<unk>  (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. There has been one study of a large number of patients with<unk> . 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. +Table 1. Summary of mutations found in patients diagnosed with<unk>  and their resulting phenotypes 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<unk>  and hyperKPP (Periodica paralytica<unk> a)Also diagnosed as a Potassium-aggravated myotoniaOriginal case reports unpublished.When exercised in a cold environmentAfter 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.
Paramyotonia congenita
Myotonia congenita
Periodic paralysis
Klumpke paralysis
Quadrigia
Paroxysmal kinesigenic choreoathetosis
Ataxic cerebral palsy
Cramp fasciculation syndrome