Multidisciplinary Management of Ataxia Telangiectasia: Current Perspectives

Abstract

Ataxia telangiectasia (A-T) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia mutated ( ATM ) gene. In the absence of a family history, the diagnosis of A-T is usually not made until the child is older and symptomatic. Classic A-T is characterized by a constellation of clinical symptoms including progressive ataxia, oculocutaneous telangiectasias and sinopulmonary disease and is usually associated with absence of ATM protein. Other laboratory features associated with A-T include elevated serum levels of alpha-fetoprotein (AFP) and increased chromosomal breakage with in vitro exposure to ionizing radiation. Sinopulmonary symptoms can occur to varying degrees across the lifespan. Some children will also have hypogammaglobulinemia and impaired antibody responses requiring supplemental gamma globulin. People with hypomorphic ATM mutations are often considered to have mild A-T with onset of ataxia and neurological progression occurring later in life with less impairment of the immune system. The risk of malignancy, however, is significantly increased in people with either classic or mild A-T. While hematological malignancies are most common in the first two decades of life, solid organ malignancies become increasingly common during young adulthood. Deterioration of neurologic function with age is associated with dysphagia with aspiration, growth faltering, loss of ambulation and decline in pulmonary function, morbidities that contribute to shortened life expectancy and decreased quality of life. Premature death is often due to malignancies or chronic respiratory insufficiency. A-T is currently managed with supportive care and symptomatic treatment. Current clinical trials, however, represent progress and hope towards disease-modifying therapies for A-T.

Childhood-Onset Movement Disorders Can Mask a Primary Immunodeficiency: 6 Cases of Classical Ataxia-Telangiectasia and Variant Forms

“…These cases fit the clinical-biological picture of variant A-T and highlight the possibility that the more residual ATM kinase activity is present, the milder the neurological features may be, often with prominent extrapyramidal features and longer preserved ambulation (7,8). The presence of residual ATM kinase activity is also associated with mild axonal polyneuropathy, late-onset anterior horn cell degeneration and adult-onset oculomotor apraxia that can mimic other neurological disorders (11,14). In addition, patients with the A-T variant might not exhibit oculomotor and bulbar signs (11).…”

“…In addition, Micol et al showed that the clinical outcome, particularly the risk of cancer, was more severe in those A-T patients with biallelic null mutations resulting in loss of expression of all ATM compared with those with hypomorphic mutations who were more prone to respiratory tract infections (12). Despite these distinctive features, the risk of malignancy is significantly increased in both types of A-T, with common haematological involvement in the first two decades of life and increased risk of solid organ malignancies during young adulthood (13,14), making crucial an early recognition that will enable proper management and follow-up (14,15).…”

Long‐Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia

“…1 Symptoms include neurodegeneration, immunodeficiency, premature aging, and cancer predisposition. [2][3][4] ATM encodes the ATM kinase, a serine/threonine kinase 5 required for DNA damage response 6 and oxidative stress signaling. 7 Individuals with loss-of-function variants have classical A-T phenotypes, whereas those with residual kinase activity may have milder phenotypes known as variant A-T. 8 The neurological manifestations of classical A-T typically begin with cerebellar ataxia, whereas other neuromotor symptoms, such as oculomotor apraxia, develop later.…”

“…Ataxia telangiectasia (A‐T) is a rare progressive multisystemic, life‐shortening disorder caused by pathogenic variants in ATM ( Ataxia Telangiectasia Mutated ) located on chromosome 11q22.3 1 . Symptoms include neurodegeneration, immunodeficiency, premature aging, and cancer predisposition 2‐4 . ATM encodes the ATM kinase, a serine/threonine kinase 5 required for DNA damage response 6 and oxidative stress signaling 7 .…”

Biomarkers of DNA Damage Response Enable Flow Cytometry-Based Diagnostic to Identify Inborn DNA Repair Defects in Primary Immunodeficiencies

“…ATM is a central player in the regulation of cell cycle checkpoints, cell survival, and DNA repair [ 25 ]. Genetic defects in ATM lead to ataxia telangiectasia (AT) presenting with cerebellar degeneration, severe cellular sensitivity to IR, genomic instability with a predisposition to cancer [ 26 ], and antibody deficiency due to impaired class switch recombination [ 27 ]. Patients with defects in proteins of the MRN complex may present with AT-like disorder (ATLD) [ 28 , 29 ], Nijmegen-Breakage Syndrome (NBS) characterized by short stature, microcephaly, “bird-like” face, mental retardation, immunodeficiency, and predisposition to develop cancers [ 30 , 31 ], or NBS-like syndrome [ 32 , 33 ].…”