title: Translational approach to address therapy in myotonia permanens due to a new SCN4A mutation.
abstract: OBJECTIVE
  We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype.
  
  
  METHODS
  Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp.
  
  
  RESULTS
  The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition.
  
  
  CONCLUSIONS
  Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual.
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. jeanfrancois.desaphy@uniba.it.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desaphy
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Carbonara
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Modoni
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Julien
authors.initials: J
authors.lastname: Roussel
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Imbrici
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pagliarani
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lucchiari
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Lo Monaco
authors.affiliation: From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, Neurosciences, and Orthopedics (A.M., M.L.M.), Institute of Neurology, Catholic University of the Sacred Heart, Rome; Dino Ferrari Centre (S.P., S.L.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; and Neurology Unit (S.P., S.L.), IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Conte Camerino
mesh_terms: D002460:Cell Line; D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D005424:Flecainide / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008801:Mexiletine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D009154:Mutation; D009224:Myotonia Congenita / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D000071185:Pharmacogenomic Testing / Q000379:methods; D057285:Precision Medicine / Q000379:methods; D057170:Translational Research, Biomedical; D061567:Voltage-Gated Sodium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D061567:Voltage-Gated Sodium Channel Blockers; D008801:Mexiletine; D005424:Flecainide