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

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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.

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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

Authors and 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
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  2. Sabrina Ravaglia
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  3. Alessandro Farinato
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  4. Raffaella Brugnoni
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  12. Massimiliano Filosto
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Corresponding author

Correspondence to Lorenzo Maggi.

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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.

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The authors declare that they have no conflict of interest.

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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

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

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