Case report: Marked electroclinical improvement by fluoxetine treatment in a patient with KCNT1-related drug-resistant focal epilepsy

Abstract

Variants in KCNT1 are associated with a wide spectrum of epileptic phenotypes, including epilepsy of infancy with migrating focal seizures (EIMFS), non-EIMFS developmental and epileptic encephalopathies, autosomal dominant or sporadic sleep-related hypermotor epilepsy, and focal epilepsy. Here, we describe a girl affected by drug-resistant focal seizures, developmental delay and behavior disorders, caused by a novel, de novo heterozygous missense KCNT1 variant (c.2809A > G, p.S937G). Functional characterization in transiently transfected Chinese Hamster Ovary (CHO) cells revealed a strong gain-of-function effect determined by the KCNT1 p.S937G variant compared to wild-type, consisting in an increased maximal current density and a hyperpolarizing shift in current activation threshold. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant KCNT1 channels. Treatment of the proband with fluoxetine led to a prolonged electroclinical amelioration, with disappearance of seizures and better EEG background organization, together with an improvement in behavior and mood. Altogether, these results suggest that, based on the proband's genetic and functional characteristics, the antidepressant drug fluoxetine may be repurposed for the treatment of focal epilepsy caused by gain-of-function variants in KCNT1. Further studies are needed to verify whether this approach could be also applied to other phenotypes of the KCNT1-related epilepsies spectrum.

Keywords: KCNT1; drug repurposing; epilepsy; fluoxetine; next generation sequencing.

Figure 1

Patient’s pharmacological treatment, EEG traces before and after fluoxetine therapy. Schematic representation of the proband’s complex pharmacological treatment over time [legend of ASMs: acetazolamide (ACZ), carbamazepine (CBZ), clobazam (CLB), clonazepam (CNZ), diazepam (DZP), lamotrigine (LTG), methyl bromide (MB), nitrazepam (NZP), oxcarbazepine (OXC), topiramate (TPM)] (A). EEG trace assessed before fluoxetine treatment, showing diffuse, low-amplitude, theta background activity, and bitemporal epileptiform abnormalities with alternating prevalence of side (red squares, B). EEG during treatment with fluoxetine, revealing the improvement of background activity with alpha-slow rhythm of increased amplitude, together with disappearance of epileptic activity (C).

Figure 2

Functional and pharmacological characterization of KCNT1 and KCNT1 p.S937G channels. Topological representation of a KCNT1 subunit and localization of the p.S937G variant (A). Partial alignment of KCNT1 protein among species (B). Representative family traces recorded in cells expressing the indicated channels in response to the voltage protocol shown below the leftmost traces (C). Current scale: 1 nA; time scale: 50 ms. Average of I_INST/I_STEADY-STATE ratios (D), current densities (E), and conductance/voltage curves (F) measured in cells expressing the indicated channels. Representative traces recorded in response to the ramp protocol shown below the leftmost traces in cells expressing the indicated channels in control solution (indicated with C), after 2-min exposure to 100 μM quinidine (QND; blue traces in panel G) or 10 μM fluoxetine (FLX; green traces in panel H), or upon drug washout (indicated with W). Current scale: 500 pA; time scale: 200 ms. ^* = p < 0.05 versus KCNT1; ^** = p < 0.05 versus KCNT1 + S937G.