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.
Mutation | Region | Myotonia | Weakness | References | ||||
---|---|---|---|---|---|---|---|---|
Cold | Exercise/ Activity |
Potassium | Cold | Exercise/ Activity |
Potassium | |||
R672C | D2S4 | ? | ? | ? | ? | ? | ? | |
I693T | D2S4-S5 | N | ? | ? | Y | Y | Y | |
T704M* | D2S5 | Y | ? | ? | Y | Y | Y | ,,, |
S804F** | D2S6 | Y | Y | Y | ? | Y | N | |
A1152D | D3S4-S5 | Y | ? | ? | ? | ? | ? | |
A1156T* | D3S4-S5 | Y | ? | ? | ? | Y | ? | , |
V1293I | D3S4 | Y | Y | N | ? | ? | N | |
G1306V** | D3-4 | Y | Y | Y | ? | ? | Y | , |
T1313A | D3-4 | Y | Y | N | Y | Y | N | |
T1313M | D3-4 | Y | Y | N | Y | Y**** | N | , |
M1360V* | D4S1 | ? | ? | ? | Y | Y | ? | |
M1370V* | D4S1 | Y | Y | N | N | N | Y | |
L1433R | D4S3 | Y | Y | Y | ? | Y***** | N | |
R1448C | D4S4 | Y | Y | N | N | Y | N | ,,, |
R1448H | D4S4 | Y | Y | Y | Y | Y | ? | ,,, |
R1448P | D4S4 | Y | Y | ? | Y | ? | N | |
R1448S | D4S4 | Y | Y | N | ? | Y | N | |
R1456E | D4S4 | Y | Y | N | N | N | N | |
V1458F*** | D4S4 | ? | ? | ? | ? | ? | ? | |
F1473S*** | D4S4-S5 | ? | ? | ? | ? | ? | ? | |
M1592V* | D4S6 | Y | Y | Y | Y | Y | Y | ,,,,,, |
E1702K | C-term | ? | ? | N | ? | ? | N | |
F1795I | C-term | Y | ? | ? | ? | ? | ? | |
* ** *** **** ***** |
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 |
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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. |
Read more about this topic: Paramyotonia Congenita