Alternative titles; symbols
SNOMEDCT: 20305008; ICD10CM: G71.12; ORPHA: 614; DO: 0081335;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q34 | Myotonia congenita, recessive | 255700 | Autosomal recessive | 3 | CLCN1 | 118425 |
A number sign (#) is used with this entry because of evidence that autosomal recessive myotonia congenita (Becker disease) is caused by homozygous or compound heterozygous mutation in the gene encoding skeletal muscle chloride channel-1 (CLCN1; 118425) on chromosome 7q34.
Autosomal dominant myotonia congenita, or Thomsen disease (160800), is caused by heterozygous mutation in the CLCN1 gene.
Autosomal recessive myotonia congenita is a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Most patients have symptom onset in the legs, which later progresses to the arms, neck, and facial muscles. Many patients show marked hypertrophy of the lower limb muscles. Some patients show transient muscle weakness (Koch et al., 1993). Becker disease is more common and more severe than Thomsen disease.
Te Kamp (1907) reported possible homozygosity in cases of myotonia congenita.
Becker (1966) concluded that a recessive form of myotonia congenita is more frequent and more severe than the dominant myotonia congenita of Thomsen. Segregation ratios and the frequency of parental consanguinity suggested recessive inheritance. Winters and McLaughlin (1970) described myotonia congenita in 2 brothers and a sister with normal parents. Harper and Johnston (1972) reported a particularly interesting family in which 3 children of first-cousin parents were affected.
Becker (1977) reviewed the features distinguishing recessive from dominant myotonia. Although called myotonia congenita, the recessive form is not manifest at birth; it manifests between 4 and 12 years and, especially in males, as late as 18 years. It is a progressive disorder, starting in the legs and in a few years affecting the arms and finally the masticatory and facial muscles.
Heiman-Patterson et al. (1988) described 2 sisters with myotonia congenita who, on halothane contracture testing of skeletal muscle in vitro, had findings consistent with susceptibility to malignant hyperthermia (145600). The proposita was a 31-year-old woman who developed generalized muscle stiffness on exposure to succinylcholine. Intubation was difficult and she had generalized muscle stiffness, including opisthotonos and decerebrate posturing. Lifelong clumsiness and rare cramping were the only neuromuscular complaints, and there was no clinical myotonia. A 42-year-old sister had a positive contracture test and, by history, muscle stiffness since early childhood that increased with exercise and involved her hands and eyelids. During 2 surgical procedures, she developed muscle rigidity without rise in temperature on exposure to succinylcholine. Neurologic examination showed lid lag and myotonia in all muscles tested. In both patients, slit-lamp was negative for the changes of myotonic dystrophy, and the EKG was normal. No information was provided on the parents.
Dupre et al. (2009) reported 27 French Canadian patients with autosomal recessive myotonia associated with biallelic CLCN1 mutations (see, e.g., 118425.0009; 118425.0015; 118425.0019). The mean age at onset was 10 years (range, 3 to 34). Clinical features included lid lag (26%), lid myotonia (37%), tongue myotonia (63%), percussion myotonia (96%), handgrip myotonia (89%), transient weakness (48%), warm-up phenomenon (100%), generalized hypertrophy (55%), generalized stiffness (93%), muscle pain (41%), exacerbation with cold temperatures (63%) and a hormonal effect in women (46%). This latter subset of woman reported aggravation of symptoms during menstrual periods, aggravation during pregnancy, or alleviation after menopause. In addition, some patients reported that alcohol alleviated symptoms. Many patients took medication for symptom alleviation. Although some were resistant, the most effective medications were phenytoin and gabapentin. Electrophysiologic studies showed more severe myotonia and larger CMAP decrements on repetitive nerve stimulation compared to patients with dominant myotonia due to heterozygous CLCN1 mutations. Dupre et al. (2009) noted that the short exercise test is less painful, but just as accurate as repetitive nerve stimulation in assessing CMAP decrements.
Among 22 patients with paramyotonia congenita (PMC; 168300), 14 with sodium channel myotonia (608390), and 18 myotonia patients with mutations in the CLCN1 gene, Fournier et al. (2006) found that cold temperature was able to exaggerate electromyographic findings in a way that enabled a clear correlation between EMG findings and genetic defects. Those with PMC showed a clear worsening of compound muscle action potential with cold temperature. Those with sodium channel myotonia tended not to show a decline in compound action muscle potentials, whereas those with myotonia due to CLCN1 mutations tended to show improvement of the muscle potential with exercise, concomitant with the clinical warm-up phenomenon.
Using both a TCRB (186940) probe and a CLCN1 probe, Koch et al. (1992) demonstrated linkage of the recessive form of generalized myotonia to the CLCN1 gene on chromosome 7q35 (maximum lod = 4.69 at theta = 0.0).
The transmission pattern of myotonia congenita in the family reported by Koch et al. (1992) was consistent with autosomal recessive inheritance.
In 3 brothers, born of consanguineous parents, with autosomal recessive myotonia congenita, Koch et al. (1992) identified a homozygous mutation in the CLCN1 gene (118425.0001).
In affected members of a German family with recessive myotonia, Lorenz et al. (1994) identified compound heterozygosity for 2 mutations in the CLCN1 gene (118425.0003; 118425.0004).
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 in the CLCN1 gene. Fifteen patients had mutations on both alleles, consistent with the recessive disorder; 2 probands had mutations in a single allele; and 2 probands had no CLCN1 mutations. In 2 families, 3 CLCN1 mutations were found in the proband, and Sun et al. (2001) suspected that this phenomenon may be underestimated because mutation search in a disease gene usually ends by the identification of 2 mutations in a family with recessive 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.
Raja Rayan et al. (2012) performed multiplex ligation-dependent probe amplification (MLPA) specific to the CLCN1 gene in 60 families with recessive myotonia congenita in whom either no mutations or only a single pathogenic CLCN1 mutation had been identified. The results were positive in 4 (6.7%) patients: 2 unrelated patients were found to have 2 different multiexon deletions within the CLCN1 gene on the second allele, and 2 additional patients had a homozygous duplication of exons 8 through 14 of the CLCN1 gene (118425.0020). The 2 patients with the duplication were both of Iraqi origin, but were unrelated. Both Iraqi patients had a severe form of the disorder with onset in infancy. Haplotype analysis suggested a founder effect for this duplication mutation. Raja Rayan et al. (2012) concluded that copy number variation involving the CLCN1 gene is an important genetic mechanism in patients with recessive myotonia congenita, and that MLPA analysis may aid in genetic counseling.
Suetterlin et al. (2022) evaluated the functional significance of 95 CLCN1 mutations, including 34 novel mutations, identified in 233 patients with myotonia congenita. Mutations that altered voltage dependence of activation clustered in the first half of the transmembrane domains and mutations resulting in absent currents clustered in the second half of the transmembrane domains. Mutations that resulted in dominant functional features clustered in the TM1 domain and variants associated with recessive functional features and without a shift in voltage dependence of activation were clustered in the TM2 domain. Mutations in the intracellular domain were not associated with a dominant inheritance pattern.
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.
The Adr/Adr ('arrested development of righting') homozygous mouse is an animal model for autosomal recessive myotonia (Watkins and Watts, 1984; Rudel, 1990; Koltgen et al., 1991). Steinmeyer et al. (1991) observed changes in chloride ion conductance in skeletal muscle of homozygous Adr/Adr mice and found that experimental blockage of chloride ion conductance in muscle elicited myotonia. Steinmeyer et al. (1991) demonstrated that the Adr mouse phenotype is caused by an inactivating mutation in the Clcn1 gene.
Becker, P. E. Zur Genetik der Myotonien. In: Kuhn, E.: Progressive Muskeldystrophie, Myotonie, Myasthenie. Berlin: Springer-Verlag (pub.) 1966. Pp. 247-255.
Becker, P. E. Myotonia congenita and syndromes associated with myotonia. Vol. III. Topics in Human Genetics. Stuttgart: Georg Thieme (pub.) 1977.
Becker, P. E. Heterozygote manifestation in recessive generalized myotonia. Hum. Genet. 46: 325-329, 1979. [PubMed: 437775] [Full Text: https://doi.org/10.1007/BF00273316]
Dupre, N., Chrestian, N., Bouchard, J.-P., Rossignol, E., Brunet, D., Sternberg, D., Brias, B., Mathieu, J., Puymirat, J. Clinical, electrophysiologic, and genetic study of non-dystrophic myotonia in French-Canadians. Neuromusc. Disord. 19: 330-334, 2009. [PubMed: 18337100] [Full Text: https://doi.org/10.1016/j.nmd.2008.01.007]
Fournier, E., Viala, K., Gervais, H., Sternberg, D., Arzel-Hezode, M., Laforet, P., Eymard, B., Tabti, N., Willer, J.-C., Vial, C., Fontaine, B. Cold extends electromyography distinction between ion channel mutations causing myotonia. Ann. Neurol. 60: 356-365, 2006. [PubMed: 16786525] [Full Text: https://doi.org/10.1002/ana.20905]
Harper, P. S., Johnston, D. M. Recessively inherited myotonia congenita. J. Med. Genet. 9: 213-215, 1972. [PubMed: 5046632] [Full Text: https://doi.org/10.1136/jmg.9.2.213]
Heiman-Patterson, T., Martino, C., Rosenberg, H., Fletcher, J., Tahmoush, A. Malignant hyperthermia in myotonia congenita. Neurology 38: 810-812, 1988. [PubMed: 3362383] [Full Text: https://doi.org/10.1212/wnl.38.5.810]
Koch, M. C., Ricker, K., Otto, M., Wolf, F., Zoll, B., Lorenz, C., Steinmeyer, K., Jentsch, T. J. Evidence for genetic homogeneity in autosomal recessive generalised myotonia (Becker). J. Med. Genet. 30: 914-917, 1993. [PubMed: 8301644] [Full Text: https://doi.org/10.1136/jmg.30.11.914]
Koch, M. C., Steinmeyer, K., Lorenz, C., Ricker, K., Wolf, F., Otto, M., Zoll, B., Lehmann-Horn, F., Grzeschik, K.-H., Jentsch, T. J. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257: 797-800, 1992. [PubMed: 1379744] [Full Text: https://doi.org/10.1126/science.1379744]
Koltgen, D., Brinkmeier, H., Jockusch, H. Myotonia and neuromuscular transmission in the mouse. Muscle Nerve 14: 775-780, 1991. [PubMed: 1653899] [Full Text: https://doi.org/10.1002/mus.880140813]
Lorenz, C., Meyer-Kleine, C., Steinmeyer, K., Koch, M. C., Jentsch, T. J. Genomic organization of the human muscle chloride channel CLC-1 and analysis of novel mutations leading to Becker-type myotonia. Hum. Molec. Genet. 3: 941-946, 1994. [PubMed: 7951242] [Full Text: https://doi.org/10.1093/hmg/3.6.941]
Raja Rayan, D. L., Haworth, A., Sud, R., Matthews, E., Fialho, D., Burge, J., Portaro, S., Schorge, S., Tuin, K., Lunt, P., McEntagart, M., Toscano, A., Davis, M. B., Hanna, M. G. A new explanation for recessive myotonia congenita: exon deletions and duplications in CLCN1. Neurology 78: 1953-1958, 2012. [PubMed: 22649220] [Full Text: https://doi.org/10.1212/WNL.0b013e318259e19c]
Rudel, R. The myotonic mouse--a realistic model for the study of human recessive generalized myotonia. Trends Neurosci. 13: 1-3, 1990. [PubMed: 1688667] [Full Text: https://doi.org/10.1016/0166-2236(90)90049-g]
Steinmeyer, K., Klocke, R., Ortland, C., Gronemeier, M., Jockusch, H., Grunder, S., Jentsch, T. J. Inactivation of muscle chloride channel by transposon insertion in myotonic mice. Nature 354: 304-308, 1991. [PubMed: 1659665] [Full Text: https://doi.org/10.1038/354304a0]
Steinmeyer, K., Ortland, C., Jentsch, T. J. Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel. Nature 354: 301-304, 1991. [PubMed: 1659664] [Full Text: https://doi.org/10.1038/354301a0]
Suetterlin, K., Matthews, E., Sud, R., McCall, S., Fialho, D., Burge, J., Jayaseelan, D., Haworth, A., Sweeney, M. G., Kullmann, D. M., Schorge, S., Hanna, M. G., Mannikko, R. Translating genetic and functional data into clinical practice: a series of 223 families with myotonia. Brain 145: 607-620, 2022. [PubMed: 34529042] [Full Text: https://doi.org/10.1093/brain/awab344]
Sun, C., Tranebjaerg, L., Torbergsen, T., Holmgren, G., Van Ghelue, M. Spectrum of CLCN1 mutations in patients with myotonia congenita in northern Scandinavia. Europ. J. Hum. Genet. 9: 903-909, 2001. Note: Erratum: Europ. J. Hum. Genet. 18: 264 only, 2010. [PubMed: 11840191] [Full Text: https://doi.org/10.1038/sj.ejhg.5200736]
Sun, S. F., Streib, E. W. Autosomal recessive generalized myotonia. Muscle Nerve 6: 143-148, 1983. [PubMed: 6855798] [Full Text: https://doi.org/10.1002/mus.880060210]
Te Kamp, (NI). Ein Beitrag zur Kenntnis der Myotonia congenita sog. Thomsenschen Krankheit. Dtsch. Med. Wschr. 33: 1005 only, 1907.
Watkins, W. J., Watts, D. C. Biological features of the new A2G-adr mouse mutant with abnormal muscle function. Lab. Anim. 18: 1-6, 1984. [PubMed: 10628777] [Full Text: https://doi.org/10.1258/002367784780865036]
Winters, J. L., McLaughlin, L. A. Myotonia congenita: a review of four cases. J. Bone Joint Surg. Am. 52: 1345-1350, 1970. [PubMed: 5469190]