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Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations

From Institut für Angewandte Physiologie (T.V.W., K.J.-R., M.G., F.L.-H., H.L.) and Neurologische Klinik (T.V.W., M.G., H.L.), Universität Ulm; and Abteilung Klinische Neurophysiologie (W.P.), Universität Göttingen, Germany.

Address correspondence and reprint requests to Prof. Dr. med. Holger Lerche, Neurologische Klinik und Institut für Angewandte Physiologie, Universität Ulm, Zentrum Klinische Forschung, Helmholtzstr. 8/1, 89081 Ulm, Germany holger.lerche{at}uni-ulm.de

Background: Peripheral nerve hyperexcitability (PNH) is characterized by muscle overactivity due to spontaneous discharges of lower motor neurons usually associated with antibodies against voltage-gated potassium channels. PNH may also occur in combination with episodic ataxia or epilepsy caused by mutations in K_V1.1 or K_V7.2 channels. Only one PNH-associated mutation has been described so far in K_V7.2 (R207W), in a family with both PNH and neonatal seizures.

Methods: PNH was characterized by video and electromyography. The KCNQ2 gene was sequenced and K_V7.2 channels were functionally characterized using two-microelectrode voltage-clamping in Xenopus oocytes.

Results: In a patient with PNH without other neurologic symptoms, we identified a novel KCNQ2 mutation predicting loss of a charged residue within the voltage sensor of K_V7.2 (R207Q). Functional analysis of both PNH-associated mutants revealed large depolarizing shifts of the conductance-voltage relationships and marked slowing of the activation time course compared to wild type (WT) channels, less pronounced for R207Q than R207W. Co-expression of both mutant with WT channels revealed a dominant negative effect reducing the relative current amplitudes after short depolarizations by >70%. The anticonvulsant retigabine, an activator of neuronal K_V7 channels, reversed the depolarizing shift.

Conclusions: Mutations in KCNQ2 can cause idiopathic PNH alone and should be considered in sporadic cases. Both K_V7.2 mutants produce PNH by changing voltage-dependent activation with a dominant negative effect on the WT channel. This distinguishes them from all hitherto examined Kv7.2 or K_V7.3 mutations which cause neonatal seizures by haploinsufficiency. Retigabine may be beneficial in treating PNH.

Abbreviations: BFNC = benign familial neonatal convulsions; EA-1 = episodic ataxia with myokymia; EMG = electromyography; PNH = peripheral nerve hyperexcitability; VGKC = voltage-gated potassium channels; WT = wild type.

Supplemental data at www.neurology.org

See also page 2036

e-Pub ahead of print on September 12, 2007, at www.neurology.org.

Supported by grants from the Bundesministerium für Bildung und Forschung (BMBF/NGFN2: 01GS0478), The European Union (EPICURE: LSH-CT-2006-037315) FP 6-Thematic priority LIFESCIHEALTH, the Landesforschungsschwerpunkt Baden-Württemberg (1423/74), the Fritz-Thyssen-Stiftung, and the Deutsche Forschungsgemeinschaft (DFG: Le1030/9-1) (to HL). TVW was supported by a fellowship from the University of Ulm. HL is a Heisenberg fellow of the DFG.

Disclosure: The authors report no conflicts of interest.

Received March 15, 2007. Accepted in final form May 21, 2007.

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