A natural mutation, H493R, in the TDP1 gene leads to a neurodegenerative disease called spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1), and the cause of this disease is not a loss of function or activity of TDP1 but a gain of function: the formation of stable covalent complexes of the mutant enzyme with DNA (Figure 2E) [11,12]. The gene discussed is TDP1; the disease is axonal neuropathy.