Skip to main content

Coexistence of CLCN1 and SCN4A mutations in one family suffering from myotonia

neurogenetics volume 18, pages 219–225 (2017)Cite this article

Abstract

Non-dystrophic myotonias are characterized by clinical overlap making it challenging to establish genotype-phenotype correlations. We report clinical and electrophysiological findings in a girl and her father concomitantly harbouring single heterozygous mutations in SCN4A and CLCN1 genes. Functional characterization of N1297S hNav1.4 mutant was performed by patch clamp. The patients displayed a mild phenotype, mostly resembling a sodium channel myotonia. The CLCN1 c.501C>G (p.F167L) mutation has been already described in recessive pedigrees, whereas the SCN4A c.3890A>G (p.N1297S) variation is novel. Patch clamp experiments showed impairment of fast and slow inactivation of the mutated Nav1.4 sodium channel. The present findings suggest that analysis of both SCN4A and CLCN1 genes should be considered in myotonic patients with atypical clinical and neurophysiological features.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Cannon SC (2015) Channelopathies of skeletal muscle excitability. Compr Physiol 5:761–790

    Article  PubMed  PubMed Central  Google Scholar 

  2. Horga A, Raja Rayan DL, Matthews E, Sud R, Fialho D, Durran SC et al (2013) Prevalence study of genetically defined skeletal muscle channelopathies in England. Neurology 80:1472–1475

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Suetterlin K, Männikkö R, Hanna MG (2014) Muscle channelopathies: recent advances in genetics, pathophysiology and therapy. Curr Opin Neurol 27:583–590

    CAS  Article  PubMed  Google Scholar 

  4. Fournier E, Arzel M, Sternberg D, Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B et al (2004) Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol 56:650–661

    CAS  Article  PubMed  Google Scholar 

  5. Fournier E, Viala K, Gervais H, Sternberg D, Arzel-Hézode M, Laforet P et al (2006) Cold extends electromyography distinction between ion channel mutations causing myotonia. Ann Neurol 60:356–365

    Article  PubMed  Google Scholar 

  6. Tan SV, Matthews E, Barber M, Burge GA, Rajakulendran S, Fialho D et al (2011) Refined exercise testing can aid DNA-based diagnosis in muscle channelopathies. Ann Neurol 69:328–340

    Article  PubMed  PubMed Central  Google Scholar 

  7. Madisen L, Hoar DI, Holroyd CD, Crisp M, Hodes ME (1987) DNA banking: the effects of storage of blood and isolated DNA on the integrity of DNA. Am J Med Genet 27:379–390

    CAS  Article  PubMed  Google Scholar 

  8. Brugnoni R, Galantini S, Confalonieri P, Balestrini MR, Cornelio F, Mantegazza R (1999) Identification of three novel mutations in the major human skeletal muscle chloride channel gene (CLCN1), causing myotonia congenita. Hum Mutat 14:447

    CAS  Article  PubMed  Google Scholar 

  9. Brugnoni R, Kapetis D, Imbrici P, Pessia M, Canioni E, Colleoni L et al (2013) 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 58:581–587

    CAS  Article  PubMed  Google Scholar 

  10. Desaphy JF, Carbonara R, D'Amico A, Modoni A, Roussel J, Imbrici P et al (2016) Translational approach to address therapy in myotonia permanens due to a new SCN4A mutation. Neurology 86:2100–2108

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Desaphy J-F, De Luca A, Tortorella P, De Vito D, George AL Jr, Conte Camerino D (2001) Gating of myotonic Na channel mutants defines the response to mexiletine and a potent derivative. Neurology 57:1849–1857

    CAS  Article  PubMed  Google Scholar 

  12. Zhang J, Bendahhou S, Sanguinetti MC, Ptacek L (2000) Functional consequences of chloride channel gene (CLCN1) mutations causing myotonia congenita. Neurology 54:937–942

    CAS  Article  PubMed  Google Scholar 

  13. Trivedi JR, Bundy B, Statland J, Salajegheh M, Rayan DR, Venance SL et al (2013) Non-dystrophic myotonia: prospective study of objective and patient reported outcomes. Brain 136:2189–2200

    Article  PubMed  PubMed Central  Google Scholar 

  14. Matthews E, Fialho D, Tan SV, Venance SL, Cannon SC, Sternberg D et al (2010) The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment. Brain 133:9–22

    CAS  Article  PubMed  Google Scholar 

  15. Desaphy JF, Gramegna G, Altamura C, Dinardo MM, Imbrici P, George AL Jr et al (2013a) Functional characterization of ClC-1 mutations from patients affected by recessive myotonia congenita presenting with different clinical phenotypes. Exp Neurol 248:530–540

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. George AL Jr, Sloan-Brown K, Fenichel GM, Mitchell GA, Spiegel R, Pascuzzi RM (1994) Nonsense and missense mutations of the muscle chloride channel gene in patients with myotonia congenita. Hum Mol Genet 3:2071–2072

    CAS  PubMed  Google Scholar 

  17. Meyer-Kleine C, Steinmeyer K, Ricker K, Jentsch TJ, Koch MC (1995) Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia. Am J Hum Genet 57:1325–1334

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Michel P, Sternberg D, Jeannet PY, Dunand M, Thonney F, Kress W et al (2007) Comparative efficacy of repetitive nerve stimulation, exercise, and cold in differentiating myotonic disorders. Muscle Nerve 36:643–650

    CAS  Article  PubMed  Google Scholar 

  19. Modoni A, D’Amico A, Dallapiccola B, Mereu ML, Merlini L, Pagliarani S et al (2011) Low-rate repetitive nerve stimulation protocol in an Italian cohort of patients affected by recessive myotonia congenita. J Clin Neurophysiol 28:39–44

    Article  PubMed  Google Scholar 

  20. Mazón MJ, Barros F, De la Peña P, Quesada JF, Escudero A, Cobo AM et al (2012) Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene. Neuromuscul Disord 22:231–243

    Article  PubMed  Google Scholar 

  21. Lucchiari S, Ulzi G, Magri F, Bucchia M, Corbetta F, Servida M et al (2013) Clinical evaluation and cellular electrophysiology of a recessive CLCN1 patient. J Physiol Pharmacol 64:669–678

    CAS  PubMed  Google Scholar 

  22. Gay S, Dupuis D, Faivre L, Masurel-Paulet A, Labenne M, Colombani M et al (2008) Severe neonatal non-dystrophic myotonia secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) gene. Am J Med Genet 146A:380–383

    CAS  Article  PubMed  Google Scholar 

  23. Mitrović N, George AL Jr, Lerche H, Wagner S, Fahlke C, Lehmann-Horn F (1995) Different effects on gating of three myotonia-causing mutations in the inactivation gate of the human muscle sodium channel. J Physiol 487:107–114

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hayward LJ, Brown RH Jr, Cannon SC (1996) Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker. J Gen Physiol 107:559–576

    CAS  Article  PubMed  Google Scholar 

  25. Stuhmer W, Conti F, Suzuki H, Wang XD, Noda M, Yahagi N et al (1989) Structural parts involved in activation and inactivation of the sodium channel. Nature 339:597–603

    CAS  Article  PubMed  Google Scholar 

  26. Desaphy J-F, Modoni A, Lo Monaco M, Conte Camerino D (2013b) Dramatic improvement of myotonia permanens with flecainide: a two-case report of a possible bench-to-bedside pharmacogenetics strategy. Eur J Clin Pharmacol 69:1037–1039

    Article  PubMed  Google Scholar 

  27. Cummins TR, Sigworth FJ (1996) Impaired slow inactivation in mutant sodium channels. Biophys J 71:227–236

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Hayward LJ, Brown RH Jr, Cannon SC (1997) Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis. Biophys J 72:1204–1219

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Skov M, Riisager A, Fraser JA, Nielsen OB, Pedersen TH (2013) Extracellular magnesium and calcium reduce myotonia in ClC.1 inhibited rat muscle. Neuromuscul Disord 23:489–502

    Article  PubMed  Google Scholar 

  30. Furby A, Vicart S, Camdessanché JP, Fournier E, Chabrier S, Lagrue E et al (2014) Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia. Neuromuscul Disord 24:953–999

    CAS  Article  PubMed  Google Scholar 

  31. Kato H, Kokunai Y, Dalle C, Kubota T, Madokoro Y, Yuasa H et al (2016) A case of non-dystrophic myotonia with concomitant mutations in the SCN4A and CLCN1 genes. J Neurol Sci 369:254–258

    CAS  Article  PubMed  Google Scholar 

  32. Sun C, Van Ghelue M, Tranebjærg L, Thyssen F, Nilssen Ø, Torbergsen T (2011) Myotonia congenita and myotonic dystrophy in the same family: coexistence of a CLCN1 mutation and expansion in the CNBP (ZNF9) gene. Clin Genet 80:574–580

    CAS  Article  PubMed  Google Scholar 

  33. Cardani R, Giagnacovo M, Botta A, Rinaldi F, Morgante A, Udd B et al (2012) Co-segregation of DM2 with a recessive CLCN1 mutation in juvenile onset of myotonic dystrophy type 2. J Neurol 259:2090–2099

    CAS  Article  PubMed  Google Scholar 

  34. Bugiardini E, Rivolta I, Binda A, Soriano Caminero A, Cirillo F, Cinti A et al (2015) SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype. Neuromuscul Disord 25:301–307

    CAS  Article  PubMed  Google Scholar 

  35. Peddareddygari LR, Grewal AS, Grewal RP (2016) Focal seizures in a patient with myotonic disorder type 2 co-segregating with a chloride voltage-gated channel 1 gene mutation: a case report. J Med Case Rep 10:167

    Article  PubMed  PubMed Central  Google Scholar 

  36. Burge JA, Hanna MG, Schorge S (2013) Nongenomic actions of progesterone and 17beta-estradiol on the chloride conductance of skeletal muscle. Muscle Nerve 48:589–591

    CAS  Article  PubMed  Google Scholar 

Download references

Funding

This research was supported by the Italian Telethon Foundation (Grant GGP14096) and the Italian Ministry of Health (Grant GR-2009-1580433).

Author information

Author notes

  1. Lorenzo Maggi, Sabrina Ravaglia and Alessandro Farinato contributed equally as first authors

  2. Pia Bernasconi, Jean-François Desaphy and Massimiliano Filosto contributed equally as senior authors

Affiliations

  1. Neurology IV – Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Via Celoria 11, 20133, Milan, Italy

    Lorenzo Maggi, Raffaella Brugnoni, Renato Mantegazza & Pia Bernasconi

  2. Istituto Neurologico IRCCS C. Mondino, Pavia, Italy

    Sabrina Ravaglia

  3. Department of Pharmacy and Drug Sciences, University of Bari Aldo Moro, Bari, Italy

    Alessandro Farinato, Concetta Altamura, Paola Imbrici & Diana Conte Camerino

  4. Center for Neuromuscular Diseases and Neuropathies, Unit of Neurology ASST “Spedali Civili”, University of Brescia, Brescia, Italy

    Alessandro Padovani & Massimiliano Filosto

  5. Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy

    Jean-François Desaphy

Authors
  1. Lorenzo Maggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabrina Ravaglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandro Farinato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Raffaella Brugnoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Concetta Altamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paola Imbrici
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Diana Conte Camerino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alessandro Padovani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Renato Mantegazza
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pia Bernasconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jean-François Desaphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Massimiliano Filosto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lorenzo Maggi.

Ethics declarations

Written informed consent for genetic analysis was obtained from the proband, her parents and her brother, as required by the Ethical Committee of the Foundation Neurological Institute Carlo Besta, in accordance with the Helsinki Declaration.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Maggi, L., Ravaglia, S., Farinato, A. et al. Coexistence of CLCN1 and SCN4A mutations in one family suffering from myotonia. Neurogenetics 18, 219–225 (2017). https://doi.org/10.1007/s10048-017-0525-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-017-0525-5

Keywords

  • Congenital myotonia
  • Skeletal muscle channelopathies
  • SCN4A gene
  • CLCN1 gene
  • Patch clamp