Ataxia telangiectasia: why should the ERS care?

Abstract

Neurological and immunological contributions to lung disease in A-T require proactive and multidisciplinary management http://ow.ly/TqT44 Why indeed should we care? The answer is that ataxia telangiectasia (A-T) patients will present to respiratory paediatricians for diagnosis, when standard testing, if the diagnosis is not made, may do irreparable harm; and both adult and paediatric respiratory physicians will be involved in managing the respiratory disease, which is a major cause of morbidity and mortality. So there is a real “need to know” which is why the ERS convened a task force on A-T, whose findings are published in the European Respiratory Review [1]. A-T is an autosomal recessive, progressive, multisystem disease caused by mutations in the gene ATM (Ataxia-Telangiectasia Mutated) (11q22.3). This gene is expressed ubiquitously and encodes ATM kinase, a serine/threonine protein kinase, which is involved in signalling following cellular stress. It activates over a hundred proteins involved in the DNA damage response, cell cycle regulation and other pathways. ATM has important roles in neuroprotection, both adaptive and innate immunity, inflammatory responses, metabolism (e.g. insulin signalling), longevity and fertility. It has been estimated that a human cell is confronted with one million DNA lesions every day, placing DNA damage response mechanisms in a position of paramount importance. This has to be a very precise and efficient system to prevent cells with damaged DNA from dividing further or being passed on through germline mutation. The DNA double strand break (DSB) represents one of the most cytotoxic DNA lesions. DSBs can be generated by exposure to ionising radiation or various chemical compounds [2]. The Orphanet registry estimates the average prevalence of A-T to be 1 per 100 000 children [3]. A-T has a large number of other complex and diverse manifestations that vary with age. Neurological symptoms, particularly progressive cerebellar ataxia and abnormalities of the eye movements appear from an early age, and malignant disease is common. Some children first come to medical attention because of recurrent sino-pulmonary infections (which affect ∼50% of children with A-T). Oculocutaneous telangiectasia may not occur until 4 or 5 years of age, so this clue is not available in early life. Laboratory tests may show an elevated alpha-fetoprotein level, immunological deficiencies and chromosomal instability; one lesson is to have a low threshold for the measurement of alpha-fetoprotein as a screening test, especially in young children with infections plus another sign, especially drooling or ataxia. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer, hence the importance of receiving respiratory management right from the start. Also, it is good to consider the diagnosis before rather than after embarking on radiological investigations such as high-resolution computed tomography (HRCT), given the sensitivity of the patients to radiation. There is n...

Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity

“…However, the exact basis of the susceptibility to lung disease in patients with A-T remains unknown. Current treatment for respiratory symptoms is largely based on extrapolation from that employed with other more common disorders such as cystic fibrosis and primary immunodeficiencies 9,10 .…”

Role of cellular senescence genes and Immune Infiltration in sepsis and sepsis-induced ARDS based on bioinformatics analysis

“…insulin signalling), longevity, and fertility. 22 In patients with ataxia-telangiectasia (A-T), a number of factors can contribute to the development of this disease, included recurrent sinus infections, immunode ciency, and aspiration due to impaired swallowing caused by neurodegenerative progression. 21,23 The immune de ciency in A-T is highly variable and affects both B-and T-cells.…”

Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience

“…Whereas the IgG2 deficiency was associated with recurrent infections due to Streptococcus pneumoniae , in patients with IgG3 deficiency no bacterial pathogens or Haemophilus parainfluenzae were cultured in the airways. Furthermore, the opportunistic pathogen, Pseudomonas aeruginosa which was cultured exclusively in patients with the HIGM A-T variant, is associated with a more severe course of lung disease and a higher risk of chronic respiratory failure ( 16 , 49 ). In our group of HIGM A-T children, impaired CSR was associated with more severe clinical phenotypes, including autoimmune phenomena, granulomatous disorders, inflammatory organ-specific immunopathology, lymphoproliferation, and malignancy, consistently with previous reports ( 18 , 24 , 33 , 34 ).…”