The loss of the Gadget Graveyard and the death of Berenice. Especially if you watched the cartoon first and got used to having them around. While Status Quo may be God in an episodic show, here, it turns out, is another matter entirely.
The ending of High Wire. After everything has gone south for the twins, they trudge back home and find it's no longer theirs. The illustration of them staring forlornly at the notice on their door is the sad and bleak note on which this book ends.
The twins separating at the end of Frost Bites.
At one point while dealing with everything, the twins suddenly wonder where their parents are. It's the first time their Parental Abandonment is brought up, and it's an unexpected somber moment that shows just how lost and on their own the twins are right then.
The Animated Series
In Its A Mad, Mad, Mad, Mad Scientist, Edgar wins a chance to become the apprentice of a famous scientist who he has idolized for a long time and tries to impress him by cloning himself. The clones get out of hand and attack Edgar, Ellen and the scientist. The scientist decides to cancel Edgars apprenticeship. Edgar is visibly saddened by this.
"Crushed" has Edgar meet a girl named Ursula and fall in love with her. It turns out that she's a Gold Digger who wants to steal his inventions and sell them to get rich. Ellen finds out about this and tries to warn Edgar, but Edgar thinks she's lying and doesn't believe her. Eventually, Ursula reveals her true plans to Edgar and steals the satchel, leaving Edgar alone and crying.
Edgar: I thought you loved me...
Episodes like "The Great Edgarini" and "Crushed" show just how much Edgar wishes to be loved; as far as we can tell, the only people in the series who actually like him are Ellen and Pet.