Novel ADPRS Missense Variant (p.Leu162Pro) Causes Stress-Induced Childhood-Onset Neurodegeneration With Ataxia and Seizures

ADP-ribosylation is a post-translational modification critical for DNA repair, chromatin remodeling, and cellular stress responses. The enzyme ARH3/ADPRHL2 (encoded by the ADPRS gene) is a member of the ADP-ribosyl-acceptor hydrolase family and plays a pivotal role in the removal of mono-ADP-ribosylation, particularly in response to DNA damage. Variants in the ADPRS gene cause stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS). Here, we present the case of an 11-year-old Brazilian girl with compound heterozygous variants in ADPRS, including a novel missense variant, c.485T>C; p.Leu162Pro, of unknown clinical significance. This study aimed to determine the pathogenicity of this variant and to test the molecular rationale of using minocycline as a therapeutic strategy for CONDSIAS cases.