Objective: To characterize neurodevelopmental phenotypes in PI3K-AKT-mTOR pathway–related disorders and report interim safety/feasibility of mTOR inhibition, focusing on a prospective PPP2R5D-related Jordan syndrome cohort, supported by a Smith-Kingsmore syndrome (SKS) case and contextual evidence from tuberous sclerosis complex (TSC). Methods: We established a registry and standardized baseline phenotyping. Fifteen individuals with PPP2R5D-related Jordan syndrome underwent clinical assessment, EEG, and MRI review when available. Fourteen initiated sirolimus per protocol with remote safety follow-up at 1 month. Magnetoencephalography (MEG) acquisition was implemented to build quantitative brain network endpoints; source analyses are ongoing. One genetically confirmed SKS patient was followed longitudinally for >2 years under sirolimus with therapeutic drug monitoring (TDM). Results: In the PPP2R5D cohort (n=15), global developmental delay was universal (100%). Common features included hypotonia (73.3%), macrocephaly (66.7%), EEG abnormalities (53.3%), autism spectrum features (40.0%), and MRI abnormalities (46.7%); p.E198K accounted for 60.0%. Among 14 sirolimus-treated participants, no serious adverse events were observed within the first month. Valid MEG recordings were obtained in 13 participants. In the SKS case (MTOR c.5663T>C, p.F1888S), sirolimus with TDM was associated with disappearance of abnormal EEG, improved seizure-risk profile, and good tolerability over >2 years. Conclusions: Early data support feasibility and short-term safety of sirolimus initiation in PPP2R5D-related Jordan syndrome and establish a foundation for MEG-based quantitative endpoints in future efficacy evaluation.