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 characterized by paradoxical myotonia, an attack of muscle stiffness that is aggravated by repeated activity, as well by cold-induced muscle stiffness. We describe the clinical and genetic features of a Japanese family with Paramyotoniacongenita. Five members of this family (four generations) were affected. Treatment with mexiletine, an antiarrhythmic drug that inhibits inward sodium current, relieved their symptoms. We identified a novel SCN4A mutation (c.3470T>A, p.Ile1157Asn) in the affected individuals. This mutation is located on the cytoplasmic loop connecting the trans-membrane segments S4 and S5 of domain 3 of the sodium channel, the site for docking with its inactivation particle. This mutation may cause the defective inactivation of the channel. Our observation provides a new insight into the genotype-phenotype correlation in sodium channel opathies.
