In some cases, Landau-Kleffner syndrome is thought to be caused by mutations(changes) in the GRIN2A  gene. This gene provides instructions to the body to make a protein that sends signals to the nerve cells (neurons) in the brain. When these signals are not being transmitted properly, they may affect the ability to understand or express language. These signals may also cause receptors in the brain to be turned on abnormally, resulting in seizures. It has been proposed that the seizures associated with LKS may cause damage to the parts of the brain responsible for speech, but this hypothesis has not been confirmed.

In about 80% of people diagnosed with LKS, no mutation is found in the GRIN2A gene. In these cases, it is thought that LKS could be caused by mutations in other genes or an interaction between genes and the environment. It has also been proposed that in some cases LKS may be the result of an autoimmune response that occurs when the body attacks itself as if it were an infection.