Ataxia-Telangiectasia

Review
In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].

Excerpt

Clinical characteristics: The phenotypic spectrum of ataxia-telangiectasia (A-T), a multisystem disorder, is a continuum ranging from classic A-T at the severe end and variant A-T at the milder end. Nonetheless, distinguishing between classic A-T and variant A-T on this spectrum helps understand differences in disease course, rate of progression, and life expectancy.

Classic A-T is characterized by childhood onset of progressive neurologic manifestations (initially cerebellar ataxia, followed typically by extrapyramidal involvement and peripheral sensorimotor neuropathy), immunodeficiency (variably associated with abnormalities of humoral immunity, cellular immunity, or combined immune deficiency), pulmonary disease (resulting from recurrent infections, immune deficiency, aspiration, interstitial lung disease, and neurologic abnormalities), and increased risk of malignancy. Although it is generally accepted that intellectual disability is not common in A-T, disturbances in cerebellar as well as non-cerebellar brain areas and networks may result in cognitive deficits. Increased sensitivity to ionizing radiation (x-ray and gamma ray) can result in severe side effects from such treatments. Life expectancy is significantly reduced due to cancer, pulmonary disease, and infections.

Variant A-T has a significantly milder disease course. While cerebellar ataxia can be absent, extrapyramidal movement disorders are common (typically dystonia and dystonic tremor) and most individuals have manifestations of axonal sensorimotor polyneuropathy. In contrast to classic A-T, immune function is generally normal, respiratory infections are not increased, and pulmonary disease is not a major feature. However, risk of developing malignancies is increased, particularly in premenopausal females who have an increased risk of developing breast cancer and hematologic malignancies.

Diagnosis/testing: The diagnosis of A-T is established in a proband with suggestive findings and biallelic pathogenic variants in ATM identified by molecular genetic testing. Of note, newborn screening (NBS) for severe combined immunodeficiency (SCID) that relies on the identification of reduced T-cell receptor excision circle (TREC) levels in blood spots most likely identifies about 50% of children with classic A-T, who require immediate subspecialty evaluation at a center with expertise in the diagnosis of SCID, its causes, and its treatment.

Management: Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications ideally involves multidisciplinary care by specialists in (pediatric) neurology, pulmonology, immunology, pediatrics (for children) and internal medicine (for adults), rehabilitation medicine, and professionals in physical therapy, speech-language therapy, occupational therapy, and nutrition. For specific issues care may be provided by specialists in oncology, medical genetics, endocrinology, orthopedics, dermatology, mental health, and social work.

Surveillance: Routine evaluations by treating clinicians is necessary to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations. Recommended surveillance is the same for individuals with classic A-T and variant A-T, with the exception that individuals who do not have evidence of lung disease at the time of initial diagnosis do not require annual screening for pulmonary disease.

Agents/circumstances to avoid: Rubella vaccination should be avoided in individuals with severe immunodeficiency as it can possibly increase the risk for granulomas; ionizing radiation (x-ray and gamma ray) is contraindicated, due to increased sensitivity; and radiation therapy is contraindicated because increased radiosensitivity may lead to very severe complications.

Evaluation of relatives at risk: It is appropriate to offer molecular genetic testing for the familial ATM pathogenic variants to apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible sibs with biallelic ATM pathogenic variants who would benefit from prompt initiation of treatment of manifestations of A-T, surveillance for malignancy, and awareness of agents/circumstances to avoid; and family members who are heterozygous for an ATM pathogenic variant and who would benefit from age-appropriate intensified surveillance for breast cancer.

Therapies under investigation: Use of intra-erythrocyte dexamethasone; the effects of nicotinamide riboside (a form of vitamin B3) on ataxia scores and immunoglobulin levels; gene therapy with antisense oligonucleotides in a single case study; effect of allogenic hematopoietic stem cell transplantation on neurologic functioning.

Genetic counseling: A-T is caused by biallelic pathogenic variants in ATM and inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ATM pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and having A-T, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial ATM pathogenic variants. Although individuals heterozygous for an ATM pathogenic variant are not at risk for A-T, their risk of developing cancer is increased compared to that of the general population (in particular, heterozygous females have an increased risk of developing breast cancer). Once the ATM pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal and preimplantation genetic testing for A-T are possible.

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