RESUMO
Ataxia telangiectasia is a rare, multi system disease caused by ATM kinase deficiency. Atm-knockout mice recapitulate premature aging, immunodeficiency, cancer predisposition, growth retardation and motor defects, but not cerebellar neurodegeneration and ataxia. We explored whether Atm loss is responsible for skeletal muscle defects by investigating myofiber morphology, oxidative/glycolytic activity, myocyte ultrastructural architecture and neuromuscular junctions. Atm-knockout mice showed reduced muscle and fiber size. Atrophy, protein synthesis impairment and a switch from glycolytic to oxidative fibers were detected, along with an increase of in expression of slow and fast myosin types (Myh7, and Myh2 and Myh4, respectively) in tibialis anterior and solei muscles isolated from Atm-knockout mice. Transmission electron microscopy of tibialis anterior revealed misalignments of Z-lines and sarcomeres and mitochondria abnormalities that were associated with an increase in reactive oxygen species. Moreover, neuromuscular junctions appeared larger and more complex than those in Atm wild-type mice, but with preserved presynaptic terminals. In conclusion, we report for the first time that Atm-knockout mice have clear morphological skeletal muscle defects that will be relevant for the investigation of the oxidative stress response, motor alteration and the interplay with peripheral nervous system in ataxia telangiectasia.
Assuntos
Senilidade Prematura/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Síndromes de Imunodeficiência/genética , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Neoplasias/genética , Animais , Ataxia Telangiectasia/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias/ultraestrutura , Músculo Esquelético/anormalidades , Músculo Esquelético/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo , Sarcômeros/ultraestruturaRESUMO
First described over 80 years ago, ataxia-telangiectasia (A-T) was defined as a clinical entity 50 years ago. Although not encountered by most clinicians, it is a paradigm for cancer predisposition and neurodegenerative disorders and has a central role in our understanding of the DNA-damage response, signal transduction and cell-cycle control. The discovery of the protein A-T mutated (ATM) that is deficient in A-T paved the way for rapid progress on understanding how ATM functions with a host of other proteins to protect against genome instability and reduce the risk of cancer and other pathologies.
Assuntos
Ataxia Telangiectasia/fisiopatologia , Animais , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiologia , Dano ao DNA , Reparo do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Predisposição Genética para Doença , Humanos , Resistência à Insulina , Síndrome Metabólica/etiologia , Camundongos , Modelos Biológicos , Mutação , Neoplasias/etiologia , Neoplasias/genética , Degeneração Neural , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologiaRESUMO
AIM: To collect preliminary functional data on ataxia telangiectasia and create a disease specific scale: the Ataxia Telangiectasia Functional Scale (ATFS). METHOD: Retrospective information on patients with ataxia telangiectasia referred to the Assistive Technology Unit was included. Functional mobility scales (the Gross Motor Function Classification System [GMFCS] and the Functional Mobility Scale [FMS]-5, FMS-50, FMS-500) and activities of daily living [ADL] parameters were recorded. We created a 51-point ATFS, that consisted of three ambulation items adapted for ataxia telangiectasia in the frame of FMS (home, school, outdoors), five ADL items, and one schooling item. RESULTS: Twenty-seven participants (17 males, 10 females; mean age 10y 8mo [SD 5y 1mo], range 1y 9mo-25y 6mo), were enrolled; 168 measurements were recorded. Patients walked at a mean age of 1 year 4 months (SD 5y 4mo) and lost ambulatory capacity at 8 years 8 months (SD 2y 1mo). GMFCS level and FMS-5, FMS-50, FMS-500 assessments correlated with age (Spearman's correlations r=0.555, -0.617, -0.639, -0.662 respectively, p<0.01 for all), but plateaued after 12 years of age. ATFS mean score was 37.46 (SD 7.88) and increased with age (Spearman's correlation r=0.585, p<0.01). The scale showed three stages of disease progression. INTERPRETATION: In this pilot study we show longitudinal functional data of ambulation and ADL skills in ataxia telangiectasia, and created a framework for a functional scale. This functional scale closely approximated disease course, but further validation is required. WHAT THIS PAPER ADDS: The Gross Motor Function Classification System and the Functional Mobility Scale are ill-suited for ataxia telangiectasia assessments. Three functional mobility scales (home, school, outdoors) suited to ataxia telangiectasia were created. The Ataxia Telangiectasia Functional Scale (ATFS) combines mobility and items of activities of daily living. The ATFS closely approximates the three-stage progression of the disorder.
MEDICIONES DE PARÁMETROS FUNCIONALES EN NIÑOS CON ATAXIA TELANGIECTASIA: OBJETIVO: Recopilar datos funcionales preliminares sobre la ataxia telangiectasia y crear una escala específica de la enfermedad: la escala funcional de la ataxia telangiectasia (ATFS). MÉTODO: Se incluyó información retrospectiva sobre pacientes con ataxia telangiectasia remitidos a la Unidad de Tecnología Asistiva. Se registraron las escalas de movilidad funcional (el sistema de clasificación de la función motora gruesa [GMFCS] y la escala de movilidad funcional [FMS-5, FMS-50, FMS-500]) y los parámetros de las actividades de la vida diaria [ADL]. Creamos un ATFS de 51 puntos, que constaba de tres elementos de asistencia a la deambulación adaptados para la ataxia telangiectasia según los requerimientos de FMS (hogar, escuela, exteriores), cinco elementos de ADL y un elemento de escolarización. RESULTADOS: Se reclutaron 27 participantes (17 varones, 10 mujeres; edad media 10a 8m[DE 5a 1m], rango 1a 9m- 25a 6m); se registraron 168 mediciones. Los pacientes caminaron a una edad promedio de 1 año y 4 meses (DE 5 y 4 meses) y perdieron la capacidad ambulatoria a los 8 años y 8 meses (DE 2 y 1 meses). Las evaluaciones GMFCS y FMS-5, FMS-50, FMS-500 se correlacionaron con la edad (correlaciones de Spearman r = 0,555, -0,617, -0,639, -0,662 respectivamente, p <0,01 para todos), pero se estancaron después de los 12 años de edad. La puntuación media de ATFS fue 37,46 (SD 7,88) y aumentó con la edad (correlación de Spearman r = 0,585, p <0,01). La escala mostró tres etapas de progresión de la enfermedad. INTERPRETACIÓN: En este estudio piloto, mostramos datos funcionales longitudinales de ambulación y habilidades de ADL en la ataxia telangiectasia, y creamos un marco para una escala funcional. Esta escala funcional se aproximó mucho al curso de la enfermedad, pero se requiere validación adicional.
MEDIDAS DE PARÂMETROS FUNCIONAIS EM CRIANÇAS COM ATAXIA TELANGIECTASIA: OBJETIVO: Coletar dados funcionais prelimiares sobre ataxia telangiectasia e criar uma escala específica para a doença: a Escala Funcional de Ataxia Telangiectasia (EFAT). MÉTODO: Informações retrospectivas sobre pacientes com ataxia telangiectasia encaminhados para a Unidade de Tecnologia Assistiva foram incluídas. Escalas de mobilidade funcional (o Sistema de Classificação da Função Motora grossa [GMFCS] e a Escala de Mobilidade Funcional [FMS]-5, FMS-50, FMS-500) e parâmetros de atividades da vida diária [AVD] foram registrados. Uma EFAT de 51 pontos foi criada, consistindo de três itens de deambulação adaptados para ataxia telangiectasia na estrutura da FMF (casa, escola, comunidade), cinco itens de AVDs, e um item sobre escolaridade. RESULTADOS: Vinte e sete participantes (17 do sexo masculino, 10 nomes do sexo feminino; média de idade 10a 8m [DP 5a 1m], variação 1a 9m-25a 6m), foram recrutados; 168 medidas foram registradas. Os pacientes deambularam com uma média de (DP 5a 4m) e perderam a capacidade deambulatória com 8a 8m (DP 2a 1m). As avaliações de GMFCS e FMS-5, FMS-50, FMS-500 se correlacionara mcom a idade (correlações de r=0,555, -0,617, -0,639, -0,662 respectivamen, p<0,01 para todos), mas atingiram platô após a idade de 12 anos. O escore médio da EFAT foi 37,46 (DP 7,88) e houve aumento com a idade (correlação de Spearman r=0,585, p<0,01). A escala mostrou três estágios de progressão da doença. INTERPRETAÇÃO: Neste estudo piloto, mostramos dados funcionais longitudinais sobre a deambulação e AVDs em ataxia telangiectasia, e criamos uma estrutura para uma escala fncional. Esta escala funcional se assemelhou com o curso da doença, porém maiores estudos para validação são necessaries.
Assuntos
Ataxia Telangiectasia/diagnóstico , Gravidade do Paciente , Atividades Cotidianas , Adolescente , Adulto , Ataxia Telangiectasia/fisiopatologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Projetos Piloto , Dados Preliminares , Estudos Retrospectivos , Instituições Acadêmicas , Caminhada , Adulto JovemRESUMO
The term "cerebral palsy mimic" is used to describe a number of neurogenetic disorders that may present with motor symptoms in early childhood, resulting in a misdiagnosis of cerebral palsy. Cerebral palsy describes a heterogeneous group of neurodevelopmental disorders characterized by onset in infancy or early childhood of motor symptoms (including hypotonia, spasticity, dystonia, and chorea), often accompanied by developmental delay. The primary etiology of a cerebral palsy syndrome should always be identified if possible. This is particularly important in the case of genetic or metabolic disorders that have specific disease-modifying treatment. In this article, we discuss clinical features that should alert the clinician to the possibility of a cerebral palsy mimic, provide a practical framework for selecting and interpreting neuroimaging, biochemical, and genetic investigations, and highlight selected conditions that may present with predominant spasticity, dystonia/chorea, and ataxia. Making a precise diagnosis of a genetic disorder has important implications for treatment, and for advising the family regarding prognosis and genetic counseling. © 2019 International Parkinson and Movement Disorder Society.
Assuntos
Paralisia Cerebral/diagnóstico , Diagnóstico Diferencial , Transtornos dos Movimentos/diagnóstico , Adenilil Ciclases/genética , Ataxia/fisiopatologia , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/fisiopatologia , Ataxia Telangiectasia/terapia , Encéfalo/diagnóstico por imagem , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/fisiopatologia , Encefalopatias Metabólicas Congênitas/terapia , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/genética , Erros Inatos do Metabolismo dos Carboidratos/fisiopatologia , Erros Inatos do Metabolismo dos Carboidratos/terapia , Paralisia Cerebral/fisiopatologia , Coreia/fisiopatologia , Creatina/deficiência , Creatina/genética , Discinesias/diagnóstico , Discinesias/genética , Discinesias/fisiopatologia , Discinesias/terapia , Distonia/fisiopatologia , Deficiência de Ácido Fólico/diagnóstico , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/fisiopatologia , Deficiência de Ácido Fólico/terapia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Humanos , Hiperargininemia/diagnóstico , Hiperargininemia/genética , Hiperargininemia/fisiopatologia , Hiperargininemia/terapia , Síndrome de Lesch-Nyhan/diagnóstico , Síndrome de Lesch-Nyhan/genética , Síndrome de Lesch-Nyhan/fisiopatologia , Síndrome de Lesch-Nyhan/terapia , Imageamento por Ressonância Magnética , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Deficiência Intelectual Ligada ao Cromossomo X/terapia , Proteínas de Transporte de Monossacarídeos/deficiência , Proteínas de Transporte de Monossacarídeos/genética , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/fisiopatologia , Transtornos dos Movimentos/terapia , Deficiência Múltipla de Carboxilase/diagnóstico , Deficiência Múltipla de Carboxilase/genéticaRESUMO
Ataxia-telangiectasia is the second most common autosomal recessive hereditary ataxia, with an estimated incidence of 1 in 100,000 births. Besides ataxia and ocular telangiectasias, eye movement abnormalities have long been associated with this disorder and is frequently present in almost all patients. A handful of studies have described the phenomenology of ocular motor deficits in ataxia-telangiectasia. Contemporary literature linked their physiology to cerebellar dysfunction and secondary abnormalities at the level of brainstem. These studies, while providing a proof of concept of ocular motor physiology in disease, i.e., ataxia-telangiectasia, also advanced our understanding of how the cerebellum works. Here, we will summarize the clinical abnormalities seen with ataxia-telangiectasia in each subtype of eye movements and subsequently describe the underlying pathophysiology. Finally, we will review how these deficits are linked to abnormal cerebellar function and how it allows better understanding of the cerebellar physiology.
Assuntos
Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/fisiopatologia , Transtornos da Motilidade Ocular/etiologia , Transtornos da Motilidade Ocular/fisiopatologia , HumanosRESUMO
BACKGROUND: Inflammation plays a critical role in accelerating the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and ataxia telangiectasia (A-T). In A-T mouse models, LPS-induced neuroinflammation advances the degenerative changes found in cerebellar Purkinje neurons both in vivo and in vitro. In the current study, we ask whether ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), can have the opposite effect and delay the symptoms of the disease. METHODS: We tested the beneficial effects of ibuprofen in both in vitro and in vivo models. Conditioned medium from LPS stimulated primary microglia (LM) applied to cultures of dissociated cortical neurons leads to numerous degenerative changes. Pretreatment of the neurons with ibuprofen, however, blocked this damage. Systemic injection of LPS into either adult wild-type or adult Atm-/- mice produced an immune challenge that triggered profound behavioral, biochemical, and histological effects. We used a 2-week ibuprofen pretreatment regimen to investigate whether these LPS effects could be blocked. We also treated young presymptomatic Atm-/- mice to determine if ibuprofen could delay the appearance of symptoms. RESULTS: Adding ibuprofen directly to neuronal cultures significantly reduced LM-induced degeneration. Curiously, adding ibuprofen to the microglia cultures before the LPS challenge had little effect, thus implying a direct effect of the NSAID on the neuronal cultures. In vivo administration of ibuprofen to Atm-/- animals before a systemic LPS immune challenge suppressed cytological damage. The ibuprofen effects were widespread as microglial activation, p38 phosphorylation, DNA damage, and neuronal cell cycle reentry were all reduced. Unfortunately, ibuprofen only slightly improved the LPS-induced behavioral deficits. Yet, while the behavioral symptoms could not be reversed once they were established in adult Atm-/- animals, administration of ibuprofen to young mutant pups prevented their symptoms from appearing. CONCLUSION: Inflammatory processes impact the normal progression of A-T implying that modulation of the immune system can have therapeutic benefit for both the behavioral and cellular symptoms of this neurodegenerative disease.
Assuntos
Ataxia Telangiectasia/prevenção & controle , Ibuprofeno/farmacologia , Animais , Animais Recém-Nascidos , Anti-Inflamatórios não Esteroides/farmacologia , Ataxia Telangiectasia/induzido quimicamente , Ataxia Telangiectasia/fisiopatologia , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Proteínas Mutadas de Ataxia Telangiectasia/genética , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Nuclear factor (erythroid-derived 2)-like factor 2 (NFE2L2, formerly Nrf2) is a transcription factor that binds to the antioxidant response element (ARE) in the upstream promoter region of various antioxidant-responsive genes. Hence, at least in nonruminants, the NFE2L2-ARE signaling pathway plays an important role in the cellular antioxidant defense system. Whether oxidative stress in bovine mammary epithelial cells alters NFE2L2 or the NFE2L2-ARE pathway is unclear. Therefore, the objective of this study was to examine the response in NFE2L2- and NFE2L2-ARE-related components in bovine mammary epithelial cells (BMEC) under oxidative stress. An in silico analysis to identify potential phosphorylation sites on NFE2L2 and the protein kinases was performed with Netphos 3.1 (http://www.cbs.dtu.dk/services/NetPhos/) and Scansite (http://scansite.mit.edu) software. Isolated BMEC were exposed to H2O2 (600 µM) for 6 h to induce oxidative stress. In silico analysis revealed ataxia telangiectasia-mutated (ATM) serine/threonine kinase as a key kinase responsible for the phosphorylation of NFE2L2. Thus, after the 6 h incubation with H2O2, BMEC were transiently transfected with ATM-small interfering RNA (siRNA) 1, 2, or 3. Compared with the control, transfection with ATM-siRNA3 resulted in proliferation rates that were 60.7 and 36.2% lower with or without H2O2. In addition, production of reactive oxygen species and malondialdehyde increased markedly, but activities of superoxide dismutase, glutathione peroxidase, catalase, and glutathione-S-transferase decreased markedly in transfected cells without or with H2O2 compared with the control. Transfected cells had markedly lower protein and mRNA expression of NFE2L2 without or with H2O2 compared with the control. In addition, fluorescent activity of the ARE in transfected BMEC indicated that NFE2L2-driven transcriptional activation decreased under oxidative stress. Overall, results indicate that ATM is a physiologically relevant NFE2L2 kinase. Furthermore, inhibition of ATM activity can cause marked alterations in oxidative stress leading to cell death as a result of diminished capacity of BMEC to cope with H2O2-induced cytotoxicity. The relevance of this kinase in vivo merits further study.
Assuntos
Antioxidantes/metabolismo , Ataxia Telangiectasia/veterinária , Doenças dos Bovinos/enzimologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Serina-Treonina Quinases/genética , Ativação Transcricional , Animais , Elementos de Resposta Antioxidante/genética , Ataxia Telangiectasia/enzimologia , Ataxia Telangiectasia/fisiopatologia , Bovinos , Doenças dos Bovinos/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Feminino , Peróxido de Hidrogênio/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/fisiologia , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
The number of primary immune deficiencies exceeds 350, approximately a quarter of them having neurological implications. Severe central nervous system infections may occur in an even higher proportion. Beyond listing in a table of all diseases with a neurological impact, the author gives detailed analysis of one typical disorder. Ataxia telangiectasia is caused by biallelic mutation of the ATM gene resulting in genomic instability, increased cancer risk, immune deficiency and a predominantly cerebellar neurodegeneration. The most common classic form is characterized by gait and limb ataxia, oculomotor apraxia, choreoathetosis, disturbance of speech and swallowing, less often by other movement disorders. There is no remarkable cognitive deficit. Telangiectasia of the conjunctivae and skin usually appears after 6 years of age. Frequent, especially severe sino-pulmonary infections may indicate the immune deficiency present in 60 to 80% of patients, who are also prone to malignancies. The clinical course is sometimes atypical or has a late onset which results in diagnostic difficulties. Serum alpha-fetoprotein level is elevated in nearly all patients. Brain MRI shows progressive cerebellar atrophy starting at the age of 7-8 years. DNA testing of the ATM gene is necessary for the diagnosis. The detected biallelic pathogenic variants provide help for family planning and for possible gene therapies in the future. Ataxia telangiectasia has to be differentiated from a number of other disorders, some of which also belong to primary immune deficiencies. The disorder has no causal treatment at present, the patients live until their young adult ages. Orv Hetil. 2018; 159(49): 2057-2064.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/fisiopatologia , Síndromes de Imunodeficiência/fisiopatologia , Adulto , Criança , Feminino , Humanos , MasculinoRESUMO
The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia telangiectasia, mutated) are critical for the cellular response to DNA damage. ATM disruption causes ataxia telangiectasia (A-T), while MRN dysfunction can lead to A-T-like disease (ATLD) or Nijmegen breakage syndrome (NBS). Neuropathology is a hallmark of these diseases, whereby neurodegeneration occurs in A-T and ATLD while microcephaly characterizes NBS. To understand the contrasting neuropathology resulting from Mre11 or Nbs1 hypomorphic mutations, we analyzed neural tissue from Mre11(ATLD1/ATLD1) and Nbs1(DeltaB/DeltaB) mice after genotoxic stress. We found a pronounced resistance to DNA damage-induced apoptosis after ionizing radiation or DNA ligase IV (Lig4) loss in the Mre11(ATLD1/ATLD1) nervous system that was associated with defective Atm activation and phosphorylation of its substrates Chk2 and p53. Conversely, DNA damage-induced Atm phosphorylation was defective in Nbs1(DeltaB/DeltaB) neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4(Nes-Cre)), and while viable, these mice showed pronounced microcephaly and a prominent age-related accumulation of DNA damage throughout the brain. Either Atm-/- or Mre11(ATLD1/ATLD1) genetic backgrounds, but not Nbs1(DeltaB/DeltaB), rescued Lig4(Nes-Cre) microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology.
Assuntos
Apoptose , Ataxia Telangiectasia/fisiopatologia , Dano ao DNA/fisiologia , Neurônios/fisiologia , Síndrome de Quebra de Nijmegen/fisiopatologia , Transdução de Sinais/genética , Animais , Apoptose/efeitos da radiação , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia , Encéfalo/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA/genética , DNA Ligase Dependente de ATP , DNA Ligases/metabolismo , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática/fisiologia , Feminino , Proteína Homóloga a MRE11 , Masculino , Camundongos , Camundongos Transgênicos , Microcefalia/patologia , Mutação , Neurônios/citologia , Neurônios/efeitos da radiação , Síndrome de Quebra de Nijmegen/genética , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Radiação Ionizante , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
OBJECTIVE: To evaluate the potential link between systemic inflammation and impaired lung function in people with ataxia-telangiectasia (A-T), we hypothesized that serum levels of interleukin (IL)-6, a proinflammatory cytokine, would correlate inversely with lung function in subjects with A-T. STUDY DESIGN: Consecutive subjects with A-T were recruited from the Johns Hopkins Outpatient A-T Clinical Center. Serum levels of IL-6 and 8 were measured by enzyme-linked immunosorbent assay. Spirometry was performed in subjects ≥ 6 years of age on the same day that serum was obtained for measurements of cytokines. RESULTS: Approximately 80% of subjects had elevated serum IL-6 levels (> 1.0 pg/mL). No association was found between elevated IL-6 and age. Elevated IL-8 levels were found in 23.6% of subjects, and all subjects with elevated IL-8 levels had elevated IL-6 levels. Subjects with elevated IL-6 levels (mean: 6.14 ± 7.47 pg/mL) had significantly lower mean percent forced vital capacity (FVC%, 50.5% ± 17.8%) compared with subjects with normal serum IL-6 levels (FVC% of 66.2 ± 16.1, P = .018). Greater IL-6 levels were associated with lower FVC% even after adjustment for receiving gamma globulin therapy (P = .024) and supplemental nutrition (P = .055). CONCLUSIONS: An association was found between elevated serum IL-6 levels and lower lung function in subjects with A-T. In addition, subjects with both elevated IL-6 and IL-8 had the lowest mean lung function. These findings indicate that markers for systemic inflammation may be useful in identifying individuals with A-T at increased risk for lower lung function and may help in assessing response to therapy.
Assuntos
Ataxia Telangiectasia/sangue , Ataxia Telangiectasia/fisiopatologia , Interleucina-6/sangue , Testes de Função Respiratória , Adolescente , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Inflamação , Interleucina-8/sangue , Masculino , Fenótipo , Espirometria , Adulto JovemRESUMO
BACKGROUND: Ataxia telangiectasia (AT) is a genetic multisystem disorder, presenting with progressive ataxia, immune deficiency, and propensity toward malignancy. Endocrine abnormalities (growth retardation, reproductive dysfunction, and diabetes) have been described, however detailed information regarding this aspect is lacking. We aimed to characterize endocrine anomalies and growth patterns in a large cohort of AT patients. METHODS: Retrospective study comprising all 52 patients (aged 2-26.2 y) followed at a national AT Clinic. Anthropometric and laboratory measurements were extracted from the charts. RESULTS: Median height-SDS was already subnormal during infancy, remaining negative throughout follow up to adulthood. Height-SDS was more impaired than weight-SDS up to age 4 y, thereafter weight-SDS steadily decreased, resulting in progressively lower BMI-SDS. IGF-I-SDS was low (-1.53 ± 1.54), but did not correlate with height-SDS. Gonadal failure was present in all 13 females older than 10 y but only in one male. Two patients had diabetes and 10 had dyslipidemia. Vitamin D deficiency was observed in 52.2% of the evaluated patients. CONCLUSION: Our results suggest a primary growth abnormality in AT, rather than secondary to nutritional impairment or disease severity. Sex hormone replacement should be considered for female patients. Vitamin D levels should be followed and supplementation given if needed.
Assuntos
Ataxia Telangiectasia/fisiopatologia , Estatura , Peso Corporal , Sistema Endócrino/fisiopatologia , Adolescente , Adulto , Antropometria , Ataxia Telangiectasia/complicações , Glicemia/metabolismo , Criança , Pré-Escolar , Estudos Transversais , Dislipidemias/complicações , Feminino , Transtornos do Crescimento , Humanos , Sistema Imunitário , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Estudos Retrospectivos , Deficiência de Vitamina D/complicações , Adulto JovemRESUMO
OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. METHODS: A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. RESULTS: Fifty-three patients, 27 (49%) boys, age 14.6â±â5.2 years (range 5.9-26.1 years), were included. Twenty-three patients (43.4%), age 9.9â±â5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8â±â73.8âIU/L, aspartate aminotransferase 70â±â50âIU/L, alkaline phosphatase 331â±â134âIU/L, and gamma glutamyl transferase 114.7â±â8âIU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (Pâ<â0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. CONCLUSIONS: Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease.
Assuntos
Ataxia Telangiectasia/fisiopatologia , Hepatopatias/etiologia , Fígado/fisiopatologia , Adolescente , Adulto , Ataxia Telangiectasia/sangue , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Biópsia , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Dislipidemias/etiologia , Feminino , Seguimentos , Humanos , Israel/epidemiologia , Fígado/diagnóstico por imagem , Fígado/patologia , Hepatopatias/diagnóstico por imagem , Hepatopatias/epidemiologia , Hepatopatias/fisiopatologia , Masculino , Mutação , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/etiologia , Prevalência , Estudos Retrospectivos , Ultrassonografia , Adulto JovemRESUMO
OBJECTIVES: Ataxia-Telangiectasia (A-T) individuals often present with respiratory muscle weakness, causing recurrent respiratory system infections, asthma-like symptoms, and chronic cough life-threatening events. The cough flow volume maneuver may reveal powerless airflow needed for efficient cough. The study aims to explore cough ability in relation to the flow/volume maneuver. METHODS: Data collected retrospectively from clinical charts of 35 A-T patients (age 12.7 ± 4.9 years) included forced expiratory and cough flow/volume maneuvers performed on the same day. Analysis compared among the maneuvers matching indices, numbers of cough-spikes, flow rate decay, and the reference data of similar ages. Adjusted to age, BMI, and number of hospitalizations prior to the tests, values were correlated with the cough indices. RESULTS: Cough peak-flow (C-PF) was propagated within 90 ± 20 ms compared with peak expiratory flow (PEF > 200 ms). C-PF measured values were higher than expiratory peak-flow measured values (3.27 ± 1.53 L/s versus 3.02 ± 1.52 L/s, respectively, but C-PF (%predicted) values were significantly lower than expiratory peak-flow (%predicted) (46 ± 15 versus 68 ± 20 %predicted, respectively, p < 0.002). The number of spikes/maneuver was low when compared with reference (2.0 ± 0.8 versus 6-12 spikes) and cough vital-capacity was lower than expiratory vital capacity (0.95 ± 0.43 versus 1.03 ± 0.47; p < 0.01). Inefficient C-PF was more prevalent in patients suffering from recurrent respiratory illness. The length of wheelchair confinement duration mostly influenced the C-VC level. CONCLUSIONS: The cough flow-volume curve can be applied as a method to follow cough ability in patients with A-T who showed a significantly reduced cough capacity. Further studies are needed to establish if the findings may aid decisions regarding cough assistance.
Assuntos
Ataxia Telangiectasia/fisiopatologia , Tosse/fisiopatologia , Adolescente , Criança , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pico do Fluxo Expiratório , Capacidade VitalRESUMO
AIM: To assess the relationship between genotype and neurological progression in ataxia-telangiectasia (A-T). METHODS: Clinical and laboratory data were extracted retrospectively from the records of patients attending the UK National Ataxia-Telangiectasia Clinic. Neurological assessments were performed using the A-T Index (Crawford Score) and the A-T Neurological Examination Scale Toolkit (A-T NEST). Variables influencing phenotype were identified by using an information-theoretic approach starting from a maximal model to generate estimates of coefficients for each variable. Per-individual progression was assessed for patients with three or more clinic attendances. RESULTS: The genotype could be determined for 125/135 patients. Crawford and A-T NEST scores were well correlated. For both scoring systems the estimated coefficients were significantly positive for Age x kinase activity but not Age x protein expression. Unlike the per-genotype analysis, the individual progression of neurological scores in the 34 patients that attended on three or more occasions was not smooth and linear (and in some cases improved over time). INTERPRETATION: Residual kinase activity confers a milder phenotype but there is no difference between kinase-dead and protein-null genotypes. The non-linear progression of individual patients' neurological scores may reflect biological complexity, day-to-day variability, limitations of the assessment methods or a combination of all three.
Assuntos
Ataxia Telangiectasia/genética , Ataxia Telangiectasia/fisiopatologia , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fatores Etários , Ataxia Telangiectasia/enzimologia , Criança , Progressão da Doença , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Estudos Longitudinais , Masculino , Exame Neurológico , Fenótipo , Estudos Retrospectivos , Estatística como Assunto , Estatísticas não Paramétricas , Reino UnidoRESUMO
ATM is a master regulator of the cellular response to DNA damage. The classical mechanism of ATM activation involves its monomerization in response to DNA double-strand breaks, resulting in ATM-dependent phosphorylation of more than a thousand substrates required for cell cycle progression, DNA repair, and apoptosis. Here, new experimental evidence for non-canonical mechanisms of ATM activation in response to stimuli distinct from DNA double-strand breaks is discussed. It includes cytoskeletal changes, chromatin modifications, RNA-DNA hybrids, and DNA single-strand breaks. Noncanonical ATM activation may be important for the pathology of the multisystemic disease Ataxia Telangiectasia.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Reparo do DNA , Animais , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/fisiopatologia , DNA/metabolismo , DNA de Cadeia Simples/metabolismo , Ativação Enzimática , Humanos , RNA/metabolismoRESUMO
The autosomal recessive disorder ataxia-telangiectasia (A-T) is characterized by genome instability, cancer predisposition and neurodegeneration. Although the role of ataxia-telangiectasia mutated (ATM) protein, the protein defective in this syndrome, is well described in the response to DNA damage, its role in protecting the nervous system is less clear. We describe the establishment and characterization of patient-specific stem cells that have the potential to address this shortcoming. Olfactory neurosphere (ONS)-derived cells were generated from A-T patients, which expressed stem cell markers and exhibited A-T molecular and cellular characteristics that included hypersensitivity to radiation, defective radiation-induced signaling and cell cycle checkpoint defects. Introduction of full-length ATM cDNA into these cells corrected defects in the A-T cellular phenotype. Gene expression profiling and pathway analysis revealed defects in multiple cell signaling pathways associated with ATM function, with cell cycle, cell death and DNA damage response pathways being the most significantly dysregulated. A-T ONS cells were also capable of differentiating into neural progenitors, but they were defective in neurite formation, number of neurites and length of these neurites. Thus, ONS cells are a patient-derived neural stem cell model that recapitulate the phenotype of A-T, do not require genetic reprogramming, have the capacity to differentiate into neurons and have potential to delineate the neurological defect in these patients.
Assuntos
Ataxia Telangiectasia/fisiopatologia , Neurônios/citologia , Condutos Olfatórios/citologia , Células-Tronco/citologia , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/patologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Diferenciação Celular , Células Cultivadas , Criança , Feminino , Humanos , Lactente , Masculino , Modelos Biológicos , Mucosa , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Células-Tronco/metabolismo , Células-Tronco/patologiaRESUMO
DNA double-strand breaks (DSBs) can lead to instability of the genome if not repaired correctly. The MRE11/RAD50/NBS1 (MRN) complex binds DSBs and initiates damage-induced signaling cascades via activation of the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia- and rad3-related (ATR) kinases. Mutations throughout MRE11 cause ataxia-telangiectasia-like disorder (ATLD) featuring cerebellar degeneration, and cancer-predisposition in certain kindreds. Here, we have examined the impact on DNA damage signaling of several disease-associated MRE11A alleles to gain greater understanding of the mechanisms underlying the diverse disease sequelae of ATLD. To this end, we have designed a system whereby endogenous wild-type Mre11a is conditionally deleted and disease-associated MRE11 mutants are stably expressed at physiologic levels. We find that mutations in the highly conserved N-terminal domain impact ATM signaling by perturbing both MRE11 interaction with NBS1 and MRE11 homodimerization. In contrast, an inherited allele in the MRE11 C-terminus maintains MRN interactions and ATM/ATR kinase activation. These findings reveal that ATLD patients have reduced ATM activation resulting from at least two distinct mechanisms: (i) N-terminal mutations destabilize MRN interactions, and (ii) mutation of the extreme C-terminus maintains interactions but leads to low levels of the complex. The N-terminal mutations were found in ATLD patients with childhood cancer; thus, our studies suggest a clinically relevant dichotomy in MRE11A alleles. More broadly, these studies underscore the importance of understanding specific effects of hypomorphic disease-associated mutations to achieve accurate prognosis and appropriate long-term medical surveillance.
Assuntos
Ataxia Telangiectasia/genética , Proteínas de Ligação a DNA/genética , Neoplasias/genética , Degenerações Espinocerebelares/genética , Alelos , Ataxia Telangiectasia/etiologia , Ataxia Telangiectasia/fisiopatologia , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , Predisposição Genética para Doença , Instabilidade Genômica , Humanos , Proteína Homóloga a MRE11 , Mutação , Neoplasias/etiologia , Neoplasias/patologia , Transdução de Sinais , Degenerações Espinocerebelares/fisiopatologiaRESUMO
BACKGROUND AND AIMS: Evaluate the nutritional status, plasma concentration of vitamin E and markers of cardiovascular risk in ataxia telangiectasia (AT) patients. METHODS: Cross-sectional study with 13 patients with AT and 22 healthy controls, evaluating the following factors: nutritional status, food intake, lipid profile, plasma concentration of vitamin E, malondialdehyde and high sensitivity C-reactive protein, linking them with atherosclerosis risk in AT patients. RESULTS: Average age was 14.6 in the AT group, 30.8% were malnourished and 23.1% had stunting. A greater impairment of lean body mass was found in these patients. Concentrations of triglycerides (TG), total cholesterol (CT), LDL-c, non-HDL cholesterol (NHDL-c) were significantly higher in patients and HDL-c, lower. Vitamin E/total lipids and vitamin E/TG ratios were lower in the AT group, and significant inverse correlation between these ratios and NHDL-c, CT/HDL-c, and LDL-c/HDL-c, log TG/HDL-c was observed in the AT group. Alanine aminotransferase correlated directly and significantly with NHDL-c, CT/HDL-c and LDL-c/HDL-c, in patients. CONCLUSION: The alterations of lipid metabolism biomarkers suggestive of atherosclerotic risk of male AT patients coupled with lower vitamin E/total lipids ratio and low lean body mass may complicate the clinical course of the disease and emphasizes the importance of multidisciplinary care, routine monitoring of cardiovascular biomarkers and appropriate nutritional guidance.
Assuntos
Ataxia Telangiectasia/fisiopatologia , Aterosclerose/etiologia , Dislipidemias/complicações , Transtornos do Crescimento/complicações , Estresse Oxidativo , Magreza/complicações , Deficiência de Vitamina E/complicações , Adolescente , Adulto , Ataxia Telangiectasia/sangue , Ataxia Telangiectasia/complicações , Aterosclerose/epidemiologia , Biomarcadores/sangue , Índice de Massa Corporal , Brasil/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Dislipidemias/epidemiologia , Feminino , Transtornos do Crescimento/epidemiologia , Humanos , Peroxidação de Lipídeos , Masculino , Prontuários Médicos , Prevalência , Risco , Fatores Sexuais , Magreza/epidemiologia , Deficiência de Vitamina E/epidemiologia , Adulto JovemRESUMO
Ataxia-telangiectasia mutated (ATM) plays a central role in DNA damage responses, and its loss leads to development of T-cell malignancies. Here, we show that ATM loss also leads to intrinsic mitochondrial abnormalities in thymocytes, including elevated reactive oxygen species, increased aberrant mitochondria, high cellular respiratory capacity, and decreased mitophagy. A fraction of ATM protein is localized in mitochondria, and it is rapidly activated by mitochondrial dysfunction. Unexpectedly, allelic loss of the autophagy regulator Beclin-1 significantly delayed tumor development in ATM-null mice. This effect was not associated with rescue of DNA damage signaling but rather with a significant reversal of the mitochondrial abnormalities. These data support a model in which ATM plays direct roles in modulating mitochondrial homeostasis and suggest that mitochondrial dysfunction and associated increases in mitochondrial reactive oxygen species contribute to the cancer-prone phenotype observed in organisms lacking ATM. Thus, ataxia-telangiectasia should be considered, at least in part, as a mitochondrial disease.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Mitocôndrias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/fisiopatologia , Proteínas Mutadas de Ataxia Telangiectasia , Autofagia , Proteína Beclina-1 , Proteínas de Ciclo Celular/genética , Células Cultivadas , Proteínas de Ligação a DNA/genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Expressão Gênica , Humanos , Immunoblotting , Estimativa de Kaplan-Meier , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Potencial da Membrana Mitocondrial , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias/genética , Mitocôndrias/fisiologia , Consumo de Oxigênio , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Timócitos/metabolismo , Timócitos/ultraestrutura , Proteínas Supressoras de Tumor/genéticaRESUMO
The human genetic disorder ataxia telangiectasia (A-T) is characterised by neurodegeneration, immunodeficiency, radiosensitivity, cell cycle checkpoint defects, genomic instability and cancer predisposition. Progressive cerebellar ataxia represents the most debilitating aspect of this disorder. At present, there is no therapy available to cure or prevent the progressive symptoms of A-T. While it is possible to alleviate some of the symptoms associated with immunodeficiency and deficient lung function, neither the predisposition to cancer nor the progressive neurodegeneration can be prevented. Significant effort has focused on improving our understanding of various clinical, genetic and immunological aspects of A-T; however, little attention has been directed towards identifying altered brain structure and function using MRI. To date, most imaging studies have reported radiological anomalies in A-T. This review outlines the clinical and biological features of A-T along with known radiological imaging anomalies. In addition, we briefly discuss the advent of high-resolution MRI in conjunction with diffusion-weighted imaging, which enables improved investigation of the microstructural tissue environment, giving insight into the loss in integrity of motor networks due to abnormal neurodevelopmental or progressive neurodegenerative processes. Such imaging approaches have yet to be applied in the study of A-T and could provide important new information regarding the relationship between mutation of the ataxia telangiectasia mutated (ATM) gene and the integrity of motor circuitry.