A Review of Variable Phenotypes and Neurodevelopmental Outcomes

Overview of Various KCNQ2 Epilepsy Mutation Types and Outcomes

KCNQ2 gene codes for parts of the potassium channel that limits repetitive signaling by the neurons. Mutations in this single gene can lead to very different paths of development and seizure activity.

There are three different categories of outcomes for those affected: 1) Benign Familial Neonatal Convulsions (BFNC), 2) Benign Familial Infantile Convulsions (BFIC), or 3) neonatal epileptic encephalopathy.  For all of these KCNQ2 childhood epilepsies, seizures usually occur within the first week after birth.

Patients with BFNS or BFIC have seizures early on, but they usually spontaneously disappear by one year and development for these children is good.

Most patients with neonatal epileptic encephalopathy present with a specific pattern on their EEG (burst suppression or multiple focal spikes) and generalized tonic, or grand mal, seizures. There are three categories of epileptic activity for these patients: 1) the development of West Syndrome, with epileptic spasms in a small portion of patients, 2) relatively good control with anti-epileptic medications, 3) seizures spontaneously disappear after the patient turns one year old. The MRI in all of these categories is typically relatively normal. However, patients have lasting and significant developmental delays.

Most of the cases of neonatal epileptic encephalopathy are de novo mutations, occurring spontaneously and not inherited from the parents. The KCNQ2 mutation occurs globally, regardless of ethnicity.

Mutations in the KCNQ2 gene are the cause of about 8% of childhood epilepsies not caused by brain trauma. There are over 80 different genotypes or specific variations in the mutation in KCNQ2. The majority of these mutations (69%) are missense mutations, meaning part of the “code” in the gene is replaced with another random sequence. Other mutations are indel 16 (21%), meaning there is an insertion or deletion of nucleotides in the middle of a sequence, or splice-site mutations (10%), meaning there is a mutation at the end of a sequence.

Depending on the specific variant, the mutation can affect a different part of the potassium channel. Which part of the potassium channel is affected appears to be related to the severity of the outcome (seizure severity and degree of disability) for the patient. However, there is not always a direct relationship between the specific variant of the KCNQ2 mutation and the outcome for the patient. For example, there have been cases of a family in which all inherited the same variant, but different members of the family had very different outcomes.  It is not understood exactly why this would happen, but there is a theory that it could be due to an interaction between KCNQ2 and other genes or due to environmental factors beyond the DNA.

Treatment approach of patients suffering from KCNQ2 related epilepsy is not dependent of which variant or severity of outcome the patient has. Most cases can be controlled with phenobarbital, oxcarbazepine, vigabatrin, and valproate. Laboratory studies of retigabine (also known as Potiga or ezogabine) showed that it reversed the functional electrical current changes in cells. Additional studies of this and other treatments are recommended for this severe disease.

Conclusion: The relationship between specific mutations in KCNQ2 and the severity of seizures and disability in patients is still not well understood by experts and additional studies are needed.

Lee, I., Yang, J., and Li, S. (2018) KCNQ2-Associated Epilepsy: A Review of Variable Phenotypes and Neurodevelopmental Outcomes Neuropsychiatry, 8(1): 318-323. doi:10.4172 1000353