KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients

Abstract

Objective: To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments.

Methods: We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype-phenotype relationships in these and 70 previously described patients.

Results: The mean seizure onset age was 1.8 ± 1.6 (SD) days. Of the 20 EEGs obtained within a week of birth, 11 showed burst suppression. When new seizure types appeared in infancy (15 patients), the most common were epileptic spasms (n = 8). At last follow-up, seizures persisted in 9 patients. Development was delayed in all, severely in 14. The KCNQ2 variants identified introduced amino acid missense changes or, in one instance, a single residue deletion. They were clustered in 4 protein subdomains predicted to poison tetrameric channel functions. EZO use (assessed by the treating physicians and parents) was associated with improvement in seizures and/or development in 3 of the 4 treated before 6 months of age, and 2 of the 7 treated later; no serious side effects were observed.

Conclusions: KCNQ2 variants cause neonatal-onset epileptic encephalopathy of widely varying severity. Pathogenic variants in epileptic encephalopathy are clustered in "hot spots" known to be critical for channel activity. For variants causing KCNQ2 channel loss of function, EZO appeared well tolerated and potentially beneficial against refractory seizures when started early. Larger, prospective studies are needed to enable better definition of prognostic categories and more robust testing of novel interventions.

Classification of evidence: This study provides Class IV evidence that EZO is effective for refractory seizures in patients with epilepsy due to KCNQ2 encephalopathy.

Figure 1.. Type and distribution within KCNQ2 protein of variants in self-limiting epilepsy vs epileptic encephalopathy

Cartoon of KCNQ2 transmembrane topology, including intracellular amino (N) and carboxy (C) terminals, 6 transmembrane segments (S1–S6), and a pore loop between S5 and S6 which partly enters the membrane. The calmodulin-binding segments within the intracellular C-terminal domain are indicated. (A) Mutations found in BFNE/BFNIS/BFIS cases are distributed among all areas of the polypeptide sequence. Each symbol (n = 98) represents a de novo case or a pedigree, placed at the location within the channel polypeptide corresponding to the sequenced genetic variant. Orange symbols (n = 41) are missense variants. Yellow symbols are all other variant types (i.e., loss of start codon, insertions or deletions changing frame, and premature stop codon). Encircled regions, with the exception of the S4 helix, do not appear enriched in missense variants. (B) In patients with KCNQ2 encephalopathy, mutations are nearly always single nucleotide substitutions resulting in a single amino acid change. In one instance (cases 19 and 20 of this series, 2 identical twins), a single amino acid is deleted within an α-helix. Each red sphere represents an unrelated case. Encircled are the 4 hot spots for variants leading to epileptic encephalopathy: the S4 voltage-sensor, the pore, the proximal C-terminal domain that binds phosphatidylinositol 4,5-bisphosphate (PIP2) and calmodulin (CaM A), and the more distal domain which binds calmodulin (CaM B). Variant details for (A) are listed in table e-2; variant details for (B) are listed in table e-3.

Figure 2.. EZO levels in infants and young children compared to adults at similar doses

Adult mean (middle line in bar) and 95%–5% range (top and bottom of bar) EZO levels are shown, along with the levels measured in this study. Adult values at 1 and 8 hours after dosing are taken from a pharmacokinetic model fit to serum EZO levels collected during regulatory trials. Adult doses of 300 mg TID (A) and 400 mg TID (B) correspond to 11.8 and 15.8 mg/kg/d, respectively (mean adult study patient weight was 76 ± 16.5 kg, n = 1,219). EZO levels measured in infants and young children, indicated by circles (red, age 6–16 months; blue, age 19 months to 6 years) were within the range observed for comparable doses in adults, and means were similar or somewhat higher than those measured in adults.