MASSETER MUSCLE RIGIDITY ASSOCIATED WITH GLYCINE(1306)-TO-ALANINE MUTATION IN THE ADULT MUSCLE SODIUM-CHANNEL ALPHA-SUBUNIT GENE

Background: Succinylcholine-induced masseter muscle rigidity (MMR) is a potentially life-threatening complication of anesthesia and is close ly correlated with the heterogeneous disorder malignant hyperthermia ( MH) susceptibility. MMR also is identified with a variety of neuromusc ular disorders, including the myotonias, that are associated with abno rmal in vitro contracture test (IVCT) results. Recently, mutations in the adult skeletal muscle sodium channel alpha-subunit gene (SCN4A) ha ve been shown to cause generalized nondystrophic myotonias, some of wh ich are associated with mild nonspecific symptoms. The purpose of the current investigation was to begin to evaluate the molecular genetic r elationship between known mutations in the SCN4A gene, MMR, and the re sults of the IVCT used to diagnose MH-susceptibility. Methods: A singl e extended pedigree of 16 individuals was ascertained through a proban d who experienced MMR and whole-body rigidity after succinylcholine ad ministration. Subsequently, four individuals were shown to have a mild form of myotonia on clinical and laboratory examination. IVCT was car ried out according to standardized protocols. Mutations in the SCN4A g ene were sought in exons 22 and 24 using single-strand conformational analyses. Variability in the SCN4A gene sequence was confirmed by dire ct DNA sequence analyses. Results: Four individuals with myotonia were shown to carry a guanine-to-cytosine mutation at nucleotide position 3917 of the reported SCN4A sequence. This DNA mutation was coinherited with MMR and an abnormal IVCT result in this family. Previous studies have demonstrated that the glycine(1306)-to-alanine substitution is a ssociated with a mild clinical syndrome referred to as myotonia fluctu ans. Conclusions: The current report provides direct evidence that suc cinylcholine-induced MMR, whole-body rigidity, and an abnormal IVCT re sult are associated with a mutation in the SCN4A gene.