Ataxia telangiectasia (A-T, OMIM #208900) is a disease which belongs to the group of DNA repair defects that play an important role in the regulation of central proteins of the signaling cascade between the identification and repair of DNA damage, including the tumor suppressor proteins p53, BRCA1, CHEK2, and NBS1. A-T is characterized by an increased sensitivity to ionizing radiation and by progressive neurological symptoms. NHL and ALL are of primary importance when it comes to a predisposition to cancer.

Key Data

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Synonym A-T
Gene ATM (Ataxia telangiectasia mutated)
Gene product Phosphatidylinsositol 3-kinase (PI3) protein family
Function ATM kinase. The ATM mutation leads to a down-regulation of ATM kinase expression and function, resulting in a faulty DNA repair signaling cascade and an accumulation of DNA strand breaks, and results in genetic instability, specifically following exposure to ionizing radiation.
Heredity Autosomal recessive
Prevalence 1:40.000-1:100.000
Genotype-phenotype correlation c.5762-1050A>G slow neurological progression, later manifestation, intermediate radiosensitivity, risk of cancer increased slightly or not at all
c.1A>G, c.7271T>G, c.8147T>C, c.8494C>T, etc. mild phenotype, longer survival, increased risk of cancer
Penetrance High. Onset of initial neurological symptoms at the age of 2-4; most children need a wheelchair at 10 years of age.
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Indicative Findings

  • Abnormal newborn screening (for reduced T-cell receptor excision circle levels, TRECs)

  • Elevated AFP (alpha-fetoprotein)

  • Reduced IgA, IgE, and IgG2 levels (60-80%)

  • Poor antibody response to pneumococcal vaccines

  • Karyotype with t(7;14)-translocation (5-15%)

  • Cerebellar hypoplasia in the MRI

  • Increased sensitivity to ionizing radiation

Confirming the Diagnosis

  • Molecular genetic testing (single-gene or multiple-gene panel): Biallelic pathogenic ATM variant (homozygous or compound heterozygous)

  • Immunoblotting (ATM protein level reduced or not evident)

Differential Diagnoses

  • Nijmegen breakage syndrome (NBS)

  • MRE11 deficiency ataxia

  • RAD50 deficiency

  • RNF168 deficiency

Clinical Presentation

Typical A-T

  • Progressive cerebellar ataxia, starting between the 1st and 4th year of life

  • Conjunctival telangiectasia

  • Oculomotor apraxia

  • Choreoathetosis

  • Immunodeficiency

  • Tendency towards infections

Atypical A-T

  • A-T with the onset of spinal muscle atrophy during adulthood

  • A-T with early-onset dystonia

Other Findings

  • Premature aging with gray hairs

  • Endocrine abnormalities with the development of insulin-resistant diabetes mellitus and premature ovarian insufficiency

Associated Predisposition to Tumors

  • NHL

  • ALL

  • When there is heterozygosity (e.g. in the parents), an increased risk of mammary and ovarian carcinoma, gastric carcinoma, melanomas, leiomyomas, and sarcomas

Therapeutic Considerations

Avoid/reduce exposure to ionizing radiation and X-ray examinations if clinically acceptable.

The treatment of any neoplasia should be adjusted accordingly (reduced doses, longer treatment intervals) due to increased therapeutic toxicity, especially in children.

It is strongly recommended to test the parents whenever A-T is newly diagnosed, since there is also an increased risk of cancer in heterozygous carriers.

Surveillance Recommendations

Surveillance Recommendations

Evidence-based standards are lacking for tumor screening, particularly during childhood. The following are the recommendations from the AACR consensus meeting in October 2016.

  • Hematology-oncology: medical history, clinical examination, annual blood count, metabolic profile along with LDH (lactate dehydrogenase)

  • Immunology: monitoring of the immunoglobulin levels according to immunological recommendations

  • Dermatology: annual skin screening

  • Pulmonology: baseline examination, pulmonary function testing according to clinical need

  • Gastroenterology/nutrition: baseline examination, swallowing tests as needed, dietary supplementation

  • Endocrinology: annual diabetes screening

  • Neurology: supportive medication

  • Orthopedics: annual scoliosis evaluation

  • Dental: six-monthly checkups

Additional Information

Open Clinical Trials / Registries

  • ESID (European Society for Immunodeficiencies) Registry, Freiburg

Support Groups