Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 702355008, 715788001; ICD10CM: G71.12, G71.19; ORPHA: 612, 99734, 99735, 99736;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q23.3 | Myotonia congenita, atypical, acetazolamide-responsive | 608390 | Autosomal dominant | 3 | SCN4A | 603967 |
A number sign (#) is used with this entry because all forms of potassium-aggravated myotonia are caused by heterozygous mutation in the SCN4A gene (603967) on chromosome 17q23. Allelic disorders with overlapping clinical phenotypes include hyperkalemic periodic paralysis (HYPP; 170500) and paramyotonia congenita (PMC; 168300).
Myotonia congenita (160800) is a distinct disorder caused by mutation in a skeletal muscle chloride channel gene (CLCN1; 118425).
In a report on the 37th ENMC Workshop, Rudel and Lehmann-Horn (1997) stated that the sodium channelopathies can be divided into 3 different forms: paramyotonia, potassium-aggravated myotonia, and periodic paralysis. Potassium-aggravated myotonia includes mild myotonia fluctuans, severe myotonia permanens, and acetazolamide-responsive myotonia.
Trudell et al. (1987) reported 14 patients from a kindred with an autosomal dominant form of myotonia characterized by painful muscle stiffness that was provoked by fasting and oral potassium administration. Acetazolamide treatment was effective.
Studies by Iaizzo et al. (1991) implicated sodium channel dysfunction as the primary defect in some forms of autosomal dominant myotonia congenita.
Lerche et al. (1993) reported 4 patients from 3 families with a form of myotonia distinct from HYPP and PMC. The first patient had severe permanent myotonia with occasional stiffness of the respiratory muscles and resultant hypoxia. A mother and son of a second family had exercise-induced myotonia, and a third unrelated patient had fluctuant myotonia. All had a nondystrophic generalized myotonia that was not associated with muscle weakness or cold, but was aggravated by oral potassium intake. Lerche et al. (1993) postulated that the underlying phenotype was the same in these patients, despite some clinical variability.
Ricker et al. (1994) defined 'myotonia fluctuans' as a disorder of the muscle sodium channel. Three families, with 17 affected members, showed myotonia caused by prolongation of relaxation times that developed 20 to 40 minutes after exercise. Potassium loading also caused myotonia, and cooling had no major effect on muscle function. Ricker et al. (1994) stated that myotonia fluctuans belongs to a third type of sodium channel disorder distinct from HYPP and PMC.
Orrell et al. (1998) reported a family with autosomal dominant inheritance of potassium-aggravated myotonia. The proband had experienced cramps in the toes, fingers, and eyelids, especially when tired or cold, throughout her life, and physical examination showed mild myotonia. There was no muscle weakness. Her mother and several other family members had a similar phenotype. An unusual feature was the occurrence of painful cramps. Orrell et al. (1998) noted that there was variability of symptoms from day to day, which is similar to myotonia fluctuans. A mild reduction in amplitude of compound muscle action potential on cooling and administration of potassium was demonstrated.
Ptacek et al. (1994) reported acetazolamide-responsive myotonia congenita in which myotonia was worsened by potassium, but episodic weakness did not occur.
Colding-Jorgensen et al. (2006) reported a family with autosomal dominant myotonia permanens spanning 5 generations. The proband and his affected son were examined in detail, but there were 10 additional family members who were reportedly affected. The proband was a 48-year-old man who had severe and painful myotonic stiffness since early childhood that was aggravated after physical exertion, cold weather, fever, or ingestion of potassium-rich foods. He has never experienced serious respiratory problems due to myotonia and had had employment requiring physical exertion. Examination showed pronounced myotonia in all muscles on exertion or percussion. Serum creatine kinase was increased, and electromyography (EMG) showed continuous myotonic activity. His 9-year-old son had similar symptoms since birth and participates in sports.
Dupre et al. (2009) reported French Canadian patients with a severe painful generalized myotonia with muscle hypertrophy associated with a mutation in the SCN4A gene (V445M; 603967.0014). Myotonia was significantly alleviated by ethanol or mexiletine in 1 of these patients.
Severe Neonatal Episodic Laryngospasm
Lion-Francois et al. (2010) reported 3 unrelated neonates with sodium channel myotonias who each experienced recurrent life-threatening episodic apnea due to laryngospasm. The attacks were associated with stridor and generalized stiffness, followed by hypotonia, cyanosis, and bradycardia. There were no apparent triggering factors, and examinations between episodes were normal in 2, although all showed feeding difficulties. EMG in all 3 children showed continuous myotonic discharges. One child died of respiratory arrest at age 2.5 months. Both surviving children showed marked muscle hypertrophy at age 6 months, with handgrip, palpebral, and tongue myotonia in one and exacerbation of myotonia with cold in the other. Carbamazapine or mexiletine were effective treatments. Lion-Francois et al. (2010) noted the severe neonatal phenotype observed in these patients, and emphasized that early recognition is imperative for proper treatment.
Among 22 patients with PMC, 14 with sodium channel myotonia, and 18 myotonia patients with mutations in the CLCN1 gene (118425), 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.
In a family with acetazolamide-responsive atypical myotonia congenita, Ptacek et al. (1992) found linkage to SCN4A; maximum lod score = 3.56 to 4.19 at theta = 0.0, depending on assumed penetrance varying from 0.7 to 1.0.
Lerche et al. (1993) identified heterozygous missense mutations in the same codon of the SCN4A gene (G1306V; 603967.0007, G1306A; 603967.0012, and G1306E; 603967.0025) in patients with exercise and potassium-aggravated myotonia, myotonia fluctuans, and myotonia permanens, respectively. Patch-clamp recordings on patient muscle samples showed slower sodium fast channel inactivation and an increase in late channel opening, resulting in a steady-state inward current, sustained muscle depolarization, and muscle fiber hyperexcitability. The findings indicated that SCN4A residue 1306 is important for sodium channel inactivation.
In a patient with acetazolamide-responsive myotonia congenita that was worsened by potassium, Ptacek et al. (1994) identified a mutation in the SCN4A gene (603967.0010).
In patients with myotonia fluctuans, Ricker et al. (1994) identified 2 mutations in the SCN4A gene (603967.0006 and 603967.0012).
In a family with potassium-aggravated myotonia, Orrell et al. (1998) identified a heterozygous missense mutation in the SCN4A gene (V1589M; 603967.0009). The authors noted that the same mutation had been identified in a family (Iaizzo et al., 1991) with paramyotonia congenita by Heine et al. (1993).
Colding-Jorgensen et al. (2006) identified a heterozygous missense mutation in the SCN4A gene (G1306E; 603967.0025) in a father and son from a family with autosomal dominant myotonia permanens spanning 5 generations.
In 3 unrelated neonates with severe neonatal episodic laryngospasm, Lion-Francois et al. (2010) identified de novo heterozygous missense mutations in the SCN4A gene, including the G1306E mutation in 2 of the children.
Lehmann-Horn et al. (1993) suggested the term 'sodium channel disease' to encompass the different allelic syndromes caused by SCN4A mutations.
Colding-Jorgensen, E., Duno, M., Vissing, J. Autosomal dominant monosymptomatic myotonia permanens. Neurology 67: 153-155, 2006. [PubMed: 16832098] [Full Text: https://doi.org/10.1212/01.wnl.0000223838.88872.da]
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]
Heine, R., Pika, U., Lehmann-Horn, F. A novel SCN4A mutation causing myotonia aggravated by cold and potassium. Hum. Molec. Genet. 2: 1349-1353, 1993. [PubMed: 8242056] [Full Text: https://doi.org/10.1093/hmg/2.9.1349]
Iaizzo, P. A., Franke, C., Hatt, H., Spittelmeister, W., Ricker, K., Rudel, R., Lehmann-Horn, F. Altered sodium channel behaviour causes myotonia in autosomal dominantly inherited myotonia congenita. Neuromusc. Disord. 1: 47-53, 1991. [PubMed: 1668369] [Full Text: https://doi.org/10.1016/0960-8966(91)90042-q]
Lehmann-Horn, F., Rudel, R., Ricker, K. Non-dystrophic myotonias and periodic paralyses. Neuromusc. Disord. 3: 161-168, 1993. [PubMed: 7689382] [Full Text: https://doi.org/10.1016/0960-8966(93)90009-9]
Lerche, H., Heine, R., Pika, U., George, A. L., Jr., Mitrovic, N., Browatzki, M., Weiss, T., Rivet-Bastide, M., Franke, C., Lomonaco, M., Ricker, K., Lehmann-Horn, F. Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker. J. Physiol. 470: 13-22, 1993. [PubMed: 8308722] [Full Text: https://doi.org/10.1113/jphysiol.1993.sp019843]
Lion-Francois, L., Mignot, C., Vicart, S., Manel, V., Sternberg, D., Landrieu, P., Lesca, G., Broussolle, E., Billette de Villemeur, T., Napuri, S., des Portes, V., Fontaine, B. Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder. Neurology 75: 641-645, 2010. [PubMed: 20713951] [Full Text: https://doi.org/10.1212/WNL.0b013e3181ed9e96]
Orrell, R. W., Jurkat-Rott, K., Lehmann-Horn, F., Lane, R. J. M. Familial cramp due to potassium-aggravated myotonia. J. Neurol. Neurosurg. Psychiat. 65: 569-572, 1998. [PubMed: 9771789] [Full Text: https://doi.org/10.1136/jnnp.65.4.569]
Ptacek, L. J., Tawil, R., Griggs, R. C., Meola, G., McManis, P., Barohn, R. J., Mendell, J. R., Harris, C., Spitzer, R., Santiago, F., Leppert, M. F. Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology 44: 1500-1503, 1994. [PubMed: 8058156] [Full Text: https://doi.org/10.1212/wnl.44.8.1500]
Ptacek, L. J., Tawil, R., Griggs, R. C., Storvick, D., Leppert, M. Linkage of atypical myotonia congenita to a sodium channel locus. Neurology 42: 431-433, 1992. [PubMed: 1310531] [Full Text: https://doi.org/10.1212/wnl.42.2.431]
Ricker, K., Moxley, R. T., III, Heine, R., Lehmann-Horn, F. Myotonia fluctuans: a third type of muscle sodium channel disease. Arch. Neurol. 51: 1095-1102, 1994. [PubMed: 7980103] [Full Text: https://doi.org/10.1001/archneur.1994.00540230033009]
Rudel, R., Lehmann-Horn, F. Paramyotonia, potassium-aggravated myotonias and periodic paralyses. 37th ENMC International Workshop, Naarden, The Netherlands, 8-10 December 1995. Neuromusc. Disord. 7: 127-132, 1997. [PubMed: 9131654] [Full Text: https://doi.org/10.1016/s0960-8966(96)00418-x]
Trudell, R. G., Kaiser, K. K., Griggs, R. C. Acetazolamide responsive myotonia congenita. Neurology 37: 488-491, 1987. [PubMed: 3822145] [Full Text: https://doi.org/10.1212/wnl.37.3.488]