KCNQ2 encephalopathy: Emerging phenotype of a neonatal epileptic encephalopathy

Objective: KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS).
A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has
not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic
encephalopathies with an early onset and whether a recognizable phenotype exists.
Methods: We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor
retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail.
Results: We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80; 10%); 6 mutations arose de novo.
One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients
had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally
resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor
impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform
activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal
ganglia and thalamus that later resolved.
Interpretation: KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic
encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2
screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.