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NeuroImage. Clinical 2020Ataxia Telangiectasia (A-T) is an inherited multisystem disorder with cerebellar neurodegeneration. The relationships between imaging metrics of cerebellar health and... (Observational Study)
Observational Study
BACKGROUND
Ataxia Telangiectasia (A-T) is an inherited multisystem disorder with cerebellar neurodegeneration. The relationships between imaging metrics of cerebellar health and neurological function across childhood in A-T are unknown, but may be important for determining timing and impact of therapeutic interventions.
PURPOSE
To test the hypothesis that abnormalities of cerebellar structure, physiology and cellular health occur in childhood A-T and correlate with neurological disability, we performed multiparametric cerebellar MRI and establish associations with disease status in childhood A-T.
METHODS
Prospective cross-sectional observational study. 22 young people (9 females / 13 males, age 6.6-17.8 years) with A-T and 24 matched healthy controls underwent 3-Tesla MRI with volumetric, diffusion and proton spectroscopic acquisitions. Participants with A-T underwent structured neurological assessment, and expression / activity of ataxia-telangiectasia mutated (ATM) kinase were recorded.
RESULTS
Ataxia-telangiectasia participants had cerebellar volume loss (fractional total cerebellar volume: 5.3% vs 8.7%, P < 0.0005, fractional 4th ventricular volumes: 0.19% vs 0.13%, P < 0.0005), that progressed with age (fractional cerebellar volumes, r = -0.66, P = 0.001), different from the control group (t = -4.88, P < 0.0005). The relationship between cerebellar volume and age was similar for A-T participants with absent ATM kinase production and those producing non-functioning ATM kinase. Markers of cerebellar white matter injury were elevated in ataxia-telangiectasia vs controls (apparent diffusion coefficient: 0.89 × 10 mm s vs 0.69 × 10 mm s, p < 0.0005) and correlated (age-corrected) with neurometabolite ratios indicating impaired neuronal viability (N-acetylaspartate:creatine r = -0.70, P < 0.001); gliosis (inositol:creatine r = 0.50, P = 0.018; combined glutamine/glutamate:creatine r = -0.55, P = 0.008) and increased myelin turnover (choline:creatine r = 0.68, P < 0.001). Fractional 4th ventricular volume was the only variable retained in the regression model predicting neurological function (adjusted r = 0.29, P = 0.015).
CONCLUSIONS
Quantitative MRI demonstrates cerebellar abnormalities in children with A-T, providing non-invasive measures of progressive cerebellar injury and markers reflecting neurological status. These MRI metrics may be of value in determining timing and impact of interventions aimed at altering the natural history of A-T.
Topics: Adolescent; Ataxia Telangiectasia; Cerebellum; Child; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Multimodal Imaging; Neuroimaging; Phenotype; Prospective Studies; White Matter
PubMed: 31855653
DOI: 10.1016/j.nicl.2019.102110 -
The International Journal of... Jun 2022The DNA damage response is an integral part of a cells' ability to maintain genomic integrity by responding to and ameliorating DNA damage, or initiating cell death for...
The DNA damage response is an integral part of a cells' ability to maintain genomic integrity by responding to and ameliorating DNA damage, or initiating cell death for irrepairably damaged cells. This response is often hijacked by cancer cells to evade cell death allowing mutant cells to persist, as well as in the development of treatment resistance to DNA damaging agents such as chemotherapy and radiation. Prostate cancer (PCa) cells often exhibit alterations in DNA damage response genes including ataxia telangiectasia mutated (ATM), correlating with aggressive disease phenotype. The recent success of Poly (ADP-ribose) polymerase (PARP) inhibition has led to several clinically approved PARP inhibitors for the treatment of men with metastatic PCa, however a key limitation is the development of drug resistance and relapse. An alternative approach is selectively targeting ATM and ataxia telangiectasia and Rad3-related (ATR) which, due to their position at the forefront of the DDR, represent attractive pharmacological targets. ATR inhibition has been shown to act synergistically with PARP inhibition and other cancer treatments to enhance anti-tumour activity. ATM-deficiency is a common characteristic of PCa and a synthetic lethal relationship exists between ATM and ATR, with ATR inhibition inducing selective cell death in ATM-deficient PCa cells. The current research highlights the feasibility of therapeutically targeting ATR in ATM-deficient prostate tumours and in combination with other treatments to enhance overall efficacy and reduce therapeutic resistance. ATM also represents an important molecular biomarker to stratify patients into targeted treatment groups and aid prognosis for personalised medicine.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; DNA Damage; Humans; Male; Neoplasm Recurrence, Local; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms
PubMed: 35609768
DOI: 10.1016/j.biocel.2022.106230 -
Anticancer Research 2008Ataxia telangiectasia (AT) is a rare neurodegenerative, autosomal recessive disorder characterized by chromosome instability, radiosensitivity, immunodeficiency and a... (Review)
Review
Ataxia telangiectasia (AT) is a rare neurodegenerative, autosomal recessive disorder characterized by chromosome instability, radiosensitivity, immunodeficiency and a predisposition for cancer. Epidemiological studies have shown that AT heterozygotes have a predisposition for cancer, especially for breast cancer in women. The disease is caused by mutations in the ATM gene, leading to total loss of the ATM protein, which normally recognizes DNA damage, activates the DNA repair machinery and the cell cycle check points in order to minimize the risk of genetic damage. This review summarizes the clinical features of AT and the natural history of the disease and puts recent molecular advances into the context of the cellular and clinical phenotype.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA-Binding Proteins; Humans; Neoplasms; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 18383876
DOI: No ID Found -
Autophagy Feb 2021Mitophagy is a selective process aimed at removing damaged or burned-out mitochondria; it is activated upon different stimuli and plays a fundamental role in preventing... (Review)
Review
Mitophagy is a selective process aimed at removing damaged or burned-out mitochondria; it is activated upon different stimuli and plays a fundamental role in preventing overproduction of reactive oxygen species (ROS) that might be generated by dysfunctional mitochondria. From this angle, mitophagy can be considered a fully-fledged antioxidant process. Such a surrogate antioxidant function is recently emerging, being shared among many molecular pathways and players that are usually not included among - and, formally, do not directly act as - antioxidants. ATM (ataxia telangiectasia mutated) is a prototype of this class of "neglected" antioxidants. In spite of its well-known role in DNA damage response, many phenotypes of ataxia telangiectasia (A-T) patients are, indeed, related to chronic oxidative stress, arguing for an additional antioxidant role of ATM. In a recent study, we discovered the mechanism through which ATM exerts antioxidant activity. In particular, we provided evidence that this involves ADH5/GSNOR (alcohol dehydrogenase 5 (class III), chi polypeptide), which, in turn, sustains mitophagy via PARK2 denitrosylation, and protects the cell from detrimental effects due to ROS.
Topics: Animals; Antioxidants; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Autophagy; Humans; Mitophagy; Reactive Oxygen Species
PubMed: 33292042
DOI: 10.1080/15548627.2020.1860490 -
Journal of Neurology, Neurosurgery, and... Feb 1964
Topics: Ataxia; Ataxia Telangiectasia; Child; Face; Palate; Sclera; South Africa; Telangiectasis
PubMed: 14123922
DOI: 10.1136/jnnp.27.1.38 -
American Journal of Human Genetics Nov 2023Certain classes of genetic variation still escape detection in clinical sequencing analysis. One such class is retroelement insertion, which has been reported as a cause...
Certain classes of genetic variation still escape detection in clinical sequencing analysis. One such class is retroelement insertion, which has been reported as a cause of Mendelian diseases and may offer unique therapeutic implications. Here, we conducted retroelement profiling on whole-genome sequencing data from a cohort of 237 individuals with ataxia telangiectasia (A-T). We found 15 individuals carrying retroelement insertions in ATM, all but one of which integrated in noncoding regions. Systematic functional characterization via RNA sequencing, RT-PCR, and/or minigene splicing assays showed that 12 out of 14 intronic insertions led or contributed to ATM loss of function by exon skipping or activating cryptic splice sites. We also present proof-of-concept antisense oligonucleotides that suppress cryptic exonization caused by a deep intronic retroelement insertion. These results provide an initial systematic estimate of the contribution of retroelements to the genetic architecture of recessive Mendelian disorders as ∼2.1%-5.5%. Our study highlights the importance of retroelement insertions as causal variants and therapeutic targets in genetic diseases.
Topics: Humans; Ataxia Telangiectasia; Retroelements; Mutation; RNA Splicing; RNA Splice Sites; Introns
PubMed: 37802069
DOI: 10.1016/j.ajhg.2023.09.008 -
Acta Medica Okayama 2012Radiotherapy plays a central part in cancer treatment, and use of radiosensitizing agents can greatly enhance this modality. Although studies have shown that several... (Review)
Review
Radiotherapy plays a central part in cancer treatment, and use of radiosensitizing agents can greatly enhance this modality. Although studies have shown that several chemotherapeutic agents have the potential to increase the radiosensitivity of tumor cells, investigators have also studied a number of molecularly targeted agents as radiosensitizers in clinical trials based on reasonably promising preclinical data. Recent intense research into the DNA damage-signaling pathway revealed that ataxia-telangiectasia mutated (ATM) and the Mre11-Rad50-NBS1 (MRN) complex play central roles in DNA repair and cell cycle checkpoints and that these molecules are promising targets for radiosensitization. Researchers recently developed three ATM inhibitors (KU-55933, CGK733, and CP466722) and an MRN complex inhibitor (mirin) and showed that they have great potential as radiosensitizers of tumors in preclinical studies. Additionally, we showed that a telomerase-dependent oncolytic adenovirus that we developed (OBP-301 [telomelysin]) produces profound radiosensitizing effects by inhibiting the MRN complex via the adenoviral E1B55kDa protein. A recent Phase I trial in the United States determined that telomelysin was safe and well tolerated in humans, and this agent is about to be tested in combination with radiotherapy in a clinical trial based on intriguing preclinical data demonstrating that telomelysin and ionizing radiation can potentiate each other. In this review, we highlight the great potential of ATM and MRN complex inhibitors, including telomelysin, as radiosensitizing agents.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Checkpoints; Cell Cycle Proteins; DNA Damage; DNA Repair; DNA-Binding Proteins; Humans; Protein Serine-Threonine Kinases; Radiation-Sensitizing Agents; Signal Transduction; Tumor Suppressor Proteins; Viral Proteins
PubMed: 22525466
DOI: 10.18926/AMO/48258 -
Molecular Medicine Reports May 2019Ataxia‑telangiectasia (A‑T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM serine/threonine kinase (ATM) gene. Typically, it...
Ataxia‑telangiectasia (A‑T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM serine/threonine kinase (ATM) gene. Typically, it presents in early childhood with progressive cerebellar dysfunction, accompanied by immunodeficiency and oculocutaneous telangiectasia. In the present study, the clinical and genetic findings of a Chinese family affected with A‑T in two live siblings, the proband (II‑2) and his elder brother (II‑1), as well as a fetus (II‑3) were reported. General health, clinical neurological, electrophysiological (motor and sensory nerve conduction) and magnetic resonance imaging evaluations revealed that patients II‑1 and II‑2 had similar symptoms of ataxia, dysarthria, conjunctival hyperemia and elevated serum α‑fetoprotein, whereas patient II‑1 had earlier A‑T onset at 2 years old and more serious problems with movement and intelligence. Targeted sequencing followed by Sanger sequencing revealed that these two patients carried the compound heterozygotes of a novel nonsense mutation c.5170G>T (p.Glu1724Ter) and a known nonsense mutation c.748C>T (p.Arg250Ter) in the ATM gene. Each mutation was inherited from an asymptomatic parent, which therefore confirmed the diagnosis of A‑T. Given this, proband's mother performed prenatal diagnosis in her third pregnancy. Unfortunately, the fetus had the same causal mutations as its siblings and the pregnancy was terminated. The findings of the present study expanded the mutation spectrum of the ATM gene and may help in understanding the genetic basis of A‑T, in order to guide genetic counseling and prenatal diagnosis.
Topics: Alleles; Asian People; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Biomarkers; Cerebellum; Computational Biology; DNA Mutational Analysis; Electromyography; Female; Genetic Association Studies; Genetic Counseling; Genotype; Humans; Magnetic Resonance Imaging; Male; Mutation; Pedigree; Phenotype; Symptom Assessment
PubMed: 30816533
DOI: 10.3892/mmr.2019.9992 -
Italian Journal of Pediatrics Sep 2023Ataxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency,...
BACKGROUND
Ataxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare.
CASE PRESENTATION
We herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (< 1). Finally, based on gait disturbances (wobbly wide-based walking), serum alfa-fetoprotein was dosed, which resulted increased at 276 ng/ml (normal value < 7 ng/ml). A diagnosis of Ataxia-Telangiectasia was made, strengthened by the presence of bulbar telangiectasia, and then confirmed by Whole Exome Sequencing (WES).
CONCLUSIONS
Although rare, A-T should always be ruled out in case of pulmonary bronchiectasis and gait disturbances even in the absence of bulbar or skin telangiectasia. Autoimmune and granulomatous disorders must to be considered as differential diagnosis.
Topics: Female; Child; Humans; Ataxia Telangiectasia; Bronchiectasis; Arthritis; B-Lymphocytes; Lung Diseases
PubMed: 37667293
DOI: 10.1186/s13052-023-01509-5 -
Redox Biology Apr 2017Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme... (Review)
Review
Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Recent studies indicate new, alternative sources of oxidative stress in A-T, BS and NBS cells, including NADPH oxidase 4 (NOX4), oxidised low-density lipoprotein (ox-LDL) or Poly (ADP-ribose) polymerases (PARP). Mitochondrial abnormalities such as changes in the ultrastructure and function of mitochondria, excess mROS production as well as mitochondrial damage have also been reported in A-T, BS and NBS cells. A-T, BS and NBS cells are inextricably linked to high levels of reactive oxygen species (ROS), and thereby, chronic oxidative stress may be a major phenotypic hallmark in these diseases. Due to the presence of mitochondrial disturbances, A-T, BS and NBS may be considered mitochondrial diseases. Excess activity of antioxidant enzymes and an insufficient amount of low molecular weight antioxidants indicate new pharmacological strategies for patients suffering from the aforementioned diseases. However, at the current stage of research we are unable to ascertain if antioxidants and free radical scavengers can improve the condition or prolong the survival time of A-T, BS and NBS patients. Therefore, it is necessary to conduct experimental studies in a human model.
Topics: Ataxia Telangiectasia; Bloom Syndrome; DNA Damage; DNA Repair; Gene Expression Regulation; Humans; Lipoproteins, LDL; Mitochondria; NADPH Oxidase 4; Nijmegen Breakage Syndrome; Oxidative Stress; Poly(ADP-ribose) Polymerases; Reactive Oxygen Species; Signal Transduction
PubMed: 28063379
DOI: 10.1016/j.redox.2016.12.030