I had this problem when I migrated from MO to MO2, but I never found the cause. It fixed itself when I started with a fresh install of MO2 and moved my profile over.
I haven't been able to play FNV in a couple of weeks, so when I re-started last night, the first thing I did was check mods for updates. There was one mod that had been updated, so I updated it and launched the game. All was fine, then I quit for a little while to eat. When I came back and fired up FNV I could immediately tell something wasn't right. The custom INI settings from the falloutcustom.ini wasn't working. I quit the game, started MO2, checked the INI Editor at the top it said "Editing Global INIs." I remembered the problem I had before and clicked the Configure Profiles button, and my current game's profile had Local Game Settings unchecked. I checked it, started the game and all was good again. I played for a few hours and quit for the night.
When I started it up again today, Local Game Settings was once again was disabled. Every time I check the box, launch the game, when I quit the game the Local Game Settings is unchecked again. It doesn't matter if I launch the game from the desktop shortcut or from within MO2.