Myotonic discharges discriminate chloride from sodium muscle channelopathies

Highlights

• Non-dystrophic myotonic syndromes represent a heterogenous group of diseases.

• These syndromes can be separated into chloride and sodium channelopathies.

• Myotonic discharge characteristics discriminated chloride from sodium channelopathy patients.

• Myotonic discharges of a single muscle guide toward a molecular diagnosis.

Abstract

Non-dystrophic myotonic syndromes represent a heterogeneous group of clinically quite similar diseases sharing the feature of myotonia. These syndromes can be separated into chloride and sodium channelopathies, with gene-defects in chloride or sodium channel proteins of the sarcolemmal membrane. Myotonia has its basis in an electrical instability of the sarcolemmal membrane. In the present study we examine the discriminative power of the resulting myotonic discharges for these disorders.

Needle electromyography was performed by an electromyographer blinded for genetic diagnosis in 66 non-dystrophic myotonia patients (32 chloride and 34 sodium channelopathy). Five muscles in each patient were examined. Individual trains of myotonic discharges were extracted and analyzed with respect to firing characteristics.

Myotonic discharge characteristics in the rectus femoris muscle almost perfectly discriminated chloride from sodium channelopathy patients. The first interdischarge interval as a single variable was longer than 30 ms in all but one of the chloride channelopathy patients and shorter than 30 ms in all of the sodium channelopathy patients. This resulted in a detection rate of over 95%.

Myotonic discharges of a single muscle can be used to better guide toward a molecular diagnosis in non-dystrophic myotonic syndromes.

Introduction

Non-dystrophic myotonic syndromes (NDMs) form a heterogeneous group of skeletal muscle disorders with myotonia as a key symptom. NDMs are caused by mutations in genes encoding the voltage gated muscle chloride (CLCN1) or sodium channel (SCN4A) [1]. Mutations in CLCN1 are responsible for recessive (RMC) and dominant myotonia congenita (DMC) and mutations in SCN4A for paramyotonia congenita (PMC), potassium aggravated myotonias (PAM) and hyperkalemic periodic paralysis with myotonia (HyperPP) [2], [3]. As suggested by Rudel et al., PAM diagnosed without a potassium-loading test is referred to as a sodium-channel myotonia (SCM) [4]. Based upon the above mentioned classification, NDMs can be subgrouped into chloride channelopathies (ClCh) and sodium channelopathies (NaCh) [5].

Before genetic testing, the various types of NDMs were based on clinical characteristics. MC was first described in 1876 by Thomsen, who suffered from the disease himself [6]. He described the myotonic stiffness, the nonprogressive character, and the dominant inheritance of the disease. In the late 1950s, Becker recognized a recessive form of MC with a more generalized myotonia than in the dominant form [7]. It was subsequently shown that membrane resistance of muscle fibers of myotonic goats was considerably increased at rest [8], which was later found to be due to a strongly reduced chloride conductance [9].

Adrian and Bryant pointed out that the discharge of a myotonic muscle fiber arises from a cumulative after-depolarization, large enough to initiate a self-maintaining activity. The development of this after-depolarization depends on the integrity of the transverse tubular system [10]. Needle electromyographical (EMG) recordings in patients with NDMs show myotonic discharges. These discharges are abnormal forms of insertional or spontaneous activity of muscle fibers and are caused by electrical instability of the muscle fiber membrane.

Until now, in order to discriminate the different NDMs, electrophysiological tests focused on stimulation studies [11], [12], [13]. Basically, these studies and surface EMG studies [14] show the inexcitability of the myotonic muscle membrane and not the hyperexcitability [3] of the muscle membrane causing myotonia. Nowadays, clinical characteristics [5], various types of repetitive nerve stimulation patterns [12], [13] and a combination of both [15] are used to propose guidelines for focused genetic testing in patients with NDMs. Quantified differences in myotonic discharges among ClCh and NaCh were not described [12], [13].

The purpose of the present study is to test the hypothesis that characteristics of the myotonic discharges are different in ClCh and NaCh, based on the underlying physiological cause. If found correct, these discharge differences can be used to separate ClCh from NaCh quickly. To our knowledge, this is the first study in which myotonic discharge characteristics are precisely quantified and systematically analyzed on a relatively large number of patients with genetically confirmed NDMs.