Our patient showed transient muscle stiffness and weakness after rest which improved with repeated contractions. The symptoms were aggravated by cold weather and stress. EMG revealed myotonic discharges and gene sequencing analysis identified novel compound heterozygous mutations in CLCN1 gene. Finally, a diagnosis of recessive myotonia congenita was established.
The CLCN1 gene encodes the major skeletal muscle chloride channel CLCN-1. CLCN-1 plays an important part in the maintenance of resting potential, which is activated during the course of depolarization. The mutations of CLCN1 gene were scattered throughout the entire sequence of the channel protein. The mutations included insertion/deletion, missense, nonsense, and splicing mutations. To the best of our knowledge, very few studies have reported splicing mutations of CLCN1 gene [1, 2, 4, 5]. The sequences associated with splicing mutation contains two splice sites: one is a donor site, which is an invariant GU at the 5′ end of the intron and another is an acceptor site, which is an invariant AG at the 3′ end of the intron. Meyer-Kleine et al... reported a 5′ splice-donor mutation (c.1471 + 1G > A) in three GM family, which can change the highly conserved consensus sequence . Gianna et al reported four cases that harbored splicing mutations(c.563G > T, c.1169-5 T > G, c.1251 + 1G > A and c.1931-2A > G), which led to skipping exons in a frameshift change during RNA translation or premature termination . In our case, the novel splicing mutation c.1401 + 1G > A in intron 12 affected the 5′ splice-donor sequences resulting in exons skipping and generation of out-of-frame mRNA. However, the specific mechanism is yet to be elucidated. Another mutation (c.1657A > T,p.Ile553Phe) has been reported in Chinese GM patients , which may induce small changes in channel properties. This indicates that the mutation may be associated with certain ethnic populations. CLCN-1 is a voltage-dependent ion channel that mediates chloride conductance in the skeletal muscle cell membrane. The mutations of CLCN1 gene may result in a decrease in channel opening probability and render the membrane hyperexcitable, which is manifested as myotonia. This can be improved by administration of Na+ blocking agents, such as mexiletine .
In conclusion, this case report of autosomal recessive myotonia congenita caused by a novel compound heterozygous mutation expands the genotypic spectrum of CLCN1 gene.