Monogenic Defects of DNA Repair: Ataxia-Telangiectasia, Xeroderma Pigmentosum, Fanconi Anemia, Bloom Syndrome
DNA repair mechanisms are essential for maintaining genomic stability.
Monogenic defects in DNA repair lead to accumulation of DNA damage, resulting in:
- chromosomal instability,
- increased cancer risk,
- tissue degeneration,
- immunodeficiency or developmental abnormalities.
These disorders are often called chromosomal instability syndromes.
I. ATAXIA-TELANGIECTASIA (AT)
Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder characterized by:
- progressive cerebellar ataxia,
- oculocutaneous telangiectasias,
- immunodeficiency,
- marked cancer predisposition.
Genetic and Molecular Basis
- Gene: ATM (chromosome 11q22–23)
- Protein: ATM kinase
- Normal function:
- Detects DNA double-strand breaks (DSBs)
- Activates DNA damage response pathways
- Coordinates cell-cycle arrest, DNA repair, or apoptosis
Pathophysiology
- 1. Loss of ATM function → inability to detect DSBs.
- 2. Failure to activate cell-cycle checkpoints (G1/S, G2/M).
- 3. Accumulation of chromosomal breaks and rearrangements.
- 4. Increased cell death in rapidly dividing tissues (brain, immune cells).
- 5. Genomic instability → high malignancy risk.
Clinical Features
- Neurologic: progressive cerebellar ataxia (childhood onset), dysarthria.
- Skin/eyes: telangiectasias on conjunctiva and sun-exposed skin.
- Immune: combined immunodeficiency (↓ IgA, IgG).
- Respiratory: recurrent sinopulmonary infections.
- Cancer risk: lymphomas and leukemias.
- Radiation sensitivity: extreme.
Diagnosis
- Elevated alpha-fetoprotein (AFP).
- Chromosomal breakage studies.
- Genetic confirmation (ATM mutation).