Ataxia-telangiectasia: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management

ABSTRACT

Introduction

Ataxia-telangiectasia (A-T) is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, and cancer predisposition. Mutations cause A-T in the ataxia telangiectasia mutated (ATM) gene encoding a serine/threonine-protein kinase.

Areas covered

The authors reviewed the literature on PubMed, Web of Science, and Scopus databases to collect comprehensive data related to A-T. This review aims to discuss various update aspects of A-T, including epidemiology, pathogenesis, clinical manifestations, diagnosis, prognosis, and management.

Expert opinion

A-T as a congenital disorder has phenotypic heterogeneity, and the severity of symptoms in different patients depends on the severity of mutations. This review provides a comprehensive overview of A-T, although some relevant questions about pathogenesis remain unanswered, probably owing to the phenotypic heterogeneity of this monogenic disorder. The presence of various clinical and immunologic manifestations in A-T indicates that the identification of the role of defective ATM in phenotype can be helpful in the better management and treatment of patients in the future.

KEYWORDS:

• Ataxia telangiectasia (A-T)
• primary immunodeficiency
• ATM
• double-strand break repair
• oxidative stress

Article highlights

• A-T patients present a broad range of clinical manifestations, including progressive neurodegeneration, telangiectasia, immunodeficiency, and susceptibility to malignancies.

• The prevalence of A-T is estimated at 1:40,000-1:300,000, and the frequency of ATM allele heterozygosity represents 1.4-2% of the general population.

• To date, more than 1400 unique mutations have been identified.

• Frequent mutations in the ATM gene comprise null mutations that lead to a truncation of the ATM protein.

• Individuals who possess deleterious ATM mutations present classic clinical of A-T features.

• Although ATM protein is predominantly present in the nucleus in most human cells, there is evidence that ATM is also localized into and function in the cytoplasm.

• In A-T patients, death at an early age is frequently due to respiratory tract failure, but malignancies are also a prevalent cause in older children and adolescents.

• The lifespan of A-T patients has been prolonged by better management, such as antibiotic treatment and immunoglobulin replacement therapy.

• The prognosis of A-T patients depends on the severity of the immunologic phenotype as it reflects the occurrence of respiratory system infections, neurodegeneration, and an increased risk of malignancy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Parisa Amirifar and Mohammad Reza Ranjouri contributed equally to this article.

Declaration of interest

The authors declare that there was no conflict of interest.

Additional information

Funding

This paper was not funded.