Ataxia-Telangiectasia: Genetics, Clinical Features, and Pathophysiology

Ataxia-telangiectasia (A-T) is a rare, autosomal recessive neurodegenerative disorder caused by mutations in the ATM gene (11q22.3). The name reflects its two hallmark features.

Etymology

• Ataxia (Greek a- "without" + taxis "order") – impaired coordination, gait instability, dysmetria, intention tremor
• Telangiectasia (Greek telos "end" + angeion "vessel" + ektasis "dilation") – dilated conjunctival and cutaneous capillaries

Genetics and Pathophysiology

• ATM (Ataxia-Telangiectasia Mutated): Serine/threonine protein kinase; master regulator of DNA double-strand break response
• Loss of ATM → defective cell cycle checkpoints, impaired DNA repair, genomic instability, radiation hypersensitivity
• Purkinje cell degeneration in cerebellum → progressive ataxia

Clinical Manifestations

• Neurologic: Truncal ataxia (toddler onset), dysarthria, oculomotor apraxia, choreoathetosis, peripheral neuropathy, cognitive decline
• Telangiectasias: Bulbar conjunctiva (age 3–6), ears, face, antecubital fossae
• Immunodeficiency: IgA, IgE, IgG₂ deficiency; lymphopenia (esp. CD4+); recurrent sinopulmonary infections
• Malignancy: 1000× risk of lymphoid tumors (lymphoma, leukemia); also solid tumors
• Endocrine: Growth retardation, insulin resistance, gonadal dysgenesis
• Radiation sensitivity: Severe toxicity from diagnostic/therapeutic radiation

Diagnosis

• Clinical suspicion + low/absent ATM protein (Western blot) or ATM kinase assay
• Genetic testing: biallelic pathogenic ATM variants
• Elevated serum AFP (α-fetoprotein) in >95% (unexplained)
• Chromosomal breakage assay (radiosensitivity)

Management (Multidisciplinary)

• Neurology: PT/OT, speech, adaptive devices
• Immunology: IVIG for recurrent infections; avoid live vaccines
• Pulmonology: Aggressive airway clearance, vaccinations (pneumococcal, influenza)
• Oncology: Surveillance (no routine radiation); chemotherapy dose reduction
• Genetic counseling for family

Prognosis

Median survival ~25 years; leading causes of death: respiratory failure, malignancy. No disease-modifying therapy; research on ATM kinase activators, gene therapy ongoing.