Add-on gabapentin improved seizure control and cognition in three KCNQ2-DEE patients with severe loss-of-function S6-segment variants, but did not improve electroencephalographic outcomes in one patient with a mixed S4 variant.
Observational (n=4)
Open-label
No
Does gabapentin improve seizure control and cognition in patients with KCNQ2-developmental epileptic encephalopathy?
Gabapentin may serve as a potential precision therapy for a subset of KCNQ2-DEE patients, particularly those with severe loss-of-function variants in the S6 domain.
KCNQ2 ‑related developmental epileptic encephalopathy ( KCNQ2 ‑DEE) is characterized by intractable epilepsy, cognitive impairment, and behavioral problems, highlighting the urgent need for precision therapies. This study aimed to promote the clinical application of gabapentin, a known Kv7 channel opener, in KCNQ2 ‑DEE by evaluating its efficacy in four patients carrying different KCNQ2 variants. Three patients with S6‑segment variants (p.A294V, p.F305I, p.F305del) showed clinical improvement in both seizure control and cognition following add‑on gabapentin. In contrast, the patient with the S4 variant p.L200P did not exhibit electroencephalographic improvement, although some developmental progress was noted. Functional analysis in homomeric expression systems revealed that the three S6 variants produced negligible currents, consistent with severe loss‑of‑function (LoF). The p.L200P variant, however, showed smaller currents than wild‑type (WT) at voltages below + 20 mV, larger currents at higher voltages, slower activation kinetics, and a depolarized shift in half‑activation voltage (V₁/₂), indicating a mixed LoF/gain‑of‑function phenotype. In heteromeric Kv7.2/Kv7.3 channels, p.L200P retained significantly higher current compared to the S6 variants, which may explain the poorer response to gabapentin in this patient. Together, these findings further support gabapentin as a potential precision therapy for a subset of KCNQ2 ‑DEE patients, addressing an unmet clinical need.
Xiong et al. (Fri,) conducted a observational in KCNQ2-developmental epileptic encephalopathy (KCNQ2-DEE) (n=4). Gabapentin was evaluated on Seizure frequency and cognitive changes. Add-on gabapentin improved seizure control and cognition in three KCNQ2-DEE patients with severe loss-of-function S6-segment variants, but did not improve electroencephalographic outcomes in one patient with a mixed S4 variant.
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