You know, I've had plenty of let-downs during my time gaming. Off the top of my head, seeing the Super Mario Bros. movie as a child, playing Perfect Dark Zero, and seeing Capcom -- now Konami, too -- deteriorating are among them.
But you're right. Nothing comes close to Other M. Until 2010, Metroid truly was a sacred cow. Each game in the core series wasn't just "good" or "great" -- each game was
sublime. Even Nintendo's two spin-offs were quality (say what you will about Hunters, but playing an online first-person shooter on a handheld in 2006 felt like the god-damned future). In my eyes, it was not only my favorite series, but it was untarnished.
I won't get into what made Other M such a blemish, as we've all been there before, but I will say that -- to this day -- I'm still in shock at exactly how abhorrent a blemish it is. Much of it is to do with the messiness of the original creator returning to his creation only to present his audience with something so shockingly awful that it shakes the whole canon to its core (we all know the very apt analogy to make here, as it mirrors the handling of a certain other media property). It somehow gives the stench a greater feeling of authenticity, as we've seen the current, creator-endorsed interpretation creep into other games as the "official" representation of Metroid.
So, yes, "nothing comes close." I can't think of another gaming-related disappointment that has had a more significant effect on me, anyway.
In the words of Ordell Robbie,
"What the fuck happened to you, Metroid? Your ass used to be beautiful."