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Paramyotonia congenita (PC), also known as paramyotonia congenita of von Eulenburg or Eulenburg disease,^[1] is a rare congenital autosomal dominant neuromuscular disorder characterized by “paradoxical” myotonia.^[2] 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.^[3]

Symptoms and signs

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 or weakness. Typical presentations of this are during squatting 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

Diagnosis of paramyotonia congenita is made upon evaluation of patient symptoms and case history. Myotonia must increase with exercise or 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.^[4]^,^[5] 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.

Pathophysiology

Paramyotonia 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.

Figure 1. Theoretical simulation of a muscle membrane potential in response to 150 ms depolarizing pulse of −45 pA. (A) Normal muscle produces only a single action potential due to such stimulus. This is due to inactivation of sodium channels, preventing their further activation even during depolarization. (B) Myotonic muscle, however, is hyperexcitable and able to produce action potentials for the duration of the stimulus pulse. This model adapted from Cannon, 1993.^[6]

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.^[7]

**Table 1.** Summary of mutations found in patients diagnosed with paramyotonia congenita and their resulting phenotypes
Mutation	Region	Myotonia			Weakness			References
Mutation	Region	Cold	Exercise/ Activity	Potassium	Cold	Exercise/ Activity	Potassium	References
R672C	D2S4	?	?	?	?	?	?	^[7]
I693T	D2S4-S5	N	?	?	Y	Y	Y	^[8]
T704M*	D2S5	Y	?	?	Y	Y	Y	^[9]^,^[10]^,^[11]^,^[12]
S804F**	D2S6	Y	Y	Y	?	Y	N	^[13]
A1152D	D3S4-S5	Y	?	?	?	?	?	^[14]
A1156T*	D3S4-S5	Y	?	?	?	Y	?	^[3]^,^[13]
V1293I	D3S4	Y	Y	N	?	?	N
G1306V**	D3-4	Y	Y	Y	?	?	Y	^[15]^,^[16]
T1313A	D3-4	Y	Y	N	Y	Y	N	^[17]
T1313M	D3-4	Y	Y	N	Y	Y****	N	^[15]^,^[18]
M1360V*	D4S1	?	?	?	Y	Y	?	^[19]
M1370V*	D4S1	Y	Y	N	N	N	Y	^[20]
L1433R	D4S3	Y	Y	Y	?	Y*****	N	^[18]
R1448C	D4S4	Y	Y	N	N	Y	N	^[8]^,^[12]^,^[21]^,^[22]
R1448H	D4S4	Y	Y	Y	Y	Y	?	^[12]^,^[18]^,^[21]^,^[22]
R1448P	D4S4	Y	Y	?	Y	?	N	^[23]
R1448S	D4S4	Y	Y	N	?	Y	N	^[24]
R1456E	D4S4	Y	Y	N	N	N	N	^[25]
V1458F***	D4S4	?	?	?	?	?	?	^[26]
F1473S***	D4S4-S5	?	?	?	?	?	?	^[26]
M1592V*	D4S6	Y	Y	Y	Y	Y	Y	^[12]^,^[18]^,^[27]^,^[28]^,^[29]^,^[30]^,^[31]
E1702K	C-term	?	?	N	?	?	N	^[7]
F1795I	C-term	Y	?	?	?	?	?	^[32]
	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.^[33] "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.

Treatment and management

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.

Epidemiology

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. There, it was estimated that the prevalence of PC is between 1:350,000 (0.00028%) and 1:180,000 (0.00056%).^[22] However, 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 seems to be responsible for most cases.^[22]^[34] The prevalence here is estimated at 1:6000 or 0.017%.

History

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, half of children in a family inherit the disorder regardless of gender.^[35]

References

^ Facts About Myopathies | MDA Publications
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^ Subramony S, Malhotra C, Mishra S (1983). "Distinguishing paramyotonia congenita and myotonia congenita by electromyography.". Muscle Nerve 6 (5): 374–9. doi:10.1002/mus.880060506. PMID 6888415.
^ Streib E; Lane, Russell J. M.; Turnbull, Douglass M.; Hudgson, Peter; Walton, John; Brumback, Roger A.; Gerst, Jeffery W.; Heckmatt, John Z. et al. (1984). "Evoked response testing in myotonic syndromes". Muscle Nerve 7 (7): 590–2. doi:10.1002/mus.880070709. PMID 6544373.
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^ ^a ^b 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. doi:10.1038/ng1092-148. PMID 1338909.
^ 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. doi:10.1113/jphysiol.2004.081018. PMC 1464511. PMID 15790667.
^ ^a ^b 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. doi:10.1016/0092-8674(92)90151-2. PMID 1310898.
^ 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. doi:10.1113/jphysiol.1993.sp019843. PMC 1143902. PMID 8308722.
^ 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. doi:10.1113/jphysiol.2003.053082. PMC 1664790. PMID 14617673.
^ ^a ^b ^c ^d 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. doi:10.1002/ana.410330312. PMID 8388676.
^ 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. doi:10.1212/wnl.49.4.1018. PMID 9339683.
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^ 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. doi:10.1002/ana.410390509. PMID 8619545.
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^ 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. doi:10.1001/archneur.56.6.692. PMID 10369308.
^ ^a ^b 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. doi:10.1016/0960-8966(93)90009-9. PMID 7689382.
^ 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. doi:10.1002/mus.880060206. PMID 6304507.
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^ 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. doi:10.1093/hmg/2.9.1349. PMID 8242056.
^ 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. doi:10.1016/S0960-8966(96)00429-4. PMID 9131651.
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External links

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

Notes

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. doi:10.1016/0960-8966(93)90009-9. PMID 7689382.
Cannon S (2006). "Pathomechanisms in channelopathies of skeletal muscle and brain". Annu Rev Neurosci 29: 387–415. doi:10.1146/annurev.neuro.29.051605.112815. PMID 16776591.

UpToDate Contents

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1. 筋強直性ジストロフィー：病因、臨床的特徴、および診断 myotonic dystrophy etiology clinical features and diagnosis
2. 先天性ミオパシー congenital myopathies
3. 筋電図検査の概要 overview of electromyography
4. 神経筋接合部の電気診断学的評価 electrodiagnostic evaluation of the neuromuscular junction
5. 遺伝性皮膚症 the genodermatoses

English Journal

Sleep and breathing disorders in myotonic dystrophy type 2.

Leonardis L1, Blagus R2, Dolenc Groselj L1.
Acta neurologica Scandinavica.Acta Neurol Scand.2015 Jul;132(1):42-8. doi: 10.1111/ane.12355. Epub 2014 Dec 11.
OBJECTIVES: In patients who exhibit myotonic dystrophy type 1 (DM1), sleep disorders and breathing impairments are common; however, in those with DM type 2 (DM2), limited studies on polysomnography (PSG) and none on phrenic compound motor action potential (CMAP) have been performed, which is the aim
PMID 25496235

What's in the Literature?

Bromberg MB1, Lacomis D, Silvestri NJ, Wolfe GI.
Journal of clinical neuromuscular disease.J Clin Neuromuscul Dis.2015 Jun;16(4):229-38. doi: 10.1097/CND.0000000000000081.
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Japanese Journal

A Novel Mutation in the SCN4A Gene in a Japanese Family with Paramyotonia Congenita

高橋悟,山本志保,田中亮介,岡山亜貴恵,荒木章子,梶野浩樹,東寛
Journal of Neurology & Neurophysiology 5(5), 1-3, 2014-09
Paramyotoniacongenita is an autosomal-dominant muscle disease caused by missense mutations in SCN4A, the gene enconding the alpha subunit of skeletal muscle sodium channel. It is clinically characteri …
NAID 120005567843

臨床研究・症例報告先天性パラミオトニアの1孤発例

新井ひでえ,田邉雄三,迫田俊一
小児科臨床 66(2), 322-326, 2013-02
NAID 40019547252

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★リンクテーブル★

リンク元	「先天性筋緊張症」「myotonic disorder」「myotonic myopathy」「先天性パラミオトニア」
関連記事	「congenita」「paramyotonia」

「先天性筋緊張症」

Paramyotonia congenita
Classification and external resources
ICD-10	G71.1
ICD-9	359.2
OMIM	168300
DiseasesDB	32105
MedlinePlus	000316
eMedicine	neuro/308
MeSH	D020967