Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K<sup>+</sup> channel

K Dedek

B Kunath

C Kananura

U Reuner

T Jentsch

O Steinlein

^{Zentrum für Molekulare Neurobiologie, Universität Hamburg, D-20246 Hamburg, Germany;}^{Institute of Human Genetics, Universitätskliniken Bonn, D-53111 Bonn, Germany; and}^{Department of Neurology, Universitätsklinikum Carl-Gustav-Carus, Technische Universität, D-01307 Dresden, Germany}

^{To whom reprint requests should be addressed. E-mail:}ed.grubmah-inu.hnmz@hcstneJ.

Communicated by Bert Sakmann, Max Planck Institute for Medical Research, Heidelberg, Germany

Received 2001 May 8; Accepted 2001 Aug 15.

Abstract

KCNQ2 and KCNQ3 are two homologous K^{channel subunits that can combine to form heterotetrameric channels with properties of neuronal M channels. Loss-of-function mutations in either subunit can lead to benign familial neonatal convulsions (BFNC), a generalized, idiopathic epilepsy of the newborn. We now describe a syndrome in which BFNC is followed later in life by myokymia, involuntary contractions of skeletal muscles. All affected members of the myokymia/BFNC family carried a mutation (R207W) that neutralized a charged amino acid in the S4 voltage-sensor segment of KCNQ2. This substitution led to a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. Myokymia is thought to result from hyperexcitability of the lower motoneuron, and indeed both KCNQ2 and KCNQ3 mRNAs were detected in the anterior horn of the spinal cord where the cells of the lower motoneurons arise. We propose that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explains why this particular KCNQ2 mutant causes myokymia in addition to BFNC.}

Abstract

Myokymia is characterized by spontaneous involuntary contraction of muscle fiber groups that can be observed as vermiform movement of the overlying skin. Electromyography typically shows continuous motor unit activity with spontaneous oligo- and multiplet-discharges of high intraburst frequency (myokymic discharges). Localized myokymic activity can have its cause in circumscribed disturbances of peripheral nerves or the central nervous system, e.g., in snake poisoning, hypoxia, radiation therapy, pontine tumors, or multiple sclerosis. Generalized myokymia, with or without associated muscle stiffness and delayed relaxation is a feature of Isaacs' syndrome (including acquired neuromyotonia) (1), episodic ataxia type 1 (2), and Morvan's fibrillary chorea (3). In some patients the spontaneous muscle movement occurs without apparent underlying cause, and the frequently positive family history (≈30%) indicates that genetic factors are among the possible causes of idiopathic generalized myokymia (IGM) (4). IGM affects men and women equally, and the disease often comes to their attention because of stiffness, cramps, weakness, and muscle twitching. The clinical features can include generalized myokymia, hyporeflexia, grip myotonia, and calf hypertrophy. The symptoms often improve with carbamazepine or phenytoin treatment.

There is evidence that one of the main pathophysiological mechanisms of peripheral nerve hyperexcitability in myokymia is a suppression of outward potassium currents. Anti-voltage-gated potassium channel antibodies are found in autoimmune Isaacs' syndrome, a disorder characterized by neuromyotonia, increased cramping, and excessive sweating (5, 6). Sera from patients with Isaacs' syndrome suppressed voltage-gated outward potassium currents in PC-12 cells (7) and induced repetitive firing of action potentials in posterior root ganglion cells (6). A similar suppression of voltage-gated K^{currents was observed with serum from a patient with Guillain-Barré syndrome, a disease often showing transient myokymic discharges during early stages (}8, 9). Antibodies to voltage-gated K^{channels are also detected in patients with Morvan's fibrillary chorea (}3).

Beside the autoimmune pathophysiology in Isaacs' syndrome, myokymic discharges can also be caused by inherited defects of K^{channels. Point mutations of the}Shaker-related voltage-gated K^{channel gene Kv1.1 (KCNA1) result in episodic ataxia type 1, an autosomal dominant neurological disorder characterized by continuous myokymia, episodic attacks of cerebellar ataxia, and, sometimes, partial epilepsy (}10). Some mutations lead to myokymia and epilepsy without ataxic episodes, or myokymia only, indicating differences in the sensitivity of the central and peripheral nervous system toward KCNA1-caused increased neuronal excitability (11).

We now describe a syndrome in which the patients are successively affected by benign familial neonatal convulsions (BFNC) and myokymia. This syndrome is caused by an amino acid exchange within the putative voltage sensor of the K^{channel KCNQ2. Other mutations in}KCNQ2 (12, 13) as well as in KCNQ3 (14), whose gene products can form heterooligomeric K^{channels (}15–17), were previously shown to cause BFNC without signs of myokymia. The electrophysiological analysis of the present KCNQ2 mutation indicates a more severe change of channel properties than previously observed (15) with mutations causing neonatal epilepsy. This observation probably explains the additional presence of myokymia. The BFNC/myokymia syndrome is another example for the important role of K^{channels in regulating both central and peripheral nerve excitability.}

Acknowledgments

We thank Christian Hübner for the spinal cord preparations, Irm Hermans-Borgmeyer for help with in situ hybridizations, and Jens Stoodt for technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft to O.K.S. (SFB400/B5, STE769/2–1), and from the European Community and the Prix Louis-Jeantet de Médecine to T.J.J.

Acknowledgments

Abbreviations

BFNC	benign familial neonatal convulsions
EMG	electromyography
EEG	electroencephalography
WT	wild type

Abbreviations

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