Ataxia-telangiectasia (AT) is a recessive hereditary genomic instability disorder occurring in between 1 out of 40,000 and 1 out of 100,000 persons worldwide.
AT is clinically characterized by early-onset progressive cerebellar ataxia, telangiectasias of the skin and bulbar conjunctiva, progressive apraxia of eye movements, increased susceptibility to sinopulmonary infections, endocrine deficiencies and lymphoreticular malignancies, and other malignant tumors. Atypical forms including adult-onset AT and AT with early-onset dystonia including levodopa-responsive dystonia may occur.
Laboratory confirmation of the diagnosis is based on a combination of increased serum α-fetoprotein level, increased in vitro radiosensitivity, decreased or absent intracellular ATM protein levels on western blotting, and mutations in the ATM gene.
AT is due to ATM gene mutations, which follow an autosomal recessive inheritance pattern. More than 600 mutations of the ATM gene have already been identified, most of which are unique to single families (private mutations). Genetic screening can be extensive and remains unsuccessful in 5% to 15% of cases.
AT variants have been recognized which include the Nijmegen breakage syndrome due to mutations in the NBS1 gene on chromosome 8q21, and AT-like disorder (ATLD) due to mutations in the MRE11.
Ataxia with ocular motor apraxia types 1 and 2 can clinically mimic AT. Other ataxia disorders including Friedreich ataxia and vitamin E-associated ataxia should also be considered.
Diagnostic Criteria and Clinical Characteristics
At least one of the following
An increased serum α-fetoprotein level (not specific)
Increased in vitro radiosensitivity
Decreased or absent intracellular ATM protein levels on western blotting
Mutations in the ATM gene
Reduced IgG or IgA levels (reduced in 80% and 60% of AT patients)
7;14 chromosome translocation
AT should be considered in the context of progressive cerebellar dysfunction with onset in infancy. This can present as
Gait instability or truncal ataxia
Dysarthria (slurred speech)
Presence of telangiectasia (which usually appears several years after the onset of neurologic symptoms), present in 97% of a series of 171 AT cases. The dilated blood vessels are most frequently found in the bulbar conjunctiva, particularly the lateral part. Ear helices, the bridge of the nose and the butterfly area of the face, the back of the hands, axillae, popliteal and antecubital fossae should also be closely examined for dilated vessels.
Extrapyramidal features appear late through the disease course, but may rarely be present early.
Dopa-responsive dystonia with confirmed ATM gene mutations has recently been described.
Susceptibility to sinopulmonary infections.
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