Pathology

Inherited as an autosomal recessive disorder.

• gene locus has been mapped to chromosome 11q - this was found to enclode a homologue of phosphatidylinositol 3-kinase which is involved in signal transduction between the cell surface and nucleus
• the mechanism to how the genotype expresses the phenotype is unknown

Neuropathologically

• this disease is characterized by cortical cerebellar degeneration
  • especially, there is a loss of Purkinje cell and granular cells from the cerebellar cortex

Notes:

• exposure of cells to ionizing radiation gives rise to a range of lesions in DNA including potentially lethal double strand breaks - as a result of this damage a number of processes are initiated or activated including recognition of the lesions, recruitment of DNA repair proteins, signaling to cell cycle checkpoints, transcriptional activation and in some cases apoptotic death
  • the protein mutated in ataxia-telangiectasia, ATM, plays a central role in a number of these processes
  • ATM is rapidly activated by ionizing radiation

Reference:

1. Furtado S et al. A review of the inherited ataxias: recent advances in genetic, clinical and neuropathologic aspects. Parkinsonism & Related Disorders; 4 (4):161-169.
2. Lavin MF et al.Functional consequences of sequence alterations in the ATM gene. DNA Repair (Amst). 2004; 3(8-9):1197-205