Identification of Novel Mutations of the CLCN-1 and SCN4A Genes in Non-dystrophic Myotonia in China

Abstract Background: The aim of our study was to characterize the genetic, pathological and clinical alterations of 17 patients in China presenting with non-dystrophic myotonia (NDM). Methods: We first sequenced the CLCN-1 gene in patients having clinical features and muscle pathology indicative of NDM. If no mutations were detected, we subsequently analyzed the SCN4A, KCNE3 and CACNA1S genes. Results: As determined by needle electromyography, patients may have accompanying atypical myopathy as well as muscle hypertrophy, secondary dystonia and joint contracture All participants in this study were administered mexiletine in combination with carbamazepine and showed significant improvements in their myotonia symptoms. Routine pathological examinations showed mild abnormalities in muscle pathology. Oxidative enzyme activity was decreased in many fibers. ATPase studies of fiber subtypes demonstrated a predominance of type 2A fibers and a complete absence of type 2B muscle fibers in patients with CLCN-1 mutations. CLCN-1 gene mutations were found in 8 cases diagnosed with myotonia congenital by gene screening. The detected mutations included 5 missense, 2 nonsense, 1 deletion and 2 insertions, and these CLCN-1 mutations were concentrated in exons 8 and 12. Further gene analysis showed 4 mutations in the SCN4A gene in patients diagnosed with paramyotonia congenita. One of these mutations was consistent with a previously reported mutation, whereas 3 mutations were novel. All of these novel mutations occurred within “hot spots” of exons 22 and 24. Five patients with NDM lacked any identifiable mutations in CLCN-1, SCN4A, CACNA1S or KCNE3. Conclusions: Myotonia congenita and paramyotonia congenita are the predominant forms of NDM in China. NDM may be best diagnosed using genetic analysis in combination with clinical features. New mutations of the CLCN-1 and SCN4A genes in patients with NDM were detected, we postulate that novel pathogenic genes for NDM occur in China.