Clinical Diversity of SCN4A-Mutation-Associated Skeletal Muscle Sodium Channelopathy

Abstract

Background and purpose: Mutations of the skeletal muscle sodium channel gene SCN4A, which is located on chromosome 17q23-25, are associated with various neuromuscular disorders that are labeled collectively as skeletal muscle sodium channelopathy. These disorders include hyperkalemic periodic paralysis (HYPP), hypokalemic periodic paralysis, paramyotonia congenita (PMC), potassium-aggravated myotonia, and congenital myasthenic syndrome. This study analyzed the clinical and mutational spectra of skeletal muscle sodium channelopathy in Korean subjects.

Methods: Six unrelated Korean patients with periodic paralysis or nondystrophic myotonia associated with SCN4A mutations were included in the study. For the mutational analysis of SCN4A, we performed a full sequence analysis of the gene using the patients' DNA. We also analyzed the patients' clinical history, physical findings, laboratory tests, and responses to treatment.

Results: We identified four different mutations (one of which was novel) in all of the patients examined. The novel heterozygous missense mutation, p.R225W, was found in one patient with mild nonpainful myotonia. Our patients exhibited various clinical phenotypes: pure myotonia in four, and PMC in one, and HYPP in one. The four patients with pure myotonia were initially diagnosed as having myotonia congenita (MC), but a previous analysis revealed no CLCN1 mutation.

Conclusions: Clinical differentiating between sodium-channel myotonia (SCM) and MC is not easy, and it is suggested that a mutational analysis of both SCN4A and CLCN1 is essential for the differential diagnosis of SCM and MC.

Keywords: SCN4A; Wordsaamyotonic disorders; familial periodic paralyses.

Fig. 1

Membrane-folding model of the sodium channel alpha subunit and locations of the missense mutations identified in the present study. A novel mutation, p.Arg 225Trp, is located at the transmembrane S3 segment of domain I.

Fig. 2

Chromatograms of the patients. A: A novel mutation in exon 5 was identified in patient 3. A substitution of cytosine to thymidine at position 673 changes the codon for arginine at position 225 into tryptophan. B: A substitution of thymidine to cytosine at position 2078 in patient 4 changes the codon for isoleucine at position 693 into threonine. C: A substitution of guanine to adenine at position 3466 in patients 2 and 5 changes the codon for alanine at position 1156 into threonine. D: A substitution of guanine to adenine at position 3917 in patients 1 and 6 changes the codon for glycine at position 1306 into glutamate.

Fig. 3

A: The results of PCR-restriction fragment length polymorphism using restriction enzyme Aci I for the identification of the novel c.673C>T (p.Arg225Trp) mutation. No similar digestion pattern was observed among 100 normal control chromosomes. M, 100-bp molecular marker; U, undigested PCR product from patient 3; P, patient 3; numbers, control. B: Multiple alignment of the homologous sodium channel alpha subunit protein between different species of eukaryotes. The mutated protein in patient 3 (p.Arg 225Trp, arrowheads) is highly conserved between species.