Nonsyndromic cerebellar ataxias associated with disorders of DNA single-strand break repair.

Hereditary cerebellar ataxias are genetically and clinically heterogeneous, and an important subgroup of these disorders are caused by defects in DNA repair. These conditions are inherited in an autosomal-recessive fashion, with the main clinical feature being ataxia due to cerebellar degeneration. The nervous system in general, and the cerebellum in particular, is especially susceptible to DNA damage, although the underlying mechanism for this vulnerability has not been fully elucidated. Defects in DNA repair result in progressive accumulation of oxidative damage to DNA. This damage causes loss of normal neuronal function which may in turn cause defense mechanisms involved in maintaining genomic integrity to trigger programmed cell death and neuronal loss. Disorders of DNA single-strand break repair almost exclusively impact the cerebellum, highlighting the critical requirement for genomic stability in this specific tissue. One possible explanation is due to the brain's dependence on high levels of oxidative metabolism and subsequent generation of free radicals, which have the potential to cause single-strand breaks in DNA. A compounding factor is that neurons do not possess alternative DNA repair processes which are present in other tissues, and therefore may be comparatively more vulnerable to defects in the DNA single-strand break repair machinery. Both neurodevelopmental and neurodegenerative diseases arise from mutations in genes coding for proteins involved in DNA repair, underscoring the importance of this process to normal cerebellar function in children and adults.