Ataxia-Telangiectasia
Epidemiology and Etiology:
- ATM gene mutations in both alleles (11q22.3)
- Protein kinase that senses DNA double-strand
breaks
- Phosphorylates p53 when activated
- P53 then halts cell cycle to allow damage to
be repaired
- When mutated, p53 is not activated, and cell
continues to divide despite DNA damage
- Carriers may also show mild phenotype
Common sites:
Gross features:
- Bulbar (brainstem minus midbrain plus
cerebellum) telangiectasia
Histologic features:
- Loss of Purkinje cells in the cerebellum
(gradual)
Immunophenotype:
Marker:
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Sensitivity:
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Specificity:
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Molecular features:
- ATM gene mutation (11q22.3)
- Cytogenetic workup:
- 50 G-banded mets for:
- chromosome 7 and 14 rearrangements
- chromosome breaks and rearrangements
- run a control sample
- 5 G-banded mets for
constitutional karyotype
- Spontaneous chromosome abnormalities
- Fragments
- Chromatid gaps
- Chromatid breaks
- Dicentric chromosomes
- Telomeric dicentrics (2 chromosomes fused at
their telomeres)
- Up to 10% of PHA-stimulated lymphocytes (T
cells) display stable translocations and inversions (40-50 X higher than
normal)
- Often involving specific breakpoints on chr 7 and 14
- (most of these are locations of immune system
genes, some TCR genes)
- Inv(7)(p13q35)
- T(7;7)(p13;q35)
- T(7;14)(p13;q11)
- T(7;14)(q35;q11)
- T(X;14)(q28;q11)
- T(14;14)(q11;q32)
- Inv(14)(q11q32)
- These may become clonal and malignant
- B cells show high levels of apparently random
chromosome rearrangement
- Thes may be tested for in the lab
- Induced chromosomal abnormalities
- Blood cultures irradiated in G2 phase show
increase in chromatid-type damage (4-20 X normal)
- Chromatid breaks
- Chromatid gaps
- Also same thing at G0 phase but less pronounced
- Best test for A-T is G2 X-irradiation
- Enhanced frequency of chromatid-type damage
- Radiomimetic drugs can also be used but less
effective
- Bleomycin
- Neocarcinostatin
- Streptonigrin
- tallysomycin
- SCE levels are at normal rate
Other features:
- Ataxia (earliest sign – infancy or early
childhood)
- Immunodeficiency
- defective lymphocyte maturation and
proliferation
- IgA deficiency
- Predisposition to lymphoid tumours
- Particularly T cell lineage
- Lymphoma
- Lymphocytic leukemias
- Acute sensitivity to ionizing radiation –
development of tumours
- Serum:
- AFP elevated
- IgA and IgE reduced
maybe
References:
- Robbins & Cotran
Pathologic Basis of Disease (2005)
- CCMG Cytogenetic Practice Guidelines (2003)