What is Ataxia Telangiectasia (AT), a rare genetic disorder?

From the Guidelines

Ataxia telangiectasia (AT) is a rare, progressive genetic disorder characterized by neurological deterioration, immune deficiency, and increased cancer risk, caused by mutations in the ATM gene, which is responsible for DNA repair and cell cycle control, as stated in the most recent study 1.

Key Characteristics of AT

• Caused by mutations in the ATM gene
• Characterized by neurological deterioration, immune deficiency, and increased cancer risk
• Patients typically present in early childhood with progressive cerebellar ataxia and telangiectasias on the eyes and skin
• No cure for AT, management focuses on supportive care and symptom control

Clinical Manifestations

• Neurological symptoms: cerebellar ataxia, dystonia, chorea, and myoclonus
• Systemic abnormalities: immunodeficiency, malignancies, oculocutaneous telangiectasias, and increased α-fetoprotein levels
• Respiratory diseases and cancer are the leading causes of death, as reported in 1 and 1

Management and Prognosis

• Early multidisciplinary care involving neurologists, immunologists, pulmonologists, and rehabilitation specialists provides the best outcomes for managing this complex condition.
• Physical therapy, occupational therapy, and speech therapy are essential to maintain function as long as possible
• Immune deficiency requires vigilant infection prevention, and some patients benefit from immunoglobulin replacement therapy
• Regular cancer screening is crucial due to the increased malignancy risk, particularly lymphomas and leukemias, as emphasized in 1
• Genetic counseling is important for affected families, as AT follows an autosomal recessive inheritance pattern
• Prognosis varies, but most patients have a shortened lifespan due to respiratory infections or cancer, with a median survival of 25 years, as reported in 1

From the Research

Definition and Characteristics of Ataxia Telangiectasia

• Ataxia-telangiectasia (A-T) is a rare inherited syndrome that primarily presents as ataxia due to cerebellar involvement and dilated capillaries in the oculocutaneous region 2.
• A-T is an autosomal recessive disorder characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity 3.
• The disorder is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene, which encodes a protein that coordinates cellular signaling pathways in response to DNA double-strand breaks, oxidative stress, and other genotoxic stress 3.

Clinical Features and Diagnosis

• Neurological symptoms of A-T most often first appear in early childhood, including ataxic gait, oculomotor apraxia, and progressive muscle weakness 3, 4.
• Immunological abnormalities, such as immunoglobulin and antibody deficiencies, and lymphopenia, are common in A-T patients 3, 5.
• Diagnosis of A-T is usually suspected by the combination of neurologic clinical features with one or more of the following: telangiectasia, frequent sinopulmonary infections, and specific laboratory abnormalities (e.g., IgA deficiency, lymphopenia, and increased alpha-fetoprotein levels) 3.
• Confirmation of the diagnosis can be made by genetic testing of the ATM gene or by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines 3.

Treatment and Management

• Treatment of A-T is symptomatic and supportive, as there are no treatments known to slow or stop the neurodegeneration 3, 6.
• Management of A-T requires a multidisciplinary approach, including neurology, immunology, pulmonology, oncology, endocrinology, and nutrition 6.
• Current clinical trials represent progress and hope towards disease-modifying therapies for A-T 5.

Complications and Prognosis

• People with A-T have an increased predisposition for cancers, particularly of lymphoid origin, and pulmonary disease is a common complication 3, 4.
• The risk of malignancy is significantly increased in people with A-T, with hematological malignancies being the major causes of death within the initial years of life 4.
• Premature death is often due to malignancies or chronic respiratory insufficiency, and the median overall survival for A-T patients is approximately 26.9 years 4.