Ataxia-Telangiectasia in Adults

Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disorder caused by biallelic ATM gene mutations on chromosome 11q22.3. ATM (ataxia-telangiectasia mutated) is a serine-threonine kinase critical for DNA double-strand break repair, cell cycle checkpoints, and oxidative stress response. Classic A-T presents in early childhood; adult variants and heterozygous carriers show milder, atypical phenotypes.

Adult phenotypes include late-onset progressive cerebellar ataxia (often misdiagnosed as cerebellar variant of multiple system atrophy or sporadic cerebellar ataxia), dystonia, polyneuropathy, oculomotor apraxia, conjunctival telangiectasias (less prominent than classic), elevated alpha-fetoprotein (95% of cases), low IgA, lymphopenia, and increased breast cancer risk in heterozygous carriers (4-fold).

Diagnostic workup includes ATM gene sequencing for biallelic mutations, alpha-fetoprotein elevation (key biomarker), reduced ATM protein on Western blot, immunoglobulin panel, lymphocyte subsets, brain MRI showing cerebellar atrophy, and chromosomal radiosensitivity testing. Management is supportive with neurorehabilitation, immunoglobulin replacement for immunodeficiency, infection prophylaxis, cancer surveillance (MRI and ultrasound preferred to ionizing radiation due to radiosensitivity), genetic counseling, and avoidance of unnecessary CT and chemotherapy with DNA-damaging agents. Heterozygous family members require breast cancer screening starting at age 30 with MRI.