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Paramyotonia Congenita (PC), also known as Paramyotonia congenita of von Eulenburg or Eulenburg disease, is a rare congenital autosomal dominant neuromuscular disorder characterized by “paradoxical” myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders, patients with PC may also have potassium provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis and there is debate as to whether the two disorders are actually distinct.
Symptoms and signsEdit
Patients typically complain of muscle stiffness that can continue to focal weakness. This muscle stiffness cannot be walked-off, in contrast to myotonia congenita. These symptoms are increased (and sometimes induced) in cold environments. For example, some patients have reported that eating ice cream leads to a stiffening of the throat. For other patients, exercise consistently induces symptoms of myotonia and/or weakness. Typical presentations of this are during squating or repetitive fist clenching. Some patients also indicate that specific foods are able to induce symptoms of paramyotonia congenita. Isolated cases have reported that carrots and watermelon are able to induce these symptoms. The canonical definition of this disorder precludes permanent weakness in the definition of this disorder. In practice, however, this has not been strictly adhered to in the literature.
Diagnosis of paramyotonia congenita is made upon evaluation of patient symptoms and case history. Myotonia must increase with exercise/movement and usually must worsen in cold temperatures. Patients that present with permanent weakness are normally not characterized as having PC. Electromyography may be used to distinguish between paramyotonia congenita and myotonia congenita., Clinicians may also attempt to provoke episodes or myotonia and weakness/paralysis in patients in order to determine whether the patient has PC, hyperkalemic periodic paralysis, or one of the potassium-aggravated myotonias. Genomic sequencing of the SCN4A gene is the definitive diagnostic determinant.
PathophysiologyEditParamyotonia congenita (as well as hyperkalemic periodic paralysis and the potassium-aggravated myotonias) is caused by mutations in a sodium channel, SCN4A. The phenotype of patients with these mutations is indicated in Table 1. These mutations affect fast inactivation of the encoded sodium channel. There are also indications that some mutations lead to altered activation and deactivation. The result of these alterations in channel kinetics is that there is prolonged inward (depolarizing) current following muscle excitation. There is also the introduction of a “window current” due to changes in the voltage sensitivity of the channel’s kinetics. These lead to a general increase in cellular excitability, as shown in figure 1.
There has been one study of a large number of patients with paramyotonia congenita. Of 26 kindreds, it found that 17 (71%) had a mutation in SCN4A while 6 (29%) had no known mutation. There is no large difference between these two groups except that patients with no known mutation have attacks precipitated less by cold but more by hunger, are much more likely to have normal muscle biopsies, and show less decreased compound muscle action potentials when compared to patients with known mutations.
Symptoms of both PC and hyperKPP (Periodica paralytica paramyotonica)
Also diagnosed as a Potassium-aggravated myotonia
Original case reports unpublished.
When exercised in a cold environment
After muscles were cooled
|This table was adapted from Vicart et al., 2005. "Cold" refers to symptoms either occurring or significantly worsening with cold temperatures. Likewise, "Exercise/Activity" refers to symptom onset or severity worsening with exercise and/or more general movement like hand clenching. "Potassium" refers to ingestion of food high in potassium or other disorders which are known to increase serum potassium levels. Mutation region nomenclature is: domain number (e.g., D1) followed by segment number (e.g., S4). Thus, D2S3 indicates that the mutation is in the 3rd membrane spanning loop of the 2nd domain. Some mutations occur between segments and are denoted similarly (e.g., D4S4-S5 occurs between the 4th and 5th segments of the 4th domain). Other mutations are located between domains and are denoted DX-Y where X and Y are domain numbers. C-term refers to the carboxy-terminus.|
Some patients do not require treatment to manage the symptoms of paramyotonia congenita. Others, however, require treatment for their muscle stiffness and often find mexiletine to be helpful. Others have found acetazolamide to be helpful as well. Avoidance of myotonia triggering events is also an effective method of mytonia prevention.
Paramyotonia congenita is considered an extremely rare disorder, though little epidemiological work has been done. Prevalence is generally higher in European derived populations and lower among Asians. Epidemiological estimates have been provided for the German population. Here, it was estimated that the prevalence of PC is between 1:350,000 (0.00028%) and 1:180,000 (0.00056%). It should be noted, however, that the German population of patients with PC is not uniformly distributed across the country. Many individuals with PC herald from the Ravensberg area in North-West Germany, where a founder effect is seems to be responsible for most cases. The prevalence here is estimated at 1:6000 or 0.017%.
Originally thought to be separate from hyperkalemic periodic paralysis and the sodium channel myotonias, there is now considerable disagreement as to whether these disorders represent separate entities or overlapping phenotypes of a complex disorder spectrum. It was once thought that Paramyotonia congenita was more common in males. Observation of the most recent generation has shown this to be untrue. On average of half of children in a family inherit the disorder regardless of gender.
- Paramyotonia congenita FAQ at the Periodic Paralysis News Desk. The site also hosts a mailing list for patients with the disorder and medical professionals interested in it.
- Fact page from the Muscular Dystrophy Association
- Lehmann-Horn F, Rüdel R, Ricker K (1993). Non-dystrophic myotonias and periodic paralyses. A European Neuromuscular Center Workshop held 4–6 October 1992, Ulm, Germany. Neuromuscul Disord 3 (2): 161–8.
- Cannon S (2006). Pathomechanisms in channelopathies of skeletal muscle and brain. Annu Rev Neurosci 29: 387–415.
- ↑ Facts About Myopathies | MDA Publications
- ↑ Eulenburg A (1886) Über eine familiäre durch 6 Generationen verfolgbare Form kongenitaler Paramyotonie. Neurol. Zentralbl. 12:265-72.
- ↑ 3.0 3.1 de Silva S, Kuncl R, Griffin J, Cornblath D, Chavoustie S (1990). Paramyotonia congenita or hyperkalemic periodic paralysis? Clinical and electrophysiological features of each entity in one family.. Muscle Nerve 13 (1): 21–6.
- ↑ Subramony S, Malhotra C, Mishra S (1983). Distinguishing paramyotonia congenita and myotonia congenita by electromyography.. Muscle Nerve 6 (5): 374–9.
- ↑ Streib E (1984). Evoked response testing in myotonic syndromes.. Muscle Nerve 7 (7): 590–2.
- ↑ Cannon S, Brown R, Corey D (1993). Theoretical reconstruction of myotonia and paralysis caused by incomplete inactivation of sodium channels.. Biophys J 65 (1): 270–88.
- ↑ 7.0 7.1 7.2 Miller T, Dias da Silva M, Miller H, Kwiecinski H, Mendell J, Tawil R, McManis P, Griggs R, Angelini C, Servidei S, Petajan J, Dalakas M, Ranum L, Fu Y, Ptácek L (2004). Correlating phenotype and genotype in the periodic paralyses.. Neurology 63 (9): 1647–55.
- ↑ 8.0 8.1 Plassart E, Eymard B, Maurs L, Hauw J, Lyon-Caen O, Fardeau M, Fontaine B (1996). Paramyotonia congenita: genotype to phenotype correlations in two families and report of a new mutation in the sodium channel gene.. J Neurol Sci 142 (1–2): 126–33.
- ↑ Ptácek L, George A, Griggs R, Tawil R, Kallen R, Barchi R, Robertson M, Leppert M (1991). Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell 67 (5): 1021–7.
- ↑ Kim J, Hahn Y, Sohn E, Lee Y, Yun J, Kim J, Chung J (2001). Phenotypic variation of a Thr704Met mutation in skeletal sodium channel gene in a family with paralysis periodica paramyotonica. J Neurol Neurosurg Psychiatry 70 (5): 618–23.
- ↑ Brancati F, Valente E, Davies N, Sarkozy A, Sweeney M, LoMonaco M, Pizzuti A, Hanna M, Dallapiccola B (2003). Severe infantile hyperkalaemic periodic paralysis and paramyotonia congenita: broadening the clinical spectrum associated with the T704M mutation in SCN4A. J Neurol Neurosurg Psychiatry 74 (9): 1339–41.
- ↑ 12.0 12.1 12.2 12.3 Ptáĉek L, Tawil R, Griggs R, Meola G, McManis P, Barohn R, Mendell J, Harris C, Spitzer R, Santiago F (1994). Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology 44 (8): 1500–3.
- ↑ 13.0 13.1 McClatchey A, McKenna-Yasek D, Cros D, Worthen H, Kuncl R, DeSilva S, Cornblath D, Gusella J, Brown R (1992). Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel. Nat Genet 2 (2): 148–52.
- ↑ Bouhours M, Luce S, Sternberg D, Willer J, Fontaine B, Tabti N (2005). A1152D mutation of the Na+ channel causes paramyotonia congenita and emphasizes the role of DIII/S4-S5 linker in fast inactivation. J Physiol 565 (Pt 2): 415–27.
- ↑ 15.0 15.1 McClatchey A, Van den Bergh P, Pericak-Vance M, Raskind W, Verellen C, McKenna-Yasek D, Rao K, Haines J, Bird T, Brown R (1992). Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita. Cell 68 (4): 769–74.
- ↑ Lerche H, Heine R, Pika U, George A, Mitrovic N, Browatzki M, Weiss T, Rivet-Bastide M, Franke C, Lomonaco M (1993). Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker. J Physiol 470: 13–22.
- ↑ Bouhours M, Sternberg D, Davoine C, Ferrer X, Willer J, Fontaine B, Tabti N (2004). Functional characterization and cold sensitivity of T1313A, a new mutation of the skeletal muscle sodium channel causing paramyotonia congenita in humans. J Physiol 554 (Pt 3): 635–47.
- ↑ 18.0 18.1 18.2 18.3 Ptacek L, Gouw L, Kwieciński H, McManis P, Mendell J, Barohn R, George A, Barchi R, Robertson M, Leppert M (1993). Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis. Ann Neurol 33 (3): 300–7.
- ↑ Wagner S, Lerche H, Mitrovic N, Heine R, George A, Lehmann-Horn F (1997). A novel sodium channel mutation causing a hyperkalemic paralytic and paramyotonic syndrome with variable clinical expressivity. Neurology 49 (4): 1018–25.
- ↑ Okuda S, Kanda F, Nishimoto K, Sasaki R, Chihara K (2001). Hyperkalemic periodic paralysis and paramyotonia congenita--a novel sodium channel mutation. J Neurol 248 (11): 1003–4.
- ↑ 21.0 21.1 Ptácek L, George A, Barchi R, Griggs R, Riggs J, Robertson M, Leppert M (1992). Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita. Neuron 8 (5): 891–7.
- ↑ 22.0 22.1 22.2 22.3 Meyer-Kleine C, Otto M, Zoll B, Koch M (1994). Molecular and genetic characterization of German families with paramyotonia congenita and demonstration of founder effect in the Ravensberg families. Hum Genet 93 (6): 707–10.
- ↑ Lerche H, Mitrovic N, Dubowitz V, Lehmann-Horn F (1996). Paramyotonia congenita: the R1448P Na+ channel mutation in adult human skeletal muscle. Ann Neurol 39 (5): 599–608.
- ↑ Bendahhou S, Cummins T, Kwiecinski H, Waxman S, Ptácek L (1999). Characterization of a new sodium channel mutation at arginine 1448 associated with moderate Paramyotonia congenita in humans. J Physiol 518 (2): 337–44.
- ↑ Sasaki R, Takano H, Kamakura K, Kaida K, Hirata A, Saito M, Tanaka H, Kuzuhara S, Tsuji S (1999). A novel mutation in the gene for the adult skeletal muscle sodium channel alpha-subunit (SCN4A) that causes paramyotonia congenita of von Eulenburg. Arch Neurol 56 (6): 692–6.
- ↑ 26.0 26.1 Lehmann-Horn F, Rüdel R, Ricker K (1993). Non-dystrophic myotonias and periodic paralyses. A European Neuromuscular Center Workshop held 4–6 October 1992, Ulm, Germany. Neuromuscul Disord 3 (2): 161–8.
- ↑ Lehmann-Horn F, Rüdel R, Ricker K, Lorković H, Dengler R, Hopf H (1983). Two cases of adynamia episodica hereditaria: in vitro investigation of muscle cell membrane and contraction parameters. Muscle Nerve 6 (2): 113–21.
- ↑ Fontaine B, Khurana T, Hoffman E, Bruns G, Haines J, Trofatter J, Hanson M, Rich J, McFarlane H, Yasek D (1990). Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science 250 (4983): 1000–2.
- ↑ Rojas C, Wang J, Schwartz L, Hoffman E, Powell B, Brown R (1991). A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis. Nature 354 (6352): 387–9.
- ↑ Heine R, Pika U, Lehmann-Horn F (1993). A novel SCN4A mutation causing myotonia aggravated by cold and potassium. Hum Mol Genet 2 (9): 1349–53.
- ↑ Kelly P, Yang W, Costigan D, Farrell M, Murphy S, Hardiman O (1997). Paramyotonia congenita and hyperkalemic periodic paralysis associated with a Met 1592 Val substitution in the skeletal muscle sodium channel alpha subunit--a large kindred with a novel phenotype. Neuromuscul Disord 7 (2): 105–11.
- ↑ Wu F, Gordon E, Hoffman E, Cannon S (2005). A C-terminal skeletal muscle sodium channel mutation associated with myotonia disrupts fast inactivation. J Physiol 565 (Pt 2): 371–80.
- ↑ Vicart S, Sternberg D, Fontaine B, Meola G (2005). Human skeletal muscle sodium channelopathies. Neurol Sci 26 (4): 194–202.
- ↑ Becker PE, Paramyotonia congenita (Eulenberg) in Fortschritte der allgemeinen und klinischen Humangenetik. Thieme, Stuttgart (1970).
- ↑ Lee, GM, Kim, JB (June 2011). Hyperkalemic periodic paralysis and paramyotonia congenita caused by a de novo mutation in the SCN4A gene. Neurology Asia 16 (2): 163–6.
Diseases of myoneural junction and muscle / neuromuscular disease (G70–G73, 358–359)
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