The Non-dystrophic Myotonias: Molecular Pathogenesis, Diagnosis and Treatment

E. Matthews; D. Fialho; S. V. Tan; S. L. Venance; S. C. Cannon; D. Sternberg; B. Fontaine; A. A. Amato; R. J. Barohn; R. C. Griggs; M. G. Hanna

Disclosures

Brain. 2010;133(1):922 

In This Article

Clinical Features

Myotonia Congenita

Myotonia congenita is the most common inherited skeletal muscle channelopathy. The autosomal dominant form was first described in the 19th century by the Danish physician Julius Thomsen in himself and his family (Thomsen, 1876). In the 1970s, the German Physician P.E. Becker fully documented the existence of the recessive form of myotonia congenita (Becker, 1977). In both forms muscle stiffness is most pronounced during rapid voluntary movements following a period of rest but improves with repeated activity—the so-called 'warm-up' phenomenon (Walsh et al., 2007; Trivedi et al., 2008; Wang et al., 2008c). Some clinical findings are more common in the recessive than in the dominant form but considerable overlap exists. Recessive myotonia congenita tends to be more severe, is more frequently associated with muscle hypertrophy and with depressed tendon reflexes (Becker, 1977; Fialho et al., 2007). Patients with recessive myotonia congenita typically experience a peculiar transient weakness on initiating an action, which is only rarely seen in dominant myotonia congenita. Although Becker found that most patients with recessive myotonia congenita presented between the ages 4 and 12 years while the dominant form usually manifested before the age of 3 years (Becker, 1977), we found no difference in the age of onset (Fialho et al., 2007).

Myotonic dystrophy types I and II can often be differentiated from myotonia congenita by the presence of systemic features. However, cases of myotonic dystrophy type II in which myotonia is the predominant complaint without any overt systemic features have been described (Fialho et al., 2007) and can lead to diagnostic difficulty.

Paramyotonia Congenita

Eulenburg first used the term paramyotonia congenita in 1886 to describe a syndrome of episodic muscle cramps and paralysis profoundly exacerbated by cold and exercise in six generations of a German family (Eulenburg, 1886). The inheritance is autosomal dominant and symptoms usually manifest in the first decade of life. The facial, tongue, and hand muscles are predominantly affected and the lower limbs are generally only mildly affected (Miller et al., 2004). The myotonia can last seconds to minutes but the weakness may persist for hours and occasionally days. Paradoxical myotonia that worsens with exercise can be demonstrated at the bedside in most patients (Trivedi et al., 2008). Muscle hypertrophy is less frequent than in myotonia congenita but in our recent series we found it to be present in ~30% of patients (Matthews et al., 2008b).

Sodium Channel Myotonia

In 1987, prior to the availability of genetic testing, it was observed that there was a group of myotonic patients who seemed clinically distinct from either myotonia congenita or paramyotonia congenita. The first kindred reported exhibited autosomal dominant inheritance of a phenotype characterized by cold insensitive painful myotonia that was markedly exacerbated by potassium ingestion. None of the affected family members reported attacks of weakness but all experienced a significant improvement in myotonic symptoms with acetazolamide treatment. The term 'acetazolamide-responsive' myotonia congenita was coined to describe this family (Trudell et al., 1987; Ptacek et al., 1994). Subsequent reports described patients with a cold insensitive pure myotonic phenotype who did not experience weakness but whose myotonia fluctuated dramatically and was profoundly worsened by potassium ingestion. Notably the myotonia tended to occur with a more delayed (10–30 min) onset after exercise rather than with the initiation of movement after rest as seen in myotonia congenita, or within seconds of exercise as seen in paramyotonia congenita. This phenotype was classified as myotonia fluctuans (Ricker et al., 1990, 1994; Lennox et al., 1992). The term myotonia permanens was introduced to describe patients with a third clinical variant characterized by very severe persistent myotonia which significantly impaired respiration (McClatchey et al., 1992b; Lerche et al., 1993). These three purely myotonic disorders shared the potassium aggravation and the absence of sensitivity to cold. Together they have become known as the potassium aggravated myotonias. Additional pure myotonic phenotypes have been described but these differ from the potassium aggravated myotonia phenotypes in that they have been reported to be cold-sensitive (Heine et al., 1993; Koch et al., 1995; Wu et al., 2001). All these pure myotonic phenotypes have now been shown to be caused by allelic point mutations in the gene encoding SCN4A.

We consider that from a practical clinical viewpoint a simplified classification of sodium channel myotonic disorders into two broad groups based on the presence or absence of episodic weakness is helpful:

Group 1 Paramyotonia congenita—characterized by a marked worsening of myotonia by cold and by the presence of clear episodes of weakness;
Group 2 Sodium channel myotonia—notable for the absence of episodic weakness but may have cold sensitivity. This includes all the pure myotonic phenotypes, including the potassium aggravated myotonias (Fournier et al., 2004, 2006).

Distinguishing chloride from sodium channel myotonias is often possible on clinical grounds alone as indicated in Table 1. However, difficulty may arise as some cases with sodium channel myotonia may have clinical features that are very similar to those seen in some cases of dominant myotonia congenita (see Table 1). For example, sodium channel myotonia may exhibit the presence of the warm up phenomenon, have minimal or absent sensitivity to cold, and have an upper limb/facial distribution of myotonia that is indistinguishable from dominant myotonia congenita (see Table 1).

In such cases the presence of transient weakness would point to dominant myotonia congenita whereas the presence of eyelid myotonia is more suggestive of sodium channel myotonia (Trip et al., 2009b). In addition specialized electrophysiological protocols can be helpful.

Myopathy

Myopathy may develop in some patients with non-dystrophic myotonia (Becker, 1977; Plassart et al., 1996; Nagamitsu et al., 2000). In a series of 49 genetically confirmed paramyotonia congenita cases, 'myopathic biopsy findings' were reported in 33% of those biopsied although full clinical details of the degree of weakness were not available (Miller et al., 2004). Permanent severe myopathy seems to be more common in patients with periodic paralysis than in the non-dystrophic myotonias (Miller et al., 2004). In periodic paralysis it has been postulated that the severity of myopathy may not relate to paralytic attack frequency (Buruma et al., 1978; Links et al., 1990) but the exact relationship remains unclear. There is some evidence that the severity of myopathy associated with periodic paralysis does correlate with increasing age (Links et al., 1990; Plassart et al., 1994). It is not known if a similar relationship between age and severity of myopathy exists in the non-dystrophic myotonias or if symptom frequency or severity has a direct influence on the development of myopathy. In periodic paralysis there is some evidence that the frequency of paralytic attacks may decline with age (Miller et al., 2004). However, it is not established if myotonia severity alters over time in patients with non-dystrophic myotonia. Importantly, there are no published studies to provide accurate detailed data on the natural history of the non-dystrophic myotonias in order to address the above questions. Such a large natural history study is currently in progress as part of the Consortium for Clinical Investigation of Neurological Channelopathies (http://rarediseasesnetwork.epi.usf.edu).

Mechanisms of Muscle Degeneration

Patients with periodic paralysis have been frequently reported to exhibit vacuoles and/or tubular aggregates on muscle biopsy. However, the myopathological findings in non-dystrophic myotonias are not defined well and are often reported to be non-specific (Miller et al., 2004). Furthermore, with the characteristic clinical history and examination findings coupled with the recent advances in electrophysiological techniques a diagnosis of non-dystrophic myotonia is usually apparent and it is now rare that a muscle biopsy will be performed in such patients other than as a research procedure.

It is clear muscle damage can occur in the non-dystrophic myotonias but its pathomechansim and frequency are unknown. It has been postulated that the abnormally prolonged intramuscular influx of sodium that is known to occur via the mutant sodium channels may be responsible for muscle degeneration (Bradley et al., 1990). There is evidence for increased intracellular sodium contributing to cell necrosis in the mouse model of Duchenne muscular dystrophy (Hirn et al., 2008). One recent study has employed ultrasound to assess permanent muscle changes in the non-dystrophic myotonias. Using ultrasound measurements of eight muscles (four upper limb and four lower limb), in a group of 63 patients with genetically confirmed non-dystrophic myotonia an increase in the mean echo intensity compared with controls from all muscles examined except the rectus femoris was observed. The ultrasound changes were considered to indicate structural muscle damage such as fatty infiltration or fibrosis. This change was most marked in the forearm flexors where the increased echogenicity correlated negatively with muscle power. There was no positive correlation between echo intensity and age for individual muscles except the rectus femoris although the sum of the scores did show a significant positive correlation (Trip et al., 2009c).

Recently, a mouse model of hyperkalaemic periodic paralysis has been engineered by introducing the murine equivalent of the SCN4A mis-sense mutation M1592V (Hayward et al., 2008). This mutation causes both myotonia and paralysis in humans (Rojas et al., 1991; Kelly et al., 1997) and was demonstrated to produce the same symptoms in the mouse indicating the validity of the model. At a few months of age the heterozygous mice displayed subtle myopathic changes. In homozygous mice significant muscle abnormalities were seen including an increase in fibre size variability, frequent internal nuclei and large scattered vacuoles. These changes were present before any spontaneous episodes of paralysis had been observed. Furthermore, they were shown to increase with age in the heterozygotes while muscle force generation declined (Hayward et al., 2008). These findings support the clinical observations that myopathy increases with age (Links et al., 1990; Plassart et al., 1994) and that it may be independent of paralytic attacks in the periodic paralyses (Buruma et al., 1978; Links et al., 1990).

It seems likely that future insights into muscle degeneration gained from the study of this model will also have implications for our understanding of paramyotonia congenita and sodium channel myotonia associated with the same SCN4A gene. The possibility that myopathy develops independently of symptom frequency or severity may influence future approaches to therapy which is currently aimed at relieving symptoms. At present many patients with minimal or manageable symptoms decline pharmacological treatment but it is possible that treatment may have a role in preventing subsequent myopathy.

Morbidity in the Non-dystrophic Myotonias

Very little is known about the impact of non-dystrophic myotonias on quality of life and these disorders have often been regarded as benign. A single study has recently examined this in a group of 62 patients with genetically confirmed non-dystrophic myotonia and found painful myotonia and fatigue to be the best predictors of poor general health perception and physical functioning (Trip et al., 2009a). In this study painful myotonia was reported in 28% of those with myotonia congenita and 57% with sodium channelopathy. In addition, there are numerous case reports where severe pain is described (Ptacek et al., 1994; Rosenfeld et al., 1997; Vicart et al., 2004; Jorgensen et al., 2006; Colding-Fialho et al., 2007; Walsh et al., 2007; Wang et al., 2008c). This suggests that pain is a frequent symptom that may have been previously under-recognized and possibly undertreated in the non-dystrophic myotonias.

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