Polymorphisms of human skeletal muscle sodium channel (SCN4A) gene in paralysis periodica paramyotonica

Abstract

Patients with paralysis periodica paramyotonica (PPP) exhibit a clinical syndrome with characteristics of both hyperkalemic periodic paralysis (HyperPP) and paramyotonia congenita. In several types of periodic paralysis associated with hyperkalemia, mutations in the skeletal muscle sodium channel gene (SCN4A) have been previously reported. Phenotypic variations of mutations in the SCN4A, however, have not been described yet. The present study was performed to evaluate genetic variations in a family with clinical and electrophysiological characteristics of paralysis periodica paramyotonica (PPP). Seven members of a family affected with symptoms of periodic paralysis and paramyotona were studied with electrophysiological and genetic analyses. Increased serum potassium levels were observed in four members of this family during paralytic attacks induced by HyperPP provocation tests. Short exercise tests (SETs) before and after cold immersion were carried out in four patients to distinguish electrophysiolgical characteristics of HyperPP and paramyotonia. Sequencing analyses of SCN4A were performed on one patient and a normal control to identify polymorphisms. Restriction fragment length polymorphism (RFLP) analysis was then performed at the identified polymorphic sites. Amplitudes of compound motor action potential (CMAP) were increased (4.0-24.3%) during voluntary muscle contraction and then decreased (7.3-28.6%) after the muscle contraction on the short exercise test. On the cold immersion tests, the CMAP amplitudes were increased markedly (6.3-43.5%) during the muscle contraction and then even more severely decreased (21.7-56.5%) in after the contraction than in shorter time (13-15 minutes) than the results on SET at room temperature. Three polymorphic sites, Gln371Glu, Thr704Met, and Aspl376Asn in SCN4A were identified. RFLP analyses showed that all affected patients carried the Thr704Met mutation, while unaffected family members and a normal control did not. Th...