Paramyotonia congenita

DiseaseDisorder infobox
Name = Paramyotonia Congenita


Caption =
DiseasesDB = 32105
ICD10 = ICD10|G|71|1|g|70
ICD9 = ICD9|359.2
ICDO =
OMIM = 168300
MedlinePlus = 000316
eMedicineSubj = neuro
eMedicineTopic = 308
MeshID = D020967

Paramyotonia Congenita (PC), also known as Paramyotonia congenita of von Eulenburg or Eulenburg disease [ [http://www.mdausa.org/publications/fa-myop-qa2.html Facts About Myopathies | MDA Publications ] ] , is a rare congenital autosomal dominant neuromuscular disorder characterized by “paradoxical” myotonia.Eulenburg A (1886) Über eine familiäre durch 6 Generationen verfolgbare Form kongenitaler Paramyotonie. "Neurol. Zentralbl." 12:265-72.] 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.cite journal | author = de Silva S, Kuncl R, Griffin J, Cornblath D, Chavoustie S | title = Paramyotonia congenita or hyperkalemic periodic paralysis? Clinical and electrophysiological features of each entity in one family. | journal = Muscle Nerve | volume = 13 | issue = 1 | pages = 21–6 | year = 1990 | pmid = 2325698 | doi = 10.1002/mus.880130106]

ymptoms 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 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

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.cite journal | author = Subramony S, Malhotra C, Mishra S | title = Distinguishing paramyotonia congenita and myotonia congenita by electromyography. | journal = Muscle Nerve | volume = 6 | issue = 5 | pages = 374–9 | year = 1983 | pmid = 6888415 | doi = 10.1002/mus.880060506] ^,cite journal | author = Streib E | title = Evoked response testing in myotonic syndromes. | journal = Muscle Nerve | volume = 7 | issue = 7 | pages = 590–2 | year = 1984 | pmid = 6544373] 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.

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.cite journal | author = 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 | title = Correlating phenotype and genotype in the periodic paralyses. | journal = Neurology | volume = 63 | issue = 9 | pages = 1647–55 | year = 2004 | pmid = 15534250]

Treatment/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. 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.Becker PE, Paramyotonia congenita (Eulenberg) in "Fortschritte der allgemeinen und klinischen Humangenetik". Thieme, Stuttgart (1970).] 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.

External links

* [http://www.hkpp.org/faq/pmc.html 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.
* [http://www.mdausa.org/disease/pc.html Fact page from the Muscular Dystrophy Association]
* [http://www.rarediseases.org/ The National Organization for Rare Disorders (NORD)]

Notes

*cite journal | author = Lehmann-Horn F, Rüdel R, Ricker K | title = Non-dystrophic myotonias and periodic paralyses. A European Neuromuscular Center Workshop held 4-6 October 1992, Ulm, Germany. | journal = Neuromuscul Disord | volume = 3 | issue = 2 | pages = 161–8 | year = 1993 | pmid = 7689382 | doi = 10.1016/0960-8966(93)90009-9
*cite journal | author = Cannon S | title = Pathomechanisms in channelopathies of skeletal muscle and brain. | journal = Annu Rev Neurosci | volume = 29 | issue = | pages = 387–415 | year = 2006 | pmid = 16776591 | doi = 10.1146/annurev.neuro.29.051605.112815

References