Ataxia-telangiectasia (OMIM #208900; ORPHA:100) is a rare syndrome, occurring in 1 in 100,000-40,000 people worldwide. The disease affects the nervous, immune and other body systems, and is characterized by progressive difficulty in coordinating movements (ataxia) beginning in early childhood, usually before age 5. Small clusters of enlarged blood vessels (telangiectasias) may appear in their eyes and skin. Individuals affected by A-T are predisposed to cancer (35% of patients develop cancer by the age of 20), mostly childhood lymphoid leukaemia/lymphomas, but they may also develop carcinomas and sarcomas at older ages.
Ataxia-telangiectasia patients are at increased risk of developing cancer following radiation treatment. Their life expectancy is highly variable and affected individuals may not survive beyond early adulthood.
A-T is caused by genetic heritable defects (pathogenic variants) in the ATM gene. ATM encodes a protein-kinase enzyme involved in cell cycle and repair of DNA damage induced by ionizing radiation.
Ataxia-telangiectasia (A-T) is an autosomal recessive syndrome. If you inherit two altered copies of the same gene, one from each parent, you can get the disease. Most A-T patients inherit different ATM pathogenic variants from each progenitor (compound heterozygotes), and only rarely, and mainly in consanguineous families or in a few population-specific founder effects, the same variant is inherited from both progenitors (homozygotes).
Heterozygous carriers of ATM pathogenic variants do not develop A-T, but present a moderately increased risk of developing breast, pancreatic and prostate cancer. In this case, the inheritance pattern is dominant.
Prenatal and preimplantation genetic diagnoses are possible if causative pathogenic variants have been identified in the parents (different legal/ethical perspectives could exist).
There are no specific guidelines for cancer surveillance in A-T patients. Regular physical examinations in a specialized centre and education on the initial manifestations of leukaemia/lymphoma should be provided. In young adults, surveillance for epithelial cancers, namely, for breast cancer (by MRI) should be offered. Heterozygous carriers may also be monitored for breast cancer (females) and possibly also for other tumours (prostate, pancreas), depending on family history.
Prenatal and preimplantation genetic testing of A-T is possible once at least one inactivating ATM pathogenic variant has been identified in the index case and should be discussed during genetic counselling consultation and the multidisciplinary team.