|I do not believe that there is any significant difference between two 4GB sticks and four 2GB sticks. the main difference is that you then have the option of adding even more memory if needed when you go with the two 4GB sticks.|
On your second question, if you go with the two 4GB sticks AND the 4GB and 2GB sticks are compatible (same voltage, latency, and timings), then yes, you can run 2x4GB + 2x2GB together. If they do not work together, try swapping slots, if that does not work, remove the 2GB sticks and either stay with 8GB or purchase another pair exactly the same.
This is assuming you have a 64bit operating system. If you have a 32bit operating system, you can use only up to 4GB but only actually use between 3.2GB and 3.5GB of the 4GB typically.
You have to be a little bit crazy to keep you from going insane.