Despite the reduced nuclear localization of the V335G mutant protein, the basal ADPr levels remain unchanged and nuclear ADPr is highly elevated after stress implicating the loss of nuclear ARH3 activity following cellular stress in the pathology of patients with ADPRHL2 mutations resulting in CONDSIAS or related disorders. Here, ADPRS is linked to neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures.