We have identified four different SCN4A
mutations (one of which has not been reported previously) in six unrelated Korean patients with nondystrophic myotonia and periodic paralysis syndrome. A novel heterozygous missense mutation c.673C>T (p.R225W) was found in patient 3, who presented with mild nonpainful pure myotonia ( and ). This mutation is located at the cytoplasmic side of transmembrane S3 segment of domain I (DI/S3; and ), and is noteworthy because most of the previously reported SCN4A
mutations are clustered in domains III or IV of the protein. Furthermore, it is the most proximal mutation ever reported in SCN4A
. Thus far only two mutations affecting domain I have been reported.11,12
This mutation is also remarkable because there is only one previous report of an SCN4A
mutation affecting the S3 segment (p.L1433R).13
Another mutation, c.2078T>C (p.I693T), was identified in patient 4, who exhibited a typical PMC phenotype. This mutation is located at the cytoplasmic link between S4 and S5 of DII, and has been reported previously in patients with PMC (, and ).14
The c.3466G>A (p.A1156T) mutation was shared by two of our patients who exhibited completely different phenotypes (, and ): while patient 2 had pure myotonia affecting the lower extremities, with warm-up phenomenon, patient 5 manifested as HYPP without clinical history or signs of myotonia. Although the mutation p.A1156T has been described previously both in patients with HYPP and PMC,15
it has never been associated with the pure myotonia phenotype, as in our patient 2. This phenotypic variability observed in individuals harboring the same SCN4A
mutation strongly suggests that the genetic background-and perhaps other epigenetic factors-influences the clinical expression of particular mutations.
The c.3917G>A (p.G1306E) mutation, located at the cytoplasmic linker between domains III and IV (ID3-4), was also found in two patients, in both of whom it manifested as pure myotonia (patients 1 and 6). This mutation had been reported in patients with PAM and has been functionally characterized (, and ).16,17
Our study shows that SCN4A mutations produce different phenotypes of nondystrophic myotonia and periodic paralysis syndrome. We have also shown that certain SCN4A mutations may not be associated with specific clinical phenotypes, suggesting poor genotype-phenotype correlations in skeletal muscle sodium channelopathy.
In sodium channelopathy, there is a group of patients who manifest with pure myotonia. These patients exhibit one of several clinical phenotypes including myotonia fluctuans, myotonia permanens, and acetazolamide-responsive myotonia.18
They are distinct from those with PMC by the absence of paradoxical myotonia and cold sensitivity. Since many such patients have myotonia that becomes much more pronounced after the ingestion of potassium-rich food, the condition has been collectively called PAM. However, some patients with SCN4A
-related pure myotonia do not exhibit such potassium sensitivity,11,19
and thus the condition may be more appropriately labeled sodium-channel myotonia. The myotonia in this group of patients is very similar to that observed in those with myotonia congenita (MC), and clinical differentiation may not be possible. The four patients with pure myotonia in our study had also initially been considered as having MC, but they were finally shown to have SCN4A
mutations. A recent study involving the screening of SCN4A
mutations in large numbers of patients with nondystrophic myotonia found that 20% of patients who had been clinically diagnosed as MC had SCN4A
Our study also showed that sodium channelopathy comprises highly variable clinical phenotypes, and that the genotype-phenotype correlation is not unequivocal. Although careful clinical evaluation is of great help, we suggest that a definite molecular diagnosis using sequence analysis of both SCN4A and CLCN1 is essential for the differential diagnosis of sodium channelopathy from other conditions, especially when a patient presents with pure myotonia.