Using the improved Nme2-ABE variants, we found that we can correct two common mutations that cause Rett syndrome [c.502 C > T (p.R168X) and c.916 C > T (p.R306C)] with little or no bystander editing and introduce additional therapeutically relevant edits by targeting splice sites for DMD and mouse Cln3. Lastly, we find that the domain-inlaid Nme2-ABE is highly active in vivo when delivered via single-AAV vector systems. Here, NME2 is linked to atypical Rett syndrome.