Autosomal dominant myotonia congenita is a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction (Sun et al., 2001). Thomsen disease is less common and less severe than ... Autosomal dominant myotonia congenita is a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction (Sun et al., 2001). Thomsen disease is less common and less severe than Becker disease. See also paramyotonia congenita (PMC; 168300) and potassium-aggravated myotonia (608390), overlapping phenotypes caused by mutations in the SCN4A gene (603967).
Myotonia congenita was first described by the Danish physician Julius Thomsen (1876) in his own family. A follow-up report (Thomasen, 1948) identified 64 affected persons in 7 consecutive generations. The pedigree of Birt (1908), who, like Thomsen, was ... Myotonia congenita was first described by the Danish physician Julius Thomsen (1876) in his own family. A follow-up report (Thomasen, 1948) identified 64 affected persons in 7 consecutive generations. The pedigree of Birt (1908), who, like Thomsen, was himself affected, showed skipped generations. Isaacs (1959) reported a mother and son with myotonia congenita. Quinine, local procaine, procainamide, insulin, injections of 50% magnesium sulfate, curarization, sodium loading and sodium depletion had no effect on the mother's myotonia. However, marked improvement occurred when potassium depletion was achieved with cortisone and chlorothiazide. The son improved when treated with chlorothiazide only. Pasternack and Lindqvist (1962) described 6 cases in 3 generations, and personally examined 4. Celesia et al. (1967) reported monomelic myotonia congenita, which may have been due to somatic mutation. Sanders (1976) reported a family with dominant inheritance of myotonia congenita. Two affected family members had painful muscle contractions and hypothyroidism; they showed improvement after thyroid replacement therapy. Becker (1977) provided a classification of the myotonias, and suggested 3, and perhaps 5, different varieties of dominant myotonia. Type I was classic Thomsen disease. Type II, represented by 4 families in Becker's series, was characterized by muscle pain and a fluctuating course. In type III, a marked relationship of myotonia to cold was noted, especially in the muscles around the eyes, nose, and mouth. It differed from paramyotonia congenita (168300) by the lack of cold-induced paralysis. Types IV and V, although not clearly distinct, were characterized by lack of involvement of facial muscles and isolated percussion myotonia of the tongue, respectively. Lehmann-Horn et al. (1995) commented that Becker had found that many forms of autosomal dominant myotonia exhibited a clinical picture that did not fit the classic form of Thomsen disease. These disorders were later found to be caused by mutations in the gene encoding the alpha subunit of the muscle sodium channel (SCN4A; 603967). These atypical Thomsen cases, now classified as potassium-aggravated myotonias (608390), are more common than Thomsen disease. Dupre et al. (2009) reported 9 French Canadian patients from 4 unrelated families with autosomal dominant myotonia caused by heterozygous CLCN1 mutations (see, e.g., S189F; 118425.0018). The mean age of onset was 13 years (range, 2 to 20). The most common clinical features included percussion myotonia (44%), handgrip myotonia (56%), warm-up phenomenon (100%), generalized hypertrophy (78%), generalized muscle stiffness (78%), and exacerbation with cold temperatures (56%). Less common features included lid lag (11%), lid myotonia (22%), tongue myotonia (22%), and muscle pain (11%). None had weakness, and none had sought to use medications to alleviate their symptoms. About half of affected females reported aggravation of symptoms during menstruation or pregnancy, and alleviation of symptoms after menopause. Some also reported symptom improvement with alcohol. Electrophysiologic studies showed less severe myotonia and less severe CMAP decrements compared to patients with recessive CLCN1 mutations, but similar results compared to patients with dominant SCN4A (603967) mutations. - Myotonia Levior Myotonia levior, a mild form of autosomal dominant myotonia, was first described by de Jong (1966). Siciliano et al. (1988) reported 2 families with myotonia levior. Affected individuals had isolated myotonia without muscle weakness, hypotrophy, or hypertrophy. They suggested that myotonia levior was a 'low expressivity variant' of Thomsen disease. Lehmann-Horn et al. (1995) reported a family in which 2 brothers and their mother had myotonia levior. The brothers had onset at age 5 years of impeded muscle relaxation which was pronounced during exercise. Physical examination showed normotrophic skeletal muscles, lid lag, percussion myotonia, mild myotonia most pronounced in the forearm muscles, 'warm-up' phenomenon, and no muscle weakness. EMG showed myotonic runs. Muscle biopsy and CT scans of thigh and leg muscles were normal.
In affected members of 3 unrelated families with autosomal dominant myotonia congenita, George et al. (1993) identified a heterozygous mutation in the CLCN1 gene (G230E; 118425.0002). The findings indicated that Thomsen disease and Becker disease are allelic. ... In affected members of 3 unrelated families with autosomal dominant myotonia congenita, George et al. (1993) identified a heterozygous mutation in the CLCN1 gene (G230E; 118425.0002). The findings indicated that Thomsen disease and Becker disease are allelic. In affected members of Thomsen's own family (Thomasen, 1948) with autosomal dominant myotonia congenita, Steinmeyer et al. (1994) identified a heterozygous mutation in the CLCN1 gene (P480L; 118425.0006). After identifying mutations in the CLCN1 gene in patients with autosomal recessive myotonia congenita, Koch et al. (1992) concluded that mutations in the CLCN1 gene can cause either dominant or recessive myotonia congenita. A recessive form was explicable on the basis of total loss of function. A mutation acting dominantly in producing Thomsen disease could be explained by a homomultimeric structure of the channel, whereby the channel subunit encoded by the mutated gene associates with and inactivates the functional subunits encoded by the normal allele. In affected members of 18 unrelated families from Norway and Sweden with both autosomal dominant (5 families) and autosomal recessive (13 families) inheritance of myotonia congenita, Sun et al. (2001) identified 8 different mutations, including 3 novel mutations, in the CLCN1 gene. Fifteen probands had mutations in both alleles; 2 had mutations in a single allele, and 2 had no CLCN1 mutations. The majority of the patients were compound heterozygous with all possible mutational combinations, even in families with a dominant pattern of inheritance. Families with apparently dominant segregation of myotonia congenita may actually represent recessive inheritance with undetected heterozygous individuals married-in as a consequence of a high population carrier frequency of some mutations. The findings, together with the very variable clinical presentation, challenged the classification into dominant Thomsen or recessive Becker disease. Sun et al. (2001) suggested that most cases of myotonia congenita show recessive inheritance with some modifying factors or genetic heterogeneity. - Myotonia Levior In 2 brothers with myotonia levior, Lehmann-Horn et al. (1995) identified a heterozygous mutation in the CLNC1 gene (118425.0007). The findings indicated the myotonia levior is a variant or allelic form of Thomsen disease due to a mutation leading to low clinical expressivity.
Sun et al. (2001) stated that the worldwide prevalence of myotonic congenita, both dominant and recessive forms, is 1:100,000. In the northern Norwegian population, Sun et al. (2001) found a prevalence of about 9:100,000, which was comparable to ... Sun et al. (2001) stated that the worldwide prevalence of myotonic congenita, both dominant and recessive forms, is 1:100,000. In the northern Norwegian population, Sun et al. (2001) found a prevalence of about 9:100,000, which was comparable to the Finnish experience.