My best guess: onboard fire.
First action is to turn off everything electrical you can (trying to pinpoint which electrical system is the source takes too long). While you're doing that the other guy points the aircraft at the nearest runway and tries to get there fast. In this case,
http://en.wikipedia.org/wiki/Swissair_Flight_111 , time from first smell of smoke to impact was 21 minutes. If you get a chance to tell ATC, good, but that is low priority.
The reported climb to 45000 feet could have been an attempt to starve the fire of oxygen- by the look of things this may have worked, but either this or some combination of fumes killed everyone on board. The aeroplane then flew on autopilot in the last direction it happened to be pointing until it ran out of fuel.
Please note, this is just a hypothesis which appears to tie in with some of the reported radar observations. Until the CVR and FDR are found (if they ever are) it is impossible to tell. There was, however, a cargo of lithium batteries on board.