Ataxia telangiectasia: a review

Abstract

Definition of the diseaseAtaxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.EpidemiologyThe world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.Clinical descriptionA-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations.EtiologyA-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.DiagnosisThe diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.Differential diagnosisThere are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing.Antenatal diagnosisAntenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis.Genetic counselingGenetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted.Management and prognosisTreatment of the neurologic problems associated wit...

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Werner syndrome is characterized by AD-like neuropathology and cognitive deficits (Leverenz et al, 1998; Rekik et al, 2017). ATM deficiency results in progressive death of cerebellar Purkinje and granule neurons and consequent impaired control of body movements (Rothblum-Oviatt et al, 2016). Interestingly, DER significantly reduces neurodegeneration and neurological deficits, and increases the lifespan of DNA excision repair-deficient mice (an animal model of accelerated aging) by attenuating the accrual of oxidative DNA lesions (Vermeij et al, 2016).…”

Non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype

“…These include genes from lower species, many of which have recognisable and often functional human homologues, or genes causing the aforementioned hereditary human conditions with radiosensitivity as one of numerous other clinical features, such as immunodeficiency, neurodegeneration and cancer-proneness (e.g., ataxia telangiectasia) (1). In contrast, very few 'radiosensitivity genes' are known in cancer radiotherapy patients.…”

Prostate cancer: unmet clinical needs and RAD9 as a candidate biomarker for patient management

“…Examples of such heritable syndromes include ataxia telangiectasia-mutated [DNA damage response signaling pathway deficiency; (20)], breast cancer associated 1 and 2 [interstrand crosslink and double-strand DNA break repair deficiency; (21)], Lynch syndrome [also known as hereditary non-polyposis colorectal cancer; mismatch repair deficiency; (22)], Nijmegen breakage syndrome [defective in sensing DNA double strand breaks; (23)], and Werner syndrome [DNA double strand break repair deficiency; (24)]. Generally, individuals afflicted with these disorders are at high risk for developing cancer, and their cells are genetically unstable as well as hypersensitive to the killing effects of DNA damaging agents.…”