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Ataxia-telangiectasia is the association of severe combined immunodeficiency (affecting mainly the humoral immune response) with progressive cerebellar ataxia. It is characterised by neurological signs, telangiectasias, increased susceptibility to infections and a higher risk of cancer.
Average prevalence is estimated at 1/100,000 children.
The severity of the neurological, immune system and pulmonary manifestations varies widely between patients. Onset usually occurs between 1 and 2 years of age with abnormal head movements and loss of balance, followed by slurred speech and abnormal eye movements. Poor coordination and trembling of the extremities may appear towards 9-10 years of age and worsen progressively. Choreoathetosis is quite common. In the majority of cases, intelligence is normal: around 30% of patients have learning difficulties or moderate intellectual deficiency. Cutaneomucosal telangiectasias appear between 3 and 6 years of age, or during adolescence. The immunodeficiency causes repeated sinus and lung infections, and the latter may cause bronchiectasis. Growth delay is also fairly frequent.
Ataxia-telangiectasia (A-T) is caused by inactivating mutations of the ATM gene (11q22.3). This gene is expressed ubiquitously and encodes a protein kinase playing a key role in the control of double-strand-break (DSB) DNA repair, notably in the Purkinje cells of the cerebellum and in cerebral, cutaneous and conjunctival endothelial cells. A-T-like disorder is a rare variant form of A-T caused by inactivation of the MRE11 gene (11q21), which also encodes a protein involved in DSB repair.
Establishing the clinical diagnosis early in the disease course is problematic but quasi-constant increases in serum alpha-foetoprotein (AFP) levels and cytogenetic analysis may help confirm the diagnosis (7;14 translocations). Molecular diagnosis is sometimes necessary.
The differential diagnosis should include Ataxia - oculomotor apraxia, types 1 and2 (see these terms).
Prenatal diagnosis is possible once at least one inactivating ATM gene mutation has been identified in the index case.
A-T is an autosomal recessive disease.
Management and treatment
Management is symptomatic and involves physiotherapy, speech therapy and treatment of the infection and pulmonary complications. Beta-blockers may reduce trembling and improve performance of fine movements. As the cells of A-T patients show an increased susceptibility to X-rays, radiotherapy, together with some forms of chemotherapy, should be used with caution. Affected children often require a wheelchair by the age of 10-11.
The prognosis is severe as it reflects the occurrence of respiratory infections, neurodegeneration, accelerated cutaneomucosal ageing and an increased risk of cancer (35% of patients develop cancer by the age of 20).