Nezir ÖZGÜN, Hasan TAŞLIDERE

Congenital myotonia: a review of twenty cases and a new splice-site mutation in the CLCN1 gene

Background and objectives. Congenital Myotonia (CM) is a disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1). Mutations can be transmitted as autosomal dominant (Thomsen's disease) or recessive (Becker's disease). CM is more common in men and Becker myotonia may be 10 times more common than Thomsen myotonia. Genotypic and phenotypic characteristics of CM may vary according to geographical region and ethnicity. Method. In this study, we present the genotypic and phenotypic characteristics of 20 Turkish CM patients all diagnosed by molecular genetic testing. The clinical and laboratory features of the patients with mutation in CLCN1 gene were retrospectively analyzed. Results. Eleven of the patients were female. c.1064+1G>A splice-site change, p.Arg338X (c.1012 C>T) stop codon, p.Gly190Ser (c.568_569delinsTC) missense mutations were detected. Eight of the 20 patients were found to be compatible with Becker type and 12 with Thomsen type, based on mode of inheritance, neurological examination findings and genetic test results. Conclusion. The c.1064+1G>A splice-site change mutation, defined for the first time in this study, expands the spectrum of mutations in the CLCN1 gene. Thomsen type and female gender were observed to be more frequent in this series of patients from Turkey.

PDF

___

1. Koch MC, Steinmeyer K, Lorenz C, et al. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 1992; 257: 797-800.

2. Pusch M. Myotonia caused by mutations in the muscle chloride channel gene CLCN1. Hum Mutat 2002; 19: 423-434.

3. Pusch M, Steinmeyer K, Koch MC, Jentsch TJ. Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel. Neuron 1995; 15: 1455-1463.

4. Lakraj AA, Miller G, Vortmeyer AO, Khokhar B, Nowak RJ, DiCapua DB. Novel mutations in the ClCN-1 gene of myotonia congenita: 2 case reports. Yale J Biol Med 2013; 86: 101-106.

5. Matthews E, Fialho D, Tan SV, et al; CINCH Investigators. The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment. Brain 2010; 133(Pt 1): 9-22.

6. Derevenciuc A, Abicht A, Hamza S, Roth C, Ferbert A. Thomsen myotonia-A 4-generation family with a new mutation and a mild phenotype. Muscle Nerve 2016; 53: 653-654.

7. Mailänder V, Heine R, Deymeer F, Lehmann-Horn F. Novel muscle chloride channel mutations and their effects on heterozygous carriers. Am J Hum Genet 1996; 58: 317-324.

8. Imbrici P, Maggi L, Mangiatordi GF, et al. ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype– phenotype correlation. J Physiol 2015; 593: 4181- 4199.

9. Dunø M, Colding-Jørgensen E. Myotonia congenita. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds). GeneReviews. Seattle WA: University of Washington, 1993-2020. 2005 Aug 3 [updated 2015 Aug 6].

10. Hahn C, Salajegheh MK. Myotonic disorders: a review article. Iran J Neurol 2016; 15: 46-53.

11. Brugnoni R, Kapetis D, Imbrici P, et al. A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene. J Hum Genet 2013; 58: 581-587.

12. Kato H, Kokunai Y, Dalle C, et al. A case of nondystrophic myotonia with concomitant mutations in the SCN4A and CLCN1 genes. J Neurol Sci 2016; 369: 254-258.

13. Horga A, Raja Rayan DL, Matthews E, et al. Prevalence study of genetically defined skeletal muscle channelopathies in England. Neurology 2013; 80: 1472-1475.

14. Fialho D, Kullman DM, Hanna MG, Schorge S. Non-genomic effects of sex hormones on ClC-1 may contribute to gender differences in myotonia congenita. Neuromuscul Disord 2008; 18: 869-872.

15. Becker PE. Myotonia congenita and syndromes associated with myotonia. In: Becker PE, Lenz W, Vogel F, Wendt GG (eds). Vol. 3, Stuttgard, Germany: Georg Thieme Verlag, 1977.

16. Fialho D, Schorge S, Pucovska U, et al. Chloride channel myotonia: exon 8 hot-spot for dominantnegative interactions. Brain 2007; 12: 3265-3274.

17. Papponen H, Toppinen T, Baumann P, et al. Founder mutations and the high prevalence of myotonia congenita in northern Finland. Neurology 1999; 53: 297-302.

18. Sun C, Tranebjaerg L, Torbergsen T, Holmgren G, Van Ghelue M. Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia. Eur J Hum Genet 2001; 9: 903-909.

19. Emery AE. Population frequencies of inherited neuromuscular diseases - a world survey. Neuromuscul Disord 1991; 1: 19-29.

20. Deymeer F, Cakirkaya S, Serdaroğlu P, et al. Transient weakness and compound muscle action potential decrement in myotonia congenita. Muscle Nerve 1998; 21: 1334-1337.

21. Deymeer F, Lehmann-Horn F, Serdaroğlu P, et al. Electrical myotonia in heterozygous carriers of recessive myotonia congenita. Muscle Nerve 1999; 22: 123-125.

22. Sahin I, Erdem HB, Tan H, Tatar A. Becker's myotonia: novel mutations and clinical variability in patients born to consanguineous parents. Acta Neurol Belg 2018; 118: 567-572.

23. Coote DJ, Davis MR, Cabrera M, Needham M, Laing NG, Nowak KJ. Clinical utility gene card for: autosomal dominant myotonia congenita (Thomsen disease). Eur J Hum Genet 2018; 26: 1072-1077.

24. Cassone M, Ferradini V, Longo G, et al. Genotypephenotype correlation of F484L mutation in three Italian families with Thomsen myotonia. Muscle Nerve 2017; 55: E24-E25.

25. Colding-Jørgensen E. Phenotypic variability in myotonia congenita. Muscle Nerve 2005; 32: 19-34.

26. Gurgel-Giannetti J, Senkevics AS, Zilbersztajn- Gotlieb D, et al. Thomsen or Becker myotonia? A novel autosomal recessive nonsense mutation in the CLCN1 gene associated with a mild phenotype. Muscle Nerve 2012; 45: 279-283.

27. Duno M, Colding-Jorgensen E, Grunnet M, Jespersen T, Vissing J, Schwartz M. Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype. Eur J Hum Genet 2004; 12: 738-743.

28. Kumar KR, Ng K, Vandebona H, Davis MR, Sue CM. A novel CLCN1 mutation (G1652A) causing a mild phenotype of thomsen disease. Muscle Nerve 2010; 41: 412-415.

29. Ulzi G, Lecchi M, Sansone V, et al. Myotonia congenita: novel mutations in CLCN1 gene and functional characterizations in Italian patients. J Neurol Sci 2012; 318: 65-71.

30. Shalata A, Furman H, Adir V, et al. Myotonia congenita in a large consanguineous Arab family: insight into the clinical spectrum of carriers and double heterozygotes of a novel mutation in the chloride channel CLCN1 gene. Muscle Nerve 2010; 41: 464-469.

31. Dupré N, Chrestian N, Bouchard JP, et al. Clinical, electrophysiologic, and genetic study of nondystrophic myotonia in French-Canadians. Neuromuscul Disord 2009; 19: 330-334.

32. Gao F, Ma FC, Yuan ZF, et al. Novel chloride channel gene mutations in two unrelated Chinese families with myotonia congenita. Neurol India 2010; 58: 743-746.

33. Fournier E, Arzel M, Sternberg D, et al. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol 2004; 56: 650-661.

34. Ørstavik K, Wallace SC, Torbergsen T, et al. A de novo mutation in the SCN4A gene causing sodium channel myotonia. J Neuromuscul Dis 2015; 2: 181- 184.

35. Ginanneschi F, Mignarri A, Lucchiari S, et al. Neuromuscular excitability changes produced by sustained voluntary contraction and response to mexiletine in myotonia congenita. Neurophysiol Clin 2017; 47: 247-252.

36. Statland JM, Bundy BN, Wang Y, et al; and the Consortium for Clinical Investigation of Neurologic Channelopathies. Mexiletine for symptoms and signs of myotonia in non-dystrophic myotonia: a randomized controlled trial. JAMA 2012; 308: 1357- 1365.

37. Conravey A, Santana-Gould L. Myotonia congenita and myotonic dystrophy: surveillance and management. Curr Treat Options Neurol 2010; 12: 16-28.

38. Arnold WD, Kline D, Sanderson A, et al. Open-label trial of ranolazine for the treatment of myotonia congenita. Neurology 2017; 89: 710-713.

39. Andersen G, Hedermann G, Witting N, Duno M, Andersen H, Vissing J. The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a doubleblind randomized study. Brain 2017; 140: 2295-2305.

40. Lyons MJ, Duron R, Molinero I, Sangiuolo F, Holden KR. Novel CLCN1 mutation in carbamazepineresponsive myotonia congenita. Pediatr Neurol 2010; 42: 365-368.