Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients

Non-dystrophic myotonias (NDM) are rare hereditary neuromuscular diseases caused predominantly by mutations in CLCN1 or SCN4A, respectively coding for the voltage-gated muscle channels ClC-1 and NaV1.4 [1, 2]. More than 150 CLCN1 and at least 100 SCN4A myotonia-associated gene variants are currently known [3]. The common feature of these diseases is the altered electrical excitability of the muscular membrane [4]. In most cases, mutations lead to hyperexcitability, which manifests itself clinically as delayed muscle relaxation after voluntary contraction, also called myotonia [5‐7]. The pathophysiological mechanism of myotonia is mainly related to reduced activity of the chloride channels and consequently reduced chloride conductivity in CLCN1, whereas in SCN4A-myotonias it is caused by an impaired inactivation of the NaV1.4 channels [5, 8].

CLCN1-myotonias, also known as myotonia congenita (MC), are to be distinguished into the autosomal dominant type Thomsen (TMC) and the autosomal recessive type Becker (BMC), related to the type of mutation. Although some CLCN1 mutations may be inherited both as autosomal recessive and dominant, making it difficult in some patients to classify them without a detailed genetic and clinical study of other family members. SCN4A-myotonias include paramyotonia congenita Eulenburg (PMC), potassium aggravated myotonia (PAM), and hyperkalemic periodic paralysis with myotonia (hyperPP) [9].

The phenotype of NDMs involves almost exclusively the skeletal muscle and, differently from dystrophic myotonias (DM), no relevant extra-muscular involvement has been described so far. The onset of symptoms is usually described in the first to the second decade of life; the lead symptom is myotonia, which is however often described by patients as stiffness, occurring especially during suddenly initiated movements after a resting period [9]. Otherwise, prolonged depolarization may temporarily reduce the excitability of the muscle membrane, causing transient weakness or periodic paralysis [8]. Significant clinical overlap exists between CLCN1 and SCN4A myotonias. Nevertheless, some features can help to distinguish both forms. CLCN1-myotonias are usually characterized by a warm-up phenomenon, worsening of myotonia under low temperature environment, and more prominent myotonia at lower limbs. Temporary weakness and segmental muscle hypertrophy occur mainly in patients with BMC [2, 10‐12]. On the other hand, patients with PMC typically show worsening of their myotonia after repetitive movements, and under low-temperature environment. The SCN4A associated myotonia commonly involves the facial muscles with eyelid myotonia; the muscle weakness can occur more frequently and may persist longer than in CLCN1 patients [2, 11]. In addition to medical history and neurological examination, the detection of myotonic runs (MR) in electromyography (EMG) is an important hallmark for suspecting a NDM. Specific EMG protocols (repetitive stimulation, the “short” and “long” exercise tests, and the provocative cold test) even allow the differentiation between chloride and sodium channel myotonia with relatively high sensitivity and specificity [13]. Nevertheless, the precise diagnosis needs genetic analysis.

Up-to-date, no causal treatments are available for NDM but several drugs can be adopted for the symptomatic treatment of myotonia in the attempt to improve patients’ quality of life [2]. Presently, anti-myotonic drugs with the highest level of evidence concerning efficacy are mexiletine and lamotrigine [14‐16]. Many other substances such as carbamazepine, flecainide, phenytoin, propafenone, or more recently cannabinoids are also being used [11, 17]. Unfortunately, many patients still do not report sufficient improvement of their core symptom myotonia.

Due to the rarity of these diseases, only a few large cohorts (n > 50) have been described in the literature to this date (Table 1). A description of a large genetically confirmed cohort of German NDM patients dates back to the year 1993 [18].

The aim of this study was to investigate the clinical features of a large cohort of German patients with NDM, highlighting some diagnostic and therapeutic challenges and expanding the genotype by describing newly detected genetic variants.

In this study, we depicted the clinical features of a large cohort of German patients with NDM thus adding valuable information to the few reported large cohorts of patients (Table 1) [12, 18, 21‐27]. The core clinical features of our NDM cohort were mostly confirmatory of literature data, highlighting the significant clinical overlap between patients with NDM-CLCN1 and NDM-SCN4A. However, some new findings could be summarized. The age of onset could be collocated in the 1st to 2nd decade of life in most patients. Myotonia was the most prominent symptom, occurring more frequently in facial muscles in NDM-SCN4A and not significantly but tendentially more frequently in the legs for NDM-CLCN1, muscle weakness tended to occur more frequently in NDM-CLCN1. Myalgia was, immediately after myotonia, the most prevalent symptom during disease progression involving 52–57% of patients, without significant differences between NDM-CLCN1 and NDM-SCN4A. In the literature, the prevalence of pain in NDMs widely ranges from 28 to 53% in NDM-CLCN1 and from 56 to 82% in NDM-SCN4A [12, 23, 24]. Some SCN4A mutations are known to be associated with myalgia (e.g., c.1333G>A, c.3917G>C, c.3466G>A), in our patients only 6/22 showed either c.1333G>A or the c.3917G>C mutation, thus explaining only a minority of myalgic patients. The presence of pain is one of the major determinants of low quality of life in NDM patients [28] and needs to be properly monitored and treated. Some myotonia characteristics are considered more archetypal for one form or the other, as warm-up phenomenon and muscle hypertrophy usually points toward NDM-CLCN1 and cold sensitivity toward NDM-SCN4A. In contrast, in our genetically confirmed cohort a more relevant clinical overlap was observed as the muscle hypertrophy, the warm-up phenomenon as well as grip- and percussion myotonia were frequently observed in both groups. Even the classic triggers were present in both NDM groups with an even higher prevalence of cold sensitivity for NDM-CLCN1 patients. This finding is untypical as usually NDM-SCN4A patients refer a more prominent worsening of symptoms with cold temperatures, but it is well known that cold may worsen symptoms also in NDM-CLCN1 patients. Similar observations were also reported by Trivedi et al. [12] and should favor a genetic tandem analysis approach rather than a single gene sequencing. Extra-muscular manifestations are thought to be non-typical for NDM patients, even though the role of SCN4A variants in causing cardiac arrhythmias and Brugada syndrome remains debated [29]. In our cohort, no patient with SCN4A mutations presented relevant cardiac involvement; on the other hand, six NDM-CLCN1 patients had cardiac arrhythmias or conduction defects, requiring the implantation of a pacemaker in three patients. In particular, patient 65 required pacemaker implantation at age 30 years and has a positive family history of dilative cardiomyopathy documented in her father’s and brother’s medical history, the latter also presented with a NDM-CLCN1-myotonia. Given the autosomal recessive nature of the two known pathogenic CLCN1 gene mutations in this patient (c.180+3A>T and c.1488G>T), we interpret this case as an obvious double-trouble situation. The ClC-1 channel is mainly expressed in the skeletal muscle and only at limited levels in smooth muscle, kidney, heart, liver, and CNS [30, 31]. Since no extra-muscular and especially cardiac manifestations of NDM are reported in other NDM-CLCN1 cohorts so far and given the low number of patients with cardiac arrhythmias in our cohort, a causal relation between CLCN1 mutation and cardiac manifestations stays unlikely. However, NDM patients must undergo regular cardiac evaluation as the intake of anti-myotonic drugs can unmask latent and potentially life-threatening arrhythmias.

The mean diagnostic delay of this cohort was quite long (16.6 ± 12.2 years), even for a rare disease. Similar results were however reported by Baumann et al. (18 ± 14 years) and Trip et al. (12.0 ± 10.4 years) [21, 24]. From our results, it appears that the longest delay occurred between the onset of symptoms and first EMG performed (12.6 ± 10.7 years). This suggests that patients are often not immediately referred to a neurologist, being misdiagnosed as fibromyalgia or chronic pain syndrome; in other cases, patients with mildly pronounced symptoms, negative family history, normal CK will not seek immediate medical consultation. A normal CK was found in 39.6% of our patients, thus this should not prevent the suspicion of NDM or the referral to a neurologist. In the current German guidelines on NDM, the measurement of CK is a mandatory part of the diagnostic testing and is stated to be no more than 5 × upper normal limits (UNL) for NDM-CLCN1 and often more than twice the UNL for SCN4A-myotonias [11]. In some patients with SCN4A-myotonia, we observed CK elevation up to 1100 U/L. These values may have been influenced by various factors, such as physical activity on the previous day. The EMG detected myotonic runs in 89% of NDM-CLCN1 and 80% of NDM-SCN4A patients without provocative cold test and confirmed to be the most valuable diagnostic tool for the identification of NDM patients and indication of genetic testing.

In our NDM-CLCN1 cohort, the common mutation c.2680C>T (p.Arg894*) was found in 50%. This typical Thomsen CLCN1 mutation, confirmed in the original Thomsen family from Northern Germany, is also frequently found in Northern Scandinavia, Russia, Denmark and to a lesser extent in The Netherlands, Spain, and Italy [32, 33]. It still has a high prevalence in northern Europe. Other mutations were most frequent in Spain (c.180+3A>T), the Netherlands (c.1238T>G, p.F413C), and Italy (c.501C>G, p.F167L) [25, 34‐36]. In our study, no clear genotype–phenotype correlations could be identified, this might be also related to the several different mutations that our patients presented throughout the genes. Some previous functional studies have demonstrated how the location of the mutations in the different channel domains deeply influences the clinical severity and response to therapy producing major differences among patients sharing the same gene defect but different mutations. On the other hand, different phenotypes have also been described in patients with the same mutation, suggesting that modifier genes and environmental condition might influence the clinical features of individual patients [37, 38].

We found 12 novel genetic variants. Although we did not perform functional studies, we included some class 3 mutations that were highly suggestive of being pathogenic due to investigation of family members, indicative clinical symptoms and the evidence of EMG myotonia. Very interestingly, patient 21 displayed the dominant c.3917G>T mutation on both alleles. This change from glycine to valine is known to cause moderate to severe myotonia [39] and this patient displayed earlier and more severe symptoms compared to other affected family members.

The main differential diagnosis of NDM were dystrophic myotonias, with a national biased approach, like myotonic dystrophy type 2 being tested slightly more frequently than myotonic dystrophy type 1 in our sample. Other genes examined in these NDM patients were CAV3, ATP2A1 (Brody disease) and HINT1 (hereditary neuromyotonia with axonal neuropathy). Since 2010 next-generation sequencing can be used in the clinical setting in Germany. Therefore, we wanted to examine whether this new sequencing technique reduced the diagnostic delay of NDMs. However, no significant differences were observed for the diagnostic delay in patients diagnosed before and after 2010. Probably because even before 2010 tandem analysis of CLCN1 and SCN4A was commonly conducted.

The effective symptomatic treatment of NDM remains a challenge. At their last follow-up visit, about 50% of our patients (44.7% NDM-CLCN1, 63.6% NDM-SCN4A) were not taking any anti-myotonic therapy. Trivedi et al. reported the use of anti-myotonic medication in 60.6% of patients, Dupré et al. in 41% of recessive (36% with significant improvement), 0% of dominant NDM-CLCN1 patients and 43% of NDM-SCN4A patients. As described by Dupré et al., phenytoin and gabapentin were most effective in patients with recessive CLCN1-myotonia, while mexiletine and carbamazepine were most effective in patients with SCN4A-myotonia [12, 22]. The most frequently used anti-myotonic drugs were carbamazepine, flecainide, mexiletine and lamotrigine in this order of frequency. Flecainide and mexiletine are the drugs of first choice according to the current German guidelines, carbamazepine was more used in the past and lamotrigine more recently after the clinical study by Anderson et al. [11, 16] Patients rated mexiletine, and lamotrigine as the most effective therapies, in accordance with recent RCTs [15, 16], whereas other medications were mainly considered as not satisfactory. This is also confirmed by the high number of tested anti-myotonic drugs (up to 11 different drugs). The good efficacy of phenytoin/gabapentin in recessive CLCN1-myotonia and carbamazepine and mexiletine in SCN4A-myotonia reported by Dupré et al. was, with exception of mexiletine, not observed in our cohort [22]. Our data however, lack information regarding the duration of anti-myotonic drug intake and patients’ compliance, which may impact the evaluation of drug efficacy.

The limitation of our study is its retrospective design. The collection of information has been likely affected by the accuracy of different physicians in record keeping. Despite this, the strength of our study lies in a large number of genetically confirmed patients, and the opportunity of a direct comparison of patients with either a CLCN1 or a SCN4A gene mutation in one single highly specialized neuromuscular center over 25 years.

In summary, this study highlights the clinical, genetic and therapeutic challenges related to the diagnosis and management of NDM patients and unmet needs are the lack of follow-up studies of large cohorts with reliable assessments of disease progression and treatment efficacy.