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A rare disorder characterized by the association of severe combined immunodeficiency (affecting mainly the humoral immune response) with progressive cerebellar ataxia. It is characterized by neurological signs, telangiectasia, increased susceptibility to infections and a higher risk of cancer.
ORPHA:100Classification level: Disorder
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).