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.

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 25% (one-in-four) chance of having another affected child.

Individual genomic counselling is advised for carriers, and for those at risk of being carriers, of an ATM pathogenic variant, owing to the increased chance of cancer that comes with pathogenic heterozygous variants in this particular gene. Carriers for AT are advised to avoid regular mammographic screening owing to their increased chance of breast cancer, and should also minimise exposure to X-ray. Heterozygous carriers of an ATM pathogenic variant may also be at an increased chance of coronary heart disease.

The Human Fertilisation and Embryology Authority has approved the use of pre-implantation genomic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis, or PGD) for couples in which both members are carriers of a likely pathogenic variant in ATM (and, in certain cases, even if only one parent is a carrier). It is best practice that discussions regarding PGT-M and other family planning options are undertaken by a specialist genetic counsellor or clinical geneticist.

Other options may include prenatal testing with termination of affected embryos, adoption, gamete donation or natural conception and pregnancy with testing of children after birth. A referral to the clinical genetics team is appropriate.

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