Ataxia telangiectasia

Ataxia telangiectasia (AT) is a progressive inherited DNA repair condition. Symptoms, which usually begin in childhood, include difficulty walking, problems with balance, involuntary jerking movements, muscle twitches and neuropathy. The condition causes neurodegeneration and multisystem disease, including immunodeficiency and cancer susceptibility.

Clinical features of AT include:

• Neurological features:
  • ataxia, which presents as unsteady balance and gait, beginning between the ages of one and four;
  • progressive oculomotor apraxia (difficulty in purposefully moving the eyes);
  • dysarthria (slurred speech);
  • choreoathetosis (involuntary movement);
  • dysfunctional swallowing;
  • the necessity of permanent wheelchair use by adolescence (this applies to most affected individuals); and
  • MRI findings that include cerebellar atrophy of the frontal and posterior vermis and both hemispheres.
• Ectodermic features:
  • scleral telangiectasia by four to eight years of age;
  • premature ageing of the skin and/or grey hairs; and
  • hyperpigmentation.
• Immunodeficiency (not progressive; can occur in up to 80% of affected individuals):
  • sinusitis;
  • bronchitis; and/or
  • pneumonia.
• Predisposition to cancer (occurs in 10%–30% of affected individuals, 15% under the age of 16):
  • particular increased chance of lymphoma and leukaemia (accounting for 85% of malignancies);
  • ovarian cancer;
  • breast cancer;
  • gastric cancers;
  • leiomyomas;
  • sarcomas; and
  • hypersensitivity to ionising radiation.
• Other features:
  • endocrine anomalies, such as growth retardation, reproductive dysfunction and diabetes mellitus; and
  • elevation of serum concentration of alpha-fetoprotein (AFP) above 10 nanograms per millilitre (present in about 95% of affected individuals).

AT is caused by biallelic pathogenic variants in the ATM gene on chromosome 11. These are typically protein truncating, loss-of-function variants that lead to absence of the ATM protein.

Absence or significant dysfunction of the ATM protein leads to an inability to activate signalling in response to double-stranded DNA breaks and DNA damage caused by radiation, certain chemicals or normal cellular metabolism. Without the ATM protein, cells become unstable and die. The cerebellum is particularly vulnerable to the loss of ATM. Accumulation of damaged DNA can also lead to tumour formation.

A clinical diagnosis of AT is typically made based on the clinical presentation and findings from neuroimaging and laboratory tests. A raised serum concentration of alpha-fetoprotein (AFP) above 10ng/mL (nanograms per millilitre) is present in the majority of affected individuals (about 95%). A molecular diagnosis can be made if genomic testing identifies biallelic pathogenic variants in the ATM gene. For information about testing, see Presentation: Clinical suspicion of Ataxia telangiectasia.

AT is inherited in an autosomal recessive pattern. The parents of most affected individuals are carriers for the condition and therefore have a one-in-four (25%) chance of having another affected child. Careful consideration should be given to other family members that could be affected, especially full siblings.

Reproductive options are available for those at risk of having an affected child. Typically options include preimplantation genetic testing or testing in early pregnancy. Genetic counselling is advised. Ideally a referral for genetic counselling should be made in good time before planning a conception. In the context of a pregnancy an urgent referral should be considered.

Typically in autosomal recessive conditions carriers are not affected with the disease. While this is true for AT, carriers do have other potential health implications that must be considered. Carriers of an ATM pathogenic variant have an increased chance of cancer.

The degree of cancer risk associated with ATM variants in heterozygous carriers depend on the variant type, with risks associated with truncating variants higher than those associated with missense variants. For this reason, when panels are undertaken for cancer-related indications, analysis and reporting is restricted to truncating variants and a few other specific variants. For more information see the UKCGG/CStAG statement on reporting practice for variants in ATM.

Other types of ATM variants (causative of AT but not reportable according to cancer guidelines) may be associated with a more modestly increased risk of breast cancer. To account for this, carrier mothers of affected children can be offered moderate-risk breast cancer screening (annual mammograms between 40–50 years of age). Cascade testing in the family from a cancer perspective is not recommended for such variants.

A diagnosis of AT is considered a relative contraindication for diagnostic radiography and radiation therapy, and MRI is preferred for breast cancer surveillance in female adults with AT, starting from 25 years of age.

Some data suggests mildly increased radiosensitivity in heterozygous carriers of ATM variants, but available data mainly relates to therapeutic doses of radiation. Heterozygous carrier status is, therefore, not considered a contraindication to radiation therapy, and mammograms are routinely recommended as the preferred method of surveillance in heterozygous carriers (annual mammograms between 40 and 50 years of age, unless higher-risk screening is otherwise indicated based on family history of cancer). The benefit of surveillance for other cancer types in heterozygous carriers of ATM variants is uncertain and is not, at present, recommended outside of research studies.

In some cases reproductive options are available to heterozygous carriers with an increased risk of cancer. Genetic counselling is recommended.

Management of patients with AT is complex and should be delivered via a multidisciplinary team; detailed suggested approaches have been published (see the references section below). Patients require long-term monitoring for growth, pubertal progression, development, malignancy and immunodeficiency. Therapeutic doses of ionising radiation should be avoided, as should X-rays where possible.

For clinicians

• GeneReviews: Ataxia-telangiectasia
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• OMIM: 208900 Ataxia-telangiectasia
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Van Os NJH, Haaxma CA, van der Flier M and others. ‘Ataxia-telangiectasia: Recommendations for multidisciplinary treatment’. Developmental Medicine & Child Neurology 2017: volume 59, issue 7, pages 665–770. DOI: 1111/dmcn.13424

For patients

• AT Society
• Contact a Family: Ataxia-telangiectasia