Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant

Abstract

Variants in KCNQ2 encoding for K_v 7.2 neuronal K⁺ channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2-related epilepsy: infantile spasms without prior neonatal seizures associated with a gain-of-function gene variant. With use of an international registry, we identified four unrelated patients with the same de novo heterozygous KCNQ2 c.593G>A, p.Arg198Gln (R198Q) variant. All were born at term and discharged home without seizures or concern of encephalopathy, but developed infantile spasms with hypsarrhythmia (or modified hypsarrhythmia) between the ages of 4 and 6 months. At last follow-up (ages 3-11 years), all patients were seizure-free and had severe developmental delay. In vitro experiments showed that Kv7.2 R198Q subunits shifted current activation gating to hyperpolarized potentials, indicative of gain-of-function; in neurons, K_v 7.2 and K_v 7.2 R198Q subunits similarly populated the axon initial segment, suggesting that gating changes rather than altered subcellular distribution contribute to disease molecular pathogenesis. We conclude that KCNQ2 R198Q is a model for a new subclass of KCNQ2 variants causing infantile spasms and encephalopathy, without preceding neonatal seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Keywords: Epileptic encephalopathy; Gene variants; Genotype-phenotype; KCNQ2; Potassium channels; axon initial segment; retigabine.

Figure 1. Functional properties of channels incorporating Kv7.2 R198Q subunits

(A) Topological representation of a Kv7.2 subunit, showing the six transmembrane segments (S₁-S₆) and the intracellular N- and C-termini. Arrow indicates the location of the variant investigated. (B) Sequence alignment of S₄ segments of the indicated K⁺ channel subunits (www.ebi.ac.uk/Tools/psa/). (C) Macroscopic currents from Kv7.2 and Kv7.2 R198Q channels. Current scale, 200 pA; time scale, 200 ms. (D) Conductance/voltage curves; continuous lines are Boltzmann fits of the experimental data. (E) Normalized and superimposed current traces from the indicated channels. (F) Time constants for ionic current activation (filled symbols) and deactivation (empty symbols) (n=6-9) for Kv7.2 and Kv7.2 R198Q channels. (G) Conductance/voltage curves for Kv7.2+Kv7.3 and Kv7.2+Kv7.2 R198Q+Kv7.3 heteromeric channels. Continuous lines are Boltzmann fits of the experimental data.