Abstract
Hyperkalemic periodic paralysis (hyperPP), paramyotonia congenita (PC) and PC with myotonia permanens are closely related muscle disorders of genetic origin due to allelic mutations in the muscle sodium channel gene, SCN4A. Seven families of French origin with hyperPP were studied. Five of these had the Thr704Met mutation, but 2 families, genetically linked to SCN4A, failed to show any of the known mutations of SCN4A. Correlations between the phenotype and the genotype were made for patients with the Thr704Met mutation. All 12 patients over 30 years old with the Thr704Met mutation presented muscle weakness due to degeneration of muscle fibers in addition to periodic paralysis. Only approximately 12.5% of patients with the Thr704Met mutation presented with clinical myotonia and about 50% with hyperkalemia. One family with PC displayed the Gly 1306Val mutation with a phenotype similar to the one already reported for this mutation. Five families with either PC or PC with myotonia permanens had the Thr 1313Met mutation indicating that the severity of myotonia and its permanence were variable. Two mutations of SCN4A were found to be predominant in these 13 families: the Thr704Met and the Thr1313Met mutations. Only 2 families with the Thr704Met mutation and 3 families with the Thr1313Met shared the same SCN4A haplotype determined with intragenic dinucleotide repeats. Recurrent mutations of SCN4A may contribute to the predominance of these two mutations in the French population.
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Acknowledgements
We acknowledge the financial support of the Association Française contre les Myopathies, the Fondation pour la Recherche Médicale, the Ministère de la Recherche, the Laboratoires Servier, and the Assistance Publique-Hôpitaux de Paris. We thank Généthon for helping us with DNA sequencing; Dr. A.I. McClatchey and Prof. J.F. Gusella for sending primers at the initial stages of this work, and Prof. C. Van Broekhoven for sending DNA from 2 patients; Prof Y. Agid, Prof. O. Lyon-Caen and Dr. N. Baumann for their constant support; Dr. L. Maurs for referring a family; V. Müller for helping to collect DNA samples from the families; patients and their families for their help and their support; Dr. Nicole Feingold (INSERM U-155 and University of Paris VII) for revising the statistics used for the genetic analysis; Dr. Alexis Brice (INSERM U-289, Paris) for critically reading the manuscript, and Dr. Marc Del Bigio and Dr. Merle Ruberg for revision of the English.
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Plassart, E., Reboul, J., Rime, CS. et al. Mutations in the Muscle Sodium Channel Gene (SCN4A) in 13 French Families with Hyperkalemic Periodic Paralysis and Paramyotonia Congenita: Phenotype to Genotype Correlations and Demonstration of the Predominance of Two Mutations. Eur J Hum Genet 2, 110–124 (1994). https://doi.org/10.1159/000472351
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DOI: https://doi.org/10.1159/000472351
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