Disk space has never been an issue to me in relation to the registry and I do not know what you consider to be the 'practical implications'.
You are right when you refer to how it 'feels', I know a lot of people are very much against registry cleaners and I would not try to change their minds.
I also know that you can do a lot of damage with them, some more than others.
My personal view is that provided you make backups, I use ERUNT, and get to learn what you can and cannot do with a particular program you should not have any problems.
Do they actually make a difference?
On XP my answer would be yes, especially over a period of time.
Certainly not as much but then again on the computer I have 7 installed on it would probably take quite a lot to slow it down compared to those I have XP on.
I also defrag the registries once a month, on XP that makes a very noticeable difference (on XP Mode as well), again not noticeably on 7.
I have followed this practice for years, using the same programs for most of that time, and never had a problem because of it.
Would I advise others to do the same?
Not unless they knew what they were doing and were prepared to take the time that I did to test whatever program they chose to use, as well as taking adequate precautions against the possibility of problems.