Ataxia-Telangiectasia – Definition
Ataxia-Teleangiectasia (A-T, OMIM #208900) is a disease belonging to the group of DNA repair defects that plays an important role in the regulation of central proteins of the signaling cascade between recognition and repair of DNA damage, including the tumor suppressor proteins p53, BRCA1, CHEK2, and NBS1. A-T is characterized by increased sensitivity to ionizing radiation and progressive neurological symptoms. In the context of cancer predisposition, NHL and ALL are in the foreground.
Synonyms:
A-T
Gene:
ATM (Ataxia telangiectasia mutated)
Gene products:
Phosphatidylinsositol-3 kinase (PI3) protein family
Function:
ATM kinase. The mutation in ATM leads to a down-regulation of ATM kinase expression and function, resulting in a defective DNA repair signal cascade, accumulating DNA strand breaks and genetic instability, particularly due to ionizing irradiation.
Inheritance:
autosomal recessive
Prevalence:
1:40.000-1:100.000
Genotype-phenotype correlation:
c.5762-1050A>G slower neurological progression, later manifestation, intermediate radiosensitivity, low to no increased cancer risk
c.1A>G, c.7271T>G, c.8147T>C, c.8494C>T, etc. mild phenotype, longer survival, increased cancer risk
Penetrance:
High. The first neurological symptoms begin at the age of 2-4 years; by the age of 10, most children are wheelchair-bound.
Ataxia-Telangiectasia – Diagnosis
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 vaccine
- Karyotype with t(7;14) translocation (5-15%)
- Cerebellar hypoplasia in MRI
- Increased sensitivity to ionizing radiation
Diagnosis Confirmation
- Molecular genetic testing (single-gene or multi-gene panel): Biallelic pathogenic ATM variant (homozygous or compound heterozygous)
- Immunoblot (ATM protein reduced or not detectable)
Differential Diagnoses
- Nijmegen Breakage Syndrome (NBS)
- MRE11 deficiency ataxia
- RAD50 deficiency
- RNF168 deficiency
Clinical Presentation
Classic A-T
- Progressive cerebellar ataxia, beginning between 1 and 4 years of age
- Conjunctival telangiectasia
- Oculomotor apraxia
- Choreoathetosis
- immunodeficiency
- Tendency to infection
Non-Classical A-T
- A-T with the onset of spinal muscular atrophy in adulthood
- A-T with early-onset dystonia
Further Findings
- Premature aging with gray hair strands
- Endocrine abnormalities with the development of insulin-resistant diabetes mellitus and premature ovarian failure
Associated Tumor Predisposition
- NHL
- ALL
- Mildly increased risk of breast cancer in heterozygosity (e.g. of parents)
Special Features of Treatment
- Avoidance/reduction of ionizing radiation and X-ray examinations if clinically justifiable.
- The treatment of any neoplasia should be adapted accordingly (dose reduction, longer treatment intervals) against the background of increased treatment toxicity, especially in children.
- Testing of parents with a new diagnosis of A-T is strongly recommended, as there is also an increased risk of cancer in heterozygosity. Carriers, such as parents, should contact specialized centers for advice on early tumor detection tests (e.g., breast centers).
Diagnosis of Ataxia-TelangiectasiaWhat's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnose Ataxia-Telangiectasia. Wie geht es weiter?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
Evidence-based standards for tumor screening are lacking, especially in childhood. Below are the recommendations from the AACR consensus meeting in October 2016.
- Hemato-oncology: medical history, clinical examination, annual blood count, metabolic profile including LDH (lactate dehydrogenase)
- Immunology: Monitoring of immunoglobulin levels according to immunological recommendations
- Dermatology: annual skin screening
- Pulmonology: Baseline examination, pulmonological function tests according to clinical need
- Gastroenterology/Nutrition: Baseline examination, swallowing tests if required, nutritional supplementation
- Endocrinology: annual diabetes screening
- Neurology: Supportive medication
- Orthopedics: Annual scoliosis evaluation
- Dentistry: Semi-annual check-ups
Ataxia-Telangiectasia – Further Information
Open Clinical Trials/ Registers
Patients can also register for the CPS registry at any time or have this done by the doctors looking after them.
Furthermore, Ataxia Teleangiectasia is being researched in our companion projects Liquid Biopsy and ADDRess, so we encourage patients to register for these in addition to the CPS Registry.
