BACKGROUND:

Ataxia Telangiectasia (AT) is a rare incurable genetic disease, caused by biallelic mutations in the Ataxia Telangiectasia-Mutated (ATM) gene. Treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this syndrome. Nevertheless, the molecular mechanism underlying the glucocorticoid action in AT patients is not yet understood. Recently, we have demonstrated that Dexamethasone treatment may partly restore ATM activity in AT lymphoblastoid cells by a new ATM transcript, namely ATMdexa1.

RESULTS:

In the present study, the new ATMdexa1 transcript was also identified in vivo, specifically in the PMBCs of AT patients treated with intra-erythrocyte Dexamethasone (EryDex). In these patients it was also possible to isolate new "ATMdexa1 variants" originating from canonical and non-canonical splicing, each containing the coding sequence for the ATM kinase domain. The expression of the ATMdexa1 transcript family was directly related to treatment and higher expression levels of the transcript in patients' blood correlated with a positive response to Dexamethasone therapy. Neither untreated AT patients nor untreated healthy volunteers possessed detectable levels of the transcripts. ATMdexa1 transcript expression was found to be elevated 8 days after the drug infusion, while it decreased 21 days after treatment.

CONCLUSIONS:

For the first time, the expression of ATM splicing variants, similar to those previously observed in vitro, has been found in the PBMCs of patients treated with EryDex. These findings show a correlation between the expression of ATMdexa1 transcripts and the clinical response to low dose dexamethasone administration.

Ataxia-telangiectasia (A-T) is a devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and cancer susceptibility. The European Workshop on Ataxia-Telangiectasia 2011 in Frankfurt focused on status quo of patient care and future clinical research directions. In Europe, approximately 600 patients are registered and many national websites have been established. During the meeting, guidelines of patient care were discussed and all participants agreed to build up an European A-T research network in near future to bring basic research and new therapies into clinical applications.

Ataxia-telangiectasia (A-T) is characterized by neuronal degeneration, cancer, diabetes, immune deficiency, and increased sensitivity to ionizing radiation. A-T is attributed to the deficiency of the protein kinase coded by the ATM (ataxia-telangiectasia mutated) gene. ATM is a sensor of DNA double-strand breaks (DSBs) and signals to cell cycle checkpoints and the DNA repair machinery. ATM phosphorylates numerous substrates and activates many cell-signaling pathways. There has been considerable debate about whether a defective DNA damage response is causative of the neurological aspects of the disease. In proliferating cells, ATM is localized mainly in the nucleus; however, in postmitotic cells such as neurons, ATM is mostly cytoplasmic. Recent studies reveal an increasing number of roles for ATM in the cytoplasm, including activation by oxidative stress. ATM associates with organelles including mitochondria and peroxisomes, both sources of reactive oxygen species (ROS), which have been implicated in neurodegenerative diseases and aging. ATM is also associated with synaptic vesicles and has a role in regulating cellular homeostasis and autophagy. The cytoplasmic roles of ATM provide a new perspective on the neurodegenerative process in A-T. This review will examine the expanding roles of ATM in cellular homeostasis and relate these functions to the complex A-T phenotype. Developmental Dynamics 247:33-46, 2018.

© 2017 Wiley Periodicals, Inc.

Ataxia-Telangiectasia (A-T) is a prototypical genomic instability disorder with multi-organ deficiency and it is caused by the defective function of a single gene, ATM (Ataxia-Telangiectasia Mutated). Radiosensitivity, among the pleiotropic symptoms of A-T, reflects the basic physiological functions of ATM protein in the double strand break (DSB)-induced DNA damage response (DDR) and also restrains A-T patients from the conventional radiation therapy for their lymphoid malignancy. In this chapter, we describe two methods that have been developed in our lab to assess the radiosensitivity of A-T patients: (1) Colony Survival Assay (CSA) and (2) Flow Cytometry of phospho-SMC1 (FC-pSMC1). The establishment of these more rapid and reliable functional assays to measure the radiosensitivity, exemplified by A-T, would facilitate the diagnosis of other genomic instability genetic disorders as well as help the treatment options for most radiosensitive patients.

Ataxia-telangiectasia is a chronic progressive disorder affecting the nervous and immune systems, caused by a genetic defect in the ATM protein. Clasmatodendrosis, a distinct form of astroglial death, has rarely been reported in ataxia-telangiectasia. Neuropathology of our patient disclosed diffuse edema of the cerebral and cerebellar white matter with prominent clasmatodendrosis, implicating ATM in the regulation of astroglial cell death.

Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, 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 classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.