of impairment of nuclear organization, chromatin structure, and DNA repair, as well as epigenetic dysregulation and mitochondrial dysfunction. In this review, the main clinical features of the lipodystrophy-associated progeroid syndromes will be described along with their causes and pathogenic mechanisms, and an attempt will be made to identify which of López-Otín's hallmarks of aging are present.
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Resistencia a la Insulina , Lipodistrofia , Progeria , Humanos , Progeria/complicaciones , Progeria/genética , Lipodistrofia/complicaciones , Lipodistrofia/genética , Síndrome , EnvejecimientoRESUMEN
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disorder characterized by short stature and atherosclerosis-induced death within teenage years. A 13-year-old male diagnosed with HGPS was administered three intravenous infusions of allogeneic cord blood (CB) cells from unrelated donors at four-month intervals to evaluate the safety and its therapeutic efficacy. Adverse events were monitored in addition to height, weight, laboratory blood tests, joint range of motion (ROM), and carotid Doppler. Cytokine and receptor assays were also performed. The patient exhibited an increase in growth rate for both height and weight. One year after therapy initiation, evident amelioration in pulse wave velocity, bilateral maximal intima-media thickness, and dyslipidemic status were observed, which were in abrupt aggravation prior to treatment. Further, an increase in flexibility occurred in some joints of the upper extremities. No serious adverse events were observed throughout the study period and one year beyond. A molecular assay revealed downregulation of proinflammatory and atherosclerosis, representing cytokine expressions following the administration of CB cells. This is the first reported case of an allogeneic CB trial in a patient with HGPS showing therapeutic effects of CB with improvements in anthropometric measures, joint ROM with amelioration of atherosclerosis, and dyslipidemia induced by anti-inflammatory and anti-atherosclerotic responses.
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Aterosclerosis/complicaciones , Aterosclerosis/terapia , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Dislipidemias/complicaciones , Dislipidemias/terapia , Progeria/complicaciones , Progeria/terapia , Adolescente , Estatura , Estudios de Seguimiento , Humanos , Masculino , Análisis de la Onda del Pulso , Rango del Movimiento Articular , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento , Aumento de PesoRESUMEN
We herein report a case of a 28-year-old man with generalized lipodystrophy-associated progeroid syndrome treated by leptin replacement. He showed symptoms of generalized lipodystrophy around onset of puberty. His body mass index was 11.9 kg/m2, and he had a short stature, birdlike facies, dental crowding due to micrognathia, partial graying and loss of hair, and a high-pitched voice, all of which are typical features of the progeroid syndrome. Laboratory examinations and abdominal ultrasonography revealed diabetes mellitus, insulin-resistance, dyslipidemia, decreased serum leptin levels (2.2 ng/mL), elevated serum hepatobiliary enzyme levels and fatty liver. Whole exome sequencing revealed de novo heterozygous LMNA p.T10I mutation, indicating generalized lipodystrophy-associated progeroid syndrome, which is a newly identified subtype of atypical progeroid syndrome characterized by severe metabolic abnormalities. Daily injection of metreleptin [1.2 mg (0.04 mg/kg)/day] was started. Metreleptin treatment significantly improved his diabetes from HbA1c 11.0% to 5.4% in six months. It also elevated serum testosterone levels. Elevated serum testosterone levels persisted even 1 year after the initiation of metreleptin treatment. To the best of our knowledge, this is the first Japanese case report of generalized lipodystrophy-associated progeroid syndrome. Furthermore, we evaluated short and long-term effectiveness of leptin replacement on generalized lipodystrophy by monitoring metabolic and endocrine profiles.
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Diabetes Mellitus/metabolismo , Dislipidemias/metabolismo , Hígado Graso/metabolismo , Hipogonadismo/metabolismo , Leptina/análogos & derivados , Lipodistrofia Generalizada Congénita/tratamiento farmacológico , Progeria/tratamiento farmacológico , Adulto , Alanina Transaminasa/metabolismo , Aspartato Aminotransferasas/metabolismo , Glucemia/metabolismo , Diabetes Mellitus/etiología , Dislipidemias/etiología , Hígado Graso/diagnóstico por imagen , Hígado Graso/etiología , Hemoglobina Glucada/metabolismo , Humanos , Hipogonadismo/etiología , Lamina Tipo A/genética , Leptina/uso terapéutico , Lipasa/metabolismo , Lipodistrofia Generalizada Congénita/complicaciones , Lipodistrofia Generalizada Congénita/genética , Lipodistrofia Generalizada Congénita/metabolismo , Masculino , Progeria/complicaciones , Progeria/genética , Progeria/metabolismo , Resultado del TratamientoRESUMEN
Mutations in the gene LMNA cause a wide spectrum of diseases that are now referred to laminopathies, such as muscular dystrophies, cardiomyopathies, and progeroid syndromes. Atypical progeroid syndrome (APS) is a type of progeroid syndrome mainly associated with LMNA mutations. Abnormal skeletal features associated with APS, such as osteoporosis and acroosteolysis, are rarely reported, and recurrent fractures have never been documented. We present a 16-year-old Chinese male patient with the typical features of APS, such as progeroid manifestations, cutaneous mottled hyperpigmentation, generalized lipodystrophy, and severe metabolic complications. The patient has also been detected with some rare and severe skeletal features, such as severe osteoporosis, generalized thinning of cortical bone, and recurrent femoral fractures. Genetic mutation detection in the LMNA gene revealed a de novo heterozygous mutation, the c. 29C>T (p. T10I).
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Fracturas del Fémur/diagnóstico , Progeria/complicaciones , Adolescente , Fracturas del Fémur/complicaciones , Fracturas del Fémur/diagnóstico por imagen , Humanos , Masculino , Progeria/diagnóstico , Recurrencia , SíndromeRESUMEN
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.
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Diabetes Mellitus/etiología , Progeria/complicaciones , Progeria/diagnóstico , Adolescente , Factores de Edad , Edad de Inicio , Niño , Trastornos por Deficiencias en la Reparación del ADN/complicaciones , Trastornos por Deficiencias en la Reparación del ADN/diagnóstico , Diabetes Mellitus/diagnóstico , Resultado Fatal , Femenino , Humanos , MasculinoAsunto(s)
Presión de las Vías Aéreas Positiva Contínua , Progeria/complicaciones , Apnea Obstructiva del Sueño , Adulto , Fatiga/etiología , Humanos , Masculino , Polisomnografía , Progeria/genética , Progeria/fisiopatología , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/terapia , Adulto JovenRESUMEN
Hutchinson-Gilford progeria syndrome is a rare genetic disorder, characterized by progressive premature aging and early death in the first or second decade of life, usually secondary to cardiovascular events (myocardial infarction and stroke). We report a case of a 14-year-old boy with progeria syndrome and cardiac arrest due to myocardial infarction, who was submitted to an immediate coronary angiography which revealed left main stem and three-vessel coronary artery disease. A prompt double bypass coronary artery grafting surgery was performed, and, despite successful coronary reperfusion, the patient remained in coma and brain death was declared on fourth day after surgery.
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Puente de Arteria Coronaria/métodos , Paro Cardíaco/cirugía , Infarto del Miocardio/cirugía , Progeria/complicaciones , Adolescente , Angiografía Coronaria , Electrocardiografía , Paro Cardíaco/diagnóstico , Paro Cardíaco/etiología , Humanos , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico , Progeria/genética , Enfermedades RarasRESUMEN
Background Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by pathogenic variants in the LMNA gene, which leads to premature aging. The median life expectancy is shortened to 13 years due to cardiovascular complications. Case report We present a boy born with a pathogenic LMNA variant c.433G > A, which causes atypical progeria syndrome (APS) and was previously described in one single patient. When investigated for poor growth prior to the diagnosis of APS, his laboratory tests revealed growth hormone (GH) deficiency and magnetic resonance imaging (MRI) of the midbrain showed partial empty sella. GH treatment had only a limited and transient effect. His first ischemic complication manifested at age 4.2 years; at the age of 7 years, he had a fatal haemorrhagic stroke. Conclusion To the best of our knowledge, this is the first patient with APS showing partial empty sella and GH deficiency that might have contributed to his poor growth. GH failed to improve long-term outcome.
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Enanismo/etiología , Hormona de Crecimiento Humana/deficiencia , Lamina Tipo A/genética , Mutación , Progeria/complicaciones , Preescolar , Enanismo/tratamiento farmacológico , Resultado Fatal , Hormona de Crecimiento Humana/administración & dosificación , Humanos , Lactante , Masculino , Progeria/genética , Progeria/patologíaRESUMEN
Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare and fatal disease with features of premature aging and cardiovascular diseases (atherosclerosis, myocardial infarction, and stroke). Several landmark studies in 2018-2019 have revealed novel mechanisms underlying cardiovascular pathologies in HGPS, and implicate future potential therapies for HGPS, and possibly physiological aging.
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Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/tratamiento farmacológico , Piperidinas/uso terapéutico , Progeria/complicaciones , Progeria/tratamiento farmacológico , Piridinas/uso terapéutico , Enfermedades Cardiovasculares/patología , Humanos , Progeria/patologíaRESUMEN
Approximately 20% of the world's population will be around or above 65 years of age by the next decade. Out of these, 40% are suspected to have cardiovascular diseases as a cause of mortality. Arteriosclerosis, characterized by increased vascular calcification, impairing Windkessel effect and tissue perfusion, and determining end-organ damage, is a hallmark of vascular pathology in the elderly population. Risk factors accumulated during aging affect the normal physiological and vascular aging process, which contributes to the progression of arteriosclerosis. Traditional risk factors, age-associated diseases, and respective regulating mechanisms influencing vascular calcification and vascular stiffness have been extensively studied for many years. Despite the well-known fact that aging alone can induce vascular damage, specific mechanisms that implicate physiological aging in vascular calcification, contributing to vascular stiffness, are poorly understood. This review focuses on mechanisms activated during normal aging, for example, cellular senescence, autophagy, extracellular vesicles secretion, and oxidative stress, along with the convergence of premature aging models' pathophysiology, such as Hutchinson-Gilford Progeria (prelamin accumulation) and Klotho deficiency, to understand vascular calcification in aging. Understanding the mechanisms of vascular damage in aging that intersect with age-associated diseases and risk factors is crucial to foster innovative therapeutic targets to mitigate cardiovascular disease. Visual Overview- An online visual overview is available for this article.
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Envejecimiento/patología , Calcificación Vascular/etiología , Animales , Autofagia , Senescencia Celular , Vesículas Extracelulares/fisiología , Glucuronidasa/deficiencia , Glucuronidasa/fisiología , Humanos , Proteínas Klotho , Osteoporosis/etiología , Estrés Oxidativo , Progeria/complicaciones , Especies Reactivas de Oxígeno/metabolismoAsunto(s)
Aterosclerosis/etiología , Susceptibilidad a Enfermedades , Progeria/complicaciones , Animales , Aterosclerosis/diagnóstico , Aterosclerosis/metabolismo , Modelos Animales de Enfermedad , Humanos , Lamina Tipo A/genética , Ratones , Terapia Molecular Dirigida , Mutación , Progeria/tratamiento farmacológico , Progeria/genética , Progeria/metabolismoRESUMEN
Hutchinson-Gilford progeria syndrome is a disorder of premature aging in children caused by de novo mutations in LMNA that lead to the synthesis of an internally truncated form of prelamin A (commonly called progerin). The production of progerin causes multiple disease phenotypes, including an unusual vascular phenotype characterized by the loss of smooth muscle cells in the arterial media and fibrosis of the adventitia. We show that progerin expression, combined with mechanical stress, promotes smooth muscle cell death. Disrupting the linker of the nucleoskeleton and cytoskeleton (LINC) complex in smooth muscle cells ameliorates the toxic effects of progerin on smooth muscle cells and limits the accompanying adventitial fibrosis.
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Enfermedades de la Aorta/complicaciones , Complejos Multiproteicos/metabolismo , Miocitos del Músculo Liso/metabolismo , Progeria/complicaciones , Progeria/metabolismo , Adventicia/metabolismo , Adventicia/patología , Animales , Aorta/metabolismo , Aorta/patología , Muerte Celular , Células Cultivadas , Colágeno Tipo VIII/biosíntesis , Modelos Animales de Enfermedad , Lamina Tipo A/metabolismo , Lamina Tipo B/metabolismo , Ratones , Miocitos del Músculo Liso/ultraestructura , FenotipoRESUMEN
Patients with Hutchinson-Gilford progeria syndrome (HGPS) have low bone mass and an atypical skeletal geometry that manifests in a high risk of fractures. Using both in vitro and in vivo models of HGPS, we demonstrate that defects in the canonical WNT/ß-catenin pathway, seemingly at the level of the efficiency of nuclear import of ß-catenin, impair osteoblast differentiation and that restoring ß-catenin activity rescues osteoblast differentiation and significantly improves bone mass. Specifically, we show that HGPS patient-derived iPSCs display defects in osteoblast differentiation, characterized by a decreased alkaline phosphatase activity and mineralizing capacity. We demonstrate that the canonical WNT/ß-catenin pathway, a major signaling cascade involved in skeletal homeostasis, is impaired by progerin, causing a reduction in the active ß-catenin in the nucleus and thus decreased transcriptional activity, and its reciprocal cytoplasmic accumulation. Blocking farnesylation of progerin restores active ß-catenin accumulation in the nucleus, increasing signaling, and ameliorates the defective osteogenesis. Moreover, in vivo analysis of the Zmpste24-/- HGPS mouse model demonstrates that treatment with a sclerostin-neutralizing antibody (SclAb), which targets an antagonist of canonical WNT/ß-catenin signaling pathway, fully rescues the low bone mass phenotype to wild-type levels. Together, this study reveals that the ß-catenin signaling cascade is a therapeutic target for restoring defective skeletal microarchitecture in HGPS. © 2018 American Society for Bone and Mineral Research.
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Enfermedades Óseas Metabólicas/complicaciones , Enfermedades Óseas Metabólicas/metabolismo , Diferenciación Celular , Osteoblastos/metabolismo , Progeria/complicaciones , Progeria/metabolismo , Transducción de Señal , beta Catenina/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Anticuerpos Neutralizantes/farmacología , Enfermedades Óseas Metabólicas/patología , Diferenciación Celular/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Glicoproteínas/inmunología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Lamina Tipo A/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones , Modelos Biológicos , Mutación/genética , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Fenotipo , Progeria/genética , Progeria/patología , Prenilación de Proteína/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
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). Recently, MDPL syndrome has been described as a new entity showing progressive lipodystrophy. Furthermore, polymerase delta 1 (POLD1) gene mutations on chromosome 19 have been identified in patients with MDPL syndrome. To date, 21 cases with POLD1-related MDPL syndrome have been reported worldwide, albeit almost entirely of European origin. Here, we identified a de novo mutation in exon 15 (p.Ser605del) of the POLD1 gene in a Japanese case by whole exome sequencing. To the best of our knowledge, this is the first identified case of MDPL syndrome in Japan. Our results provide further evidence that mutations in POLD1 are responsible for MDPL syndrome and serve as a common genetic determinant across different ethnicities.
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Anomalías Múltiples/diagnóstico , ADN Polimerasa III/genética , Sordera/complicaciones , Lipodistrofia/complicaciones , Micrognatismo/complicaciones , Progeria/complicaciones , Anomalías Múltiples/genética , Sordera/congénito , Sordera/diagnóstico , Sordera/genética , Diagnóstico Tardío , Diagnóstico Diferencial , Femenino , Humanos , Japón , Lipodistrofia/congénito , Lipodistrofia/diagnóstico , Lipodistrofia/genética , Mandíbula/anomalías , Micrognatismo/diagnóstico , Micrognatismo/genética , Persona de Mediana Edad , Mutación , Progeria/diagnóstico , Progeria/genética , SíndromeRESUMEN
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that shows a characteristic progeria phenotype. We conducted a questionnaire survey of 1173 tertiary hospitals in Japan and reviewed the academic reports, to identify the characteristics of Asian patients with classical HGPS. As a result, four Japanese patients were identified; this was estimated to account for approximately two-third of the prevalence in Japan. Three Asian patients who had definitively been diagnosed with classical HGPS were identified in the literature; in total, the clinical characteristics of seven patients were evaluated. Most of the clinical phenotypes of Asian patients were essentially similar to those of patients of other ethnicities, such as sclerodermatous skin, growth failure, loss of scalp hair or severe complications of cardiovascular and cerebral ischemic disease. In conclusion, to circumvent or minimalize severe vascular complication, an early diagnosis, careful observation and, promisingly, new intervention with farnesylation inhibitors may improve the prognosis of classical HGPS patients.
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Anomalías Múltiples/genética , Pueblo Asiatico/genética , Enfermedades Cardiovasculares/genética , Progeria/genética , Enfermedades de la Piel/genética , Anomalías Múltiples/diagnóstico , Adolescente , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/diagnóstico , Niño , Preescolar , Resultado Fatal , Femenino , Humanos , Japón , Masculino , Fenotipo , Progeria/complicaciones , Progeria/diagnóstico , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/diagnóstico , Encuestas y CuestionariosRESUMEN
Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-ß-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-ß-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence.