Altered sodium channel behaviour causes myotonia in dominantly inherited myotonia congenita

The cause of increased excitability in autosomal dominant myotonia congenita (MyC) was studied in resealed > 3-cm long segments of muscle fibres from eight patients. Three hours after biopsy only about 50% of the fibre segments had regained a normal resting potential. This differs from our experiences with normal muscle or other disorders of myotonia (e.g. recessive generalized myotonia) where nearly all cut fibres reseal and repolarize during this time. When the depolarized MyC fibre segments were placed in a solution containing 1 μM tetrodotoxin (TTX) they repolarized to -80 to -90 mV. In fibre segments with normal resting potential, in the absence of TTX, spontaneous myotonic runs were recorded intracellularly, occasionally with double spikes. For only one of the eight patients, the Cl^- conductance was reduced (50% of the total membrane conductance vs the usual 75%), for the rest of the patients the steady-state current-voltage relationship was normal. Sodium currents through single membrane channels were recorded with a patch clamp. For every patient re-openings of the Na⁺ channels were observed throughout 10-ms depolarizing pulses. These are very uncommon in normal muscle. At potentials positive to the resting potential, the duration of the re-openings increased, but the current amplitude was the same. It is concluded that in myotonia congenita re-openings of Na⁺ channels are the major cause of hyperexcitability and that Cl^- conductance is normal. If it is reduced in rare cases, it may potentiate the myotonia.