-
Respiratory Medicine Jul 2015Forced vital capacity (FVC) values decrease with progress of the disease in Ataxia telangiectasia (AT).
RATIONALE
Forced vital capacity (FVC) values decrease with progress of the disease in Ataxia telangiectasia (AT).
OBJECTIVE
To study the effect of this process on airway obstruction determination and life span in AT.
METHODS
Clinical data and yearly best spirometry maneuvers were collected retrospectively from 37 AT patients (196 spirometry tests) during 5.4 ± 1.8yrs (initial age 4-21 y). Twelve patients were walking (7 of them had recurrent respiratory system infections); 25 subjects were confined to wheelchair, of them 8 patients were towards end-stage lung disease. Spirometry indices included Forced Vital Capacity (FVC), mid-expiratory-flow (FEF25-75), and tidal volume (VT). We calculated FEF25-75/FVC and VT/FVC ratios.
RESULTS
FVC declined from 67 ± 8 while walking to 19 ± 6 %predicted values. FEF25-75 values that were elevated (116 ± 23 %predicted) while walking, decreased to 69 ± 27 %predicted at end-stage where 7 patients responded to bronchodilators. VT/FVC ratio was 0.25 ± 0.06 while walking, increased to 0.35 once on wheelchairs, and further increased to 0.57 ± 0.19 at end-stage disease. FEF25-75/FVC ratio was 2.54 ± 0.70 above normal (∼1.0) increasing to 4.16 ± 0.75 at end stage. A sharp elevation was seen in FEF25-75/FVC ratio when FEV1 was still ∼45 %predicted and 2-years prior to death.
CONCLUSIONS
Having a low baseline-FVC (60% predicted) artificially raises FEF25-75 values, so FEF25-75 of "mild obstruction" values may indicate severe airway obstruction in AT subjects. VT/FVC and FEF25-75/FVC ratios may therefore assist in revealing higher than normal breathing effort. The results further suggest adding VT/FVC and FEF25-75/FVC ratios to pulmonary function assessments in patients with AT.
Topics: Adolescent; Airway Obstruction; Ataxia Telangiectasia; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Lung; Male; Maximal Midexpiratory Flow Rate; Retrospective Studies; Vital Capacity; Young Adult
PubMed: 26033643
DOI: 10.1016/j.rmed.2015.05.013 -
AJNR. American Journal of Neuroradiology Jan 2014Ataxia-telangiectasia, an autosomal recessive disorder caused by defect of the ataxia-telangiectasia mutated gene, is characterized by progressive neurologic impairment...
Ataxia-telangiectasia, an autosomal recessive disorder caused by defect of the ataxia-telangiectasia mutated gene, is characterized by progressive neurologic impairment with cerebellar atrophy, ocular and cutaneous telangiectasia, immunodeficiency, heightened sensitivity to ionizing radiation and susceptibility to developing lymphoreticular malignancy. Supratentorial brain abnormalities have been reported only rarely. In this study, brain MRI was performed in 10 adults with ataxia-telangiectasia having stable neurologic impairment. Intracerebral telangiectasia with multiple punctate hemosiderin deposits were identified in 60% of subjects. These lesions were apparently asymptomatic. They are similar in appearance to radiation-induced telangiectasia and to cryptogenic vascular malformations. Also noted, in the 2 oldest subjects, was extensive white matter T2 hyperintensity, and in 1 of these a space-occupying fluid collection consistent with transudative capillary leak and edema as evidenced by reduced levels of metabolites on MR spectroscopic imaging. Asymptomatic supratentorial vascular abnormalities appear to be common in adults with ataxia-telangiectasia.
Topics: Adult; Ataxia Telangiectasia; Brain Edema; Central Nervous System Vascular Malformations; Female; Humans; Magnetic Resonance Imaging; Male; Reproducibility of Results; Sensitivity and Specificity; Young Adult
PubMed: 23886747
DOI: 10.3174/ajnr.A3646 -
Proceedings of the Royal Society of... May 1970
Topics: Adult; Ataxia Telangiectasia; Female; Humans; Intelligence
PubMed: 5453421
DOI: No ID Found -
Scientific Reports Jan 2019Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR)....
Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to ATM loss remains unclear. In this study we assessed on human iPSC-derived neurons whether the abnormal accumulation of DNA-Topoisomerase 1 adducts (Top1ccs) found in A-T impairs transcription elongation, thus favoring neurodegeneration. Furthermore, whether neuronal activity-induced immediate early genes (IEGs), a process involving the formation of DNA breaks, is affected by ATM deficiency. We found that Top1cc trapping by CPT induces an ATM-dependent DDR as well as an ATM-independent induction of IEGs and repression especially of long genes. As revealed by nascent RNA sequencing, transcriptional elongation and recovery were found to proceed with the same rate, irrespective of gene length and ATM status. Neuronal activity induced by glutamate receptors stimulation, or membrane depolarization with KCl, triggered a DDR and expression of IEGs, the latter independent of ATM. In unperturbed A-T neurons a set of genes (FN1, DCN, RASGRF1, FZD1, EOMES, SHH, NR2E1) implicated in the development, maintenance and physiology of central nervous system was specifically downregulated, underscoring their potential involvement in the neurodegenerative process in A-T patients.
Topics: Ataxia Telangiectasia; DNA Damage; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells; Male; Neurons; Transcription, Genetic
PubMed: 30679601
DOI: 10.1038/s41598-018-36912-0 -
Frontiers in Immunology 2019Ataxia-telangiectasia (A-T) is a multisystem disorder with progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and increased cancer... (Clinical Trial)
Clinical Trial
Ataxia-telangiectasia (A-T) is a multisystem disorder with progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and increased cancer susceptibility. Cellular immunodeficiency is based on naïve CD4 and CD8 T-cell lymphopenia. Hematopoietic stem cell transplantation (HSCT) offers a potential to cure immunodeficiency and cancer due to restoration of the lymphopoietic system. The aim of this investigation was to analyze the effect of HSCT on naïve CD4 as well as CD8 T-cell numbers in A-T. We analyzed total numbers of peripheral naïve (CD45RACD62L) and memory (CD45ROCD62L) CD4 and CD8 T-cells of 32 A-T patients. Naïve (CD62LCD44) and memory (CD62LCD44) T-cells were also measured in Atm-deficient mice before and after HSCT with GFP-expressing bone marrow derived hematopoietic stem cells. In addition, we analyzed T-cells in the peripheral blood of two A-T patients after HLA-identic allogeneic HSCT. Like in humans, naïve CD4 as well as naïve CD8 lymphocytes were decreased in -deficient mice. HSCT significantly inhibited thymic lymphomas and increased survival time in these animals. Donor cell chimerism increased up to more than 50% 6 months after HSCT accompanied by a significant increase of naïve CD4 and CD8 T-cell subpopulations, but not of memory T-cells. This finding was also identified in the blood of the A-T patients after HSCT. HSCT seems to be a feasible strategy to overcome immunodeficiency and might be a conceivable strategy to avoid T-cell driven cancer in A-T at higher risk for malignancy. Naïve CD4 and CD8 T-cells counts are suitable markers for monitoring immune reconstitution post-HSCT. However, risks and benefits of HSCT in A-T have to be properly weighted.
Topics: Adolescent; Adult; Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Immune Reconstitution; Immunologic Memory; Lymphocyte Count; Male; Mice; Mice, Knockout; Young Adult
PubMed: 31849966
DOI: 10.3389/fimmu.2019.02785 -
Frontiers in Immunology 2022Ataxia-telangiectasia (A-T) is a neurodegenerative and primary immunodeficiency disorder (PID) characterized by cerebellar ataxia, oculocutaneous telangiectasia,...
Ataxia-telangiectasia (A-T) is a neurodegenerative and primary immunodeficiency disorder (PID) characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classical ataxia-telangiectasia (classical A-T) phenotype, a variant phenotype (variant A-T) exists with partly overlapping but some distinctive disease characteristics. Here we present a case series of 6 patients with classical A-T and variant A-T, which illustrates the phenotypic variability of A-T that can present in childhood with prominent extrapyramidal features, with or without cerebellar ataxia. We report the clinical data, together with a detailed genotype description, immunological analyses, and related expression of the ATM protein. We show that the presence of some residual ATM kinase activity leads to the clinical phenotype variant A-T that differs from the classical A-T. Our data illustrate that the diagnosis of the variant form of A-T can be delayed and difficult, while early recognition of the variant form as well as the classical A-T is a prerequisite for providing a correct prognosis and appropriate rehabilitation and support, including the avoidance of diagnostic X-ray procedures, given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment.
Topics: Adolescent; Adult; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Child; Child, Preschool; Cross-Sectional Studies; Delayed Diagnosis; Diagnosis, Differential; Female; Genetic Testing; Genotype; Humans; Male; Movement Disorders; Mutation; Neurodegenerative Diseases; Phenotype; Retrospective Studies; Young Adult
PubMed: 35154108
DOI: 10.3389/fimmu.2022.791522 -
Frontiers in Immunology 2021DNA damage occurs constantly in every cell triggered by endogenous processes of replication and metabolism, and external influences such as ionizing radiation and... (Comparative Study)
Comparative Study
DNA damage occurs constantly in every cell triggered by endogenous processes of replication and metabolism, and external influences such as ionizing radiation and intercalating chemicals. Large sets of proteins are involved in sensing, stabilizing and repairing this damage including control of cell cycle and proliferation. Some of these factors are phosphorylated upon activation and can be used as biomarkers of DNA damage response (DDR) by flow and mass cytometry. Differential survival rates of lymphocyte subsets in response to DNA damage are well established, characterizing NK cells as most resistant and B cells as most sensitive to DNA damage. We investigated DDR to low dose gamma radiation (2Gy) in peripheral blood lymphocytes of 26 healthy donors and 3 patients with ataxia telangiectasia (AT) using mass cytometry. γH2AX, p-CHK2, p-ATM and p53 were analyzed as specific DDR biomarkers for functional readouts of DNA repair efficiency in combination with cell cycle and T, B and NK cell populations characterized by 20 surface markers. We identified significant differences in DDR among lymphocyte populations in healthy individuals. Whereas CD56CD16 NK cells showed a strong γH2AX response to low dose ionizing radiation, a reduced response rate could be observed in CD19CD20 B cells that was associated with reduced survival. Interestingly, γH2AX induction level correlated inversely with ATM-dependent p-CHK2 and p53 responses. Differential DDR could be further noticed in naïve compared to memory T and B cell subsets, characterized by reduced γH2AX, but increased p53 induction in naïve T cells. In contrast, DDR was abrogated in all lymphocyte populations of AT patients. Our results demonstrate differential DDR capacities in lymphocyte subsets that depend on maturation and correlate inversely with DNA damage-related survival. Importantly, DDR analysis of peripheral blood cells for diagnostic purposes should be stratified to lymphocyte subsets.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Biomarkers; Case-Control Studies; Cell Cycle; Cell Proliferation; Cell Survival; Cells, Cultured; Checkpoint Kinase 2; DNA Damage; Flow Cytometry; Histones; Humans; Lymphocyte Subsets; Phenotype; Phosphorylation; Tumor Suppressor Protein p53
PubMed: 34594342
DOI: 10.3389/fimmu.2021.739675 -
Scientific Reports Jun 2014Ataxia telangiectasia is a neurodegenerative inherited disease with chromosomal instability and hypersensitivity to ionizing radiation. iPS cells lacking ATM (AT-iPS...
Ataxia telangiectasia is a neurodegenerative inherited disease with chromosomal instability and hypersensitivity to ionizing radiation. iPS cells lacking ATM (AT-iPS cells) exhibited hypersensitivity to X-ray irradiation, one of the characteristics of the disease. While parental ataxia telangiectasia cells exhibited significant chromosomal abnormalities, AT-iPS cells did not show any chromosomal instability in vitro for at least 80 passages (560 days). Whole exome analysis also showed a comparable nucleotide substitution rate in AT-iPS cells. Taken together, these data show that ATM is involved in protection from irradiation-induced cell death.
Topics: Animals; Apoptosis; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Blotting, Western; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cellular Reprogramming; Child; Chromosomal Instability; Exome; Fluorescent Antibody Technique; High-Throughput Nucleotide Sequencing; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Induced Pluripotent Stem Cells; Karyotyping; Male; Mice; Mice, Inbred NOD; Mice, SCID; RNA, Messenger; Radiation Tolerance; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Teratoma; X-Rays
PubMed: 24970375
DOI: 10.1038/srep05421 -
Developmental Medicine and Child... Oct 2016This cross-sectional investigation aimed to assess the value of non-invasive measures of temporal respiratory-swallow coupling in individuals with ataxic swallowing.
AIM
This cross-sectional investigation aimed to assess the value of non-invasive measures of temporal respiratory-swallow coupling in individuals with ataxic swallowing.
METHOD
Twenty participants (11 males, 9 females; range 9-21y) with ataxia telangiectasia were presented with water and pudding boluses. Their 193 swallows were compared with 2200 swallows from 82 age-matched healthy controls. The two components of airway protection during swallowing that were analyzed were: direction of peri-deglutitive airflow and duration of deglutitive inhibition of respiratory airflow (DIORA).
RESULTS
Safe expiratory patterns of peri-deglutitive airflow occurred significantly less often in participants with ataxia telangiectasia than in age-matched control participants (younger p<0.015 and older p<0.001). The frequency of an expiratory pattern of peri-deglutitive airflow increased with age in participants in the comparison group (p=0.006), but not in those with ataxia telangiectasia (p=0.234). With age, mean duration of DIORA decreased in controls (p<0.001) but was unchanged in participants with ataxia telangiectasia (p=0.164).
INTERPRETATION
Non-invasive quantitative measures of respiratory-swallow coupling capture temporal relationships that plausibly contribute to airway compromise from dysphagia. Changes in respiratory-swallow coupling observed with advancing age in control participants were not seen in participants with ataxia telangiectasia. Measures of perturbations may herald swallowing problems prior to development of pulmonary and nutritional sequelae.
Topics: Adolescent; Adult; Ataxia Telangiectasia; Child; Cross-Sectional Studies; Deglutition Disorders; Female; Humans; Male; Pulmonary Ventilation; Respiration; Young Adult
PubMed: 27214374
DOI: 10.1111/dmcn.13156 -
Journal of Neurology, Neurosurgery, and... Aug 2009Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterised by progressive neurological deficits, including prominent ocular motor dysfunction. Unstable...
BACKGROUND AND AIMS
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterised by progressive neurological deficits, including prominent ocular motor dysfunction. Unstable fixation often leads to difficulty reading and blurred vision. Here we characterise the disturbance of visual fixation in A-T.
METHODS
Eye movements were recorded from 13 A-T patients (with dual search coils in five patients and video oculography in seven) during attempted fixation.
RESULTS
Two abnormalities--nystagmus and saccadic intrusions--were common. Horizontal, vertical and torsional nystagmus was present in straight ahead (spontaneous nystagmus) and eccentric gaze (gaze evoked nystagmus). In eight patients the horizontal nystagmus changed directions--periodic alternating nystagmus (PAN). Two types of saccadic intrusions were seen--micro-saccadic oscillations (SO) and square wave saccadic intrusions (SWSI). SO were small amplitude (0.1-0.9 degrees) and high frequency (14-33 Hz) back to back horizontal saccades. SWSI ranged between 1 degree and 18 degrees (median 3 degrees) with an intersaccadic interval ranging between 50 and 800 ms (median 300 ms). The potential impact of abnormal gaze stabilisation on vision was quantified.
DISCUSSION
Degeneration of cerebellar Purkinje neurons disinhibit the caudal fastigial oculomotor region (FOR) and vestibular nuclei (VN). Disinhibition of VN can cause nystagmus, including PAN, while disinhibition of FOR can affect saccade generating mechanisms, leading to SWSI and SO.
Topics: Adolescent; Adult; Ataxia Telangiectasia; Data Interpretation, Statistical; Electrophysiology; Eye Movements; Female; Fixation, Ocular; Humans; Male; Middle Aged; Nystagmus, Optokinetic; Purkinje Fibers; Saccades; Tremor; Young Adult
PubMed: 19357126
DOI: 10.1136/jnnp.2008.170522