RESUMEN
Transcription is extremely important for cellular processes but can be hindered by RNA polymerase II (RNAPII) pausing and stalling. Cockayne syndrome protein B (CSB) promotes the progression of paused RNAPII or initiates transcription-coupled nucleotide excision repair (TC-NER) to remove stalled RNAPII. However, the specific mechanism by which CSB initiates TC-NER upon damage remains unclear. In this study, we identified the indispensable role of the ARK2N-CK2 complex in the CSB-mediated initiation of TC-NER. The ARK2N-CK2 complex is recruited to damage sites through CSB and then phosphorylates CSB. Phosphorylation of CSB enhances its binding to stalled RNAPII, prolonging the association of CSB with chromatin and promoting CSA-mediated ubiquitination of stalled RNAPII. Consistent with this finding, Ark2n-/- mice exhibit a phenotype resembling Cockayne syndrome. These findings shed light on the pivotal role of the ARK2N-CK2 complex in governing the fate of RNAPII through CSB, bridging a critical gap necessary for initiating TC-NER.
Asunto(s)
Síndrome de Cockayne , ADN Helicasas , Enzimas Reparadoras del ADN , Reparación del ADN , Proteínas de Unión a Poli-ADP-Ribosa , ARN Polimerasa II , Enzimas Reparadoras del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , ARN Polimerasa II/metabolismo , ARN Polimerasa II/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , Humanos , Animales , Ratones , ADN Helicasas/metabolismo , ADN Helicasas/genética , Síndrome de Cockayne/genética , Síndrome de Cockayne/metabolismo , Transcripción Genética , Fosforilación , Quinasa de la Caseína II/metabolismo , Quinasa de la Caseína II/genética , Ratones Noqueados , Daño del ADN , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/genética , Cromatina/metabolismo , Ubiquitinación , Reparación por EscisiónRESUMEN
BACKGROUND: Cockayne syndrome is an inherited heterogeneous defect in transcription-coupled DNA repair (TCR) cause severe clinical syndromes, which may affect the nervous system development of infants and even lead to premature death in some cases. ERCC8 diverse critical roles in the nucleotide excision repair (NER) complex, which is one of the disease-causing genes of Cockayne syndrome. METHODS AND RESULTS: The mutation of ERCC8 in the patient was identified and validated using WES and Sanger sequencing. Specifically, a compound heterozygous mutation (c.454_460dupGTCTCCA p. T154Sfs*13 and c.755_759delGTTTT p.C252Yfs*3) of ERCC8 (CSA) was found, which could potentially be the genetic cause of Cockayne syndrome in the proband. CONCLUSION: In this study, we identified a novel heterozygous mutation of ERCC8 in a Chinese family with Cockayne syndrome, which enlarging the genetic spectrum of the disease.
Asunto(s)
Síndrome de Cockayne , Humanos , Pueblo Asiatico , Núcleo Celular , Síndrome de Cockayne/genética , Enzimas Reparadoras del ADN/genética , Reparación por Escisión , Mutación/genética , Factores de TranscripciónRESUMEN
Microwave thermotherapy (MWT) has shown great potential in cancer treatment due to its deep tissue penetration and minimally invasive nature. However, the poor microwave absorption (MA) properties of the microwave thermal sensitizer in the medical frequency band significantly limit the thermal effect of MWT and then weaken the therapeutic efficacy. In this paper, a Ni-based multilayer heterointerface nanomissile of MOFs-Ni-Ru@COFs (MNRC) with improved MA performance in the desired frequency band via introducing magnetic loss and dielectric loss is developed for MWT-based treatment. The loading of the Ni nanoparticle in MNRC mediates the magnetic loss, introducing the MA in the medical frequency band. The heterointerface formed in the MNRC by nanoengineering induces significant interfacial polarization, increasing the dielectric loss and then enhancing the generated MA performance. Moreover, MNRC with the strong MA performance in the desired frequency range not only enhances the MW thermal effect of MWT but also facilitates the electron and energy transfer, generating reactive oxygen species (ROS) at tumor sites to mediate microwave dynamic therapy (MDT). The strategy of strengthening the MA performance of the sensitizer in the medical frequency band to improve MWT-MDT provides a direction for expanding the clinical application of MWT in tumor treatment.
Asunto(s)
Síndrome de Cockayne , Neoplasias , Humanos , Microondas , Transferencia de EnergíaRESUMEN
(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed this, presenting a series of patients with genetically confirmed CSB. (2) Materials and Methods: We retrospectively collected demographic, clinical, genetic, neuroimaging, and serum neurofilament light-chain (sNFL) data about CSB patients; diagnostic and severity scores were also determined. (3) Results: Data of eight ERCC6/CSB patients are presented. Four patients had CS I, three patients CS II, and one patient CS III. Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. Mean age at diagnosis was lower in the type II form, in which classic CS signs were more evident. Interestingly, sNFL determination appeared to reflect clinical classification. Two novel premature stop codon and one novel missense variants were identified. All CS I subjects harbored the p.Arg735Ter variant; the milder CS III subject carried the p.Leu764Ser missense change. (4) Conclusion: Our work confirms clinical variability also in the ERCC6/CSB type, where manifestations may range from severe involvement with prenatal or neonatal onset to normal psychomotor development followed by progressive ataxia. We propose, for the first time in CS, sNFL as a useful peripheral biomarker, with increased levels compared to currently available reference values and with the potential ability to reflect disease severity.
Asunto(s)
Síndrome de Cockayne , ADN Helicasas , Enzimas Reparadoras del ADN , Proteínas de Unión a Poli-ADP-Ribosa , Factores de Transcripción , Humanos , Síndrome de Cockayne/genética , Síndrome de Cockayne/patología , Síndrome de Cockayne/diagnóstico , Proteínas de Unión a Poli-ADP-Ribosa/genética , Enzimas Reparadoras del ADN/genética , Femenino , Masculino , ADN Helicasas/genética , Niño , Preescolar , Adolescente , Estudios Retrospectivos , Adulto , Lactante , Estudios de Asociación Genética , Adulto JovenRESUMEN
Cockayne syndrome (CS) is a rare hereditary autosomal recessive disorder primarily caused by mutations in Cockayne syndrome protein A (CSA) or B (CSB). While many of the functions of CSB have been at least partially elucidated, little is known about the actual developmental dysregulation in this devasting disorder. Of particular interest is the regulation of cerebral development as the most debilitating symptoms are of neurological nature. We generated neurospheres and cerebral organoids utilizing Cockayne syndrome B protein (CSB)-deficient induced pluripotent stem cells derived from two patients with distinct severity levels of CS and healthy controls. The transcriptome of both developmental timepoints was explored using RNA-Seq and bioinformatic analysis to identify dysregulated biological processes common to both patients with CS in comparison to the control. CSB-deficient neurospheres displayed upregulation of the VEGFA-VEGFR2 signalling pathway, vesicle-mediated transport and head development. CSB-deficient cerebral organoids exhibited downregulation of brain development, neuron projection development and synaptic signalling. We further identified the upregulation of steroid biosynthesis as common to both timepoints, in particular the upregulation of the cholesterol biosynthesis branch. Our results provide insights into the neurodevelopmental dysregulation in patients with CS and strengthen the theory that CS is not only a neurodegenerative but also a neurodevelopmental disorder.
Asunto(s)
Síndrome de Cockayne , Células Madre Pluripotentes Inducidas , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , ADN Helicasas/genética , Enzimas Reparadoras del ADN/metabolismo , Síndrome de Cockayne/genética , Síndrome de Cockayne/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Encéfalo/metabolismo , Organoides/metabolismoRESUMEN
Cockayne syndrome (CS) is a rare autosomal recessive disorder that affects the DNA repair process. It is a progeroid syndrome predisposing patients to accelerated aging and to increased susceptibility to respiratory infections. Here, we studied the immune status of CS patients to determine potential biomarkers associated with pathological aging. CS patients, as well as elderly and young, healthy donors, were enrolled in this study. Complete blood counts for patients and donors were assessed, immune cell subsets were analyzed using flow cytometry, and candidate cytokines were analyzed via multi-analyte ELISArray kits. In CS patients, we noticed a high percentage of lymphocytes, an increased rate of intermediate and non-classical monocytes, and a high level of pro-inflammatory cytokine IL-8. In addition, we identified an increased rate of particular subtypes of T Lymphocyte CD8+ CD28- CD27-, which are senescent T cells. Thus, an inflammatory state was found in CS patients that is similar to that observed in the elderly donors and is associated with an immunosenescence status in both groups. This could explain the CS patients' increased susceptibility to infections, which is partly due to an aging-associated inflammation process.
Asunto(s)
Síndrome de Cockayne , Inmunosenescencia , Humanos , Anciano , Linfocitos T CD8-positivos , Envejecimiento , Citocinas , BiomarcadoresRESUMEN
Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. Due to the large variation in clinical presentation the diseases pose a diagnostic challenge for clinicians which consequently restricts medical research. To accommodate the challenge, we compiled a list of known progeroid syndromes and calculated the mean prevalence of their associated phenotypes, defining what we term the 'progeria phenome'. The data were used to train a support vector machine that is available at https://www.mitodb.com and able to classify progerias based on phenotypes. Furthermore, this allowed us to investigate the correlation of progeroid syndromes and syndromes with various pathogenesis using hierarchical clustering algorithms and disease networks. We detected that ataxia-telangiectasia like disorder 2, spastic paraplegia 49 and Meier-Gorlin syndrome display strong association to progeroid syndromes, thereby implying that the syndromes are previously unrecognized progerias. In conclusion, our study has provided tools to evaluate the likelihood of a syndrome or patient being progeroid. This is a considerable step forward in our understanding of what constitutes a premature aging disorder and how to diagnose them.
Asunto(s)
Envejecimiento Prematuro , Síndrome de Cockayne , Progeria , Humanos , Progeria/genética , Progeria/patología , Envejecimiento Prematuro/genética , Envejecimiento , Fenotipo , Trastornos del Crecimiento/complicacionesRESUMEN
Mutations in the Cockayne Syndrome group B (CSB) gene cause cancer in mice, but premature aging and severe neurodevelopmental defects in humans. CSB, a member of the SWI/SNF family of chromatin remodelers, plays diverse roles in regulating gene expression and transcription-coupled nucleotide excision repair (TC-NER); however, these functions do not explain the distinct phenotypic differences observed between CSB-deficient mice and humans. During investigating Cockayne Syndrome-associated genome instability, we uncover an intrinsic mechanism that involves elongating RNA polymerase II (RNAPII) undergoing transient pauses at internal T-runs where CSB is required to propel RNAPII forward. Consequently, CSB deficiency retards RNAPII elongation in these regions, and when coupled with G-rich sequences upstream, exacerbates genome instability by promoting R-loop formation. These R-loop prone motifs are notably abundant in relatively long genes related to neuronal functions in the human genome, but less prevalent in the mouse genome. These findings provide mechanistic insights into differential impacts of CSB deficiency on mice versus humans and suggest that the manifestation of the Cockayne Syndrome phenotype in humans results from the progressive evolution of mammalian genomes.
Asunto(s)
Síndrome de Cockayne , ADN Helicasas , Enzimas Reparadoras del ADN , Inestabilidad Genómica , Proteínas de Unión a Poli-ADP-Ribosa , Estructuras R-Loop , ARN Polimerasa II , Síndrome de Cockayne/genética , Síndrome de Cockayne/patología , Síndrome de Cockayne/metabolismo , ARN Polimerasa II/metabolismo , ARN Polimerasa II/genética , Animales , Humanos , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Ratones , ADN Helicasas/metabolismo , ADN Helicasas/genética , Estructuras R-Loop/genética , Reparación del ADN , Elongación de la Transcripción Genética , Ratones NoqueadosRESUMEN
Covalent DNA-protein cross-links (DPCs) are toxic DNA lesions that block replication and require repair by multiple pathways. Whether transcription blockage contributes to the toxicity of DPCs and how cells respond when RNA polymerases stall at DPCs is unknown. Here we find that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Using genetic screens and a method for the genome-wide mapping of DNA-protein adducts, DPC sequencing, we discover that Cockayne syndrome (CS) proteins CSB and CSA provide resistance to DPC-inducing agents by promoting DPC repair in actively transcribed genes. Consequently, CSB- or CSA-deficient cells fail to efficiently restart transcription after induction of DPCs. In contrast, nucleotide excision repair factors that act downstream of CSB and CSA at ultraviolet light-induced DNA lesions are dispensable. Our study describes a transcription-coupled DPC repair pathway and suggests that defects in this pathway may contribute to the unique neurological features of CS.
Asunto(s)
Síndrome de Cockayne , ADN Helicasas , Enzimas Reparadoras del ADN , Reparación del ADN , Proteínas de Unión a Poli-ADP-Ribosa , ARN Polimerasa II , Humanos , Síndrome de Cockayne/genética , Síndrome de Cockayne/metabolismo , Síndrome de Cockayne/patología , Aductos de ADN/metabolismo , Aductos de ADN/genética , Daño del ADN , ADN Helicasas/metabolismo , ADN Helicasas/genética , Enzimas Reparadoras del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Reparación por Escisión , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , Receptores de Interleucina-17 , ARN Polimerasa II/metabolismo , ARN Polimerasa II/genética , Factores de Transcripción , Transcripción Genética , Ubiquitinación , Rayos UltravioletaRESUMEN
Neurodegenerative diseases are the second most prevalent cause of death in industrialized countries. Alzheimer's Disease is the most widespread and also most acknowledged form of dementia today. Together with Parkinson's Disease they account for over 90â¯% cases of neurodegenerative disorders caused by proteopathies. Far less known are the neurodegenerative pathologies in DNA repair deficiency syndromes. Such diseases like Cockayne - or Werner Syndrome are described as progeroid syndromes - diseases that cause the premature ageing of the affected persons, and there are clear implications of such diseases in neurologic dysfunction and degeneration. In this review, we aim to draw the attention on commonalities between proteopathy-associated neurodegeneration and neurodegeneration caused by DNA repair defects and discuss how mitochondria are implicated in the development of both disorder classes. Furthermore, we highlight how nematodes are a valuable and indispensable model organism to study conserved neurodegenerative processes in a fast-forward manner.
Asunto(s)
Reparación del ADN , Enfermedades Neurodegenerativas , Humanos , Animales , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Mitocondrias/metabolismo , Mitocondrias/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Trastornos por Deficiencias en la Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/metabolismo , Síndrome de Cockayne/genética , Síndrome de Cockayne/metabolismoRESUMEN
El Síndrome de Progeria de Hutchinson-Gilford es una enfermedad que se caracteriza por el envejecimiento prematuro en niños, debido a una mutación en el gen de Lámina tipo A involucrado en la mitosis celular. En el presente trabajo, con el objetivo de dar difusión al conocimiento de esta enfermedad, se señalan los procesos involucrados en su desarrollo, así como los avances científicos y el alcance de nuevas ventanas terapéuticas. La revisión se realizó consultando artículos en español e inglés empleando los motores de búsqueda Pubmed y Google Académico. La actualización del personal de salud sobre las enfermedades genéticas congénitas es de vital importancia para mejorar su detección, atención y manejo(AU)
Hutchinson-Gilford Progeria Syndrome is a disease characterized by premature aging in children, due to a mutation in the Lamina type A, gene involved in cellular mitosis. In the present work, with the aim of spreading the knowledge of this disease, the processes involved in its development, the scientific advances, and the scope of new therapeutic treatments were summarized. The review was carried out by consulting articles in Spanish and English using the Pubmed and Google Academic search engines. The updating of health personnel on congenital genetic diseases is of vital importance to improve their detection, care and management(EU)
Asunto(s)
Humanos , Enfermedades Genéticas Congénitas , Envejecimiento Prematuro , Síndrome de Cockayne/fisiopatología , Lamina Tipo ARESUMEN
Abstract Cockayne syndrome is an autosomal recessive multi-systemic disorder due to DNA repair failure. It was originally described in 1936 in children of small stature, retinal atrophy and deafness, characterized by dwarfism, cachexia, photosensitivity, premature aging and neurologic deficits. The most typical feature is described as birdlike facies: protruding maxilla, facial lipoatrophy, sunken eyes, large ears and thin nose. Difficult airway management with subglottic stenosis and risk of gastric content aspiration has been described. Although the clinical characteristics of Cockayne syndrome have been well described in pediatric publications, there is only one report in the literature on anesthesia for an obstetric patient. We report the case of a pregnant patient diagnosed with Cockayne syndrome, submitted successfully to spinal anesthesia for a cesarean section due to cephalopelvic disproportion. In view of the difficult decision between inducing general anesthesia in a patient with a likely difficult airway, or neuraxial anesthesia in a patient with cardiovascular, respiratory and neurocognitive limitations, we suggest tailored management to reach the best results for the mother and newborn.
Resumo A síndrome de Cockayne é doença multissistêmica autossômica recessiva devido à falha no reparo do DNA. Originalmente descrita em 1936 em crianças com baixa estatura, atrofia retiniana e surdez, é caracterizada por nanismo, caquexia, fotossensibilidade, envelhecimento acelerado e déficits neurológicos. O mais típico é a fácies, descrita como similar à de um pássaro: maxila proeminente, atrofia do coxim adiposo bucal, olhos profundos, orelhas grandes e nariz fino. Tem sido descrita dificuldade no manejo da via aérea com estreitamento subglótico e risco de aspiração gástrica. Embora as características clínicas da síndrome de Cockayne sejam bem relatadas em publicações pediátricas, há apenas um relato de anestesia em paciente obstétrica na literatura. Relatamos o caso de gestante com diagnóstico de síndrome de Cockayne, submetida com sucesso a raquianestesia para parto cesariano por desproporção cefalopélvica. Diante da difícil decisão entre induzir anestesia geral em paciente com provável via aérea difícil ou anestesia neuroaxial, em meio a limitações cardiovasculares, respiratórias e neurocognitivas da paciente, conduta individualizada é sugerida para alcançar os melhores resultados para a gestante e o neonato.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Complicaciones del Embarazo , Cesárea , Síndrome de Cockayne , Anestesia Obstétrica , Anestesia RaquideaRESUMEN
<p><b>OBJECTIVE</b>Cockayne syndrome is a rare disease and difficult to be recognized. This study aimed to expand the knowledge of the clinical and molecular characteristics of the children with Cockayne syndrome (CS).</p><p><b>METHOD</b>Clinical data of two siblings with classic CS of Guangzhou Women and Children's Medical Center from July 2013 to November 2014 were obtained and analyzed. The whole DNA of peripheral blood was collected from two CS siblings and their parents. Amplification of all exons and adjacent introns for ERCC6 gene was conducted using PCR, and measurement of reaction product was performed to find mutation sites by two-way sequencing.</p><p><b>RESULT</b>Two affected siblings were males, and came from unconsanguineous parents, 7 years and 5 months old and 4 years and 8 months old, respectively. They were in treatment because of developmental and mental retardation for years. When they were younger than one year of age, their heights and weight were within normal limits. However, poor growth of height and weight and psychomotor retardation appeared after one and a half years of age, as well as skin and eye sensitivity to sunshine, hearing impairment, optic nerve atrophy, microcephaly, and deep-set eyes. The proband's height was 90.8 cm, and weight 9.1 kg, head circumference 41 cm, and chest circumference 44 cm when he was taken to hospital. The elder brother of the proband had a height of 92 cm, weight 11.2 kg, head circumference 41 cm, and chest circumference 44 cm when he was taken to hospital. When the proband was four and a half years old, ventricular enlargement, hypomyelination, and brain atrophy were detected for his elder brother at 7 years of age by cranial MRI. MRS imaging indicated that damages occurred at the left and right sides of dorsal thalamus, lobus insularis, along with the left half circle of central neurons. Symmetrical calcification on bilateral basal ganglia was found on the brain CT scan. Pathogenic compound heterozygous c. 1357C > T (p.Arg453Ter) and c. 1607T > G (p.Leu536Trp) mutations of ERCC6 gene were identified in the two siblings which were separately inherited from their unaffected parents.</p><p><b>CONCLUSION</b>CS children are usually normal at birth, however, they have severe clinical characteristics such as poor growth, psychomotor retardation, cerebral injury, microcephalus, deep-set eyes, and skin sensitivity to sunshine. ERCC6 gene mutation usually occurs, and it is easy to misdiagnose CS as cerebral palsy, primary microcephaly, and so on.</p>
Asunto(s)
Niño , Preescolar , Humanos , Masculino , Pueblo Asiatico , Síndrome de Cockayne , Genética , ADN Helicasas , Genética , Análisis Mutacional de ADN , Enzimas Reparadoras del ADN , Genética , Exones , Heterocigoto , Imagen por Resonancia Magnética , Mutación , Proteínas de Unión a Poli-ADP-Ribosa , Reacción en Cadena de la Polimerasa , HermanosRESUMEN
Ultraviolet light(UV)-sensitive disorders refer to a group of diseases due to damages to the nucleotide excision repair mechanism which cannot effectively repair DNA damage caused by ultraviolet radiation. The inheritance pattern of such diseases, mainly including xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, is autosomal recessive and known to involve 13 genes. As proteins encoded by such genes are involved in DNA repair and transcription pathways. There is overlap between the symptoms of such diseases, and their genotype - phenotype correlations are quite complex. To facilitate genetic and prenatal diagnosis for such diseases, a summary of the research progress is provided, which mainly focused on mutation research and genotype - phenotype correlation studies. We also propose a strategy for their genetic diagnosis based on recent findings of our group.
Asunto(s)
Humanos , Investigación Biomédica , Métodos , Síndrome de Cockayne , Genética , Daño del ADN , Reparación del ADN , Genética , Predisposición Genética a la Enfermedad , Genética , Piel , Metabolismo , Patología , Efectos de la Radiación , Síndromes de Tricotiodistrofia , Genética , Rayos Ultravioleta , Xerodermia Pigmentosa , GenéticaRESUMEN
<p><b>OBJECTIVE</b>To identify potential mutations among three sisters from a Chinese family suspected with Cockayne syndrome for growth and psychomotor retardation, and to offer genetic counseling and prenatal diagnosis for the family.</p><p><b>METHODS</b>G-banded karyotyping, microarray comparative genomic hybridization (CM-CGH), whole genome exon high-throughput sequencing and Sanger sequencing were employed to identify potential genetic variations for the three patients and their parents.</p><p><b>RESULTS</b>Whole exome sequencing has identified two novel missense mutations, i.e., c.1595A>G (p.Asp532Gly) and c.1607T>G (p.Leu536Trp), in exon 7 of excision repair cross-complementing rodent repair deficiency, complementation group 6 (ERCC6) gene. Sanger sequencing confirmed that all of the three sisters have inherited one of the mutations (c.1607T>G) from their father and another (c.1595A>G) from their mother.</p><p><b>CONCLUSION</b>Three sisters have all been identified as double heterozygote for mutations c.1607T>G and c.1595A>G and were diagnosed with Cockayne syndrome.</p>
Asunto(s)
Adulto , Preescolar , Femenino , Humanos , Lactante , Masculino , Pueblo Asiatico , Genética , Secuencia de Bases , Síndrome de Cockayne , Diagnóstico , Genética , ADN Helicasas , Genética , Enzimas Reparadoras del ADN , Genética , Exones , Heterocigoto , Datos de Secuencia Molecular , Linaje , Mutación Puntual , Proteínas de Unión a Poli-ADP-RibosaRESUMEN
Objetivos: Relatar casos de síndrome de Cockayne em dois irmãos, descrevendo a apresentação e a evoluçãoclínica.Descrição dos casos: Apresentam-se os casos de dois irmãos, uma menina de 8 anos e um menino de 13 anos, ambos com deficiência global do desenvolvimento, microcefalia, nanismo e facies peculiar (face triangular, microftalmia, microstomia e micrognatia). No seguimento, surgiram novos problemas, como surdez neurossensorial, hipermetropia e fotossensibilidade. Pela clínica foi sugerida a hipótese de síndrome de Cockayne, que foi confirmada por teste genético molecular.Conclusões: A síndrome de Cockayne é um distúrbio raro (1/100.000), autossômico recessivo. Seu diagnóstico pode ser moroso, pois os sinais e sintomas vão surgindo progressiva e lentamente. A conjugação dos critérios de diagnóstico pode levar anos, sendo de extrema importância a suspeição clínica.
Aims: To report cases of Cockayne syndrome in two siblings, describing the clinical presentation and evolution.Case description: We describe the cases of two siblings, an 8 years old girl and a 13 years old boy, both with global developmental disability, microcephaly, dwarfism and peculiar facies (triangular face, microphthalmia, microstomia and micrognathia). New problems emerged during follow-up: sensorineural hearing loss, hypermetropia and photosensitivity. Clinical features suggested Cockayne syndrome, which was confirmed by molecular genetictesting.Conclusions: Cockayne?s syndrome is a rare (1/100,000), recessive autosomal disorder. Its diagnosis may be delayed because the signs and symptoms arise gradually and slowly. Obtaining the diagnostic criteria can take years and clinical suspicion is extremely important.
Asunto(s)
Discapacidades del Desarrollo , Facies , Enanismo , Síndrome de CockayneRESUMEN
Introducción: el síndrome de Cockayne es un trastorno genético autosómico recesivo, caracterizado por detención del crecimiento, retraso del desarrollo, envejecimiento prematuro y fotosensibilidad. La prevalencia es de 1/100.000 nacidos vivos; es más frecuente en el sexo masculino con una relación 3:1. Desde el punto de vista genético se han descrito dos grupos: A: mutación del gen CSA (CKN1, ERCC8) en el cromosoma 5q12; B: mutación del gen CSB (ERCC6) en el cromosoma 10q11. Presentamos dos casos diagnosticados sobre bases clínicas pero en los que carecemos de estudios genéticos. Caso 1. Niña escolar producto de padres consanguíneos quien desde el nacimiento presenta hipotonía e hipomotilidad, retardo global del desarrollo, déficit pondoestatural, cara envejecida, rasgos dismórficos, fotosensibilidad, espasticidad e hipoacusia neurosensorial y hallazgos tomográficos característicos del síndrome. Actualmente está en rehabilitación. Caso 2. Adolescente de sexo femenino con crisis convulsivas desde los dos meses, poco progreso en el desarrollo psicomotor y pondoestatural, rasgos dismórficos y cara envejecida, hipoacusia neurosensorial bilateral, distonías repetitivas; en varias oportunidades sufrió procesos infecciosos respiratorios uno de los cuales, con neumonía bilateral, la llevó a la muerte a los 14 años. Conclusión: se presentan estos casos y se revisa la literatura para llamar la atención sobre este síndrome de modo que se lo sospeche tempranamente en pacientes con retardo del desarrollo psicomotor, envejecimiento prematuro y fotosensibilidad. El diagnóstico temprano es la base para brindar consejería genética a los padres.
Introduction: Cockayne syndrome is an autosomal, recessive genetic disorder, characterized by poor growth, development impairment, premature aging, and photosensitivity. Prevalence is 1/100.000 live births, and it is more frequent in males with a ratio of 3:1. From the genetic point of view two groups have been described: Group A: mutation of the CSA gene (CKN1, ERCC8) on chromosome 5q12. Group B: mutation of the CBS gene (ERCC6) on chromosome 10q11. We report two cases that were diagnosed solely on clinical bases because no genetic studies were available. Case 1. A school-girl, born from consanguineous parents. Since birth she has suffered from hypotonia and hypomotility. She has development delay, low weight and height gain, aged face, dysmorphic features, photosensitivity, spasticity, sensorineural hearing loss, and typical findings in the CT scan. She is currently on rehabilitation. Case 2. A female teenager with seizures from the age of two months; she made slow progress in psychomotor development, and had low weight and height gain. Her features were dysmorphic and her face aged. She had bilateral sensorineural hearing loss, and repeated dystonias. She suffered from repeated respiratory infections and died, aged 14, from respiratory failure secondary to bilateral pneumonia. Conclusion: We report these two cases and a review of the literature in order to attract attention to Cockayne syndrome so that early diagnoses can be made in children with psychomotor development delay, premature aging and photosensitivity. Early diagnoses are the basis for genetic counseling.
Asunto(s)
Niño , Envejecimiento Prematuro , Síndrome de Cockayne , Trastornos PsicomotoresRESUMEN
Cockayne syndrome is a rare autosomal recessive disease. This paper reports a case of Cockayne syndrome confirmed by gene analysis. The baby (male, 7 years old) was referred to Peking University Third Hospital with recurrent desquamation, pigmentation and growth and development failure for 6 years, and recurrent dental caries and tooth loss for 2 years. Physical examination showed very low body weight, body length and head circumference, yellow hair, a lot of fawn spots on the face, skin dry and less elastic, and subcutaneous lipopenia. He had an unusual appearance with sunken eyes, sharp nose, sharp mandible, big auricle and dental caries and tooth loss. Crura spasticity and ataxia with excessive tendon reflexion, and ankle movement limitation while bending back were observed. He had slured speech. The level of serum insulin like growth factor I was low, and the results of blood and urinary amino acid analysis suggested malnutrition. The results of blood growth hormone, thyroxin, parathyroxin, liver function, renal function, lipoprotein profile and blood glucose and electrolytes were all within normal limit. An electronic hearing examination showed moderate neural hearing loss. The sonogram of eyes revealed small eye axis and vitreous body opacity of right side. MRI of brain revealed bilateral calcification of basal ganglia and generalized cerebral and cerebellar atrophy, and brainstem and callus were also atrophic. Genetic analysis confirmed with CSA gene mutation. So the boy was definitely diagnosed with Cockayne syndrome. He was discharged because of no effective treatment.