Clinical Diversity of SCN4A-Mutation-Associated Skeletal Muscle Sodium Channelopathy
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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.
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.
참고문헌 (20)
- George AL Jr, "Assignment of a human skeletal muscle sodium channel alpha-subunit gene (SCN4A) to 17q23.1-25.3", Genomics, 9, pp.555~556 (1991)
- George AL Jr, "Molecular basis of Thomsen’s disease (autosomal dominant myotonia congenita)", Nat Genet, 3, pp.305~310 (1993)
- Stenson PD, "Human Gene Mutation Database (HGMD): 2003 update", Hum Mutat, 21, pp.577~581 (2003)
- Ptácek LJ, "Identification of a mutation in the gene causing hyperkalemic periodic paralysis", Cell, 67, pp.1021~1027 (1991)
- McClatchey AI, "Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel", Nat Genet, 2, pp.148~152 (1992)
- Orrell RW, "Familial cramp due to potassium-aggravated myotonia", J Neurol Neurosurg Psychiatry, 65, pp.569~572 (1998)
- Bulman DE, "A novel sodium channel mutation in a family with hypokalemic periodic paralysis", Neurology, 53, pp.1932~1936 (1999)
- Tsujino A, "Myasthenic syndrome caused by mutation of the SCN4A sodium channel", Proc Natl Acad Sci U S A, 통권 : 100, pp.7377~7382 (2003)
- Cannon SC, "Spectrum of sodium channel disturbances in the nondystrophic myotonias and periodic paralyses", Kidney Int, 57, pp.772~779 (2000)
- 문인수, "Novel CLCN1 Mutations and Clinical Features of Korean Patients with Myotonia Congenita", Journal of Korean Medical Science, 24(6), pp.1038~1044 (2009), 대한의학회
- Wu FF, "A new mutation in a family with cold-aggravated myotonia disrupts Na(+) channel inactivation", Neurology, 56, pp.878~884 (2001)
- Rosenfeld J, "A novel muscle sodium channel mutation causes painful congenital myotonia", Ann Neurol, 42, pp.811~814 (1997)
- Ptacek LJ, "Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis", Ann Neurol, 33, pp.300~307 (1993)
- Plassart E, "Paramyotonia congenita: genotype to phenotype correlations in two families and report of a new mutation in the sodium channel gene", J Neurol Sci, 142, pp.126~133 (1996)
- McClatchey AI, "Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel", Nat Genet, 2, pp.148~152 (1992)
- Lerche H, "Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker", J Physiol, 470, pp.13~22 (1993)
- Mitrović N, "Different effects on gating of three myotonia-causing mutations in the inactivation gate of the human muscle sodium channel", J Physiol, 487, pp.107~114 (1995)
- Rüdel R, "Paramyotonia, potassium-aggravated myotonias and periodic paralyses", 37th ENMC International Workshop, 통권 : 7, pp.127~132 (1995)
- Schoser BG, "A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene", Muscle Nerve, 35, pp.599~606 (2007)
- Trip J, "In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia", Eur J Hum Genet, 16, pp.921~929 (2008)